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Health-Related Quality of Life in Cancer Patients Treated with PD-(L)1 Inhibitors: A Systematic Review
Abstract
Areas covered: Citations from PubMed and the American Society of Clinical Oncology meeting library were examined. Cross-references from original studies and review articles were also reviewed. Eligible trials included randomized controlled trials of cancer patients treated with one of the PD-(L)1 inhibitors and reporting HRQoL outcomes. A total of 11 studies were included in the current review. PD-(L)1 inhibitors were associated with a consistent prolongation of the time to symptomatic deterioration. This was shown with the three agents (nivolumab, pembrolizumab, and atezolizumab) as well as across a variety of solid tumors (lung cancer, melanoma, head and neck cancer and urothelial cancer). Moreover, PD-(L)1 inhibitor therapy was associated with better symptomatic control at different follow-up points. This was observed regardless of the agent used of the solid tumor treated.
Expert Commentary: Across a variety of solid tumor indications as well as a variety of PD-(L)1 inhibitors, the use of PD-(L)1 inhibitors is associated with an improvement in the quality of life. The utility of patient-reported outcomes in predicting clinical benefit from these agents needs to be explored further.
... Abdel-Rahman et al. (2018) performed a systematic review to explore time to HRQOL deterioration among cancer patients receiving PD-(L)1 inhibitors compared to those receiving traditional cytotoxic therapy. The results showed that PD-(L)1 inhibitors were associated with a consistent prolongation of the time to symptomatic deterioration [11]. Recently, Hall et al. (2019), in their systematic review, suggested that ICIs are well tolerated in terms of HRQOL compared to other anticancer therapies. ...
... Previous studies [11,12] showed that patients receiving ICIs experience similar-to-improve HRQOL compared to patients receiving other treatments for advanced cancer (such as chemotherapy, placebo, everolimus or gp100). Based on our findings, these results must be interpreted with caution in view of a number of potential weaknesses associated with the RCTs included. ...
... Failure to pre-specify hypotheses might generate spurious HRQOL results, potentially emphasising findings that are statistically, but not clinically, relevant [25]. Consequently, we should be careful to avoid interpreting the HRQOL results of previous studies [11,12] as if based on a confirmatory analysis. ...
Objective
Immune checkpoint inhibitors (ICIs) have recently shown tremendous promise in the treatment of diverse cancers. The available data suggests that ICIs are well tolerated in terms of health-related quality of life (HRQOL) compared to other anticancer therapies. However, it appears that instruments currently used to evaluate HRQOL in this context may fail to capture important symptomatology unique to ICIs. This systematic review was designed to assess the adequacy of methods used to report HRQOL in cancer patients treated with ICIs and to identify the quality of life scales used.
Method
A systematic review was performed (systematic registration number: PROSPERO: CRD42019121427). A search of the PubMed, PsycINFO, PsycARTICLES, Psychology and Behavioral Sciences collection, and SocINDEX databases was carried out for publications in English and in French. Relevant databases were searched from the earliest records through to March 2019. Publications were selected if they reported on HRQOL in patients with cancer treated by ICIs. Risk of bias was scored using the Cochrane Collaboration bias assessment tool.
Results
Our search identified 144 publications between 2012 and 2019, of which 15 RCTs met the inclusion criteria. The results suggest that even though the overall reporting of HRQOL was deemed to be of good quality, the data available was marred by methodological aspects such as the lack of HRQOL research hypotheses and the lack of questionnaires validated for cancer patients treated with immunotherapy.
Conclusion
This study provides a comprehensive analysis of the current state of the art and identifies gaps in knowledge on HRQOL analysis with respect to ICIs. It also suggests avenues for further research.
... Understanding clinical benefits associated with ICI now goes beyond traditional outcomes of survival and objective responses, though overall survival (OS) remains the gold standard endpoint. 6 Other long-term measures, such as depth of response (DepOR), 7 treatment-free survival (TFS), 8 9 efficacy in brain metastases, [10][11][12][13][14][15] improved health-related quality of life (HRQOL), 16 and durable responses, have evolved as additional hallmarks associated with ICI-based therapies, with the possibility for a cure in some patients. 5 ICI combinations bring the prospect of improved outcomes to specific tumor types and disease settings. ...
... In a systematic review of PD-(L)1 therapies associated with consistent prolongation of time to symptomatic deterioration across therapies and solid tumors compared with cytotoxic therapy, PD-(L)1 was associated with better symptomatic control at various follow-up points. 16 With combination therapies showing greater toxicity, there is concern that HRQOL may be diminished. However, nivolumab plus ipilimumab maintained HRQOL in a manner similar to nivolumab monotherapy in patients with advanced melanoma at a 5-year analysis, despite having marked differences in rates of immune-mediated adverse reactions (IMARs). ...
Introduction
Immuno-oncology therapies, including immune checkpoint inhibitors (ICIs), have transformed cancer care and have brought into question whether classic oncology efficacy assessments adequately describe the distinctive responses observed with these agents. With more ICI-based therapies being approved across multiple tumor types, it is essential to define unique clinical hallmarks of these agents and their associated assessments to better reflect the therapeutic impact for both patients and physicians. Long-term survival and objective responses, such as depth and durability of responses, treatment-free survival, efficacy in brain metastases, improved health-related quality of life, and unique safety profiles, are among the hallmarks that have emerged for ICI therapies. An established clinical hallmark is a sustained long-term survival, as evidenced by a delayed separation of Kaplan-Meier survival curves, and a plateau at ~3 years. Combination ICI therapies provide the opportunity to raise this plateau, thereby affording durable survival benefits to more patients. Deepening of responses over time is a unique clinical ICI hallmark, with patients responding long term and with more durable complete responses. Depth of response has demonstrated prognostic value for long-term survival in some cancers, and several ICI studies have shown sustained responses even after discontinuing ICI therapy, offering the potential for treatment-free intervals. Although clinical evidence supporting efficacy in brain metastases is limited, favorable ICI intracranial responses have been seen that are largely concordant with extracranial responses. While patient outcomes can be significantly improved with ICIs, they are associated with unique immune-mediated adverse reactions (IMARs), including delayed ICI toxicities, and may require multidisciplinary management for optimal care. Interestingly, patients discontinuing ICIs for IMARs may maintain responses similar to patients who did not discontinue for an IMAR, whether they restarted ICI therapy or not.
Conclusion
Herein, we comprehensively review and refine the clinical hallmarks uniquely associated with ICI therapies, which not only will rejuvenate our assessment of ICI therapeutic outcomes but also will lead to a greater appreciation of the effectiveness of ICI therapies.
... 8 Evidence from immunotherapy trials has demonstrated that monotherapy with PD-1 inhibitors can provide efficacy benefits and tolerable safety while maintaining or improving HRQOL in patients with solid tumours. 18,19 In a systematic review of HRQOL outcomes, there was a consistent prolongation of the time to symptom deterioration and better symptom control at different follow-up points with nivolumab, pembrolizumab and atezolizumab in patients with lung cancer, melanoma, head and neck cancer and urothelial cancer. 18 Findings from the present analysis of KEYNOTE-062 demonstrate the ability of pembrolizumab monotherapy to maintain HRQOL in the first-line setting in patients with gastric/GEJ cancer. ...
... 18,19 In a systematic review of HRQOL outcomes, there was a consistent prolongation of the time to symptom deterioration and better symptom control at different follow-up points with nivolumab, pembrolizumab and atezolizumab in patients with lung cancer, melanoma, head and neck cancer and urothelial cancer. 18 Findings from the present analysis of KEYNOTE-062 demonstrate the ability of pembrolizumab monotherapy to maintain HRQOL in the first-line setting in patients with gastric/GEJ cancer. ...
Background:
In the randomised phase III KEYNOTE-062 study, pembrolizumab was non-inferior to chemotherapy for overall survival in patients with programmed death-ligand 1 (PD-L1)-positive [combined positive score (CPS) ≥1] advanced gastric/gastroesophageal junction (GEJ) cancer. We present findings of prespecified health-related quality-of-life (HRQOL) analyses for pembrolizumab versus chemotherapy in this population.
Materials and methods:
HRQOL, a secondary endpoint, was measured in patients who received ≥1 dose of study treatment and completed ≥1 HRQOL questionnaire [European Organisation for the Research and Treatment of Cancer (EORTC) 30-question quality-of-life (QLQ-C30), EORTC 22-question quality-of-life gastric-cancer-specific module (QLQ-STO22)]. Least squares mean (LSM) change (baseline to week 18) in global health status/quality of life (GHS/QOL; EORTC QLQ-C30) and time to deterioration (TTD) in GHS/QOL, nausea/vomiting and appetite loss scores (EORTC QLQ-C30) and abdominal pain/discomfort scores (EORTC QLQ-STO22) were evaluated.
Results:
The HRQOL population comprised 495 patients with CPS ≥1 (pembrolizumab, 252; chemotherapy, 243). Compliance rates at week 18 were similar for pembrolizumab and chemotherapy (EORTC QLQ-C30, 87.9% and 81.9%; EORTC QLQ-STO22, 87.9% and 81.3%, respectively). There was no between-arm difference in LSM score change in GHS/QOL [-0.16; 95% confidence interval (CI) -5.01 to 4.69; P = 0.948]. The LSM score change for most subscales showed comparable worsening in both arms. TTD for GHS/QOL [hazard ratio (HR), 0.96; 95% CI, 0.67-1.38; P = 0.826], appetite loss (HR, 0.83; 95% CI, 0.58-1.20; P = 0.314) and pain (HR, 1.22; 95% CI, 0.78-1.91; P = 0.381) were similar between arms. Longer TTD was observed for pembrolizumab versus chemotherapy for nausea/vomiting (HR, 0.61; 95% CI, 0.44-0.85; P = 0.003).
Conclusions:
HRQOL was maintained with first-line treatment with pembrolizumab in patients with PD-L1-positive advanced gastric/GEJ cancer and was similar between pembrolizumab and chemotherapy in this population.
... 5 In comparison with conventional therapies like chemotherapy, various studies report smaller impairments in health-related QoL scales, a longer time until deterioration in QoL and better control of symptoms after immunotherapy. [6][7][8][9] This may be related to a lower risk of side effects from immunotherapy compared with chemotherapy. 10 However, this evidence has largely come from clinical trials which have strict eligibility criteria; for example, these data exclude patients with poor performance status (PS, Eastern Cooperative Oncology Group PS>1), concomitant cancers or comorbidities. ...
Background
The introduction of immune checkpoint inhibitors (ICIs) has modified treatment modalities for patients with lung cancer, offering new alternatives for treatment. Despite improved survival benefits, ICIs may cause side effects impacting patients’ quality of life (QoL). We aim to study the changes in global QoL (gQoL) of patients with advanced-stage lung cancer up to 18 months after treatment with ICIs between 2015 and 2021.
Methods and analysis
A longitudinal cohort study was conducted using the Oncological Life Study: Living well as a cancer survivor data-biobank from the University Medical Center Groningen. Participants completed the European Organisation for Research and Treatment of Cancer QoL 30-item questionnaire, at the beginning of their ICI treatment (baseline) and then at 6, 12 and 18 months. Using joint modelling, changes in predicted mean gQoL were studied by treatment regimens from baseline to 18 months, while accounting for the competing risk of death and adjusting for prespecified covariates.
Results
Of the 418 participants with median age of 66 years, 39% were women. Patients receiving first-line immuno-monotherapy with palliative intent had a small improvement in their gQoL within 6 months and no clinically significant change thereafter. Patients receiving first-line immune-chemotherapy with palliative intent had a small improvement in their gQoL within 12 months and no clinically significant change thereafter. Patients with second/further line immunotherapy with palliative intent or first-line chemoradiotherapy followed by durvalumab with curative intent had no clinically significant change in their gQoL over 18 months.
Conclusion
The changes in gQoL over time among patients with advanced-stage lung cancer may vary by treatment regimens based on drug intensity, line and intent of treatment, which will help clinicians and patients understand the potential dynamic of treatments on QoL. It may further influence treatment decisions and patient management strategies, reflecting the practical implications of different treatment regimens.
... PD-1/PD-L1 pathway inhibitors, either as monotherapy or combined with chemotherapy, with anti-CTLA4, and with or without bevacizumab, have markedly improved the overall survival (OS) and quality of life of NSCLC patients in different settings [10][11][12][13][14][15]. In pretreated NSCLC patients, PD-1/PD-L1 inhibitors led to significantly better overall responses, a longer OS, and reduced overall toxicity compared with chemotherapy [16]. ...
Introduction:
There are currently three first-line immunotherapy options used as monotherapy in advanced non-small cell lung cancer (NSCLC) patients with high programmed death ligand 1 (PD-L1) expression (≥50%). This manuscript aims to evaluate the available data on atezolizumab (AT), cemiplimab (CEMI), and pembrolizumab (PEMBRO) and to study the results obtained during pivotal trials, especially regarding patient subgroups.
Methods:
Nominal group and Delphi techniques were used. Eight Spanish experts in lung cancer (the scientific committee of the project) analyzed the use of immunotherapy monotherapy as first-line treatment in patients with NSCLC and high PD-L1 expression. The expert scientific committee formulated several statements based on a scientific review and their own clinical experience. Subsequently, 17 additional Spanish lung cancer experts were selected to appraise the committee's statements through two Delphi rounds. They completed a Delphi round via an online platform and voted according to a scale from 1 (strongly disagree) to 10 (strongly agree). The statements were approved if ≥70% of experts voted 7 or more.
Results:
A total of 20 statements were proposed covering the following areas: (1) general characteristics of pivotal clinical trials; (2) overall main outcomes of pivotal clinical trials; and (3) subgroup analysis. All statements reached consensus in the first round.
Conclusions:
AT, CEMI, and PEMBRO as monotherapy can be considered the standard of care in patients with advanced NSCLC and high PD-L1 expression (≥50%). Moreover, some differences noted among the drugs analyzed in this document might facilitate treatment decision-making, especially in clinically relevant patient subgroups, when using PD-1/PD-L1 inhibitors. The high level of agreement reached among experts supports the proposed statements.
... To the best of our knowledge, there are no studies indicating lower appetite loss after immunotherapy while loss of appetite has been commonly reported after chemotherapy, radiotherapy or surgery [29]. Moreover, PD-(L)1 inhibitors like nivolumab, pembrolizumab and atezolizumab have been observed to be associated with consistent delay in time to symptomatic deterioration in QoL among patients with solid tumours [30] compared to traditional cytotoxic therapy. This was also reflected in our study where we could not see a significant impact of immunotherapy on QoL at baseline while chemotherapy was associated with poorer global QoL, and lower physical and role functioning. ...
Objective
To investigate associations between quality of life (QoL) and 1) immunotherapy and other cancer treatments received three months before QoL measurements, and 2) the comorbidities at the time of completion or in the year prior to QoL measurements, among patients with advanced cancer.
Methods
A cross-sectional study is conducted on patients with advanced cancer in the Netherlands. The data come from the baseline wave of the 2017–2020 eQuiPe study. Participants were surveyed via questionnaires (including EORTC QLQ-C30). Using multivariable linear and logistic regression models, we explored statistical associations between QoL components and immunotherapy and other cancer treatments as well as pre-existing comorbidities while adjusting for age, sex, socio-economic status.
Results
Of 1088 participants with median age 67 years, 51% were men. Immunotherapy was not associated with global QoL but was associated with reduced appetite loss (odds ratio (OR) = 0.6, 95%CI = [0.3,0.9]). Reduced global QoL was associated with chemotherapy (adjusted mean difference (β) = − 4.7, 95% CI [− 8.5,− 0.8]), back pain (β = − 7.4, 95% CI [− 11.0,− 3.8]), depression (β = − 13.8, 95% CI [− 21.5,− 6.2]), thyroid diseases (β = − 8.9, 95% CI [− 14.0,− 3.8]) and diabetes (β = − 4.5, 95% CI [− 8.9,− 0.5]). Chemotherapy was associated with lower physical (OR = 2.4, 95% CI [1.5,3.9]) and role (OR = 1.8, 95% CI [1.2,2.7]) functioning, and higher pain (OR = 1.9, 95% CI [1.3,2.9]) and fatigue (OR = 1.6, 95% CI [1.1,2.4]).
Conclusion
Our study identified associations between specific cancer treatments, lower QoL and more symptoms. Monitoring symptoms may improve QoL of patients with advanced cancer. Producing more evidence from real life data would help physicians in better identifying patients who require additional supportive care.
... However, respondents' health assessment based on marital status and monthly income is a parameter that assesses patients' quality of life in the same way as QLQ-30 scores. In addition, place of residence and monthly income influence how patients assess their health ( In our study, we tried to evaluate the quality of life of cancer patients who underwent the method of ICI, as other researchers have done in the past [18][19][20][21]. Similar studies, also, have found a statistically significant association between socioeconomic and demographic characteristics and quality of life in cancer patients, such as marital status, age, and gender [22][23][24][25]. ...
The aim of this study is to assess the quality of life of patients receiving immune checkpoint inhibitors (ICI) by evaluating their physical and psychological well-being as well as their social and spiritual functioning. The 36-item Short Form Health Survey (SF-36) and quality of life core 30 (QLQ-C30) questionnaires were used to measure the quality of life of people receiving checkpoint inhibitors. An attempt was also made to make a rough estimate of the cost of checkpoint inhibitors in selected cases. The present study was conducted at the Oncology Day Hospital of the General University Hospital of Patras and the sample consisted of 100 subjects. The results of the two questionnaires show that the subjective evaluation of the patient's quality of life is satisfactory and functional since most of the respondents evaluate their quality of life as good to very good. Regarding the duration of immunotherapy, their health status seems to have improved, as 49% of respondents report having no pain, while the QLQ-C30 shows that 93% of patients have no problems with personal hygiene. Important determinants related to the limitation of work and daily activities were influenced by patients' age and marital status. Finally, age, monthly income, and education level seem to exert a general influence on a person's physical condition.
... PD-1 inhibitors provide antitumor activity and manageable safety while maintaining or improving HRQoL in various cancers [23,24]. In R/M HNSCC, HRQoL benefits with pembrolizumab and nivolumab have been observed in patients whose disease progressed during or after platinum-based chemotherapy [3,5,8,25]. ...
Objectives
To assess health-related quality of life (HRQoL) with first-line pembrolizumab, pembrolizumab-chemotherapy, or cetuximab-chemotherapy in recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) in the phase 3 KEYNOTE-048 trial (NCT02358031).
Materials and Methods
HRQoL was measured using the European Organisation for Research and Treatment of Cancer 30-question quality-of-life (EORTC QLQ-C30), the EORTC 35-question quality-of-life head and neck cancer–specific module (EORTC QLQ-H&N35), and the EuroQol 5-dimension 3-level instruments (EQ-5D-3L). Secondary endpoints included mean change from baseline in EORTC QLQ-C30 global health status/quality of life (GHS/QoL) at week 15 and time to deterioration (TTD) in EORTC QLQ-C30 GHS/QoL and EORTC QLQ-H&N35 pain and swallowing.
Results
Of 882 enrolled participants, 844 received ≥ 1 dose of study treatment and completed ≥ 1 HRQoL assessment; adherence was ≥ 79% at week 15 across treatment groups. At week 15, EORTC QLQ-C30 GHS/QoL scores remained stable; no clinically meaningful between-group differences were observed (least squares mean difference, pembrolizumab vs cetuximab-chemotherapy, 0.24; 95% CI, −3.34 to 3.82; pembrolizumab-chemotherapy vs cetuximab-chemotherapy, 0.40; 95% CI, −3.46 to 4.26). Median TTD in EORTC QLQ-C30 GHS/QoL and EORTC QLQ-H&N35 pain and swallowing scores was not reached over 51 weeks across groups, showing stable HRQoL. TTD was similar between groups for EORTC QLQ-C30 GHS/QoL (pembrolizumab vs cetuximab-chemotherapy: HR, 1.38; 95% CI, 0.95–2.00; pembrolizumab-chemotherapy vs cetuximab-chemotherapy: HR, 1.37; 95% CI, 0.94–2.00), as was TTD in EORTC QLQ-H&N35 pain and swallowing scores.
Conclusions
Pembrolizumab monotherapy and pembrolizumab-chemotherapy extended OS while maintaining HRQoL, further supporting first-line use for R/M HNSCC.
... Independent of their length and severity, irAEs may affect patients detrimentally, substantially decreasing HRQoL [13]. However, other studies indicate that melanoma patients treated with CPIs maintain better HRQoL than those treated with other anti-neoplastic therapies [12,14] and, aside from fatigue, long-term melanoma survivors have moderate symptom burden and good quality of life (QoL) one year after treatment initiation [15]. The fact that patients experience severe irAEs may not automatically result in impaired HRQoL. ...
Introduction
In a randomized controlled trial, we previously investigated if melanoma patients receiving checkpoint inhibitors had fewer severe immune-related adverse events (irAEs) when they reported symptoms using electronic patient-reported outcomes (ePRO) with triggered alerts as an add-on to standard care, compared to standard care alone. The aim of this study is to examine between-group differences in health-related quality of life (HRQoL) and associations between irAEs severity and HRQoL.
Methods
The study population of 138 patients completed the EuroQol EQ-5D-5L Index and FACT-M questionnaires at baseline and weeks 24 and 48. We analyzed HRQoL from all patients who completed at least one questionnaire. Missing FACT-M items were imputed following existing guidelines.
Results
There was no difference in HRQoL at baseline as measured EQ-5D-5L between the intervention and the control group. Between baseline and 48 weeks, mean EQ-5D-5L scores were unchanged among patients in the intervention group ( p = 0.81) but decreased significantly among patients in the control group ( p = 0.03). Consequently, patients in the intervention group had higher mean scores than those in the control group ( p = 0.05) at 48 weeks. Mean FACT-M scores did not differ significantly between the two groups at any of the time points. There were observed no between-group differences in mean EQ-5D-5 and mean FACT-M scores between patients with severe irAEs and patients who had none.
Conclusion
Melanoma patients receiving CPIs who self-reported irAEs using ePRO with triggered alerts as a supplement to standard care maintained their HRQoL compared to patients who received standard care alone. Patients in the intervention group had a significantly better HRQoL measured by EQ-5D-5L than controls 48 weeks after baseline. The results suggest that including ePRO in standard care increases melanoma patients´ well-being. Further and larger studies are needed to confirm this finding and examine the impact of severe irAEs on cancer patients’ HRQoL.
Trial registration : Clinicaltrials.gov NCT03073031 Registered 8 March 2017, Retrospectively registered https://clinicaltrials.gov/ .
... Emerging evidence from clinical trials investigating immunotherapy in several solid tumor types has revealed that anti-programmed death-1 monotherapy can improve efficacy while maintaining or improving HRQoL. 20 In the phase III ATTRACTION-3 study of nivolumab versus chemotherapy in patients with previously treated advanced esophageal SCC enrolled in Denmark, Germany, Italy, Japan, South Korea, Taiwan, the United Kingdom, and the United States, HRQoL assessed by the EQ-5D-3L was a prespecified exploratory end point that was measured every 6 weeks during treatment. 21 Nivolumab provided an overall significant on-treatment improvement in both EQ-5D-3L VAS (P 5 .00069) ...
PURPOSE
In the phase III KEYNOTE-181 study ( NCT02564263 ) of patients with advanced esophageal cancer (EC), pembrolizumab monotherapy prolonged overall survival versus chemotherapy as second-line therapy in patients with programmed death ligand 1 combined positive score (CPS) ≥ 10. We present the results of the prespecified health-related quality-of-life (HRQoL) analyses of the squamous cell carcinoma (SCC), CPS ≥ 10, and CPS ≥ 10 SCC populations.
PATIENTS AND METHODS
HRQoL was measured using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30), EORTC QLQ EC questionnaire (OES18), and EuroQol 5-dimension questionnaire (EQ-5D). Data were analyzed in patients who received ≥ 1 dose of study treatment and completed ≥ 1 HRQoL assessment. Key analyses included baseline to week 9 least squares mean change in global health status/quality of life, functional or symptom subscales, and time to deterioration (≥ 10-point deterioration) for specific subscales.
RESULTS
The HRQoL population included 387 patients with SCC. Compliance and completion rates for all three questionnaires were similar in both treatment groups at baseline and week 9. No clinically meaningful differences in global health status/quality of life scores were observed between treatment groups from baseline to week 9 (least squares mean difference, 2.80; 95% CI, –1.48 to 7.08); patients in both treatment groups generally exhibited stable functioning and symptom scores of the QLQ-C30 and QLQ-OES18 from baseline to week 9. Time to deterioration for pain (hazard ratio [HR], 1.22; 95% CI, 0.79 to 1.89), reflux (HR, 2.38; 95% CI, 1.33 to 4.25), and dysphagia (HR, 1.53; 95% CI, 1.02 to 2.31) subscales were similar between treatment groups. These findings were generally similar in the CPS ≥ 10 (n = 218) and CPS ≥ 10 SCC (n = 166) subgroups.
CONCLUSION
In patients with advanced EC, pembrolizumab monotherapy and chemotherapy maintained HRQoL in patients with SCC, CPS ≥ 10, and CPS ≥ 10 SCC.
... Growing evidence from immunotherapy trials has shown that monotherapy with PD-1 inhibitors provides efficacy and safety benefits while maintaining or improving HRQoL in several tumour types [30]. The results of KEY-NOTE-629 and a phase 2 trial of cemiplimab further support the benefits of PD-1 inhibitors in cSCC, with both studies reporting durable responses with stable or improved HRQoL in patients with advanced cSCC receiving treatment with a PD-1 inhibitor [13,14,31]. ...
IntroductionPembrolizumab provided durable responses and acceptable safety in recurrent or metastatic (R/M) cutaneous squamous cell carcinoma (cSCC) in the KEYNOTE-629 study. In this elderly, fragile population with disfiguring tumours, preservation of health-related quality of life (HRQoL) is critical. Here, we present pre-specified exploratory HRQoL analyses from the first interim analysis of KEYNOTE-629.Methods
Patients with R/M cSCC not amenable to surgery or radiation therapy received pembrolizumab 200 mg every 3 weeks for ≤ 24 months. HRQoL end points included change from baseline to week 12 in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) global health status (GHS)/QoL, functioning, symptom and European Quality of Life 5-Dimension 5-Level (EQ-5D-5L) scores and change from baseline through week 48 in EORTC QLQ-C30 GHS/QoL and physical functioning scores. Improvement (≥ 10-point increase post-baseline with confirmation) was assessed using the exact binomial method.ResultsAnalyses included 99 patients for EORTC QLQ-C30 and 100 for EQ-5D-5L. Compliance was > 80% at week 12. Mean scores were stable from baseline to week 12 for GHS/QoL (4.95 points; 95% confidence interval, −1.00 to 10.90) and physical functioning (−3.38 points; 95% confidence interval, −8.80 to 2.04). EORTC-QLQ-C30 functioning, symptom, and EQ-5D-5L scores remained stable at week 12. Post-baseline scores were improved in 29.3% of patients for GHS/QoL, 17.2% for physical functioning, and in a numerically higher proportion of responders versus non-responders (GHS/QoL, 55.6% versus 16.1%; physical functioning, 36.1% versus 7.1%).Conclusions
In elderly patients with R/M cSCC, the clinical efficacy of pembrolizumab translates into a benefit validated by HRQoL preservation or improvement during treatment.Trial RegistrationClinicalTrials.gov identifier: NCT03284424.
... Compared with patients treated with non-ICI regimens, they also reported less appetite loss, insomnia, and pain, but more dyspnea. These findings are broadly consistent with previous qualitative reviews (42)(43)(44) and a meta-analysis (4) on this topic. However, the only previous meta-analysis available did not examine CTLA-4 inhibitors, except as a comparator, and numerous recent trials have been conducted using novel agents and for different indications. ...
Background:
Trials of immune checkpoint inhibitors (ICIs) have published patient-reported quality of life (QOL), but the size and heterogeneity of this literature can make patient education difficult. This meta-analysis aimed to describe change in QOL and symptomatology in patients receiving ICIs for cancer.
Methods:
Following PRISMA guidelines, databases were searched through November 2019 for articles or abstracts of prospective, original studies reporting longitudinal QOL in adult cancer patients treated with ICIs. The prespecified primary outcomes were change in global QOL among patients treated with ICIs and difference in change since baseline in global QOL between patients treated with ICI vs. non-ICI active treatment. Secondary outcomes included physical functioning and symptomatology. All statistical tests were 2-sided.
Results:
Twenty-six of 20,323 publications met inclusion criteria. Global QOL did not change over time in patients treated with ICIs (k = 26, n = 6,974, P = .19). Larger improvements in global QOL was observed in patients receiving ICI vs. non-ICI regimens (k = 16, ICI n = 3,588, non-ICI n = 2,948, P < .001). Physical functioning did not change in patients treated with ICIs (k = 14, n = 3,169, P=.47); there were no differences in mean change between ICI vs. non-ICI regimens (k = 11, n = 4,630, P=.94. Regarding symptoms, appetite loss, insomnia, and pain severity decreased but dyspnea severity increased in patients treated with ICIs (k = 14, n = 3,243-3,499) (Ps < 0.001). Insomnia severity was higher in patients treated with ICIs than non-ICI regimens (k = 11, n = 4,791) (P < .001).
Conclusions:
This study is among the first to quantitatively summarize QOL in patients treated with ICIs. Findings suggest ICI recipients report no change in global QOL and higher QOL than patients treated with non-ICI regimens.
... The patients receiving PD-(L)1 inhibitors reported better quality of life than those who did not receive PD-(L)1 inhibitors. 28 The KEYNOTE-002 melanoma trial showed that in addition to a prolonged progression-free survival, GHQ scores were significantly higher in the pembrolizumab group than in the chemotherapy group. 29 Moreover, the KEYNOTE-006 advanced melanoma trial, which showed a prolonged progression-free survival and overall survival, 30 reported some additional benefits on HRQOL, and more specifically a more stable GHQ and a longer time to deterioration of HRQOL, in the pembrolizumab group than in the ipilimumab group. ...
Background
The European Organisation for Research and Treatment of Cancer (EORTC) 1325-MG/KEYNOTE-054 trial in patients with resected, high-risk stage III melanoma demonstrated improved recurrence-free survival with adjuvant pembrolizumab compared with placebo (hazard ratio 0·57 [98·4% CI 0·43–0·74]; p<0·0001). This study reports the results from the health-related quality-of-life (HRQOL) exploratory endpoint.
Methods
This double-blind, randomised, controlled, phase 3 trial was done at 123 academic centres and community hospitals across 23 countries. Patients aged 18 years or older with previously untreated histologically confirmed stage IIIA, IIIB, or IIIC resected cutaneous melanoma, and an Eastern Cooperative Oncology Group performance status score of 1 or 0 were eligible. Patients were randomly assigned (1:1) using a central interactive voice-response system on the basis of a minimisation technique stratified for stage and geographic region to receive intravenously 200 mg pembrolizumab or placebo. Treatment was administered every 3 weeks for 1 year, or until disease recurrence, unacceptable toxicity, or death. The primary endpoint of the trial was recurrence-free survival (reported elsewhere). HRQOL was a prespecified exploratory endpoint, with global health/quality of life (GHQ) over 2 years measured by the EORTC QLQ-C30 as the primary analysis. Analyses were done in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT02362594, and EudraCT, 2014-004944-37, and long-term follow-up is ongoing.
Findings
Between Aug 26, 2015, and Nov 14, 2016, 1019 patients were assigned to pembrolizumab (n=514) or placebo (n=505). Median follow-up was 15·1 months (IQR 12·8–16·9) at the time of this analysis. HRQOL compliance was greater than 90% at baseline, greater than 70% during the first year, and greater than 60% thereafter for both groups. Because of low absolute compliance numbers at later follow-up, the analysis was truncated to week 84. Baseline GHQ scores were similar between groups (77·55 [SD 18·20] in the pembrolizumab group and 76·54 [17·81] in the placebo group) and remained stable over time. The difference in average GHQ score between the two groups over the 2 years was −2·2 points (95% CI −4·3 to −0·2). The difference in average score during treatment was −1·1 points (95% CI −3·2 to 0·9) and the difference in average score after treatment was −2·2 points (−4·8 to 0·4). These differences are within the 5-point clinical relevance threshold for the QLQ-C30 and are therefore clinically non-significant.
Interpretation
Pembrolizumab does not result in a clinically significant decrease in HRQOL compared with placebo when given as adjuvant therapy for patients with resected, high-risk stage III melanoma. These results support the use of adjuvant pembrolizumab in this setting.
Funding
Merck Sharp & Dohme.
... Compared with patients treated with non-ICI regimens, they also reported less appetite loss, insomnia, and pain, but more dyspnea. These findings are broadly consistent with previous qualitative reviews (42)(43)(44) and a meta-analysis (4) on this topic. However, the only previous meta-analysis available did not examine CTLA-4 inhibitors, except as a comparator, and numerous recent trials have been conducted using novel agents and for different indications. ...
... Our findings are consistent with previous reports showing an improved impact on symptom burden and HRQoL for immunotherapy versus chemotherapy across first-line [22] and previously treated [8,10,23,24] NSCLC. Immunotherapies have also shown a similar trend in other tumour types [25,26]. It should be noted that it is difficult to compare PRO results across studies given differences in disease setting and study design. ...
Background:
In the phase III CheckMate 227 study, first-line nivolumab + ipilimumab significantly prolonged progression-free survival (co-primary end-point) versus chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC) and high tumour mutational burden (TMB; ≥10 mutations/megabase).
Aim:
To evaluate patient-reported outcomes (PROs) in this population.
Methods:
Disease-related symptoms and general health status were assessed using the validated PRO questionnaires Lung Cancer Symptom Scale (LCSS) and EQ-5D, respectively. LCSS average symptom burden index (ASBI) and three-item global index (3-IGI) and EQ-5D visual analogue scale (VAS) and utility index (UI) scores and changes from baseline were analysed descriptively. Longitudinal changes were assessed by mixed-effect model repeated measures (MMRMs) and time to first deterioration/improvement analyses.
Results:
In the high TMB population, PRO questionnaire completion rates were ∼90% at baseline and >80% for most on-treatment assessments. During treatment, mean changes from baseline with nivolumab + ipilimumab showed early, clinically meaningful improvements in LCSS ASBI/3-IGI and EQ-5D VAS/UI; with chemotherapy, symptoms and health-related quality of life remained stable (LCSS ASBI/3-IGI, EQ-5D UI) or improved following induction (EQ-5D VAS). MMRM-assessed changes in symptom burden were improved with nivolumab + ipilimumab versus chemotherapy. Symptom deterioration by week 12 was lower with nivolumab + ipilimumab versus chemotherapy (22.3% versus 35.0%; absolute risk reduction: 12.7% [95% confidence interval 2.4-22.5]), irrespective of discontinuation. Time to first deterioration was delayed with nivolumab + ipilimumab versus chemotherapy across LCSS and EQ-5D summary measures.
Conclusion:
First-line nivolumab + ipilimumab demonstrated early, sustained improvements in PROs versus chemotherapy in patients with advanced NSCLC and high TMB.
Clinical trial registration:
NCT02477826.
... Studies also demonstrate that including cancer patients in the reporting of symptoms may increase their quality of life [16], and that the general acceptability of routine data collection is high [8]. With regard to immunotherapy, previous studies have examined the quality of life during treatment [17,18], but no study has examined whether patient reporting of side effects also results in improved toxicity monitoring. Therefore, we designed a randomized controlled trial (RCT), PROMelanoma (ClinicalTrials.gov ...
Background:
The benefits of electronic patient reported outcomes (PRO) questionnaires have been demonstrated in many settings, including in hospitals and patient homes. However, it remains to be investigated how melanoma patients and their treating clinicians experience the electronic self-reporting of side effects and the derived communication.
Objective:
The primary objective of this study was to examine patients' and clinicians' experiences with an eHealth intervention for weekly monitoring of side effects during treatment with immunotherapy.
Methods:
An eHealth intervention based on questions from the PRO-Common Terminology Criteria for Adverse Events (CTCAE) library was used and tested in a randomized clinical trial with patients receiving immunotherapy for malignant melanoma and clinicians at a university hospital in Denmark. On a weekly basis, patients reported their symptoms from home during the treatment via a provided tablet. The electronic patient reports were available to clinicians in the outpatient clinic. A mixed methods approach was applied to investigate the patients' and clinicians' experiences with the intervention. Data from patient experiences were collected in a short survey, the Patient Feedback Form. Moreover, a subset of the patients participating in the survey was interviewed about their experience. Furthermore, one focus group interview with clinicians was carried out to elucidate their views.
Results:
A total of 57 patients completed the Patient Feedback Form, and 14 patients were interviewed. The focus group interview included 5 clinicians. Overall, patients and clinicians were satisfied with the tool. They believed it enhanced patients' awareness of side effects and increased their feeling of involvement. The patients reported that it was easy to fill out the questionnaire and that it made sense to do so. However, a minority of the patients expressed in the interviews that they did not believe that the health care professionals had seen their reports when they came to the clinic, and that the reporting did not lead to increased contact with the department.
Conclusions:
Overall, satisfaction with the eHealth intervention was high among patients and their treating clinicians. The tool was easy to use and contributed to greater symptom awareness and patient involvement. Thus, in terms of patient and clinician satisfaction with the tool, it makes sense to continue using the tool beyond the project period.
Trial registration:
ClinicalTrials.gov NCT03073031; https://tinyurl.com/tjx3gtu.
Introduction
Segmental necrotizing granulomatous neuritis (SNGN) is a rare complication of leprosy involving peripheral nerves. It can appear alone in cases of pure neuritic leprosy or in combination with cutaneous lesions.
Case Presentation
A 15-year-old female diagnosed with borderline tuberculoid leprosy who received prior multidrug therapy presented 2 years later with occasional pain and tingling sensations along the inner aspect of her right arm and forearm. Imaging findings suggested SNGN, which was corroborated by cytopathological examination. She was considered relapsed from leprosy, and multi-drug therapy and steroids were started, following which she reported a decrease in the size of the swelling along with no further deterioration of the sensorineural deficit.
Discussion
SNGN, which is one of the rare complications of leprosy, can create diagnostic dilemmas as its differential diagnoses include reversal reactions, and peripheral nerve tumors (such as schwannoma and neurofibroma), which have been outlined in this article. SNGN is more likely when magnetic resonance imaging (MRI) shows a well-defined ovoid lesion with central necrosis and peripheral rim enhancement.
Conclusion
The incidence of SNGN is on the rise due to multi-drug therapy. In our case, the patient developed SNGN, which was considered a relapse from leprosy, and multi-drug therapy and steroids were started, following which the patient reported a significant reduction in the size of the swelling with no further deterioration of the sensorineural deficit. Hence, an appropriate diagnosis of SNGN through ultrasonography and MRI will lead to favorable outcomes, ultimately benefiting the patient.
Advanced gynecologic cancers have historically lacked effective treatment options. Recently, immune checkpoint inhibitors (ICIs) have been approved by the US Food and Drug Administration for the treatment of cervical cancer and endometrial cancer, offering durable responses for some patients. In addition, many immunotherapy strategies are under investigation for the treatment of earlier stages of disease or in other gynecologic cancers, such as ovarian cancer and rare gynecologic tumors. While the integration of ICIs into the standard of care has improved outcomes for patients, their use requires a nuanced understanding of biomarker testing, treatment selection, patient selection, response evaluation and surveillance, and patient quality of life considerations, among other topics. To address this need for guidance, the Society for Immunotherapy of Cancer (SITC) convened a multidisciplinary panel of experts to develop a clinical practice guideline. The Expert Panel drew on the published literature as well as their own clinical experience to develop evidence- and consensus-based recommendations to provide guidance to cancer care professionals treating patients with gynecologic cancer.
Introduction
Immunotherapies, such as immune checkpoint inhibitors and chimeric antigen receptor T-cell therapy, have significantly improved the clinical outcomes of various malignancies. However, they also cause immune-related adverse events (irAEs) that can be challenging to predict, prevent and treat. Although they likely interact with health-related quality of life (HRQoL), most existing evidence on this topic has come from clinical trials with eligibility criteria that may not accurately reflect real-world settings. The QUALITOP project will study HRQoL in relation to irAEs and its determinants in a real-world study of patients treated with immunotherapy.
Methods and analysis
This international, observational, multicentre study takes place in France, the Netherlands, Portugal and Spain. We aim to include about 1800 adult patients with cancer treated with immunotherapy in a specifically recruited prospective cohort, and to additionally obtain data from historical real-world databases (ie, databiobanks) and medical administrative registries (ie, national cancer registries) in which relevant data regarding other adult patients with cancer treated with immunotherapy has already been stored. In the prospective cohort, clinical health status, HRQoL and psychosocial well-being will be monitored until 18 months after treatment initiation through questionnaires (at baseline and 3, 6, 12 and 18 months thereafter), and by data extraction from electronic patient files. Using advanced statistical methods, including causal inference methods, artificial intelligence algorithms and simulation modelling, we will use data from the QUALITOP cohort to improve the understanding of the complex relationships among treatment regimens, patient characteristics, irAEs and HRQoL.
Ethics and dissemination
All aspects of the QUALITOP project will be conducted in accordance with the Declaration of Helsinki and with ethical approval from a suitable local ethics committee, and all patients will provide signed informed consent. In addition to standard dissemination efforts in the scientific literature, the data and outcomes will contribute to a smart digital platform and medical data lake. These will (1) help increase knowledge about the impact of immunotherapy, (2) facilitate improved interactions between patients, clinicians and the general population and (3) contribute to personalised medicine.
Trial registration number
NCT05626764 .
Resumo: Quando atingimos 60 anos de idade , acumulamos 40.000 defeitos (mutações) em média, apenas considerando as células de nossa pele no envelhecimento; isso pode ser chamado de entropia genética do envelhecimento, EGE; que é também aumentada devido EGP (entropia genética populacional) que é a tendência da população ir acumulando defeitos genéticos na ordem de 74 mutações deletérias por geração, pois "a melhor estimativa atual da taxa média de mutação SNV da linhagem germinativa humana é de 1,18 × 10 −8 por posição 2 , o que corresponde a aproximadamente 74 novos SNVs por genoma por geração." [1][2]. Diante deste quadro aterrador, a humanidade e os seres vivos já teriam se extinguindo não fosse o sistema epigenético controlador da célula que remanejam e compensam as falhas genéticas; logo, levar em conta falhas , como por exemplo, nos trechos que expressam microRNAs controladores de expressão gênica, é muito mais assertivo e estratégico na hora de diagnosticar tanto a doenças como o tratamentos, que pode inclusive existir por meio de plantas medicinais que compensem faltas ou excessos de microRNAs. Isso aliado a vacinas específicas e personalizadas da célula cancerosa , que podem ser feitas por meio de biópsias e/ou verrugas congeladas e descongeladas diversas vezes (pra fragmentar) introduzida na pessoa usando veículo gorduroso para que nossa apresentação de fragmentos da célula cancerosa vá para a corrente linfática; isso pode representar uma altíssima eficiência de tratamento em relação aos tratamentos usuais. As vacinas produzidas por meio de verrugas que são células cancerosas da pessoa, podem ser diferentes do câncer da biópsia, ou possuir a mesma especificidade quanto a microRNAs controladores. Além disso, diversos aspectos multifatoriais do câncer são aqui apresentados junto com propostas multifatoriais de tratamento, o que pode elevar ainda mais a expectativa de sucesso em quaisquer tratamentos oncológicos, que julgamos que deve reunir principalmente ações compensatórias julgadas pelo médico, ao fazer a anamnese do paciente (algo raro de acontecer no Brasil devido a baixa proporção de médicos para a população-1,8 para cada 1000 pessoas, fabricada pela alta cúpula e lobby da poderosa categoria, em ação conjunta com o MEC ministério da educação, que tem impedido a abertura de universidades de medicina neste país). Introdução No mercado de medicamentos anticâncer percebemos um quadro trágico social, onde os ricos possuem acesso aos modernos e super caros medicamentos , enquanto os pobres são jogados a quimioterapias agressivas de baixa eficiência (com baixíssima média de 2,1 a 2,3% de sobrevida em 5 anos na Austrália e EUA). Vacinas personalizadas anticâncer de altíssima eficiência comprovadas em ensaios clínicos chegam a custar U$ 400.000 dólares. Neste trabalho de projeto de ensaio clínico randomizado , apresentaremos formas simples e baratas de se fabricar vacinas anticâncer ,
Resumo: Quando atingimos 60 anos de idade , acumulamos 40.000 defeitos (mutações) em média, apenas considerando as células de nossa pele no envelhecimento; isso pode ser chamado de entropia genética do envelhecimento, EGE; que é também aumentada devido EGP (entropia genética populacional) que é a tendência da população ir acumulando defeitos genéticos na ordem de 74 mutações deletérias por geração, pois "a melhor estimativa atual da taxa média de mutação SNV da linhagem germinativa humana é de 1,18 × 10 −8 por posição 2 , o que corresponde a aproximadamente 74 novos SNVs por genoma por geração." [1][2]. Diante deste quadro aterrador, a humanidade e os seres vivos já teriam se extinguindo não fosse o sistema epigenético controlador da célula que remanejam e compensam as falhas genéticas; logo, levar em conta falhas , como por exemplo, nos trechos que expressam microRNAs controladores de expressão gênica, é muito mais assertivo e estratégico na hora de diagnosticar tanto a doenças como o tratamentos, que pode inclusive existir por meio de plantas medicinais que compensem faltas ou excessos de microRNAs. Isso aliado a vacinas específicas e personalizadas da célula cancerosa , que podem ser feitas por meio de biópsias e/ou verrugas congeladas e descongeladas diversas vezes (pra fragmentar) introduzida na pessoa usando veículo gorduroso para que nossa apresentação de fragmentos da célula cancerosa vá para a corrente linfática; isso pode representar uma altíssima eficiência de tratamento em relação aos tratamentos usuais. As vacinas produzidas por meio de verrugas que são células cancerosas da pessoa, podem ser diferentes do câncer da biópsia, ou possuir a mesma especificidade quanto a microRNAs controladores. Além disso, diversos aspectos multifatoriais do câncer são aqui apresentados junto com propostas multifatoriais de tratamento, o que pode elevar ainda mais a expectativa de sucesso em quaisquer tratamentos oncológicos, que julgamos que deve reunir principalmente ações compensatórias julgadas pelo médico, ao fazer a anamnese do paciente (algo raro de acontecer no Brasil devido a baixa proporção de médicos para a população-1,8 para cada 1000 pessoas, fabricada pela alta cúpula e lobby da poderosa categoria, em ação conjunta com o MEC ministério da educação, que tem impedido a abertura de universidades de medicina neste país). Introdução No mercado de medicamentos anticâncer percebemos um quadro trágico social, onde os ricos possuem acesso aos modernos e super caros medicamentos , enquanto os pobres são jogados a quimioterapias agressivas de baixa eficiência (com baixíssima média de 2,1 a 2,3% de sobrevida em 5 anos na Austrália e EUA). Vacinas personalizadas anticâncer de altíssima eficiência comprovadas em ensaios clínicos chegam a custar U$ 400.000 dólares. Neste trabalho de projeto de ensaio clínico randomizado , apresentaremos formas simples e baratas de se fabricar vacinas anticâncer ,
Introduction:
Despite comprising many cancer diagnoses, few treatments are suitable for patients with advanced non-small cell lung cancer (aNSCLC). Trials suggest blockade of programmed death 1 (PD1) or its ligand (PDL1) may be effective for these patients. However, this therapy's impact on outcomes other than survival, and outcomes of patients not in trials, remains largely unknown. Therefore, we compared the effectiveness of PD1 and PDL1 immunotherapy to chemotherapy and placebo across multiple clinical outcomes.
Methods:
Six databases were searched on 12-13 October 2019 for randomised controlled trials (RCTs) and observational studies investigating nivolumab, pembrolizumab, atezolizumab or durvalumab. Study selection was performed independently by two reviewers. Data for overall survival, progression-free survival, adverse effects (AEs) and quality of life (QoL) were descriptively and meta-analysed. Factors impacting treatment outcomes, including PDL1 expression, were explored. The similarity between RCT and observational data was assessed.
Results:
From 5423 search results, 139 full texts and abstracts were included. Immunotherapy was associated with a lower risk of death than both comparators. In RCTs, the incidence of treatment-related AEs was approximately 20% lower among patients using immunotherapy compared with chemotherapy. However, no other consistent benefits were observed. Progression-free survival results were inconsistent. Improvements to QoL varied according to the instrument used; however, QoL was not recorded widely. Survival results were similar between study designs; however, AEs incidence was lower in observational studies.
Discussion:
Among patients with aNSCLC, immunotherapy improved overall survival and incidence of treatment-related AEs compared with chemotherapy. Benefits to progression-free survival and QoL were less consistent.
Prospero registration number:
CRD42019153345.
Purpose
System science offers a unique set of tools, including causal loop diagrams (CLDs), for stakeholders to better grasp the complexity of factors surrounding quality of life. Because the health-related quality of life (HRQoL) of cancer immunotherapy patients exists within an intricate system affected by and affecting many factors across multiple dimensions, the development of a systems-level model can provide a powerful framework to aid the understanding of this complexity. We developed a CLD for HRQoL of cancer immunotherapy patients.
Methods
We first applied a literature-based approach to construct a CLD for patients following immunotherapy. We then iteratively reviewed and enhanced the CLD through interviews with subject matter experts.
Results
Based on the reviewed literature and subject matter expert input, we produced a CLD representing the system surrounding cancer immunotherapy patients’ HRQoL. Several feedback loops are identified that span clinical experiences, oncology teams’ perceptions about immunotherapy, social support structures, and further research and development in cancer immunotherapy, in addition to other components. The CLD enables visualization of thought experiments regarding how a change anywhere in the system can ultimately worsen or improve patients’ HRQoL.
Conclusion
The CLD illustrates the valuable contribution of a systems perspective to quality-of-life research. This systems-based qualitative representation gives insight on strategies to inhibit harmful effects, enhance beneficial effects, and inherent tradeoffs within the system. The CLD identifies gaps in the literature and offers a communication tool for diverse stakeholders. Our research method provides an example for studying the complexities of quality of life in other health domains.
Sodré, GBN ; Siman, HLH cancer linfoci to@g mail.c om Quatro abordagens de melhora clínica básica para aumento de quantidade e qualidade de TILs verificadas na segunda biópsia comparada a primeira biópsia do diagnóstico, analisadas por NGS e testes proteômicos, sob propostas de estudo comparativo com tecidos adjacentes saudáveis Protocolos cultivo e sensibilização de dendríticas seguido de ACT-Incentivo e manipulação de expansão de TILs usando IL-2, IL-18, uso de PBL radiado como nutriente , cultivo e re-infusão. Incentivo de Nk com Il-15, 21, 18 associado a suplementação PO marcador de membrana seletiva de células cancerígenas.
Background:
The aim of this systematic review is to identify, in a comprehensive manner, the impact of lung cancer on the employment status of survivors.
Methods:
The Preferred Reported Items for Systematic Reviews and Meta-analyses (PRISMA) statement was used as a formal guideline. The systematic review includes scientific papers published between January 2000 and October 2018. The search strategy queried the database MEDLINE. Inclusion criteria comprised: (1) inclusion of patients diagnosed with lung cancer (LC) (2); assessment of employment status or employment outcomes or work adjustments or return to work (3); inclusion of scientific papers published in peer-reviewed journals (4); inclusion of articles written either in English or in French. Literature reviews were not included.
Results:
A total of 642 scientific papers were retrieved. Twenty-three articles were included in the systematic review: 5 longitudinal studies and 18 cross-sectional studies. LC survivors are 2-3 times more likely to be unemployed as compared with control groups. Previous studies highlight a median duration of sickness absence increased for LC survivors compared to control groups. The strongest decline in earnings was observed among LC survivors as compared to other cancer types.
Conclusions:
LC is associated with a significant impact on employment of patients. The promising results of recent therapeutic strategies could lead to a better social and professional prognosis. A reduction of indirect costs is to be expected.
Background:
Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer associated with poor survival outcomes in patients with distant metastatic disease (mMCC). In an initial analysis from JAVELIN Merkel 200, a phase 2, prospective, open-label, single-arm trial in mMCC, avelumab-a human anti-programmed death-ligand 1 (PD-L1) monoclonal antibody-showed promising efficacy and a safety profile that was generally manageable and tolerable. Here, we report the efficacy of avelumab after ≥1 year of follow-up in patients with distant mMCC that had progressed following prior chemotherapy for metastatic disease.
Patients and methods:
Patients received avelumab 10 mg/kg by 1-h intravenous infusion every 2 weeks until confirmed disease progression, unacceptable toxicity, or withdrawal. The primary endpoint was best overall response. Secondary endpoints included duration of response (DOR), progression-free survival (PFS), and overall survival (OS).
Results:
Patients (N = 88) were followed for a minimum of 12 months. The confirmed objective response rate was 33.0% (95% CI, 23.3%-43.8%; complete response: 11.4%). An estimated 74% of responses lasted ≥1 year, and 72.4% of responses were ongoing at data cutoff. Responses were durable, with the median DOR not yet reached (95% CI, 18.0 months-not estimable), and PFS was prolonged; 1-year PFS and OS rates were 30% (95% CI, 21%-41%) and 52% (95% CI, 41%-62%), respectively. Median OS was 12.9 months (95% CI, 7.5-not estimable). Subgroup analyses suggested a higher probability of response in patients receiving fewer prior lines of systemic therapy, with a lower baseline disease burden, and with PD-L1-positive tumors; however, durable responses occurred irrespective of baseline factors, including tumor Merkel cell polyomavirus status.
Conclusions:
With longer follow-up, avelumab continues to show durable responses and promising survival outcomes in patients with distant mMCC whose disease had progressed after chemotherapy.
Trial registration:
Clinicaltrials.gov identifier: NCT02155647.
Objective:
Report results of patient-reported health-related quality of life (HRQoL) and symptoms from phase III KEYNOTE-006 study of pembrolizumab versus ipilimumab in patients with ipilimumab-naive advanced melanoma.
Patients and methods:
Patients received pembrolizumab 10 mg/kg every 2 (Q2W) or every 3 weeks (Q3W) for up to 2 years, or four cycles of ipilimumab 3 mg/kg Q3W. The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) was administered at baseline and throughout the study. Patient-reported outcome (PRO) analyses were pre-specified exploratory endpoints; the primary PRO assessment was the score change from baseline to week 12 in EORTC QLQ-C30 global health status (GHS)/HRQoL score between the arms using constrained longitudinal data analysis.
Results:
The PRO analysis population included 776 patients: pembrolizumab Q2W (n = 270); pembrolizumab Q3W (n = 266); ipilimumab (n = 240). Baseline GHS was similar across arms. QLQ-C30 compliance rates at week 12 were 87% (n = 214), 97% (n = 226), and 96% (n = 178), for the pembrolizumab Q2W, pembrolizumab Q3W, and ipilimumab arms, respectively. From baseline to week 12, GHS/HRQoL scores were better maintained with pembrolizumab than with ipilimumab (decrease of -1.9 and -2.5 for pembrolizumab versus -10.0 for ipilimumab; p < 0.001 for each pembrolizumab arm versus ipilimumab). Fewer patients treated with pembrolizumab experienced deterioration in GHS at week 12 (31% for pembrolizumab Q2W; 29% for Q3W and 44% for ipilimumab), with similar trends observed for individual functioning and symptoms scales.
Conclusions:
HRQoL was better maintained with pembrolizumab than with ipilimumab in patients with ipilimumab-naive advanced melanoma. CLINICALTRIALS.
Gov identifier:
NCT01866319.
Background
Patients with platinum-refractory recurrent or metastatic squamous cell carcinoma of the head and neck have few treatment options and poor prognosis. Nivolumab significantly improved survival of this patient population when compared with standard single-agent therapy of investigator's choice in Checkmate 141; here we report the effect of nivolumab on patient-reported outcomes (PROs).
Methods
CheckMate 141 was a randomised, open-label, phase 3 trial in patients with recurrent or metastatic squamous cell carcinoma of the head and neck who progressed within 6 months after platinum-based chemotherapy. Patients were randomly assigned (2:1) to nivolumab 3 mg/kg every 2 weeks (n=240) or investigator's choice (n=121) of methotrexate (40–60 mg/m² of body surface area), docetaxel (30–40 mg/m²), or cetuximab (250 mg/m² after a loading dose of 400 mg/m²) until disease progression, intolerable toxicity, or withdrawal of consent. On Jan 26, 2016, the independent data monitoring committee reviewed the data at the planned interim analysis and declared overall survival superiority for nivolumab over investigator's choice therapy (primary endpoint; described previously). The protocol was amended to allow patients in the investigator's choice group to cross over to nivolumab. All patients not on active therapy are being followed for survival. As an exploratory endpoint, PROs were assessed at baseline, week 9, and every 6 weeks thereafter using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire–Core 30 (QLQ-C30), the EORTC head and neck cancer-specific module (EORTC QLQ-H&N35), and the three-level European Quality of Life–5 Dimensions (EQ-5D) questionnaire. Differences within and between treatment groups in PROs were analysed by ANCOVA among patients with baseline and at least one other assessment. All randomised patients were included in the time to clinically meaningful deterioration analyses. Median time to clinically meaningful deterioration was analysed by Kaplan-Meier methods. CheckMate 141 was registered with ClinicalTrials.org, number NCT02105636.
Findings
Patients were enrolled between May 29, 2014, and July 31, 2015, and subsequently 361 patients were randomly assigned to receive nivolumab (n=240) or investigator's choice (n=121). Among them, 129 patients (93 in the nivolumab group and 36 in the investigator's choice group) completed any of the PRO questionnaires at baseline and at least one other assessment. Treatment with nivolumab resulted in adjusted mean changes from baseline to week 15 ranging from −2·1 to 5·4 across functional and symptom domains measured by the EORTC QLQ-C30, with no domains indicating clinically meaningful deterioration. By contrast, eight (53%) of the 15 domains in the investigator's choice group showed clinically meaningful deterioration (10 points or more) at week 15 (change from baseline range, −24·5 to 2·4). Similarly, on the EORTC QLQ-H&N35, clinically meaningful worsening at week 15 was seen in no domains in the nivolumab group and eight (44%) of 18 domains in the investigator's choice group. Patients in the nivolumab group had a clinically meaningful improvement (according to a difference of 7 points or greater) in adjusted mean change from baseline to week 15 on the EQ-5D visual analogue scale, in contrast to a clinically meaningful deterioration in the investigator's choice group (7·3 vs −7·8). Differences between groups were significant and clinically meaningful at weeks 9 and 15 in favour of nivolumab for role functioning, social functioning, fatigue, dyspnoea, and appetite loss on the EORTC QLQ-C30 and pain and sensory problems on the EORTC QLQ-H&N35. Median time to deterioration was significantly longer with nivolumab versus investigator's choice for 13 (37%) of 35 domains assessed across the three questionnaires.
Interpretation
In this exploratory analysis of CheckMate 141, nivolumab stabilised symptoms and functioning from baseline to weeks 9 and 15, whereas investigator's choice led to clinically meaningful deterioration. Nivolumab delayed time to deterioration of patient-reported quality-of-life outcomes compared with single-agent therapy of investigator's choice in patients with platinum-refractory recurrent or metastatic squamous cell carcinoma of the head and neck. In view of the major unmet need in this population and the importance of maintaining or improving quality of life for patients with recurrent or metastatic squamous cell carcinoma of the head and neck, these data support nivolumab as a new standard-of-care option in this setting.
Funding
Bristol-Myers Squibb.
Background:
Nivolumab, a monoclonal antibody of immune checkpoint programmed death 1 on T cells (PD-1), combined with ipilimumab, an immune checkpoint cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitor, as combination therapy on the one hand and nivolumab as monotherapy on the other, have both demonstrated improved efficacy compared with ipilimumab alone in the CheckMate 067 study. However, the combination resulted in a higher frequency of grade 3/4 adverse events (AEs), which could result in diminished health-related quality of life (HRQoL). Here we report analyses of HRQoL for patients with advanced melanoma in clinical trial CheckMate 067.
Patients and methods:
HRQoL was assessed at weeks 1 and 5 per 6-week cycle for the first 6 months, once every 6 weeks thereafter, and at two follow-up visits using the European Organization for Research and Treatment of Care Core Quality of Life Questionnaire and the EuroQoL Five Dimensions Questionnaire. In addition to the randomised population, patient subgroups, including BRAF mutation status, partial or complete response, treatment-related AEs of grade 3/4, and those who discontinued due to any reason and due to an AE, were investigated.
Results:
Nivolumab and ipilimumab combination and nivolumab alone both maintained HRQoL, and no clinically meaningful deterioration was observed over time compared with ipilimumab. In addition, similar results were observed across patient subgroups, and no clinically meaningful changes in HRQoL were observed during follow-up visits for patients who discontinued due to any cause.
Conclusion:
These results further support the clinical benefit of nivolumab monotherapy and nivolumab and ipilimumab combination therapy in patients with advanced melanoma. The finding that the difference in grade 3/4 AEs between the arms did not translate into clinically meaningful differences in the reported HRQoL may be relevant in the clinical setting.
Study number:
NCT01844505.
Background:
Atezolizumab is a humanised antiprogrammed death-ligand 1 (PD-L1) monoclonal antibody that inhibits PD-L1 and programmed death-1 (PD-1) and PD-L1 and B7-1 interactions, reinvigorating anticancer immunity. We assessed its efficacy and safety versus docetaxel in previously treated patients with non-small-cell lung cancer.
Methods:
We did a randomised, open-label, phase 3 trial (OAK) in 194 academic or community oncology centres in 31 countries. We enrolled patients who had squamous or non-squamous non-small-cell lung cancer, were 18 years or older, had measurable disease per Response Evaluation Criteria in Solid Tumors, and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients had received one to two previous cytotoxic chemotherapy regimens (one or more platinum based combination therapies) for stage IIIB or IV non-small-cell lung cancer. Patients with a history of autoimmune disease and those who had received previous treatments with docetaxel, CD137 agonists, anti-CTLA4, or therapies targeting the PD-L1 and PD-1 pathway were excluded. Patients were randomly assigned (1:1) to intravenously receive either atezolizumab 1200 mg or docetaxel 75 mg/m(2) every 3 weeks by permuted block randomisation (block size of eight) via an interactive voice or web response system. Coprimary endpoints were overall survival in the intention-to-treat (ITT) and PD-L1-expression population TC1/2/3 or IC1/2/3 (≥1% PD-L1 on tumour cells or tumour-infiltrating immune cells). The primary efficacy analysis was done in the first 850 of 1225 enrolled patients. This study is registered with ClinicalTrials.gov, number NCT02008227.
Findings:
Between March 11, 2014, and April 29, 2015, 1225 patients were recruited. In the primary population, 425 patients were randomly assigned to receive atezolizumab and 425 patients were assigned to receive docetaxel. Overall survival was significantly longer with atezolizumab in the ITT and PD-L1-expression populations. In the ITT population, overall survival was improved with atezolizumab compared with docetaxel (median overall survival was 13·8 months [95% CI 11·8-15·7] vs 9·6 months [8·6-11·2]; hazard ratio [HR] 0·73 [95% CI 0·62-0·87], p=0·0003). Overall survival in the TC1/2/3 or IC1/2/3 population was improved with atezolizumab (n=241) compared with docetaxel (n=222; median overall survival was 15·7 months [95% CI 12·6-18·0] with atezolizumab vs 10·3 months [8·8-12·0] with docetaxel; HR 0·74 [95% CI 0·58-0·93]; p=0·0102). Patients in the PD-L1 low or undetectable subgroup (TC0 and IC0) also had improved survival with atezolizumab (median overall survival 12·6 months vs 8·9 months; HR 0·75 [95% CI 0·59-0·96]). Overall survival improvement was similar in patients with squamous (HR 0·73 [95% CI 0·54-0·98]; n=112 in the atezolizumab group and n=110 in the docetaxel group) or non-squamous (0·73 [0·60-0·89]; n=313 and n=315) histology. Fewer patients had treatment-related grade 3 or 4 adverse events with atezolizumab (90 [15%] of 609 patients) versus docetaxel (247 [43%] of 578 patients). One treatment-related death from a respiratory tract infection was reported in the docetaxel group.
Interpretation:
To our knowledge, OAK is the first randomised phase 3 study to report results of a PD-L1-targeted therapy, with atezolizumab treatment resulting in a clinically relevant improvement of overall survival versus docetaxel in previously treated non-small-cell lung cancer, regardless of PD-L1 expression or histology, with a favourable safety profile.
Funding:
F. Hoffmann-La Roche Ltd, Genentech, Inc.
Background:
In KEYNOTE-002, pembrolizumab significantly prolonged progression-free survival and was associated with a better safety profile compared with chemotherapy in patients with advanced melanoma that progressed after ipilimumab. We present health-related quality of life (HRQoL) outcomes from KEYNOTE-002.
Methods:
Patients were randomly assigned 1:1:1 to pembrolizumab 2 or 10 mg/kg every 3 weeks (Q3W) or investigator-choice chemotherapy. HRQoL was assessed using the European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire-Core 30 instrument. A constrained longitudinal data analysis model was implemented to assess between-arm differences in HRQoL scores. The study is registered with ClinicalTrials.gov, number NCT01704287.
Results:
Of the 540 patients enrolled, 520 were included in the HRQoL analysis. Baseline global health status (GHS) was similar across treatment arms. Compliance rates at week 12 were 76.6% (n = 108), 82.3% (n = 121), and 86.4% (n = 133) for the control, pembrolizumab 2 mg/kg Q3W, and pembrolizumab 10 mg/kg Q3W arms, respectively. From baseline to week 12, GHS/HRQoL scores were maintained to a higher degree in the pembrolizumab arms compared with the chemotherapy arm (decrease of -2.6 for each pembrolizumab arm versus -9.1 for chemotherapy; P = 0.01 for each pembrolizumab arm versus chemotherapy). Fewer patients treated with pembrolizumab experienced deterioration in GHS at week 12 (31.8% for pembrolizumab 2 mg/kg, 26.6% for 10 mg/kg, and 38.3% for chemotherapy), with similar trends observed for the individual functioning and symptoms scales.
Conclusions:
HRQoL was better maintained with pembrolizumab than with chemotherapy in KEYNOTE-002, supporting the use of pembrolizumab in patients with ipilimumab-refractory melanoma.
Background
Nivolumab has shown significant survival benefit and a favorable safety profile compared with dacarbazine chemotherapy among treatment-naïve patients with metastatic melanoma in the CheckMate 066 phase 3 study. Results from the health-related quality of life (HRQoL) analyses from CheckMate 066 are presented.
Patients and Methods
HRQoL was evaluated at baseline and every 6 weeks while on treatment using the European Organisation for Research and Treatment of Care (EORTC) Core Quality of Life Questionnaire (QLQ-C30) and the EuroQoL Five Dimensions Questionnaire (EQ-5D). Via a multi-step statistical plan, data were analyzed descriptively, cross-sectionally, and longitudinally, adjusting for baseline covariates, in patients having baseline plus ≥1 post-baseline assessment.
Results
Baseline-adjusted completion rates for all HRQoL questionnaires across treatment arms were 65% and 70% for dacarbazine and nivolumab, respectively, and remained similar throughout treatment. Mean baseline HRQoL scores were similar for patients treated with nivolumab and dacarbazine. Baseline HRQoL levels with nivolumab were maintained over time. This exploratory analysis showed a between-arm difference in favor of nivolumab on the EQ-5D utility index and clinically meaningful EQ-5D improvements from baseline at several time points for patients receiving nivolumab. Patients treated with nivolumab did not show increased symptom burden as assessed by the EORTC QLQ-C30. No HRQoL change was noted with dacarbazine patients up to Week 43, although the high attrition rate after Week 13 did not allow any meaningful analyses. Patients receiving nivolumab deteriorated significantly later than those receiving dacarbazine on several EORTC QLQ-C30 scales and the EQ-5D utility index.
Conclusions
In addition to prolonged survival, these exploratory HRQoL results show that nivolumab maintains baseline HRQoL levels to provide long-term quality of survival benefit, compared with dacarbazine in patients with advanced melanoma.
Anti-programmed cell death-1 and anti-programmed cell death ligand-1 (PD-L1) monotherapies have shown promising clinical activity in advanced, refractory non-small cell lung cancer (NSCLC), but antitumour activity appears to be greater in patients with PD-L1+ tumours compared with patients harbouring PD-L1– tumours. Combining the anti-PD-L1 antibody durvalumab and the anti-cytotoxic T-lymphocyte antigen 4 antibody tremelimumab offers the potential for antitumour activity in patients with advanced NSCLC, regardless of PD-L1 tumour status. ARCTIC (NCT02352948) is a global, Phase III, randomised, open-label multicentre study in patients with advanced NSCLC assessing the safety and clinical activity of durvalumab vs. standard of care (SoC; erlotinib; gemcitabine; or vinorelbine) in patients with PD-L1+ tumours (≥25% of tumour cells with membrane staining using VENTANA PD-L1 [SP263] CDx Assay) (Sub-study A) and the combination of durvalumab + tremelimumab or either agent as monotherapy vs. SoC in patients with PD-L1– tumours (Sub-study B). Eligible patients are those with locally advanced or metastatic NSCLC (Stage IIIB/IV), without epidermal growth factor receptor tyrosine kinase activating mutations or anaplastic lymphoma kinase rearrangements, who have received at least two prior systemic regimens, including one platinum-based chemotherapy regimen. Co-primary endpoints are progression- free survival and overall survival. Secondary endpoints include: proportion of patients alive at 12 months, objective response rate, duration of response, progression-free survival at 6 and 12 months, safety and tolerability, pharmacokinetics, immunogenicity and quality of life. Exploratory endpoints will assess potential biomarkers of treatment response. Recruitment started in January 2015 and is ongoing.
Background:
We performed a meta-analysis of the risk of endocrine adverse events associated with immune check point inhibitors.
Methods:
Eligible studies included randomized trials of cancer patients on immune checkpoint inhibitors; describing events of hypothyroidism, hyperthyroidism, hypophysitis and adrenal insufficiency.
Results:
A total of ten clinical trials were eligible for the meta-analysis. The relative risk of all-grade hypothyroidism, hyperthyroidism, hypophyisitis and adrenal insufficiency were 8.26 (95% CI: 4.67-14.62; p < 0.00001), 5.48 (95% CI: 1.33-22.53; p = 0.02); 22.03 (95% CI: 8.52-56.94; p < 0.00001), 3.87 (95% CI: 1.12-13.41; p = 0.03), respectively.
Conclusion:
Our meta-analysis has demonstrated that the use of immune check point inhibitors is associated with an increased risk of hypothyroidism, hyperthyroidism, hypophysitis and adrenal insufficiency compared with control.
Aim:
We performed a meta-analysis of the risk of selected gastrointestinal toxicities associated with immune checkpoint inhibitors.
Patients & methods:
Eligible studies included randomized trials of patients with solid tumors on ipilimumab, nivolumab, pembrolizumab, tremelimumab, pidilizumab and atezolizumab, describing events of diarrhea, vomiting or colitis.
Results:
After exclusion of ineligible studies, a total of ten clinical trials were considered eligible for the meta-analysis. The relative risk of all-grade diarrhea, vomiting and colitis was 1.64 (95% CI: 1.19-2.26; p = 0.002), 0.72 (95% CI: 0.49-1.07; p = 0.1), 10.35 (95% CI: 5.78-18.53; p < 0.00001), respectively.
Conclusion:
Our meta-analysis has demonstrated that immune checkpoint inhibitors are associated with a significantly increased risk of all grade and high-grade colitis.
We performed a meta-analysis of the risk of cutaneous toxicities associated with immune checkpoint inhibitors.
Eligible studies included randomized trials of patients with solid tumors on immune checkpoint inhibitors (ipilimumab, nivolumab, tremelimumab, pidlizumab and pembrolizumab); describing events of rash, vitiligo and pruritus.
A total of nine clinical trials were considered eligible for the meta-analysis. The relative risk of all-grade rash, vitiligo and pruritus was 4.06 (95% CI: 3.35-4.91; p < 0.0001), 16.3 (95% CI: 3.21-82.8; p = 0.0008) and 3.4 (95% CI: 2.24-5.16; p < 0.00001), respectively.
Our meta-analysis demonstrates that immune checkpoint inhibitors are associated with an increased risk of all grade skin rash, vitiligo and pruritus. Clinicians should perform regular clinical cutaneous monitoring.
T-lymphocytes have the potential to recognize cancer antigens as foreign and therefore eliminate them. However, immune checkpoints such as cytotoxic T-lymphocyte-associated antigen (CTLA)-4 and programmed cell death (PD)-1 receptor and its ligands (PD-L1, PD-L2) suppress the activity of T-lymphocytes. Advances in the understanding of immunology and its role in cancer have led to the development of immune checkpoint inhibitors that block CTLA-4 and PD-1 and result in durable responses in patients with a wide range of cancers. PD-1 and PD-L1 inhibitors are currently in many stages of clinical investigation, and the anti-PD-1 antibody, pembrolizumab, was recently approved by the US Food and Drug Administration. Many questions remain to be answered, such as the optimal administration schedule, biomarkers that associate with benefit, and potential for use of PD-1 agents in combination approaches. Nonetheless, immunotherapy with PD-1 blocking antibodies is now becoming an integral part in the management of cancer.
Ipilimumab monotherapy (at a dose of 3 mg per kilogram of body weight), as compared with glycoprotein 100, improved overall survival in a phase 3 study involving patients with previously treated metastatic melanoma. We conducted a phase 3 study of ipilimumab (10 mg per kilogram) plus dacarbazine in patients with previously untreated metastatic melanoma.
We randomly assigned 502 patients with previously untreated metastatic melanoma, in a 1:1 ratio, to ipilimumab (10 mg per kilogram) plus dacarbazine (850 mg per square meter of body-surface area) or dacarbazine (850 mg per square meter) plus placebo, given at weeks 1, 4, 7, and 10, followed by dacarbazine alone every 3 weeks through week 22. Patients with stable disease or an objective response and no dose-limiting toxic effects received ipilimumab or placebo every 12 weeks thereafter as maintenance therapy. The primary end point was overall survival.
Overall survival was significantly longer in the group receiving ipilimumab plus dacarbazine than in the group receiving dacarbazine plus placebo (11.2 months vs. 9.1 months, with higher survival rates in the ipilimumab-dacarbazine group at 1 year (47.3% vs. 36.3%), 2 years (28.5% vs. 17.9%), and 3 years (20.8% vs. 12.2%) (hazard ratio for death, 0.72; P<0.001). Grade 3 or 4 adverse events occurred in 56.3% of patients treated with ipilimumab plus dacarbazine, as compared with 27.5% treated with dacarbazine and placebo (P<0.001). No drug-related deaths or gastrointestinal perforations occurred in the ipilimumab-dacarbazine group.
Ipilimumab (at a dose of 10 mg per kilogram) in combination with dacarbazine, as compared with dacarbazine plus placebo, improved overall survival in patients with previously untreated metastatic melanoma. The types of adverse events were consistent with those seen in prior studies of ipilimumab; however, the rates of elevated liver-function values were higher and the rates of gastrointestinal events were lower than expected on the basis of prior studies. (Funded by Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00324155.).
To determine the significance to patients of changes in health-related quality-of-life (HLQ) scores assessed by the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30).
A subjective significance questionnaire (SSQ), which asks patients about perceived changes in physical, emotional, and social functioning and in global quality of life (global QL) and the QLQ-C30 were completed by patients who received chemotherapy for either breast cancer or small-cell lung cancer (SCLC). In the SSQ, patients rated their perception of change since the last time they completed the QLQ-C30 using a 7-category scale that ranged from "much worse" through "no change" to "much better." For each category of change in the SSQ, the corresponding differences were calculated in QLQ-C30 mean scores and effect sizes were determined.
For patients who indicated "no change" in the SSQ, the mean change in scores in the corresponding QLQ-C30 domains was not significantly different from 0. For patients who indicated "a little" change either for better or for worse, the mean change in scores was about 5 to 10; for "moderate" change, about 10 to 20; and for "very much" change, greater than 20. Effect sizes increased in concordance with increasing changes in SSQ ratings and QLQ-C30 scores.
The significance of changes in QLQ-C30 scores can be interpreted in terms of small, moderate, or large changes in quality of life as reported by patients in the SSQ. The magnitude of these changes also can be used to calculate the sample sizes required to detect a specified change in clinical trials.
Great progress has been made in the field of tumor immunology in the past decade, but optimism about the clinical application of currently available cancer vaccine approaches is based more on surrogate endpoints than on clinical tumor regression. In our cancer vaccine trials of 440 patients, the objective response rate was low (2.6%), and comparable to the results obtained by others. We consider here results in cancer vaccine trials and highlight alternate strategies that mediate cancer regression in preclinical and clinical models.
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Background: In KEYNOTE-045 (NCT02256436) (N = 542), pembro 200 mg Q3W significantly improved OS over investigator’s choice of paclitaxel, docetaxel, or vinflunine as second-line therapy for advanced UC following platinum-based chemo (HR 0.73; P = 0.0022). Fewer treatment-related AEs were reported with pembro. We present results of the prespecified HRQoL analysis of KEYNOTE-045. Methods: The EORTC QLQ-C30 HRQoL instrument was administered electronically at cycles 1–4, then every 2 cycles for up to 1 y and 30 d after discontinuation. The key HRQoL end points were 1) change from baseline to wk 15 and 2) time to deterioration (TTD) (defined as ≥10-point decrease from baseline) in the QLQ-C30 global health status/QoL score. HRQoL was assessed in patients (pts) who received ≥1 dose of assigned study treatment and completed ≥1 HRQoL instrument (N = 520). Score change from baseline was compared using a constrained longitudinal data analysis model. TTD was compared using a stratified log-rank test and Cox proportional hazards model. Results: Baseline global health status/QoL scores were similar between arms. HRQoL compliance at wk 15 was 88% for both arms. From baseline to wk 15, scores were stable for pembro (n = 266) (least squares [LS] mean +0.75 [95% CI –2.34 to +3.83]) but worsened for chemo (n = 254) (LS mean –8.30 [95% CI –11.76 to –4.83]); the difference in LS means between arms was 9.05 (95% CI 4.61-13.48; nominal 2-sided P < 0.001). At wk 15, pts without PD had improved scores with pembro but worsened scores with chemo (LS mean +5.97 vs –4.31), while pts with PD had less worsening with pembro (LS mean –3.54 vs –13.95). TTD was prolonged with pembro (HR 0.70; 95% CI 0.55-0.90; nominal 1-sided P = 0.002; median 3.5 mo vs 2.2 mo). Rates of improvement (defined as ≥10-point increase from baseline) at wk 15 were 31.2% with pembro and 22.0% with chemo; rates of deterioration were 28.9% and 40.6%, respectively. Conclusions: Pembro was associated with substantially better HRQoL for a longer duration than investigator-choice chemo in pts with previously treated advanced UC. Along with superior OS, these data support pembro as a new standard-of-care in this population. Clinical trial information: NCT02256436.
e14593
Background: Therapy with immune checkpoint inhibitors (ICI) changed the paradigm of treatment in many solid tumors including NSCLC. Recently several ICI were approved for NSCLC second and first line. By now data on Nivo benefits/risks in NSCLC is quite limited. The aim of this study was to evaluate clinical and patient-reported outcomes on Nivo in second plus line within the expanded access program in NSCLC. We report interim analysis on response rates, safety and QoL. Methods: Adult pts with advanced refractory NSCLC received Nivo 3 mg/kg q2w. Tumor response was assessed using RECIST v. 1.1., adverse events (AEs) with NCI CTCAE v3.0. and QoL by RAND SF-36. Group comparisons were made using Wilcoxon test. Results: From July of 2015 to January of 2017, 157 pts were enrolled in 7 centers in RF. Median follow-up time was 14 weeks. Clinical characteristics: 66% – males; median age – 62 (29−80); ECOG PS 0-1/2-3 – 81%/19%; former/current smokers – 73%; non squamous NSCLC – 64%; ≥2 lines of previous systemic treatment – 51%. We observed 1.5 increase of Integral QoL index in 53% of pts at 4 weeks; significant improvement was observed for emotional functioning (33.3 vs 50.0; p < 0.05). Efficacy was evaluated in 56 pts: PR – 6/56, SD – 35/56, PD – 15/56. Clinical improvement was noticed in 36 pts. Early deaths from cancer occurred in 9 pts; early deaths not related to cancer – 2 pts. 18 pts discontinued Nivo prematurely ( < 8 weeks) because of rapid clinical worsening. 72 pts were not evaluated for response on cut-off. More pts with quick worsening as compared with responders were with non squamous NSCLC (75% vs 50%) and had brain mets (20% vs 0%). Among responders 33% were with PS > 1 and were > 65 y.o; pts in this group had no brain mets. AEs were registered in 40 pts (median of Nivo treatment – 6 weeks); among them 11 with grade 3-4 AEs. Conclusions: Early data from this study supports thata large number of pts benefits fromNivo treatment. Nivo is well tolerated by this population, with 7% of grade 3 or 4 toxicities. Nivo treatment is accompanied with significant QoL improvement in 53% pts.
Aim:
Numerous trials for PD-(L)1 inhibitors in the management of advanced urinary cancers (urothelial carcinoma and renal cell carcinoma) were published recently. It is not known exactly what should be the optimal surrogate end point for overall survival (OS) in this context.
Materials & methods:
PubMed database and ASCO meeting library were searched till August 2017. Eligible studies included prospective clinical studies evaluating PD-(L)1 inhibitors for the management of advanced urothelial carcinoma or renal cell carcinoma. The review author extracted relevant data on the characteristics of participants and the outcomes of the different studies. In order to conduct a proper correlation analysis, normality testing using Shapiro-Wilk test was first used. Based on the result of the normality testing, either Pearson's product-moment correlation or Spearman's rank correlation was used.
Results:
Thirteen trials (nine urothelial carcinoma and four renal cell carcinoma trials) with 2792 participants were included. The correlation of overall response rate with median OS was very weak to weak (for urothelial carcinoma: r = -0.120, n = 9, p = 0.758; for renal cell carcinoma: r = -0.397, n = 6, p = 0.436). Likewise, the correlation of progression-free survival with median OS was very weak to weak (for urothelial carcinoma: r = -0.024, n = 8, p = 0.955; for renal cell carcinoma: r = 0.394, n = 6, p = 0.440). On the other hand, 1-year survival rate may be a better surrogate end point for median OS (for urothelial carcinoma: r = 0.806, n = 8, p = 0.016; for renal cell carcinoma: r = 0.941, n = 6, p = 0.005).
Conclusion:
RECIST-defined overall response rate and progression-free survival are not reliable surrogate end points for median OS in trials of PD-(L)1 inhibitor therapy for urinary cancers. The use of other surrogate end points (e.g., 1-year survival) in early phase studies may be considered.
Background:
In the phase 3 KEYNOTE-024 trial, treatment with pembrolizumab conferred longer progression-free survival than did platinum-based therapy in patients with treatment-naive, advanced non-small-cell lung cancer (NSCLC) with a programmed cell death-ligand 1 (PD-L1) tumour proportion score of 50% or greater (PD-L1-positive). Here we report the prespecified exploratory endpoint of pembrolizumab versus chemotherapy on patient-reported outcomes (PROs).
Methods:
In this multicentre, international, randomised, open-label, phase 3 trial, we recruited patients with treatment-naive, stage IV NSCLC in 102 sites in 16 countries. Eligible patients had measurable disease (per RECIST version 1.1) and an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. Patients were randomly assigned (1:1) via an interactive voice response system and integrated web response system to receive either pembrolizumab 200 mg every 3 weeks (35 cycles) or investigator-choice platinum-doublet chemotherapy (4-6 cycles or until documented disease progression or unacceptable toxicity). Randomisation was stratified according to geography, ECOG performance status, and histology. PROs were assessed at day 1 of cycles 1-3, every 9 weeks thereafter, at the treatment discontinuation visit, and at the 30-day safety assessment visit using the European Organisation for the Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 items (QLQ-C30), the EORTC Quality of Life Questionnaire Lung Cancer 13 items (QLQ-LC13), and the European Quality of Life 5 Dimensions-3 Level (EQ-5D-3L) questionnaire. The key exploratory PRO endpoints (analysed for all patients who received at least one dose of study treatment and completed at least one PRO instrument at at least one timepoint) were baseline-to-week-15 change in the QLQ-C30 global health status (GHS)/quality-of-life (QOL) score and time to deterioration of the composite of cough, chest pain, and dyspnoea in the QLQ-LC13. This study is registered with ClinicalTrials.gov, number NCT02142738, and is ongoing but no longer enrolling patients.
Findings:
Between Sept 19, 2014, and Oct 29, 2015, 305 patients were randomly assigned to pembrolizumab (n=154) or chemotherapy (n=151). Three patients in each group did not complete any PRO instruments at any timepoints, and so 299 patients were included in the full analysis set. Of these patients, one in each group did not complete any PRO instruments before week 15, and so were not included in analyses of change from baseline to week 15. PRO compliance was greater than 90% at baseline and approximately 80% at week 15 for both groups. Least-squares mean baseline-to-week-15 change in QLQ-C30 GHS/QOL score was 6·9 (95% CI 3·3 to 10·6) for pembrolizumab and -0·9 (-4·8 to 3·0) for chemotherapy, for a difference of 7·8 (2·9 to 12·8; two-sided nominal p=0·0020). Fewer pembrolizumab-treated patients had deterioration in the QLQ-LC13 composite endpoint than did chemotherapy-treated patients (46 [31%] of 151 patients vs 58 [39%] of 148 patients). Time to deterioration was longer with pembrolizumab than with chemotherapy (median not reached [95% CI 8·5 to not reached] vs 5·0 months [3·6 to not reached]; hazard ratio 0·66, 95% CI 0·44-0·97; two-sided nominal p=0·029).
Interpretation:
Pembrolizumab improves or maintains health-related QOL compared with that for chemotherapy, and might represent a new first-line standard of care for PD-L1-expressing, advanced NSCLC.
Funding:
Merck & Co.
Introduction:
In the phase III CheckMate 017 study, nivolumab prolonged overall survival versus docetaxel in previously treated patients with advanced squamous non-small cell lung cancer (NSCLC). Study objectives included health-related quality of life (HRQoL) and symptom assessments.
Methods:
Patients serially completed Lung Cancer Symptom Scale (LCSS) and European Quality of Life Five Dimensions (EQ-5D) questionnaires. The LCSS average symptom burden index (ASBI; mean score for six lung cancer-specific symptoms; range, 0-100), LCSS 3-item global index, EQ-5D utility index, and EQ-5D visual analog scale scores were analyzed. The proportion of patients exhibiting clinically meaningful improvement (≥10-point decrease) in ASBI scores by week 12 was a secondary end point. Mixed-effect model repeated measures analysis of HRQoL changes from baseline and analyses of time to HRQoL deterioration were conducted.
Results:
Baseline mean (SD) LCSS ASBI scores were similar in nivolumab (29.6 [16.4]) and docetaxel (29.6 [14.7]) groups. By week 12, the proportion of patients (95% CI) with clinically meaningful improvement in ASBI scores was 20.0% (13.6-27.7) with nivolumab and 21.9% (15.3-29.8) with docetaxel. At weeks 16-54, significant improvements in ASBI scores from baseline were seen with nivolumab; clinically meaningful improvements were observed at weeks 42-84. No significant changes in ASBI scores from baseline were observed with docetaxel; at week 36, a clinically meaningful deterioration was seen. Improvements in HRQoL with nivolumab versus docetaxel were supported by other measures, and time to first HRQoL deterioration was longer.
Conclusion:
Nivolumab alleviates symptom burden and improves health status versus docetaxel as second-line squamous NSCLC treatment.
Aim: The use of immune checkpoint inhibitors in the treatment of solid tumors has been expanding recently. Standard response evaluation criteria are not well suited to evaluate the clinical benefit from these agents. To systematically review the incidence and characteristics of nonconventional patterns of benefit observed in solid tumors treated with immune checkpoint inhibitors. Materials & methods: MEDLINE and EMBASE databases have been searched. Moreover, reference lists of relevant articles were checked for cross-references. Selection criteria: Clinical studies evaluating PD-(L)1 inhibitors for the management of advanced solid tumors irrespective of the publication status or language. The review author extracted relevant data on the characteristics of participants and the outcomes of the different studies. Results: Nineteen prospective trials with 5404 participants were included. Among patients experiencing RECIST-defined progression and continued treatment beyond progression, rates of response beyond progression ranged from 4 to 10% (of the total number of included patients). These findings were similarly observed regardless of the PD-(L)1 inhibitor used, the disease treated, or the dose used indicating that these findings are part of the inherent characteristics of PD-(L)1 inhibitors for solid tumors. These findings need confirmation from the results of other prospective studies. Many additional ongoing trials were identified evaluating the use of PD-(L)1 inhibitors for the management of solid tumors. Conclusion: Traditional RECIST criteria are not suited for proper assessment of response to PD-(L)1 inhibitors; and more tailored criteria (e.g. immune-related response criteria) should be employed for patients treated with PD-(L)1 inhibitors; moreover in patients with an evidence of disease progression on initial disease evaluation, treatment should not be stopped except after confirmation of progressive disease with a second evaluation at least 4 weeks later.
Background
Nivolumab has been associated with longer overall survival than docetaxel among patients with previously treated non–small-cell lung cancer (NSCLC). In an open-label phase 3 trial, we compared first-line nivolumab with chemotherapy in patients with programmed death ligand 1 (PD-L1)–positive NSCLC.
Methods
We randomly assigned, in a 1:1 ratio, patients with untreated stage IV or recurrent NSCLC and a PD-L1 tumor-expression level of 1% or more to receive nivolumab (administered intravenously at a dose of 3 mg per kilogram of body weight once every 2 weeks) or platinum-based chemotherapy (administered once every 3 weeks for up to six cycles). Patients receiving chemotherapy could cross over to receive nivolumab at the time of disease progression. The primary end point was progression-free survival, as assessed by means of blinded independent central review, among patients with a PD-L1 expression level of 5% or more.
Results
Among the 423 patients with a PD-L1 expression level of 5% or more, the median progression-free survival was 4.2 months with nivolumab versus 5.9 months with chemotherapy (hazard ratio for disease progression or death, 1.15; 95% confidence interval [CI], 0.91 to 1.45; P=0.25), and the median overall survival was 14.4 months versus 13.2 months (hazard ratio for death, 1.02; 95% CI, 0.80 to 1.30). A total of 128 of 212 patients (60%) in the chemotherapy group received nivolumab as subsequent therapy. Treatment-related adverse events of any grade occurred in 71% of the patients who received nivolumab and in 92% of those who received chemotherapy. Treatment-related adverse events of grade 3 or 4 occurred in 18% of the patients who received nivolumab and in 51% of those who received chemotherapy.
Conclusions
Nivolumab was not associated with significantly longer progression-free survival than chemotherapy among patients with previously untreated stage IV or recurrent NSCLC with a PD-L1 expression level of 5% or more. Overall survival was similar between groups. Nivolumab had a favorable safety profile, as compared with chemotherapy, with no new or unexpected safety signals. (Funded by Bristol-Myers Squibb and others; CheckMate 026 ClinicalTrials.gov number, NCT02041533.)
29 Background: Patient-centered outcomes are important quality metrics of value-based cancer care. For NSCLC, these include chemotherapy administration within 30 days of death and end of life hospitalizations. Nivolumab was initially FDA approved in March 2015 for second-line therapy of squamous NSCLC and subsequently for non-squamous NSCLC. To evaluate the impact of post-approval nivolumab use on patient-centered outcomes, a retrospective review was performed of patients (pts) with metastatic NSLCC receiving nivolumab at TCI main campus and regional centers. Methods: All pts with NSCLC receiving nivolumab from 3/4/15 to 10/5/15 were identified (cohort A) and treatment characteristics were collected from pharmacy, billing, and tumor registry databases and manual chart review. Similar data for a cohort of NSCLC pts (cohort B) initiating care with 4 academic thoracic and 12 community TCI oncologists from 1/1/12 to 7/1/13 and who received second-line therapy were used for comparison. Results: 113 cohort A pt...
Aims:
We carried out a meta-analysis to determine the risk of treatment-related death associated with immune checkpoint inhibitor use in cancer patients.
Materials and methods:
We examined data from the Medline and Google Scholar databases. We also examined original studies and review articles for cross-references. Eligible studies included randomised phase II and phase III trials of patients with cancer treated with ipilimumab, pembrolizumab; nivolumab; tremelimumab and atezolizumab. The authors extracted relevant information on participants, characteristics, treatment-related death and information on the methodology of the studies.
Results:
After exclusion of ineligible records, 18 clinical trials were included in the analysis. The odds ratio for treatment-related death for CTLA-4 inhibitors (ipilimumab and tremelimumab) was 1.80 (95% confidence interval 1.25, 2.59; P=0.002) and for PD-1/PD-L1 inhibitors (nivolumab, pembrolizumab and atezolizumab) was 0.63 (95% confidence interval 0.31, 1.30; P=0.22). Treated cancer seems to have no effect on the risk of treatment-related death.
Conclusions:
Analysis of our data showed that CTLA-4 inhibitors (ipilimumab and tremelimumab) in a higher dose (10 mg/kg) seem to be associated with a higher risk of treatment-related death compared with control regimens, whereas PD-1/PD-L1 inhibitors (nivolumab, pembrolizumab and atezolizumab) do not cause the same risk. Clinicians have to be fully aware of these differential risks and council their patients appropriately.
Aims:
Fatigue is one of the most prominent side-effects of immune checkpoint inhibition. Therefore, we assessed the risk of fatigue associated with inhibitors of the immune checkpoints.
Materials and methods:
We examined data from the Medline and Google Scholar databases. We also examined original studies and review articles for cross-references. Eligible studies included randomised phase II and phase III trials of patients with cancer treated with ipilimumab, nivolumab, pembrolizumab and tremelimumab. The authors extracted relevant information on participants(') characteristics, all-grade and high-grade fatigue and information on the methodology of the studies.
Results:
In total, 17 trials were considered eligible for the meta-analysis. The odds ratio for all-grade fatigue for CTLA-4 inhibitors was 1.23 (95% confidence interval 1.07, 1.41; P = 0.003) and for high-grade fatigue was 1.72 (95% confidence interval 1.26, 2.33; P = 0.0005). Moreover, the odds ratio for all-grade fatigue for PD-1 inhibitors was 0.72 (95% confidence interval 0.62, 0.84; P < 0.0001) and for high-grade fatigue was 0.36 (95% confidence interval 0.23, 0.56; P < 0.00001).
Conclusions:
The analysis of data showed that CTLA-4 inhibitors seem to be associated with a higher risk of all- and high-grade fatigue compared with control regimens, whereas PD-1 inhibitors seem to be associated with a lower risk of all- and high-grade fatigue compared with control regimens.
Background:
In the phase 3 CheckMate 025 study, previously treated patients with advanced renal cell carcinoma who were randomly assigned to nivolumab had an overall survival benefit compared with those assigned to everolimus. We aimed to compare health-related quality of life (HRQoL) between treatment groups in this trial.
Methods:
CheckMate 025 was an open-label study done at 146 oncology centres in 24 countries. Patients were randomly assigned to treatment between Oct 22, 2012, and March 11, 2014. Patients with advanced renal cell carcinoma were randomly assigned (1:1, block size of four) to receive nivolumab every 2 weeks or everolimus once per day. The study was stopped early at the planned interim analysis in July, 2015, because the study met its primary endpoint. A protocol amendment permitted patients in the everolimus group to cross over to nivolumab treatment. All patients not on active study therapy are being followed up for survival. At the interim analysis, HRQoL was assessed with the Functional Assessment of Cancer Therapy-Kidney Symptom Index-Disease Related Symptoms (FKSI-DRS) and European Quality of Life (EuroQol)-5 Dimensions (EQ-5D) questionnaires. Prespecified endpoints were to assess, in each treatment group, disease-related symptom progression rate based on the FKSI-DRS and changes in reported global health outcomes based on the EQ-5D. Other endpoints were post hoc. We calculated the proportion of FKSI-DRS questionnaires completed using the number of patients with non-missing data at baseline and at least one post-baseline visit. We defined FKSI-DRS completion as completion of five or more of the nine items in the questionnaire; otherwise data were treated as missing. FKSI-DRS symptom index score was prorated for missing items. We made no adjustments for missing EQ-5D data. We used descriptive statistics and multivariate analyses, including mixed-effects model repeated-measures, for between group comparisons. Analyses were powered according to the original study protocol, and we analysed FKSI-DRS and EQ-5D data for all patients who underwent randomisation and had a baseline assessment and at least one post-baseline assessment. CheckMate 025 is registered with ClinicalTrials.gov, number NCT01668784.
Findings:
HRQoL data were collected at baseline for 362 (88%) of 410 patients in the nivolumab group and 344 (84%) of 411 patients in the everolimus group. The mean difference in FKSI-DRS scores between the nivolumab and everolimus groups was 1·6 (95% CI 1·4-1·9; p<0·0001) with descriptive statistics and 1·7 (1·2-2·1; p<0·0001) with mixed-effects model repeated-measures analysis. In terms of FKSI-DRS score, more patients had a clinically meaningful (ie, an increase of at least 2 points from baseline) HRQoL improvement with nivolumab (200 [55%] of 361 patients) versus everolimus (126 [37%] of 343 patients; p<0·0001). Median time to HRQoL improvement was shorter in patients given nivolumab (4·7 months, 95% CI 3·7-7·5) than in patients given everolimus (median not reached, NE-NE).
Interpretation:
Nivolumab was associated with HRQoL improvement compared with everolimus in previously treated patients with advanced renal cell carcinoma.
Funding:
Bristol-Myers Squibb.
Background:
Outcomes are poor for patients with previously treated, advanced or metastatic non-small-cell lung cancer (NSCLC). The anti-programmed death ligand 1 (PD-L1) antibody atezolizumab is clinically active against cancer, including NSCLC, especially cancers expressing PD-L1 on tumour cells, tumour-infiltrating immune cells, or both. We assessed efficacy and safety of atezolizumab versus docetaxel in previously treated NSCLC, analysed by PD-L1 expression levels on tumour cells and tumour-infiltrating immune cells and in the intention-to-treat population.
Methods:
In this open-label, phase 2 randomised controlled trial, patients with NSCLC who progressed on post-platinum chemotherapy were recruited in 61 academic medical centres and community oncology practices across 13 countries in Europe and North America. Key inclusion criteria were Eastern Cooperative Oncology Group performance status 0 or 1, measurable disease by Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1), and adequate haematological and end-organ function. Patients were stratified by PD-L1 tumour-infiltrating immune cell status, histology, and previous lines of therapy, and randomly assigned (1:1) by permuted block randomisation (with a block size of four) using an interactive voice or web system to receive intravenous atezolizumab 1200 mg or docetaxel 75 mg/m(2) once every 3 weeks. Baseline PD-L1 expression was scored by immunohistochemistry in tumour cells (as percentage of PD-L1-expressing tumour cells TC3≥50%, TC2≥5% and <50%, TC1≥1% and <5%, and TC0<1%) and tumour-infiltrating immune cells (as percentage of tumour area: IC3≥10%, IC2≥5% and <10%, IC1≥1% and <5%, and IC0<1%). The primary endpoint was overall survival in the intention-to-treat population and PD-L1 subgroups at 173 deaths. Biomarkers were assessed in an exploratory analysis. We assessed safety in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01903993.
Findings:
Patients were enrolled between Aug 5, 2013, and March 31, 2014. 144 patients were randomly allocated to the atezolizumab group, and 143 to the docetaxel group. 142 patients received at least one dose of atezolizumab and 135 received docetaxel. Overall survival in the intention-to-treat population was 12·6 months (95% CI 9·7-16·4) for atezolizumab versus 9·7 months (8·6-12·0) for docetaxel (hazard ratio [HR] 0·73 [95% CI 0·53-0·99]; p=0·04). Increasing improvement in overall survival was associated with increasing PD-L1 expression (TC3 or IC3 HR 0·49 [0·22-1·07; p=0·068], TC2/3 or IC2/3 HR 0·54 [0·33-0·89; p=0·014], TC1/2/3 or IC1/2/3 HR 0·59 [0·40-0·85; p=0·005], TC0 and IC0 HR 1·04 [0·62-1·75; p=0·871]). In our exploratory analysis, patients with pre-existing immunity, defined by high T-effector-interferon-γ-associated gene expression, had improved overall survival with atezolizumab. 11 (8%) patients in the atezolizumab group discontinued because of adverse events versus 30 (22%) patients in the docetaxel group. 16 (11%) patients in the atezolizumab group versus 52 (39%) patients in the docetaxel group had treatment-related grade 3-4 adverse events, and one (<1%) patient in the atezolizumab group versus three (2%) patients in the docetaxel group died from a treatment-related adverse event.
Interpretation:
Atezolizumab significantly improved survival compared with docetaxel in patients with previously treated NSCLC. Improvement correlated with PD-L1 immunohistochemistry expression on tumour cells and tumour-infiltrating immune cells, suggesting that PD-L1 expression is predictive for atezolizumab benefit. Atezolizumab was well tolerated, with a safety profile distinct from chemotherapy.
Funding:
F Hoffmann-La Roche/Genentech Inc.
Background: This meta-analysis has been conducted to determine the risk of elevated transaminases associated with immune checkpoint inhibitors use in patients with cancer.
Methods: Studies eligible for our analysis included randomized Phase II and III trials of patients with cancer on ipilimumab, nivolumab, pembrolizumab, tremelimumab and pidilizumab, which describe events of elevated transaminases [alanine aminotransferase (ALT) and aspartate aminotransferase (AST)].
Results: Initial database search revealed 210 relevant citations. After excluding noneligible studies, 10 trials were considered eligible for the quantitative synthesis. The RR of all-grade elevated ALT and AST was 2.36 (95% CI 1.20–4.66; p = 0.01) and 1.53 (95% CI 0.73–3.22; p = 0.26), respectively, whereas for high-grade elevated ALT and AST, it was 11.27 (95% CI 5.38–23.63; p < 0.0001) and 4.9 (95% CI 2.97–8.09; p < 0.0001), respectively.
Conclusions: Our study has shown that the use of immune checkpoint inhibitors has a causal relationship to an increased risk of high-grade elevated ALT and AST. Clinicians using these agents should be attentive of this risk.
Background:
Nivolumab, a fully human IgG4 programmed death 1 (PD-1) immune-checkpoint-inhibitor antibody, disrupts PD-1-mediated signaling and may restore antitumor immunity.
Methods:
In this randomized, open-label, international phase 3 study, we assigned patients with nonsquamous non-small-cell lung cancer (NSCLC) that had progressed during or after platinum-based doublet chemotherapy to receive nivolumab at a dose of 3 mg per kilogram of body weight every 2 weeks or docetaxel at a dose of 75 mg per square meter of body-surface area every 3 weeks. The primary end point was overall survival.
Results:
Overall survival was longer with nivolumab than with docetaxel. The median overall survival was 12.2 months (95% confidence interval [CI], 9.7 to 15.0) among 292 patients in the nivolumab group and 9.4 months (95% CI, 8.1 to 10.7) among 290 patients in the docetaxel group (hazard ratio for death, 0.73; 96% CI, 0.59 to 0.89; P=0.002). At 1 year, the overall survival rate was 51% (95% CI, 45 to 56) with nivolumab versus 39% (95% CI, 33 to 45) with docetaxel. With additional follow-up, the overall survival rate at 18 months was 39% (95% CI, 34 to 45) with nivolumab versus 23% (95% CI, 19 to 28) with docetaxel. The response rate was 19% with nivolumab versus 12% with docetaxel (P=0.02). Although progression-free survival did not favor nivolumab over docetaxel (median, 2.3 months and 4.2 months, respectively), the rate of progression-free survival at 1 year was higher with nivolumab than with docetaxel (19% and 8%, respectively). Nivolumab was associated with even greater efficacy than docetaxel across all end points in subgroups defined according to prespecified levels of tumor-membrane expression (≥1%, ≥5%, and ≥10%) of the PD-1 ligand. Treatment-related adverse events of grade 3 or 4 were reported in 10% of the patients in the nivolumab group, as compared with 54% of those in the docetaxel group.
Conclusions:
Among patients with advanced nonsquamous NSCLC that had progressed during or after platinum-based chemotherapy, overall survival was longer with nivolumab than with docetaxel. (Funded by Bristol-Myers Squibb; CheckMate 057 ClinicalTrials.gov number, NCT01673867.).
Background:
We assessed the efficacy and safety of programmed cell death 1 (PD-1) inhibition with pembrolizumab in patients with advanced non-small-cell lung cancer enrolled in a phase 1 study. We also sought to define and validate an expression level of the PD-1 ligand 1 (PD-L1) that is associated with the likelihood of clinical benefit.
Methods:
We assigned 495 patients receiving pembrolizumab (at a dose of either 2 mg or 10 mg per kilogram of body weight every 3 weeks or 10 mg per kilogram every 2 weeks) to either a training group (182 patients) or a validation group (313 patients). We assessed PD-L1 expression in tumor samples using immunohistochemical analysis, with results reported as the percentage of neoplastic cells with staining for membranous PD-L1 (proportion score). Response was assessed every 9 weeks by central review.
Results:
Common side effects that were attributed to pembrolizumab were fatigue, pruritus, and decreased appetite, with no clear difference according to dose or schedule. Among all the patients, the objective response rate was 19.4%, and the median duration of response was 12.5 months. The median duration of progression-free survival was 3.7 months, and the median duration of overall survival was 12.0 months. PD-L1 expression in at least 50% of tumor cells was selected as the cutoff from the training group. Among patients with a proportion score of at least 50% in the validation group, the response rate was 45.2%. Among all the patients with a proportion score of at least 50%, median progression-free survival was 6.3 months; median overall survival was not reached.
Conclusions:
Pembrolizumab had an acceptable side-effect profile and showed antitumor activity in patients with advanced non-small-cell lung cancer. PD-L1 expression in at least 50% of tumor cells correlated with improved efficacy of pembrolizumab. (Funded by Merck; KEYNOTE-001 ClinicalTrials.gov number, NCT01295827.).
Nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, can result in durable responses in patients with melanoma who have progressed after ipilimumab and BRAF inhibitors. We assessed the efficacy and safety of nivolumab compared with investigator's choice of chemotherapy (ICC) as a second-line or later-line treatment in patients with advanced melanoma.
In this randomised, controlled, open-label, phase 3 trial, we recruited patients at 90 sites in 14 countries. Eligible patients were 18 years or older, had unresectable or metastatic melanoma, and progressed after ipilimumab, or ipilimumab and a BRAF inhibitor if they were BRAF(V 600) mutation-positive. Participating investigators randomly assigned (with an interactive voice response system) patients 2:1 to receive an intravenous infusion of nivolumab 3 mg/kg every 2 weeks or ICC (dacarbazine 1000 mg/m(2) every 3 weeks or paclitaxel 175 mg/m(2) combined with carboplatin area under the curve 6 every 3 weeks) until progression or unacceptable toxic effects. We stratified randomisation by BRAF mutation status, tumour expression of PD-L1, and previous best overall response to ipilimumab. We used permuted blocks (block size of six) within each stratum. Primary endpoints were the proportion of patients who had an objective response and overall survival. Treatment was given open-label, but those doing tumour assessments were masked to treatment assignment. We assessed objective responses per-protocol after 120 patients had been treated with nivolumab and had a minimum follow-up of 24 weeks, and safety in all patients who had had at least one dose of treatment. The trial is closed and this is the first interim analysis, reporting the objective response primary endpoint. This study is registered with ClinicalTrials.gov, number NCT01721746.
Between Dec 21, 2012, and Jan 10, 2014, we screened 631 patients, randomly allocating 272 patients to nivolumab and 133 to ICC. Confirmed objective responses were reported in 38 (31·7%, 95% CI 23·5-40·8) of the first 120 patients in the nivolumab group versus five (10·6%, 3·5-23·1) of 47 patients in the ICC group. Grade 3-4 adverse events related to nivolumab included increased lipase (three [1%] of 268 patients), increased alanine aminotransferase, anaemia, and fatigue (two [1%] each); for ICC, these included neutropenia (14 [14%] of 102), thrombocytopenia (six [6%]), and anaemia (five [5%]). We noted grade 3-4 drug-related serious adverse events in 12 (5%) nivolumab-treated patients and nine (9%) patients in the ICC group. No treatment-related deaths occurred.
Nivolumab led to a greater proportion of patients achieving an objective response and fewer toxic effects than with alternative available chemotherapy regimens for patients with advanced melanoma that has progressed after ipilimumab or ipilimumab and a BRAF inhibitor. Nivolumab represents a new treatment option with clinically meaningful durable objective responses in a population of high unmet need.
Bristol-Myers Squibb.
Copyright © 2015 Elsevier Ltd. All rights reserved.
Background:
Endogenous or iatrogenic antitumour immune responses can improve the course of follicular lymphoma, but might be diminished by immune checkpoints in the tumour microenvironment. These checkpoints might include effects of programmed cell death 1 (PD1), a co-inhibitory receptor that impairs T-cell function and is highly expressed on intratumoral T cells. We did this phase 2 trial to investigate the activity of pidilizumab, a humanised anti-PD1 monoclonal antibody, with rituximab in patients with relapsed follicular lymphoma.
Methods:
We did this open-label, non-randomised trial at the University of Texas MD Anderson Cancer Center (Houston, TX, USA). Adult (≥18 years) patients with rituximab-sensitive follicular lymphoma relapsing after one to four previous therapies were eligible. Pidilizumab was administered at 3 mg/kg intravenously every 4 weeks for four infusions, plus eight optional infusions every 4 weeks for patients with stable disease or better. Starting 17 days after the first infusion of pidilizumab, rituximab was given at 375 mg/m(2) intravenously weekly for 4 weeks. The primary endpoint was the proportion of patients who achieved an objective response (complete response plus partial response according to Revised Response Criteria for Malignant Lymphoma). Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00904722.
Findings:
We enrolled 32 patients between Jan 13, 2010, and Jan 20, 2012. Median follow-up was 15.4 months (IQR 10.1-21.0). The combination of pidilizumab and rituximab was well tolerated, with no autoimmune or treatment-related adverse events of grade 3 or 4. The most common adverse events of grade 1 were anaemia (14 patients) and fatigue (13 patients), and the most common adverse event of grade 2 was respiratory infection (five patients). Of the 29 patients evaluable for activity, 19 (66%) achieved an objective response: complete responses were noted in 15 (52%) patients and partial responses in four (14%).
Interpretation:
The combination of pidilizumab plus rituximab is well tolerated and active in patients with relapsed follicular lymphoma. Our results suggest that immune checkpoint blockade is worthy of further study in follicular lymphoma.
Funding:
National Institutes of Health, Leukemia and Lymphoma Society, Cure Tech, and University of Texas MD Anderson Cancer Center.
An improvement in overall survival among patients with metastatic melanoma has been an elusive goal. In this phase 3 study, ipilimumab--which blocks cytotoxic T-lymphocyte-associated antigen 4 to potentiate an antitumor T-cell response--administered with or without a glycoprotein 100 (gp100) peptide vaccine was compared with gp100 alone in patients with previously treated metastatic melanoma.
A total of 676 HLA-A*0201-positive patients with unresectable stage III or IV melanoma, whose disease had progressed while they were receiving therapy for metastatic disease, were randomly assigned, in a 3:1:1 ratio, to receive ipilimumab plus gp100 (403 patients), ipilimumab alone (137), or gp100 alone (136). Ipilimumab, at a dose of 3 mg per kilogram of body weight, was administered with or without gp100 every 3 weeks for up to four treatments (induction). Eligible patients could receive reinduction therapy. The primary end point was overall survival.
The median overall survival was 10.0 months among patients receiving ipilimumab plus gp100, as compared with 6.4 months among patients receiving gp100 alone (hazard ratio for death, 0.68; P<0.001). The median overall survival with ipilimumab alone was 10.1 months (hazard ratio for death in the comparison with gp100 alone, 0.66; P=0.003). No difference in overall survival was detected between the ipilimumab groups (hazard ratio with ipilimumab plus gp100, 1.04; P=0.76). Grade 3 or 4 immune-related adverse events occurred in 10 to 15% of patients treated with ipilimumab and in 3% treated with gp100 alone. There were 14 deaths related to the study drugs (2.1%), and 7 were associated with immune-related adverse events.
Ipilimumab, with or without a gp100 peptide vaccine, as compared with gp100 alone, improved overall survival in patients with previously treated metastatic melanoma. Adverse events can be severe, long-lasting, or both, but most are reversible with appropriate treatment. (Funded by Medarex and Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00094653.)
Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement
- D Moher
- A Liberati
- J Tetzlaff
Interpreting the significance of changes in health-related quality-of-life scores
- D Osoba
- G Rodrigues
- J Myles