No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
RAINFALL: A randomized, double-blind, placebo-controlled phase III study of cisplatin (Cis) plus capecitabine (Cape) or 5FU with or without ramucirumab (RAM) as first-line therapy in patients with metastatic gastric or gastroesophageal junction (G-GEJ) adenocarcinoma.
Abstract
5
Background: Ramucirumab, a VEGFR-2 IgG1 human monoclonal antibody, is the only biologic with proven efficacy as both a single-agent and in combination with paclitaxel in the second-line treatment of G-GEJ adenocarcinoma. RAINFALL (NCT02314117) is a global, double-blind, placebo-controlled randomized clinical trial addressing the hypothesis that adding ramucirumab to first-line Cis plus Cape or 5-fluorouracil (5FU) produces significant clinical benefit. Methods: Metastatic G-GEJ cancer patients eligible for first-line chemotherapy with ECOG performance status 0-1 were randomized 1:1 to receive either RAM (8 mg/kg iv D1, D8) or placebo (PL), every 21d. All patients received Cape (or 5FU)+Cis. Cis was given for up to 6 cycles. Cape+RAM/placebo was continued until progressive disease, toxicity or other discontinuation criteria. The primary endpoint was progression-free survival (PFS) for the first 508 patients; overall survival (OS) for ITT population was a powered secondary endpoint. Results: 645 patients were randomized to receive RAM+Cape/Cis (n=326) or PL+Cape/Cis (n=319). PFS was significantly prolonged in patients treated with RAM+Cape/Cis versus PL+Cape/Cis (HR, 0.75; 95% CI 0.61–0.94; p=0.011; median, 5.7 vs 5.4 mos), meeting the primary endpoint. There was no survival benefit for patients treated with RAM+Cape/Cis versus PL+Cape/Cis (HR, 0.96; 95% CI 0.80–1.16; p=0.68; median, 11.2 vs 10.7 mos). ORR in the ITT population was 41.1% in the RAM arm (95% CI 35.8–46.4) and 36.4% (95% CI 31.1–41.6) in the PL arm. Grade ≥3 adverse events in ≥10% of patients in the RAM arm were: neutropenia (26.3% RAM; 27.0% PL), anemia (12.1% RAM; 14.0% PL), and hypertension (9.9% RAM; 1.6% PL). No new safety signals were observed. Conclusions: In treatment-naïve patients with metastatic G-GEJ adenocarcinoma, the addition of ramucirumab to first-line chemotherapy conferred a significant 25% reduction in the risk of disease progression or death in the primary endpoint of PFS; however, ramucirumab was not associated with an improved OS. Clinical trial information: NCT02314117.
... Despite these encouraging findings in the refractory disease setting, randomized trials assessing antiangiogenic therapy in combination with standard front-line chemotherapy have failed to extend survival when it has been used as the initial treatment for patients with esophagogastric adenocarcinoma (AVAGAST, AVATAR, and RAINFALL). [9][10][11] Ziv-aflibercept is a recombinant fusion protein that binds vascular endothelial growth factor A (VEGF-A), VEGF-B, and placental growth factor with a high affinity. 12 The phase 3 VELOUR study demonstrated that the addition of ziv-aflibercept to second-line irinotecan, leucovorin, and 5-fluorouracil (FOLFIRI) prolonged survival in previously treated patients with metastatic colorectal cancer. ...
... Two phase 3 studies (AVAGAST and AVATAR) combining bevacizumab with capecitabine/cisplatin, 1 randomized phase 2 trial combining ramucirumab with mFOLFOX6, and 1 phase 3 trial (RAINFALL) combining ramucirumab with capecitabine/5-fluorouracil and cisplatin all failed to demonstrate a survival advantage for antiangiogenic agents in chemotherapy-naive esophagogastric cancer. [9][10][11]15 The lack of efficacy in our trial and other first-line studies stands in contrast to the success of ramucirumab in the second-line setting. 6,7,[9][10][11]15 Potential explanations for the disappointing results in our trial include the increased toxicity observed in the mFOLFOX6/ ziv-aflibercept arm and the resultant decreased exposure to mFOLFOX6. ...
... [9][10][11]15 The lack of efficacy in our trial and other first-line studies stands in contrast to the success of ramucirumab in the second-line setting. 6,7,[9][10][11]15 Potential explanations for the disappointing results in our trial include the increased toxicity observed in the mFOLFOX6/ ziv-aflibercept arm and the resultant decreased exposure to mFOLFOX6. There was no significant difference in the rates of subsequent exposure to ramucirumab between the 2 arms. ...
Background
Antiangiogenic therapy is a proven therapeutic modality for refractory gastric and gastroesophageal junction adenocarcinoma. This trial assessed whether the addition of a high affinity angiogenesis inhibitor, ziv‐aflibercept, could improve the efficacy of first‐line mFOLFOX6 (oxaliplatin, leucovorin, and bolus plus infusional 5‐ fluorouracil) in metastatic esophagogastric adenocarcinoma.
Methods
Patients with treatment‐naive metastatic esophagogastric adenocarcinoma were randomly assigned (in a 2:1 ratio) in a multicenter, placebo‐controlled, double‐blind trial to receive first‐line mFOLFOX6 with or without ziv‐aflibercept (4 mg/kg) every 2 weeks. The primary endpoint was 6‐month progression‐free survival (PFS).
Results
Sixty‐four patients were randomized to receive mFOLFOX6 and ziv‐aflibercept (43 patients) or mFOLFOX6 and a placebo (21 patients). There was no difference in the PFS, overall survival, or response rate. Patients treated with mFOLFOX6/ziv‐aflibercept tended to be more likely to discontinue study treatment for reasons other than progressive disease (P = .06). The relative dose intensity of oxaliplatin and 5‐fluorouracil was lower in the mFOLFOX6/ziv‐aflibercept arm during the first 12 and 24 weeks of the trial. There were 2 treatment‐related deaths due to cerebral hemorrhage and bowel perforation in the mFOLFOX6/ziv‐aflibercept cohort.
Conclusions
Ziv‐aflibercept did not increase the anti‐tumor activity of first‐line mFOLFOX6 in metastatic esophagogastric cancer, potentially because of decreased dose intensity of FOLFOX. Further evaluation of ziv‐aflibercept in unselected, chemotherapy‐naive patients with metastatic esophagogastric adenocarcinoma is not warranted.
... 38 In the United States, the most widely accepted regimen is modified FOLFOX, which has shown similar outcomes and improved toxicity compared with 5-FU and cisplatin in a phase 3 study in patients with advanced EGC. 39 FOLFOX has an RR of approximately 40% and median PFS and OS of about 6 and 11 months, respectively. [39][40][41] Intensifying treatment by adding a third drug is controversial. In the United Kingdom, the addition of an anthracycline to platinum and fluoropyrimidine is a standard of care. ...
... with no improvement in RR or OS. 40 On the basis of these results, this agent will not move forward in first-line therapy. Bevacizumab also failed to improve outcomes when added to first-line therapy in the phase 3 AVAGAST trial. ...
Although recent decades have witnessed incremental improvements in the treatment of gastroesophageal junction (GEJ) carcinoma, outcomes remain modest. For locally advanced esophageal cancer, the addition of chemotherapy and/or radiation to surgery is considered the standard of care. Chemotherapy remains the primary treatment for metastatic disease and improves survival over best supportive care. However, the prognosis for patients with GEJ cancers, which are treated along the same paradigms as esophageal and gastric carcinomas, remain poor because of the emergence of chemoresistance and limited targeted therapeutic approaches, which include agents that target the HER2 and vascular endothelial growth factor pathways. Evaluation of immune checkpoint inhibitors in the chemorefractory setting have confirmed the activity of immunotherapy in esophagogastric cancer. Ongoing immunotherapeutic strategies are being evaluated in both the locally advanced and metastatic settings. This review focuses on the treatment of locally advanced and metastatic GEJ carcinomas, which encompass all tumors that have an epicenter within 5 cm proximal or distal to the anatomical Z‐line (Siewert classification). Because the vast majority of GEJ tumors are adenocarcinoma, the management of adenocarcinoma is the focus of this review. Evolving approaches and areas of clinical equipoise are discussed.
... The median OS was 12.1 months with bevacizumab and chemotherapy vs 10.1 with placebo and chemotherapy. Rainfall trial used ramucirumab, a VEGF receptor monoclonal antibody, in first line of treatment in combination with chemotherapy(cisplatin and capecitabine) [27]. By adding ramucirumab to chemotherapy the OS (secondary endpoint) was not improved, even if the primary endpoint-PFSwas significantly prolonged and it is not recommended as firstline treatment (Table 6). ...
... In the first line, neither bevacizumab, a monoclonal antibody targeting VEGF-A nor ramucirumab has shown benefit in combination with platinum-based chemotherapy [46][47][48]. An ongoing phase II/III study is assessing ramucirumab in combination with FOLFIRI versus ramucirumab/paclitaxel in patients who have failed one prior line of chemotherapy, results are awaited (NCT03081143). ...
Introduction
Gastric cancer (GC) is a leading cause of cancer-related death and a significant global health burden. Chemotherapy remains the mainstay of treatment in advanced disease and only trastuzumab in combination with upfront fluoropyrimidine/platinum chemotherapy for human epidermal growth factor receptor 2 (HER2) positive disease and ramucirumab together with paclitaxel in the second line have demonstrated a significant survival benefit over chemotherapy alone. Despite the focus on a molecularly targeted approach, treatment gains have been modest and GC remains an area of great unmet need.
Areas covered
In this review, we provide an overview of the continuum of care in GC, the molecular characterization of GC, targeted therapies currently under investigation and the role of immunotherapy.
Expert commentary
Gastric cancer is a heterogeneous disease. A targeted approach based upon molecular phenotype holds promise for improving outcomes.
... Compared to placebo, ramucirumab did not improve PFS (6.4 versus 6.7 months; HR 0.98) or OS (11.7 versus 11.5 months; HR 1.08). RAIN-FALL (NCT02314117), a phase III study, randomized 645 patients with HER2-nonexpressing advanced GC to receive cisplatin plus a fluoropyrimidine with ramucirumab (326 patients) or placebo (319 patients) as firstline treatment [66]. Ramucirumab was given at a higher dose of 8 mg/kg on days 1 and 8 every 21 days in RAIN-FALL rather than 8 mg/kg every 14 days as in REGARD and RAINBOW trials, since a higher concentration of ramucirumab was shown to correlate with improved OS in both REGARD and RAINBOW [67]. ...
The systemic treatment options for advanced gastric cancer (GC) have evolved rapidly in recent years. We have reviewed the recent data of clinical trial incorporating targeted agents, including inhibitors of angiogenesis, human epidermal growth factor receptor 2 (HER2), mesenchymal–epithelial transition, epidermal growth factor receptor, mammalian target of rapamycin, claudin-18.2, programmed death-1 and DNA. Addition of trastuzumab to platinum-based chemotherapy has become standard of care as front-line therapy in advanced GC overexpressing HER2. In the second-line setting, ramucirumab with paclitaxel significantly improves overall survival compared to paclitaxel alone. For patients with refractory disease, apatinib, nivolumab, ramucirumab and TAS-102 have demonstrated single-agent activity with improved overall survival compared to placebo alone. Pembrolizumab has demonstrated more than 50% response rate in microsatellite instability-high tumors, 15% response rate in tumors expressing programmed death ligand 1, and non-inferior outcome in first-line treatment compared to chemotherapy. This review summarizes the current state and progress of research on targeted therapy for advanced GC.
... p = 0.68). There was also no significant difference between ramucirumab and placebo in the ORR (41 vs. 36%; p = 0.17) or the DCR (82 vs. 77%; p = 0.10) (32). Based on these findings, ramucirumab will not play a role in front line therapy in unselected patients. ...
In 2014, the survival benefits seen in REGARD and RAINBOW studies led the way for the regulatory approval of ramucirumab in the second line setting in oesophagogastric (OG) cancer. Trials of other drugs targeting the vascular endothelial growth factor (VEGF) pathway have met with mixed results but this remains an important pathway for evaluation in OG cancer. Perhaps the most interesting ongoing trials are those which target VEGF in combination with immunotherapy, which have a sound scientific rationale. Given the emerging role of immunotherapy in OG cancer, this is an important area of innovation. This review aims to outline targeting VEGF in OG cancer, the rationale behind the continued interest in this mechanism and possible future directions in combination with immunotherapy.
... Previous international and national trials on the VEGF inhibitor bevacizumab in a curative settings in the ST03 trial and in palliative settings, such as the Chinese AVATAR-trial or the international AVAGAST-trial, failed to show benefits in the experimental arm [17][18][19]. Additionally, in the RAINFALL-trial the use of ramucirumab as the first-line treatment had no benefits in terms of overall survival [20]. ...
Esophagogastric junction (EGJ) cancer is a solid tumor entity with rapidly increasing incidence in the Western countries. Given the high proportion of advanced cancers in the West, treatment strategies routinely employed include surgery and chemotherapy perioperatively, and chemoradiation in neoadjuvant settings. Neoadjuvant chemoradiation and perioperative chemotherapy are mostly performed in esophageal cancer that extends to the EGJ and gastric as well as EGJ cancers, respectively. Recent trials have tried to combine both strategies in a perioperative context, which might have beneficial outcomes, especially in patients with EGJ cancer. However, it is difficult to recruit patients for trials, exclusively for EGJ cancers; therefore, the results have to be carefully reviewed before establishing a standard protocol. Trastuzumab was the first drug for targeted therapy that was positively evaluated for this tumor entity, and there are several ongoing trials investigating more targeted drugs in order to customize effective therapies based on tissue characteristics. The current study reviews the multimodal treatment concept for EGJ cancers in the West and summarizes the latest reports.
... Given the positive results of both randomized trials and reports from clinical experiences [10,11,18], ramucirumab either alone or in combination with paclitaxel has proved to be a safe and active option for second line treatment in gastric cancer. Unfortunately, RAINFALL study failed to prove a clinically relevant benefit of a ramucirumab-based regimen in the first-line setting, as compared to chemotherapy doublets [19]. Nevertheless, the early administration of an active, non-cross resistant treatment after the first-line therapy, before disease progression occurs, might prolong the benefit of first-line treatment and could delay clinical deterioration [20][21][22]. ...
Background
Platinum/fluoropyrimidine regimens are the backbone of first-line chemotherapy for advanced gastric cancer (AGC). However response rates to first line chemotherapy range from 30 to 50% and disease progression occurs after 4–6 cycles. The optimal duration of first-line therapy is still unknown and its continuation until disease progression represents the standard. However this strategy is often associated with cumulative toxicity and rapid development of drug resistance. Moreover, only about 40% of AGC pts. are eligible for second-line treatment.
Methods
This is a randomized, open-label, multicenter phase III trial. It aims at assessing whether switch maintenance to ramucirumab plus paclitaxel will extend the progression-free survival (PFS) of subjects with HER-2 negative AGC who have not progressed after 3 months of a first-line with a platinum/fluoropyrimidine regimen (either FOLFOX4, mFOLFOX6 or XELOX). The primary endpoint is to compare Progression-Free Survival (PFS) of patients in ARM A (switch maintenance to ramucirumab and placlitaxel) versus ARM B (continuation of the same first-line therapy with oxaliplatin/fluoropyrimidine). Secondary endpoints are: overall survival, time-to-treatment failure, overall response rate, duration of response, percentage of patients that will receive a second line therapy according to arm treatment, safety, quality of life. Exploratory studies including Next-Generation Sequencing (NGS) in archival tumor tissues are planned in order to identify potential biomarkers of primary resistance and prognosis.
Discussion
The ARMANI study estimates if patients treated with early swich with ramucirumab plus paclitaxel received benefit when compared to those treated with continuation of first line therapy. The hypothesis is that the early administration of an active, non-cross resistant second-line regimen such as ramucirumab plus paclitaxel may prolong the time in which patients are progression-free, and consequently have a better quality of life. Moreover, this strategy may rescue all those subjects that become ineligible for second-line therapy due to the rapid deterioration of health status after the first disease progression.
Trial registration
ARMANI is registered at ClinicalTrials.gov (NCT02934464, October 17, 2016) and EudraCT(2016–001783-12, April 202,016).
... Survival for patients with advanced disease is poor and treatment options beyond first line are limited. Only trastuzumab, for human epidermal growth factor receptor 2 (HER2)-positive cancers in the first-line advanced setting [7] and ramucirumab in the second-line [8], has shown significant benefit in addition to standard chemotherapy, underlining the need for novel therapies and the unmet need in this area, especially given the lack of progress in recent years in the front-line setting [9][10][11][12][13]. ...
... tak v kombinaci s taxany (18,19,20). ...
Although the incidence of gastric cancer progressively decreases, high mortality still persists and stomach cancer is one of the most aggressive diseases. Based on the meta-analysis of the benefit of chemotherapy in palliative treatment, for good combination regimens with fluorouracil were evaluated oxaliplatin, irinothecan and docetaxel in first-line treatment, and the benefit of anthracyclines and capecitabine would be assessed as unconvincing. The standard for treatment of the first line in HER-positive carcinoma has become a combination with trastuzumab; for the II line treatment, however, no further HER receptor blockers have been confirmed as effective. The only effective biological agent for the treatment of the II line is currently evaluated with ramucirumab. The benefit of immunotherapy has so far been tested and it appears that further predictors will be needed for this treatment, including pathological assessment.
... The gastric and oesophageal cohort (259 patients), which reported recently, demonstrated a response rate of 11.6% with a median duration of response of 8.4 months. 81 Patients with PD-L1-positive tumours had a response rate of 15.5% compared with 6.4% for the PD-L1negative group. In the KEYNOTE-061 trial, a randomized phase III trial of pembrolizumab versus paclitaxel in previously treated gastric or GEJ cancers, patients with a PD-L1 combined positive score (CPS) ⩾1 were included in the final analysis. ...
Metastatic gastric cancer is associated with a poor prognosis and novel treatment options are desperately needed. The development of targeted therapies heralded a new era for the management of metastatic gastric cancer, however results from clinical trials of numerous targeted agents have been mixed. The advent of immune checkpoint inhibitors has yielded similar promise and results from early trials are encouraging. This review provides an overview of the systemic treatment options evaluated in metastatic gastric cancer, with a focus on recent evidence from clinical trials for targeted therapies and immune checkpoint inhibitors. The failure to identify appropriate predictive biomarkers has hampered the success of many targeted therapies in gastric cancer, and a deeper understanding of specific molecular subtypes and genomic alterations may allow for more precision in the application of novel therapies. Identifying appropriate biomarkers for patient selection is essential for future clinical trials, for the most effective use of novel agents and in combination approaches to account for growing complexity of treatment options.
... There was no impact on OS, and QoL was not reported. 14 We severely doubt that any patient holds an interest in a PFS of 9 days with no data on QoL, and neither should clinicians or regulatory authorities. On a related note, the marketing authorization holder (MAH) withdrew its EMA application for adjuvant sunitinib treatment in renal cell carcinoma. ...
Overall survival (OS) is the undisputed gold standard efficacy endpoint in cancer drug trials. It is with growing concern that we observe how progression‐free survival (PFS) gains ground as surrogate endpoint in its place. PFS has appeal because it is resource‐efficient, but it has severe shortcomings. Our concern is that uncritical use of PFS will harm the evidence‐based evaluation of cancer drugs when considering them for standard use in publicly financed health care systems. PFS is only valid as a surrogate endpoint for OS if it correlates strongly with OS and if the cancer drug being investigated has the same effect on PFS and OS such that effects on one predicts effects on the other. The latter might be less obvious than the former but is no less critical. Research indicates that in a majority of cases, correlation between surrogate endpoints and OS is of medium strength or lower. PFS is therefore unreliable as a surrogate for OS. We do not find it justified to use PFS as surrogate for OS without first having assessed its validity. Stakeholders who take part in evaluating cancer drugs considered for standard use in a health care system must be particularly vigilant about this issue to minimize the risk of introducing cancer drugs that have an unacceptable cost‐risk‐benefit profile.
This article is protected by copyright. All rights reserved.
... On that positive basis, ramucirumab has been tested in first line setting in combination with cisplatin-based standard chemotherapy within the RAINFALL trial [64]: although the study formally met its primary endpoint, with an improvement in mPFS from 5.4 months (placebo arm) to 5.7 months (ramucirumab arm) (HR: 0.75, p = 0.011), there was no survival benefit for patients treated with RAM + Capecitabin/Cisplatin versus placebo + Capecitabin/Cisplatin (mOS 11.2 months versus 10.7 months, HR: 0.96, p = 0.68), making the results negative de facto and not significant for clinical practice. ...
Despite some remarkable innovations and the advent of novel molecular classifications the prognosis of patients with advanced gastric cancer (GC) remains overall poor and current clinical application of new advances is disappointing. During the last years only Trastuzumab and Ramucirumab have been approved and currently used as standard of care targeted therapies, but the systemic management of advanced disease did not radically change in contrast with the high number of molecular drivers identified. The Cancer Genome Atlas (TCGA) and Asian Cancer Research Group (ACRG) classifications paved the way, also for GC, to that more contemporary therapeutic approach called “precision medicine” even if tumor heterogeneity and a complex genetic landscape still represent a strong barrier. The identification of specific cancer subgroups is also making possible a better selection of patients that are most likely to respond to immunotherapy. This review aims to critically overview the available molecular classifications summarizing the main druggable molecular drivers and their possible therapeutic implications also taking advantage of new technologies and acquisitions.
Gastroesophageal (GE) adenocarcinoma is among the most solid tumor common malignancies worldwide. Despite the declining incidence, prognosis remains dismal, where the malignancy is refractory to conventional cytotoxic chemotherapy and associated with poor prognosis. While therapeutic advances over the past several years have resulted in improved patient outcomes, the observed benefits have been modest, highlighting the need for the identification and usage of novel predictive and diagnostic therapeutic targets. Advances in our understanding of the genomic alterations in key signaling pathways, genetic and epigenetic, hold promise for better treatment outcomes and improvement in patient outcomes in the near future.
The human genome project, completed in 2003, provided the first reference map for the whole human genome and stimulated enormous advances in DNA sequencing technology. These technologies allowed for an increasingly detailed description of the molecular landscape of cancer, including gastrointestinal (GI) cancers. Widespread availability of next-generation sequencing (NGS) has led to extensive use of this method in the clinic and at the individual patient level. In-depth molecular knowledge can offer unique opportunities for exploring cancer pathogenesis, germline mutation inheritance, and early cancer detection. NGS has the capability to identify unique features of an individual’s cancer, hence the potential for personalizing diagnostic and therapeutic strategies. Despite the potential benefits, integration of cancer genomics care delivery, especially in the area of solid cancer treatments, including gastrointestinal (GI) malignancies, has been challenging. In rare cases, cancers are dependent in their survival on one prominent driver mutation or genetic aberration, and pharmacological targeting of these driver mutation/aberrations can effectively control that cancer type. However, in most solid tumors, multiple mutations/genetic alterations are present and are undergoing dynamic clonal evolution, making it difficult to identify key mutations and prioritize treatment based on them. Temporal and spatial heterogeneity of the tumor, lack of availability of adequate tissue, limited access to clinical trials, and off-label treatments are all among challenges faced while utilizing clinical genomics in clinical practice. Nevertheless, recent progress in targeting molecular features, such as mismatch repair deficiency, or strong oncogenic genomic events, such as NTRK fusions, demonstrate the promising potential of this approach.
Introduction: Colorectal cancer (CRC) is one of the main causes of cancer-related morbidity and mortality worldwide. Mortality is most often attributable to metastatic disease. Despite the progress achieved so far, life expectancy continues to be limited in most patients. Ramucirumab, a most recent antiangiogenic drug, is vying in the race to mCRC treatment since its approval by the FDA, based on the results of the RAISE study.
Areas covered: This article reviews the role of ramucirumab in mCRC, including clinical indication, safety issues and future perspectives.
Expert opinion: The use of Ramucirumab in clinical practice is still limited, probably due to economic burden and the lack of specific biomarkers. Future efforts will be addressed to improve our knowledge in the use of this drug and better guide us in patients’ care.
Background:
Nivolumab is approved as an option for third- or later-line treatment of advanced gastric/gastroesophageal junction (G/GEJ) cancer in several countries after ATTRACTION-2. To further improve the therapeutic efficacy of first-line therapy, exploration of a nivolumab-chemotherapy combination is warranted. In part 1 (phase II) of ATTRACTION-4, the safety and efficacy of nivolumab combined with S-1 plus oxaliplatin (SOX) or capecitabine plus oxaliplatin (CapeOX) as first-line therapy for unresectable advanced or recurrent human epidermal growth factor receptor 2 (HER2)-negative G/GEJ cancer were evaluated.
Patients and methods:
Patients were randomized (1 : 1) to receive nivolumab (360 mg intravenously every 3 weeks) plus SOX (S-1, 40 mg/m2 orally twice daily for 14 days followed by 7 days off; oxaliplatin, 130 mg/m2 intravenously on day 1 every 3 weeks) or CapeOX (capecitabine, 1000 mg/m2 orally twice daily for 14 days followed by 7 days off; oxaliplatin, 130 mg/m2 intravenously on day 1 every 3 weeks) until disease progression, unacceptable toxicity, or consent withdrawal.
Results:
Of 40 randomized patients, 39 (nivolumab plus SOX, 21; nivolumab plus CapeOX, 18) and 38 (21 and 17, respectively) comprised the safety and efficacy populations, respectively. Most frequent (>10%) grade 3/4 treatment-related adverse events were neutropenia (14.3%) in the nivolumab plus SOX group, and neutropenia (16.7%), anemia, peripheral sensory neuropathy, decreased appetite, type 1 diabetes mellitus, and nausea (11.1% each) in the nivolumab plus CapeOX group. No treatment-related death occurred. Objective response rate was 57.1% (95% confidence interval 34.0-78.2) with nivolumab plus SOX and 76.5% (50.1-93.2) with nivolumab plus CapeOX. Median overall survival was not reached (NR) in both groups. Median progression-free survival was 9.7 months (5.8-NR) and 10.6 months (5.6-12.5), respectively.
Conclusion:
Nivolumab combined with SOX/CapeOX was well tolerated and demonstrated encouraging efficacy for unresectable advanced or recurrent HER2-negative G/GEJ cancer. ATTRACTION-4 has proceeded to part 2 (phase III) to compare nivolumab plus SOX/CapeOX versus placebo plus SOX/CapeOX.
Clinicaltrials.gov id:
NCT02746796.
Metastatic or unresectable esophageal and gastroesophageal junction adenocarcinoma represent a devastating disease with 5-year survival rate of <5%. Although cytotoxic chemotherapy with platinum doublet based regimens is initially effective, patients inevitably progress. Patients often decline rapidly after this initial progression, making later lines of therapy a challenge to successfully administer. There have been multiple efforts to incorporate biologic agents, targeting pathways known to be dysregulated in esophageal adenocarcinoma and gastroesophageal junction adenocarcinoma, into existing chemotherapy backbones. Other than therapeutics targeting human epidermal growth factor receptor-2 (HER2) and vascular endothelial growth factor receptor (VEGFR), other strategies have failed. Given the mixed success of biologic agents, along with the promise of immunotherapy to generate durable and sometimes complete responses, immune-agent based trials are a major area of interest for patients with this disease. Checkpoint inhibitors blocking programmed cell death protein-1 (PD-1) and programmed death-ligand 1 (PD-L1) have demonstrated modest single-agent efficacy in patients with progressive esophageal adenocarcinoma and gastroesophageal junction adenocarcinoma. However, other approaches such as novel checkpoint combinations, vaccine-based approaches and autologous T cells hold more promise to change the trajectory of disease.
Purpose of review:
To review the recent literature regarding treatment of gastric cancer.
Recent findings:
Addition of postoperative radiation therapy to perioperative chemotherapy offers no survival benefit. Fluoropyrimidines, in particular 5-fluorouracil (5-FU), are the backbone for gastric cancer chemotherapy. S-1, an oral prodrug of 5-FU, has become the mainstay for gastric cancer chemotherapy in Japan. In a Japanese adjuvant chemotherapy trial, addition of docetaxel to standard S-1 chemotherapy improved disease-free survival; this regimen will become their new standard for adjuvant therapy. Microsatellite instability (MSI) high status is emerging as a favorable prognostic marker in resected gastric cancer and may indicate a group of patients who do not gain additional benefit from treatment with adjuvant chemotherapy. In metastatic gastric cancer, the addition of ramucirumab, an antivascular endothelial growth factor receptor 2-targeted antibody, to first-line chemotherapy did not improve survival over chemotherapy alone. Trifluridine/tipiracil treatment in chemotherapy-refractory gastric cancer improved survival compared to placebo and will emerge as a late-line therapy option. Phase II and III trials indicate activity for the immune checkpoint inhibitors pembrolizumab and nivolumab in chemotherapy-refractory gastric cancer and have led to US regulatory approval for pembrolizumab in chemotherapy-refractory programmed death ligand 1-positive or MSI-high gastric cancer, and approval in Japan for nivolumab in chemotherapy-refractory gastric cancer. However, a phase III trial in advanced gastric cancer failed to show a survival benefit for pembrolizumab over conventional paclitaxel. The poly ADP ribose polymerase inhibitor, olaparib, added to second-line paclitaxel in advanced gastric cancer failed to improve overall survival compared with paclitaxel alone.
Summary:
Perioperative or postoperative adjuvant chemotherapy without radiation therapy remains the standard of care in gastric cancer. Addition of docetaxel to adjuvant S-1 will likely emerge as a new care standard. Pembrolizumab and nivolumab improve survival and now are treatment options in chemotherapy-refractory gastric cancer, especially for programmed death ligand 1-positive or MSI-high cancers.
There is increasing evidence that treatment beyond second line provides significant survival benefit for selected advanced oesophageal and gastric adenocarcinoma patients, and important randomised controlled trials of both chemotherapy, targeted therapy and immunotherapy have recently been reported in this space. Despite this growing evidence base there are presently no formal guidelines for third line treatment available to clinicians, and as these agents move into routine clinical practice patient selection and rational sequencing of treatment will become an increasingly relevant clinical challenge. This review critically appraises the current evidence base for third line treatment and discusses patient selection, potential predictive biomarkers and future directions for third line treatment in this challenging condition.
Gastric adenocarcinoma (GAC) is one of the most aggressive malignancies and has a dismal prognosis. Therefore, multimodality therapies to include surgery, chemotherapy, targeted therapy, immunotherapy, and radiation therapy are needed to provide advantage. For locally advanced GAC (>cT1B), the emerging strategies have included preoperative chemotherapy, postoperative adjuvant chemotherapy, and (occasionally) postoperative chemoradiation in various regions. Several novel therapies have been assessed in clinical trials, but only trastuzumab and ramucirumab (alone and in combination with paclitaxel) have shown overall survival advantage. Pembrolizumab has been approved by the US Food and Drug Administration on the basis of response rate only for patients with microsatellite instability (MSI-H) or if PD-L1 expression is positive (≥1% labeling index in tumor/immune cells in the presence of at least 100 tumor cells in the specimen). Nivolumab has been approved in Japan on the basis of a randomized trial showing significant survival advantage for patients who received nivolumab compared with placebo in the third or later lines of therapy. The cure rate of patients with localized GAC in the West is only about 40% and that for metastatic cancer is very poor (only 2–3%). At this stage, much more target discovery is needed through molecular profiling. Personalized therapy of patients with GAC remains a challenge.
Surgery represents the only chance of cure for patients with gastroesophageal adenocarcinoma; however surgery alone does not cure most patients. Over the past decade, several multimodality adjunctive treatments have improved survival for patients with operable gastroesophageal adenocarcinoma who are undergoing surgical resection; these include peri-operative chemotherapy, neoadjuvant chemoradiotherapy, adjuvant chemotherapy and adjuvant chemoradiotherapy. More recently, the results of several large randomised trials are leading to a shift in the peri-operative treatment of gastroesophageal cancer, away from anthracycline-based and towards taxane-based chemotherapy regimens. Emerging data supports an increased focus on patients who are at high risk for poor operative outcomes such as R1 resection, and on patients who are at high risk for relapse following surgery such as those with lymph node metastases (N1+). Future developments may include use of fluorodeoxyglucose-positron emission tomography (FDG-PET) to inform a switch to non-cross resistant chemotherapy pre-operatively and substitution of alternative treatments for chemotherapy in high risk postoperative node positive patients. Conversely, in molecularly selected subgroups such as microsatellite unstable gastroesophageal cancer, peri-operative or adjuvant chemotherapy may not be helpful, and treatments such as immunotherapy may be considered. In this review the most up-to-date clinical trials and translational research in the field of operable gastroesophageal cancer are discussed; with a focus on how best to risk stratify patients with operable disease for peri-operative treatment plus surgery, and how novel therapies might be integrated into standard treatments in order to improve survival outcomes in this patient group.
ResearchGate has not been able to resolve any references for this publication.