Article

What is the best treatment option for second line in long responders to the first-line TKI in metastatic renal cell carcinoma (mRCC) patients (pts): TKI-TKI or TKI-mTORi? A European retrospective study.

Authors:
  • Association Pour La Recherche Des Thérapeutiques Innovantes En Cancérologie
To read the full-text of this research, you can request a copy directly from the authors.

Abstract

375 Background: The question regarding the benefit of a TKI rechallenge versus switch to an mTOR inhibitor (mTORi) in mRCC pts who responded to a previous line of TKI remains unanswered and is a common dilemma in clinical practice. We report results of a retrospective study to address this question. Methods: This study retrospectively investigated Duration of Treatment (DT), best radiological response (OR) and predictive factors in pts treated with either TKI-TKI or TKI-mTORi sequences for clear-cell mRCC. Eligibility criteria: 1 TKI in 1 st line (L1) followed by another TKI or mTORi as 2 nd line (L2). Prior immunotherapy was allowed but not intermediate lines with other drugs. Pts characteristics and Heng’s prognostic factors were collected at each line initiation. Response (resp) was classified with regard to DT and OR using 2 different definitions: def1 = Non Responders (NR): < 4months (m) + PD; Short-Term responders (STR): [4–6]m + SD/PR, Long-term Responders (LTR): >6m + SD/PR, and def2 = NR: < 4m + PD, STR: [4–12]m + SD/PR, LTR: >12m + SD/PR. Results: 127 pts from 7 European centers were retrospectively analyzed. Based on def1, resp to L1 was: LTR=93, STR=20, NR=14; among LTR pts, 54 received a L2=TKI and 39 a L2=mTORi. Based on def2, resp to L1 was: LTR=59, STR=53, NR=15; among LTR pts, 35 received a L2=TKI and 24 a L2=mTORi. Whether def1 or def2, resp (L1 and L2) was never related to Heng’s score. Among LTR pts at L1, 26 out of 54 were LTR after L2=TKI vs 18 out of 39 after L2=mTORi (p=0.85, Z-test) for def1 and 9 out of 35 were LTR after L2=TKI vs 6 out of 24 after L2=mTORi (p=0.95) for def2 (see table). For both def1 and def2, median DT was 7.2m and 6.9m for L2=TKI and L2=mTORi, respectively (p=0.86 and p=0.95, Log-Rank). Conclusions: Results suggest that long-term responders on 1 st line TKI could benefit both from TKI and mTORi as 2 nd line and there is no evidence to favor one sequence over the other. [Table: see text]

No full-text available

Request Full-text Paper PDF

To read the full-text of this research,
you can request a copy directly from the authors.

... A retrospective analysis of 127 patients in Europe found no evidence to favour one sequence (TKI-TKI) over the other (TKI-mTORi) but suggested that treatment of patients with disease relapse using a TKI or an mTORi can provide clinical benefit, regardless of the patient's response to the initial TKI [45]. An analysis of data from RenIS on 483 patients with mRCC that relapsed on initial TKI therapy found no difference in OS times between patients given regimens of TKIeverolimus-TKI versus TKI-TKI-everolimus [46]. ...
... A longer time on previous VEGF-targeted therapy seemed to associate with extended periods free of disease (although this association was not significant), but the duration of everolimus treatment was independent of time of first-line TKI [38]. Moreover, a retrospective analysis of long-term responders (>6 months) to a first TKI showed similar clinical benefit when patients were rechallenged with a TKI or switched to everolimus [45]. Therefore, studies that have stratified patients by treatment duration have shown that a long response to a first TKI does not preclude everolimus as a second-line treatment. ...
Article
Full-text available
Sequential targeted therapies are the standard of care for patients with metastatic renal cell carcinoma (mRCC). Several drugs are available for patients whose disease progresses while they receive initial tyrosine kinase inhibitor (TKI) therapy; these include nivolumab (an inhibitor of PD-1 receptor), everolimus (an inhibitor of the mechanistic target of rapamycin) or additional TKIs. Until now, there has been no clinical evidence to support the use of one strategy versus another, so investigators and physicians rely on experience, judgement and findings from molecular analyses to select the appropriate treatment. However, with the arrival of nivolumab and cabozantinib that provide an overall survival higher than other alternative treatments, therapeutic strategies may have changed. Here, we discuss findings from preclinical and clinical studies that might help clinicians to choose the optimal treatment approach for patients with mRCC who progress to initial therapy.
... It is tempting to assume that those patients should best continue anti-VEGF directed therapy in the second-line. However, results from a European retrospective study (121) suggested that long-term first-line VEGFR-TKI responders may benefit from both, further VEGFR-TKI or mTOR inhibitors in the second-line. Taken together, for these patients the sequence of therapy may only be of minor relevance. ...
Article
The spectrum of drugs that have shown activity in advanced or metastatic renal cell carcinoma (RCC) has led to a debate on the optimal sequence of treatments. There is agreement on recommending targeted agents as the standard of care in this disease. Uncertainty, however, remains on the best first-line drug choice. Physicians and patients may select sunitinib, bevacizumab in combination with interferon-alpha (IFN-a), pazopanib, or-in poor risk patients-temsirolimus. There are also a variety of therapies with proven efficacy on hand in the second-line setting: sorafenib, pazopanib, axitinib, and everolimus. While most randomized RCC trials assessed progression free survival (PFS) as primary endpoint, some agents were shown to improve median overall survival (OS), and given in sequence they have extended the life expectancy of RCC patients from 13 months in the cytokine era to over 30 months. Despite the progress made, there are sobering aspects to the oncologic success story in RCC, as the new treatments do not obtain an objective response or disease stabilization (SD) in all patients. There are also as yet no predictors to select patients who might benefit and those who are primary resistant to specific drugs, and ultimately almost all patients will experience disease progression. Bearing inevitable treatment failure in mind, availability of further drugs and switching therapy while the patient is in a condition to continue pharmacotherapy is essential. Of note, depending on the setting, only 33-59% of patients receive second-line treatment. In this review we present data on first-, second-, and third-line treatment in RCC, and discuss the difficulties in their interpretation in the context of treatment sequence. We summarize biological aspects and discuss mechanisms of resistance to anti-angiogenic therapy and their implications for treatment selection.
... To date, only a few studies are available, and they provide conflicting evidence. In this context, the paradigm of switching the mechanism of action from a TKI to EVE as the best choice for most second-line patients seems to be challenged by recent reports [3], some of which even suggest a detrimental effect [4]. The aim of the present study is to analyze the clinical outcomes of a cohort of patients with advanced RCC who received sequential treatment with 3 targeted agents and to compare the course of those treated with the sequence TKI-TKI-EVE with those treated with the sequence TKI-EVE-TKI. ...
Article
Full-text available
We retrospectively analyzed metastatic renal cell carcinoma (RCC) patients treated with 3 targeted agents. Patients started the sequence with a tyrosine kinase inhibitor (TKI), sunitinib or sorafenib, and were divided into 2 groups based on the order in which they received the other reciprocal TKI and everolimus (EVE): TKI-TKI-EVE group (n = 19) and TKI-EVE-TKI group (n = 14). Median progression-free survival (PFS) with first TKI was 13 months in the TKI-TKI-EVE group and 10 months in the TKI-EVE-TKI group. PFS with the second agent showed a trend in favor of the TKI-TKI-EVE sequence, with a median of 11 versus 6.5 months, whereas median PFS with the third agent was 6 months in both groups. Total PFS also showed a trend in favor of the TKI-TKI-EVE sequence with a median of 31 versus 23 months. Median overall survival (OS) was 38 months in both groups, with more patients receiving subsequent treatment in the TKI-EVE-TKI group. The subgroup of patients no long-term responders (≤9 months) to first TKI showed similar outcomes irrespective of the sequence. The subgroup of long-term responders to first TKI (>9 months) who received the other TKI instead of EVE had better outcomes in terms of median PFS with the second agent (13 vs. 5.5 months; p = 0.0271), median total PFS (39.5 vs. 23.5 months; p = 0.0415), and median OS (46 vs. 38 months). In conclusion, no apparent advantage was observed with early use of EVE in advanced RCC, even in those patients who did not benefit long from first-line TKI, whereas long-term duration of first-line TKI seems to be predictor of second-line TKI efficacy.
Article
Purpose of review: Targeted therapies have recently replaced cytokine treatments as the gold standard for management of metastatic renal cell carcinoma (mRCC). Currently approved treatments include the tyrosine kinase inhibitors sunitinib, pazopanib, axitinib, sorafenib, cabozantinib and lenvatinib; the vascular endothelial growth factor (VEGF) inhibitor bevacizumab; the mammalian target of rapamycin (mTOR) inhibitors everolimus and temsirolimus; and the immunologic nivolumab. The purpose of this review is to provide an updated analysis of the clinical data supporting the use of these agents in the first-line and second-line setting. Recent findings: In the first-line setting, pazopanib may be better tolerated than sunitinib, an individualized dosing sunitinib regimen based on toxicity might improve survival and cabozantinib appears to be an emerging option. In the second-line setting, three new therapies (cabozantinib, lenvatinib/everolimus and nivolumab) have shown superiority against everolimus, the previous standard therapy. The International Metastatic RCC Database Consortium prognostic model may be useful in guiding the selection of subsequent therapy and patients eligible for metastasectomy. Summary: Targeted therapies are the standard treatment for mRCC. Despite advancements in survival, progression-free survival and tolerability, these targeted therapies remain largely noncurative. Further characterization of the RCC oncogenic pathway, and the ongoing clinical trials should help optimize the management of mRCC.
Article
Full-text available
Background: Second targeted therapies for mRCC include mammalian target of rapamycin inhibitors (mTORi) and tyrosine kinase inhibitors (TKI). This observational study compares overall survival (OS) and progression-free survival (PFS) of patients treated with everolimus (an mTORi) and axitinib (a TKI) following first TKI, and assesses the impact of type and duration of first TKI on the relative effectiveness of these second targeted therapies. Methods: Retrospective reviews of medical records were conducted by medical oncologists or hematologists/oncologists recruited from a nationwide panel. Included patients with mRCC were required to have discontinued a first TKI (sunitinib, sorafenib, or pazopanib) for medical reasons, and to have initiated everolimus or axitinib as second targeted therapy between February 2012 and January 2013. OS and PFS were compared between patients treated with everolimus vs. axitinib using multivariable Cox proportional hazards regression models. Comparative results were also stratified by type and duration of first TKI. Results: Included patients (n=325 for everolimus and n=127 for axitinib) had a mean age of 61 years and 31% were female. Sunitinib was the most commonly used first TKI (73%). After adjusting for patient characteristics, no statistically significant differences were observed in OS or PFS between everolimus and axitinib. When stratifying by type and duration of first TKI, there was no statistically significant difference in OS between everolimus and axitinib in all subgroups except for patients with < 6 months on sunitinib or sorafenib as first TKI. No significant difference in PFS was observed in any subgroup. Limitations: Important limitations include potential missing or inaccurate data in medical charts, and confounding due to unobserved factors. Conclusions: In this retrospective chart review, no significant differences were detected in OS or PFS between axitinib and everolimus as second targeted therapy. Longer duration of first TKI was not associated with increased effectiveness of subsequent axitinib compared to everolimus.
Article
Full-text available
The optimal sequencing of targeted therapies for metastatic renal cell carcinoma (mRCC) is unknown. Observational studies with a variety of designs have reported differing results. The objective of this study is to systematically summarize and interpret the published real-world evidence comparing sequential treatment for mRCC. A search was conducted in Medline and Embase (2009-2013), and conference proceedings from American Society of Clinical Oncology (ASCO), ASCO Genitourinary Cancers Symposium (ASCO-GU), and European Society for Medical Oncology (ESMO) (2011-2013). We systematically reviewed observational studies comparing second-line mRCC treatment with mammalian target of rapamycin inhibitors (mTORi) versus vascular endothelial growth factor (VEGF) tyrosine kinase inhibitors (TKI). Studies were evaluated for 1) use of a retrospective cohort design after initiation of second-line therapy, 2) adjustment for patient characteristics, and 3) use of data from multiple centers. Meta-analyses were conducted for comparisons of overall survival (OS) and progression-free survival (PFS). Ten studies reported OS and exhibited significant heterogeneity in estimated second-line treatment effects (I2 = 68%; P = 0.001). Four of these were adjusted, multicenter, retrospective cohort studies, and these showed no evidence of heterogeneity (I2 = 0%; P = 0.61) and a significant association between second-line mTORi (>75% everolimus) and longer OS compared to VEGF TKI (>60% sorafenib) (HR = 0.82, 95% CI: 0.68 to 0.98) in a meta-analysis. Seven studies comparing PFS showed significant heterogeneity overall and among the adjusted, multicenter, retrospective cohort studies. Real-world observational data for axitinib outcomes was limited at the time of this study. Real-world studies employed different designs and reported heterogeneous results comparing the effectiveness of second-line mTORi and VEGF TKI in the treatment of mRCC. Within the subset of adjusted, multicenter observational studies, second-line use of mTORi was associated with significantly prolonged survival compared with second-line use of VEGF TKI.
Article
Prognosis of metastatic renal cell carcinoma (mRCC) has markedly improved in the recent years. Several factors such as precocious diagnosis, better supportive care, and an increased number of targeted therapies are responsible for this progress. From 2006 to date, 7 drugs have been approved for treatment of mRCC, and among these only 2 are recommended for the second line of therapy with grade 1 evidence. Tyrosine kinase inhibitors (TKIs) and mammalian target of rapamycin (mTOR) inhibitors are the strategies with more evidence, but no comparative studies are available and what is the best second line remains an open issue. Herein, we review the available evidence on the second-line treatment focusing mainly on prospective studies. We identify a special population of patients in whom more evidence is available, and we propose a possible strategy for the management of progressed mRCC and for primary resistant lesions as well as for patients who need a rapid response in lesions. In the majority of patients, several factors should be considered: toxicity reported during first-line therapy, performance status, the absence of correlation between the length of first-line therapy and the probability to respond to second-line therapy, and the lack of comparative trials between mTOR inhibitors and TKI. When an mTOR inhibitor is selected, everolimus must be preferred, although in the RECORD1 trial only the increase in progression-free survival has been reported and the increase in terms of overall survival has not been reached. When another TKI is the choice, there are no strong pieces of evidence that favor the use of a defined molecule. In every case, we recommend to start the selected targeted agents at standard dosage and to pursue therapy as long as possible because the control of disease should be the primary endpoint for the management of mRCC.
Article
With seven targeted agents, directed against the VEGF/VEGF receptor (VEGFR) axis or the mTOR pathway, approved for the treatment of metastatic renal cell carcinoma and more active agents in advanced phase of clinical testing, questions have arisen with regard to their optimal use, either in combination or in sequence. One of the most compelling (and debated) issues is whether continued VEGF/VEGFR inhibition with agents hitting the same targets (TKI-TKI) affords better results than switching mechanisms of action by alternating VEGFR and mTOR inhibition (TKI-mTOR). In this article, the authors review the (little) available evidence coming from randomized Phase III clinical trials and try to fill in the (many) remaining gaps using evidence from small-size, single-arm Phase II studies and retrospective series, as well as reviewing preclinical evidence supporting either strategy.
ResearchGate has not been able to resolve any references for this publication.