Dr. Schmidinger elegantly highlighted a few background points regarding VEGF-inhibitor trials for first-line mRCC: (i) all first line agents received approval based on statistically significant benefits in progression free survival (PFS) and objective response rate (ORR) and not based on overall survival (OS), since OS was not significant in these previous trials; (ii) OS would have been confounded considering that patients in the control arm of these trials could cross over to VEGF-inhibitor therapy after treatment failure; (iii) comparative phase II/III trials between established first line agents did not have superiority in PFS or OS as a primary endpoint, but rather non-inferiority PFS or patient preference; (iv) sunitinib has never been defeated by another agent in a phase III superiority trial, suggesting that sunitinib is the ideal comparator in the CheckMate 214 trial.
Indeed, the current study assessing nivolumab + ipilimumab vs sunitinib is the first to demonstrate a statistically significant OS benefit, allowing Dr. Schmidinger to conclude that nivolumab + ipilimumab can be considered as a new standard of care in this patient population. Furthermore, the response rates (including complete response) observed in CheckMate 214 are among the highest ever reported and the response duration is the longest ever observed. These points lead Dr. Schmidinger to pose the question “Does this imply that VEGF-inhibitors are no longer the primary choice in first line mRCC?” and second “What could prompt us to perceive nivolumab + ipilimumab as a new option rather than THE new standard of care?” According to Dr. Schmidinger, there are five areas that merit a second thought regarding the status of nivolumab + ipilimumab:
(1) Is it about the timing of nivolumab + ipilimumab or about nivolumab + ipilimumab in general?
According to Dr. Schmidinger, based on the phase Ib trial , there is little doubt that the combination of nivolumab + ipilimumab is highly efficacious. In CheckMate 214, patients had access to nivolumab + ipilimumab only if they were assigned to this arm of the trial, as patients assigned to sunitinib never had access to nivolumab + ipilimumab throughout the course of their disease. This raises the question as to how these patients would perform if they would have been given the chance to receive nivolumab + ipilimumab after sunitinib failure? Dr. Schmidinger suggests that although cross-over is a well-known confounder of OS, could the lack of cross-over in CheckMate 214 also be a confounder for OS since patients assigned to sunitinib didn’t have the chance to receive nivolumab + ipilimumab? Thus, according to Dr. Schmidinger, we don’t know whether it is a matter of first-line nivolumab + ipilimumab or access to nivolumab + ipilimumab in general that is most important.
(2) Is the population addressed for the primary endpoints in the trial a clear-cut population?
The current guidelines recommend treatment based on favorable/intermediate risk vs poor risk, whereas Dr. Schmidinger notes that CheckMate 214 combined intermediate + poor risk patients and looked separately at favorable risk patients. As such, favorable risk patients did better on sunitinib and intermediate/poor risk patients did better with nivolumab + ipilimumab. Dr. Schmidinger points out that the biology of intermediate and favorable risk disease can be quite close, given that only one IMDC risk factor is sufficient to be classified as intermediate risk. Thus, do we really know if certain intermediate risk patients would benefit more from sunitinib or nivolumab + ipilimumab?
(3) Are there other strategies for intermediate-poor risk patients that we may be tempted to use instead of nivolumab + ipilimumab?
Dr. Schmidinger notes that one such agent that we may use instead of nivolumab + ipilimumab is cabozantinib. The CABOSUN trial  was a randomized phase II trial in intermediate/poor risk patients randomizing to cabozantinib vs sunitinib in the first line setting. Cabozantinib demonstrated a PFS and ORR benefit compared to sunitinib, however the trial was not designed to test for differences in OS. Patients in CABOSUN more frequently had bone metastases and poorer ECOG status compared to patients in CheckMate 214. Dr. Schmidinger states that since cabozantinib targets the bone microenvironment and has an effect on immune-mediated killing of tumor cells, clinicians may be tempted to choose cabozantinib first.
(4) Should we always consider a VEGFR-TKI in favorable risk patients or is nivolumab + ipilimumab an option?
Since favorable risk patients in CheckMate 214 did much better on sunitinib than nivolumab + ipilimumab, the initial perception that checkpoint inhibitors may work best when patients are healthiest appears inaccurate. According to Dr. Schmidinger, this may be a matter of low PD-L1 expression in favorable risk patients, considering that the favorable risk group in CheckMate 214 only had 11% PD-L1 expression ≥1% compared to higher levels in intermediate/poor risk patients. As such, should we get PD-L1 status in favorable risk patients and choose between nivolumab + ipilimumab or sunitinib based on PD-L1 status?
(5) How relevant are the results showing association of PD-L1 expression and outcome?
An exploratory endpoint in CheckMate 214 showed that PD-L1 positive patients derived a particular benefit with nivolumab + ipilimumab, specifically for improved PFS (HR 0.48, 95%CI 0.28-0.82). However, considering that the majority of patients were PD-L1 negative, these results should be perceived as hypothesis generating according to Dr. Schmidinger, and the role of PD-L1 status as a predictive biomarker remains unclear. Ultimately, once the PD-L1 expression biomarker issue is resolved, will this be enough to know whether a patient will benefit from immunotherapy and derive no benefit from TKIs?
Dr. Schmidinger concluded her presentation with several take-home points: (i) the superiority of nivolumab + ipilimumab over sunitinib is a paradigm change in mRCC first-line treatment considering that sunitinib has never been defeated in superiority trials; (ii) nivolumab + ipilimumab induces a high rate of objective responses, including a number of complete responses with impressive durability; (iii) although check-point inhibitor first-line treatment is a new standard of care with an impressive impact, it is not the final picture yet; (iv) further delineation of tumor biology (ie PD-L1 status) will allow us to better individualize treatment; (v) multiple TKI-checkpoint inhibitor phase III trials are ongoing, several of which will likely be included as standard of care options.
Speaker: Manuela Schmidinger, Medical University of Vienna, Vienna, Austria
Written By: Zachary Klaassen, MD, Urologic Oncology Fellow, University of Toronto, Princess Margaret Cancer Centre, Twitter: @zklaassen_md at the European Society for Medical Oncology Annual Congress - September 8 - 12, 2017 - Madrid, Spain
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2. Hammers HJ, Plimack ER, Infante JR, et al. Safety and efficacy of nivolumab in combination with ipilimumab in metastatic renal cell carcinoma: The CheckMate 016 study. J Clin Oncol 2017 [Epub ahead of print].
3. Choueiri TK, Halabi S, Sanford BL, et al. Cabozantinib versus Sunitinib as initial targeted therapy for patients with metastatic renal cell carcinoma of poor or intermediate risk: The Alliance A031203 CABOSUN Trial. J Clin Oncol 2017;35(6):591-597.