The treatment landscape for patients with advanced renal cell carcinoma has changed drastically over the past several years with the introduction of many new therapeutic options for patients. The revolution began with the U.S. Food and Drug Administration (FDA) approval of nivolumab and ipilimumab in April 2018.1 Since that time, two additional regimens have demonstrated impressive outcomes, including the combination of pembrolizumab plus axitinib2 and avelumab plus axitinib,3 resulting in FDA approvals in April 2019 and May 2019, respectively.
Predictive biomarkers to immunotherapy regimens remain in the early stages of development, and ongoing studies are warranted to identify the optimal platforms to personalize therapy.— Rana R. McKay, MD
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As reviewed in this issue of The ASCO Post and published in The Lancet Oncology, Motzer and colleagues reported on the long-term efficacy and safety results from the landmark phase III CheckMate 214 trial.4 With a median follow-up of 32.4 months, these data provide critical information regarding the extended outcomes of treatment with nivolumab and ipilimumab. As immunotherapy combinations populate the front-line setting for patients with advanced renal cell carcinoma and we review the study findings, it is important to understand (1) the unique patterns of response and efficacy endpoints of immunotherapy-based regimens; (2) the distinct safety profiles and quality-of-life outcomes associated with immunotherapy use; and (3) the evolving biomarkers to predict response to treatment.
CheckMate 214: Comparing Initial and Updated Analyses
Updated results from CheckMate 214 demonstrate that 30-month overall survival was 60% vs 47% for intermediate- and poor-risk patients receiving nivolumab and ipilimumab compared with sunitinib—a clear benefit with the combination. When evaluating the Kaplan-Meier curves for overall survival in this population, we see an early and consistent separation of the curves. With longer follow-up, we can better understand the clinical benefit in progression-free survival.
At the initial study analysis, the median progression-free survival, as assessed by independent radiology review, was 11.6 months with nivolumab and ipilimumab compared with 8.4 months with sunitinib.1 This did not meet the alpha level for clinical significance of P < .009, as the overall alpha of 0.05 was split among the three co-primary endpoints of objective response, progression-free survival, and overall survival. With longer follow-up, 30-month progression-free survival as assessed by investigator for intermediate- and poor-risk patients was 28% with nivolumab and ipilimumab vs 12% with sunitinib. The Kaplan-Meier curves for progression-free survival begin to separate at around 9 months, after the median for both arms has been reached (median progression-free survival of 8.2 vs 8.3 months for nivolumab and ipilimumab vs sunitinib), and a plateau emerges at 30 months, suggesting a delayed benefit in progression-free survival.
It is important to note that the initial study analysis reported progression-free survival as assessed by independent radiology review; however, the current analysis presents investigator-assessed progression-free survival. Meta-analysis data highlight differences in progression-free survival estimates by independent review and investigator assessment, so it is critical for studies to report both outcomes to transfer trial results to real-world practices and decision-making.5
Rethinking Traditional Clinical Trial Endpoints
The unique mechanism of action of checkpoint inhibitors, which engage T cells with inherent capacity for adaptability and memory, necessitates that we rethink traditional clinical trial endpoints. Although overall survival remains the most compelling primary endpoint, additional endpoints to consider in the context of immunotherapy include the depth and durability of response. Treatment with nivolumab and ipilimumab resulted in a complete response in 11% of patients with intermediate- or poor-risk disease. Of these patients, 88% continue to have a durable complete response, suggesting a glimmer of a potential cure for a small subset of patients with advanced renal cell carcinoma. Additionally, the median time to an objective response was 2.8 months, shorter than the observed 4.0 months seen with sunitinib, highlighting that responses to immunotherapy occur early.
While the number of patients with favorable-risk disease was small (23% of the total population), it is important to understand the outcomes of these patients. Cross-trial comparisons are limited, but the independent radiology-assessed and investigator-assessed progression-free survivals of 25.1 months and 19.9 months, respectively, in the favorable-risk patients in the sunitinib control arm of CheckMate 214 outperformed other contemporary immunotherapy-combination trials.2,3 Nonetheless, overall survival and progression-free survival favored sunitinib in patients with favorable-risk disease. Although the numbers are small, 8% of patients (n = 10) had a complete response with nivolumab and ipilimumab, and the response was ongoing in 90% of patients at the time of analysis.
It is important to highlight the extreme responders to immune checkpoint blockade, but it is also critical to evaluate the patients who derive little or no benefit to therapy. In the intention-to-treat population, 22% of patients had progressive disease as best response, highlighting the need to improve biomarkers for patient selection for treatment. Interestingly, in an exploratory analysis of the impact of baseline clinical features on overall survival, programmed cell death ligand 1 expression was not prognostic of overall survival in patients treated with combination immune checkpoint blockade.
Benefit-Risk Profile of Combination Therapy
The safety profile of checkpoint inhibitors differs from that of targeted therapy, given the mechanism of action of these agents. Immune checkpoint inhibitors can cause immune-related adverse events, which are unique in terms of organs involved, onset patterns, and severity. Most grade 3 or 4 treatment-related adverse events occurred early during the combination induction phase and resolved within 4 to 6 months of treatment, apart from select endocrinopathies requiring ongoing hormonal therapies.
In the original study report, 152 patients received high-dose steroids (≥ 40 mg of prednisone/d or its equivalent) of a denominator of 436 patients treated with nivolumab and ipilimumab who had a treatment-related adverse event (35%).1 In the current analysis, 157 patients received high-dose steroids of a more appropriate denominator of 547 patients who received at least one dose of treatment and were included in the safety analysis (29%). In a separate analysis from CheckMate 214, treatment with nivolumab and ipilimumab resulted in fewer side effects and improved health-related quality of life compared with sunitinib, supporting the favorable benefit-risk profile of this combination.6
Need for Improved Prognostic Markers
During thetargeted therapy era, the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk model was developed to predict outcomes to targeted therapy. It has been utilized to risk-stratify patients enrolled on clinical trials, including recent clinical trials of immunotherapy combination regimens. In an exploratory multivariable analysis to evaluate the effect of baseline clinical features on the probability of overall survival in the intention-to-treat population, baseline IMDC factors (eg, anemia, neutrophilia, thrombocytosis, and time from diagnosis to treatment) were not prognostic of overall survival in the study population. Although exploratory and post hoc in nature, this analysis highlights the limitations of the IMDC risk model, given the lack of validation in the context of immunotherapy-based treatments and the need for improved prognostic models that integrate a better understanding of the underlying tumor biology.
As immunotherapy combinations populate the front-line setting for patients with advanced renal cell carcinoma, clinicians are left with a dilemma regarding selection of the optimal regimen for each individual patient. This decision will only get more complicated as the results of additional phase III combination studies are on the horizon; they include the CLEAR trial of lenvatinib with pembrolizumab (ClinicalTrials.gov identifier NCT02811861), the CheckMate 9ER trial of cabozantinib with nivolumab (NCT03141177), and the COSMIC-313 trial of cabozantinib with nivolumab and ipilimumab (NCT03937219). Clinical considerations including patient factors, safety, and efficacy drive much of the current decision-making. Predictive biomarkers to immunotherapy regimens remain in the early stages of development, and ongoing studies are warranted to identify the optimal platforms to personalize therapy. ■
Dr. McKay is Assistant Professor of Medicine, University of California San Diego, Moores Cancer Center, La Jolla.
DISCLOSURE: Dr. McKay has served as an advisor/consultant for Janssen, Dendreon, Novartis, Bristol-Myers Squibb, Pfizer, Tempus, and Exelixis and has received institutional research funding from Pfizer and Bayer.
REFERENCES
1. Motzer RJ, Tannir NM, McDermott DF, et al: Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med 378:1277-1290, 2018.
2. Rini BI, Plimack ER, Stus V, et al: Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med 380:1116-1127, 2019.
3. Motzer RJ, Penkov K, Haanen J, et al: Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med 380:1103-1115, 2019.
4. Motzer RJ, Rini BI, McDermott DF, et al: Nivolumab plus ipilimumab versus sunitinib in first-line treatment for advanced renal cell carcinoma: Extended follow-up of efficacy and safety results from a randomised, controlled, phase 3 trial. Lancet Oncol 20:1370-1385, 2019.
5. Liang W, Zhang J, He Q, et al: Comparison of assessments by blinded independent central reviewers and local investigators: An analysis of phase III randomized control trials on solid cancers (2010–2015). Ann Oncol 27(suppl 6):316P, 2016. Abstract.
6. Cella D, Grunwald V, Escudier B, et al: Patient-reported outcomes of patients with advanced renal cell carcinoma treated with nivolumab plus ipilimumab versus sunitinib (CheckMate 214): A randomised, phase 3 trial. Lancet Oncol 20:297-310, 2019.
