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Associate Professor of Oncology and Urology
Division of Medical Oncology
Brian A. Costello, MD, has no relevant conflicts of interest to report.
Division of GU Medical Oncology
Department of Medicine
Memorial Sloan Kettering Cancer Center
Weill Cornell Medical College
New York, New York
Martin H. Voss, MD, has disclosed that he has received consulting fees from Calithera, Corvus, Eisai, Exelixis, GlaxoSmithKline, Novartis, and Pfizer; funds for research support from Bristol-Myers Squibb, Genentech, and Pfizer; and fees for non-CME/CE services from AstraZeneca, Eisai, and Takeda.
It is a great time to be caring for patients with advanced renal cell carcinoma (RCC) because recent progress has yielded real survival benefits with the addition of immuno-oncology (IO) combinations to our arsenal of frontline treatment. In this commentary, Brian A. Costello, MD, and Martin H. Voss, MD, discuss the latest clinical data and strategies to incorporate IO combinations as frontline therapy for patients with advanced RCC.
Brian A. Costello, MD
CheckMate 214: Nivolumab Plus Ipilimumab vs Sunitinib
CheckMate 214 is a phase III trial of nivolumab plus ipilimumab vs sunitinib as first-line treatment for patients with advanced RCC. Updated results from this study were presented by Tannir and colleagues at ASCO GU 2020 with a minimum follow-up of 42 months. In the overall population, 56% of patients receiving nivolumab plus ipilimumab and 47% of patients receiving sunitinib were alive at 42 months (HR: 0.72; P = .0002).
If we look at the exploratory population of favorable-risk patients, the 42-month OS rate was almost equivalent between the treatment arms. In addition, patients in the sunitinib arm had a significantly higher ORR and longer median PFS compared with those receiving nivolumab plus ipilimumab. Although the OS outcomes need to be followed longer, these results suggest that nivolumab plus ipilimumab is not a better frontline option than sunitinib for favorable-risk patients with advanced RCC.
KEYNOTE-426: Pembrolizumab Plus Axitinib vs Sunitinib
KEYNOTE-426 is a phase III trial comparing pembrolizumab plus axitinib with sunitinib in patients with untreated advanced RCC. Plimack and colleagues presented updated data from KEYNOTE-426 at the 2020 ASCO virtual meeting with a minimum follow-up of 23 months. In the overall population, the 24-month OS rate was 74% in the combination arm vs 66% in the sunitinib arm (HR: 0.68; P < .001). Similarly, PFS was also significantly improved with pembrolizumab plus axitinib vs sunitinib.
Among favorable-risk patients in this study, the 24-month OS rate was almost identical. PFS was in favor of the combination arm with a 24-month PFS rate of 45% with pembrolizumab plus axitinib vs 35% with sunitinib. But I think one of the biggest findings here is an ORR of nearly 70% with the IO/TKI combination vs 50% with sunitinib, which has never been seen in advanced RCC. In addition, CR rate was 11% and 6%, respectively. It is important to keep in mind that pembrolizumab plus axitinib yielded impressive response rates besides PFS benefit.
To summarize, pembrolizumab plus axitinib is the preferred frontline IO combination regimen in favorable-risk patients with advanced RCC who require systemic therapy, based on the outstanding response rates and improvement in PFS.
Martin H. Voss, MD
NCCN Guidelines Recommendations
For intermediate-risk/poor-risk advanced disease with clear-cell histology, the NCCN guidelines recommend either nivolumab plus ipilimumab or pembrolizumab plus axitinib as preferred first-line therapy with level 1 evidence based on data from CheckMate 214 and KEYNOTE-426. Here, I compare key outcomes from these 2 trials focusing on patients with intermediate-risk/poor-risk disease. It should be noted that these side-by-side comparisons are not for direct number-to-number comparison, but to get a general idea of the data trends with these 2 combinations.
CheckMate 214 vs KEYNOTE-426: OS
Both CheckMate 214 and KEYNOTE-426 demonstrated a clear OS benefit with IO combinations over sunitinib in intermediate-risk/poor-risk patients. These are the first studies in more than a decade to demonstrate an OS benefit in the first-line setting for advanced RCC over a standard of care. So this was a big deal to the field and it certainly moved the needle quite a bit. In both studies, the OS curves separate early and similar outcome was observed in the control arm between the 2 trials. The OS signal is important because it is what matters the most to our patients.
To be noted, CheckMate 214 has longer follow-up than KEYNOTE-426, and we can begin to see a leveling off of OS with nivolumab plus ipilimumab at the tail end of the curve for patients with intermediate-risk/poor-risk disease, suggesting that some patients have long-term survival benefit with this IO/IO combination. The 42-month OS rate was 52% with the IO/IO combination vs 39% with sunitinib (HR: 0.66; 95% CI: 0.55-0.80; P < .0001).
In KEYNOTE-426, there appears to also be an OS benefit for patients with intermediate-risk/poor-risk disease, but it is still too early to tell if there is a similar long-term benefit with the IO/TKI combination. At 24-months, the OS rate was 69% with pembrolizumab plus axitinib vs 56% with sunitinib (HR: 0.63; 95% CI: 0.50-0.81).
CheckMate 214 vs KEYNOTE-426: Duration of Response
Looking at duration of response from these 2 trials, there is apparently flattening of the curve for nivolumab plus ipilimumab at the 24-month mark, meaning that responses tend to be durable once patients are past that time point compared with sunitinib where the number of patients still in response continues to decline. There is precedence for immunotherapy and its ability to result in meaningful long-term effects for subgroups of patients who have apparent radiographic benefit from therapy, namely the experience with high-dose IL-2. On the other hand, if we look at KEYNOTE-426, we do not yet have long enough follow-up to see whether the curve will plateau with pembrolizumab plus axitinib.
CheckMate 214 vs KEYNOTE-426: Response Rates
In terms of shorter-term outcomes from these studies, the confirmed ORR for patients with intermediate-risk/poor-risk disease with nivolumab plus ipilimumab was 42% whereas the ORR was higher with pembrolizumab plus axitinib at 56%. We all care quite a bit about CR because it is the highest goal for our patients in many ways. The CR rate with nivolumab plus ipilimumab was 10%, and it was similar with pembrolizumab plus axitinib at 8%. It cannot be overstated how big an improvement these CR rates are for our patients as we were not able to produce the same CR rates in the era of TKI monotherapies. The advent of newer IO combination therapy has made it a reality.
What about early failure and rapid progression? Of note, in patients with intermediate-risk/poor-risk disease with no response, the progressive disease rate was higher with nivolumab plus ipilimumab at 27% compared with pembrolizumab plus axitinib at 14.6%, reflecting a lower risk of early failure with the combination that incorporates TKI and IO therapy; 2 distinctly different mechanisms of action.
CheckMate 214 vs KEYNOTE-426: PFS
Another way to understand early effects of these combinations is to assess the PFS trends in the early timepoints in the trials. If we look at the PFS data for patients with intermediate-risk/poor-risk disease treated on CheckMate 214, there is no separation of the curves until the 9-month mark because it takes time to see benefit from nivolumab plus ipilimumab in patients who truly have a tumor-directed immune response. In comparison, there is early separation of the PFS curves in KEYNOTE-426 with the IO/TKI combination vs sunitinib and those curves stay separate over time.
In CheckMate 214, beyond the 30-month mark, there is flattening of the PFS curve with the IO/IO combination, meaning that patients receiving nivolumab plus ipilimumab who have not suffered progression by this time point seem to be less likely to have progression events. At 42-months, the PFS rate was 35% with nivolumab plus ipilimumab vs 19% with sunitinib, in which the PFS curve of the comparator arm continues to trend downward. In KEYNOTE-426, however, we cannot appreciate that same flattening of the curve just yet due to shorter follow-up and the 24-month PFS rate was 34% pembrolizumab plus axitinib vs 23% with sunitinib, with both curves still trending downward at this point.
To summarize the PFS data, the great promise of nivolumab plus ipilimumab is that more than one third of the patients with intermediate-risk/poor-risk disease seem to have long-term PFS benefit, which is not something that we have seen with TKI monotherapy. These patients should be considered for nivolumab plus ipilimumab as a frontline regimen due to these favorable long-term outcomes, whereas we do not know yet whether that is also true for pembrolizumab plus axitinib. However, as we consider our patients for nivolumab plus ipilimumab, we must be true to the fact that there is a substantial proportion of patients who face the risk of early failure, more so than patients treated with pembrolizumab plus axitinib. Those patients who are considered at high risk for adverse outcomes if early failure were to occur, particularly patients who one worries may not make it to second-line therapy due to rapidly progressive disease and high tumor burden, are better served with pembrolizumab plus axitinib as first-line therapy.
CheckMate 214 vs KEYNOTE-426: Toxicities
In CheckMate 214, the toxicity profile of nivolumab plus ipilimumab was quite different from that of sunitinib. Toxicities associated with nivolumab plus ipilimumab tend to happen in the early months. There are some rare toxicities, so it is important to educate patients and the care team on the fact that patients can have immune-mediated adverse events long after their treatment initiation, but the vast majority of them occur early on. Approximately 20% of patients discontinued immunotherapy due to toxicity and the mortality rate was 1%. Approximately 60% of the patients who received nivolumab plus ipilimumab had corticosteroids administered at any given time point and approximately 30% required high-dose corticosteroids. So it is relevant to keep in mind as you select this regimen for your patients that there is a good chance that they may need corticosteroids for immune-mediated adverse events at some point. Eighty percent of toxicities were ultimately resolved, which tells you that some of them, especially endocrinopathies and skin toxicities, can be long lasting and patients should know about this before they start treatment.
If we look at KEYNOTE-426, pembrolizumab plus axitinib produced a very similar toxicity signal to sunitinib, suggesting that it is predominantly the kinase inhibitor that drives the toxicities. Approximately one quarter of the patients discontinued one of the drugs and 8% had to discontinue both drugs due to toxicity with a mortality rate of 0.9%. Approximately one half of the patients receiving pembrolizumab plus axitinib had immune-mediated adverse events at some point and approximately 10% of them were high grade. There are no data on the rate of corticosteroids use and resolution of immune-mediated adverse events with this regimen. However, there are chronic toxicities from axitinib that can have an ongoing impact on quality of life.
Applying These Data to Clinical Decisions
It is relevant to think through these 2 different perspectives: short-term efficacy and long-term efficacy. For short-term efficacy, PFS and time to response were superior to sunitinib with both the IO/IO combination and the IO/TKI combination. We do know that the progressive disease rate was notably higher with nivolumab plus ipilimumab compared with pembrolizumab plus axitinib. As for long-term efficacy, we have a lot more data from CheckMate 214 showing long-term benefits for a notable proportion of patients treated with nivolumab plus ipilimumab. The follow-up with pembrolizumab plus axitinib is shorter so we are not sure yet about its long-term benefits.
How do I make a treatment decision in my clinic for patients with intermediate-risk/poor-risk disease? I typically look at these patients and think about the dynamics of their cancer. For patients who are facing rapid disease progression or have symptomatic disease that need immediate control, I consider pembrolizumab plus axitinib due to the low failure rate and a high likelihood of rapid response. For other patients, like those with lower burden of disease or those who need to avoid potential TKI-related adverse events, I keep in mind that nivolumab plus ipilimumab has longer follow-up data and a proportion of patients can do very well long term, some of them without the need for further therapy.
Last, the comorbidities of patients matter as well. For example, extensive cardiovascular disease or poorly controlled hypertension despite a multi-drug antihypertensive regimen may turn me away from prescribing a TKI-based regimen. Preexisting autoimmunity certainly is more of a concern if more immunotherapy is given. I think quite a bit about the higher likelihood of requiring corticosteroids that I see with nivolumab plus ipilimumab, so patients who are not going to fare well with high-dose corticosteroids based on comorbidities (eg, poorly controlled diabetes, history of dementia or steroid psychosis), may not be a good candidate for a regimen that makes it very likely that they will need treatment for adverse events.
Ultimately, the decision process for optimal treatment selection is multi-factorial and should integrate information on disease kinetics, comorbidities, and patient preference after a detailed consent discussion with each patient, including all of the above.
How do you apply IO combinations as frontline treatment for patients with advanced RCC? Please share your thoughts and questions in the discussion box below.
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