Navigating the Nuances: Evaluating Avelumab and Axitinib in Metastatic Renal Cell Carcinoma Treatment
Dr. Ilya Tsimafeyeu: Thank you for having me. The primary motivation behind the RAVE-Renal study was to assess the real-world efficacy and safety of avelumab plus axitinib as a first-line treatment for mRCC. While clinical trials like the JAVELIN Renal 101 provide invaluable data under controlled conditions, they often have strict inclusion criteria that don't fully represent the broader patient population seen in everyday clinical practice. Real-world data helps bridge this gap by including a more diverse set of patients, often with varying comorbidities and disease characteristics. This provides a more complete understanding of how avelumab and axitinib treatment works outside of randomized pivotal trials.
What were the key findings of the RAVE-Renal study in terms of progression-free survival (PFS) and objective response rate (ORR)?
Dr. Tsimafeyeu: Our ambispective study enrolled 125 patients and found that the median PFS for patients treated with avelumab plus axitinib was 14.9 months, which aligns closely with the results seen in the JAVELIN Renal 101 trial. The objective response rate was 44.3%, with a clinical benefit rate, including responses and stable disease, of 93.4%. These findings suggest that the combination of avelumab and axitinib is effective in a real-world population, providing significant disease control for patients with mRCC.
How do the results of the RAVE-Renal study compare with other real-world studies, such as the J-DART study in Japan and the UK multicenter study?
Dr. Tsimafeyeu: The RAVE-Renal study results are quite consistent with those of the J-DART study, which reported a median PFS of 15.3 months and an ORR of 48.8%. However, the UK study showed a higher ORR of 62%, potentially due to a longer follow-up period. The median PFS in the UK study was also similar at 13.5 months. It's interesting to note the differences in patient demographics and clinical characteristics across these studies. For example, the UK study had a lower prevalence of clear-cell carcinoma and fewer patients with prior nephrectomy, which could influence treatment outcomes.
What were the most serious adverse events reported in the RAVE-Renal study, and how did they compare with those reported in clinical trials?
Dr. Tsimafeyeu: The most serious adverse events included diarrhea, fatigue, and hypertension, which were also consistent with those observed in the JAVELIN Renal 101 trial. These are typical side effects associated with immune checkpoint inhibitors and tyrosine kinase inhibitors. However, less than 20% of patients had Grade 3 and higher adverse event, so, combination is well tolerated in daily practice.
Are you concerned that the OS results from the 2024 ASCO Annual Meeting didn't demonstrate a clear advantage of avelumab and axitinib over sunitinib in the JAVELIN Renal 101 study?
Dr. Tsimafeyeu: It's a valid concern, but I believe we need to keep the broader context in mind. The lack of a clear OS advantage for avelumab and axitinib over sunitinib in the JAVELIN Renal 101 study isn't surprising, and it certainly shouldn't be cause for panic.
Firstly, this outcome aligns with what we've seen across other immunotargeted combinations, which typically show hazard ratios around 0.8.
Secondly, many anticancer drugs that are approved by the FDA with immature OS data don't show significant OS improvement after longer follow-ups. The real benefit of these newer therapies, particularly immunotherapy, often manifests in terms of long-term disease control and PFS.
In the case of avelumab and axitinib, investigators saw a substantial 34% reduction in the risk of disease progression compared to sunitinib. This led to a nearly threefold increase in the number of patients remaining progression-free at five years. Moreover, the response rate was significantly higher in the combination group. These benefits underscore the efficacy of avelumab and axitinib in controlling the disease.
The similar OS curves between the two groups can likely be attributed to the effective subsequent therapies received by patients in both arms of the study. Many patients initially treated with sunitinib went on to receive checkpoint inhibitors or targeted therapies upon progression, while those in the avelumab and axitinib group received VEGFR inhibitors only. This “real-life” crossover dilutes the apparent OS benefit of the initial treatment. In fact, in the poor-risk subgroup, we observed a significant reduction in the risk of death and a doubling of OS in the combination group compared to sunitinib alone because fewer patients received subsequent therapy.
Thus, while OS is a crucial endpoint, it may not fully capture the benefits of first-line immunotargeted therapies, given the availability of effective subsequent lines of treatment. We should perhaps shift our focus more toward PFS as primary endpoint. These metrics more accurately reflect the immediate benefits of treatment in the current therapeutic landscape. I would advocate for OS to be a secondary endpoint in future studies unless they are designed with preplanned subsequent therapies, which can provide a clearer picture of the impact of each treatment line.
Ultimately, my key takeaway is that avelumab and axitinib remain a potent first-line treatment option, providing significant benefits in terms of efficacy and safety confirmed in real-world studies. This, combined with the strategic use of subsequent therapies, offers our patients the best chance for long-term survival.
Speaker: Ilya Tsimafeyeu, MD, Bureau of Cancer Research, Moscow, Russian Federation
Related Content:
Avelumab plus axitinib for first-line treatment of advanced renal cell carcinoma: A real-world ambispective RAVE-Renal study.