Avelumab + Axitinib Did Not Improve Overall Survival in Patients with Metastatic Renal Cell Carcinoma: Don’t Panic!

“Final overall survival (OS) and progression-free survival (PFS) results for patients with metastatic clear cell renal cell carcinoma (RCC) who received first-line avelumab in combination with axitinib were presented at the ASCO Annual Meeting, based on the Javelin Renal 101 trial[1].

Although there were some absolute numerical benefits, the combination did not significantly improve OS compared with sunitinib alone. In the ITT population, the median OS was 44.8 months in the avelumab plus axitinib group and 38.9 months in the sunitinib group (HR=0.88).

Among PD-L1 positive patients, the median OS was 43.2 months and 36.2 months (HR=0.86), respectively. Significantly prolonged PFS and objective response rate (ORR) benefits were consistent with long-term follow-up, and a higher proportion of patients had highly durable responses with avelumab plus axitinib compared to sunitinib.

Should we be upset and panic? Absolutely not!

First of all, nothing unexpected happened. All immuno-targeted combinations show hazard ratio figures around 0.8 [2-4]. For combinations of avelumab or pembrolizumab with axitinib, a 5-year OS rate exceeding 30% is already known. We did not have such data during the era of the tyrosine kinase inhibitors, and these improvements are attributable to the immunotherapy component.

Second, most cancer drugs that have immature OS data when approved by FDA do not demonstrate significant improvement in OS after approval [5].

Third, there was a significant 34% reduction in the risk of disease progression with avelumab and axitinib, resulting in an almost threefold increase in the number of patients surviving 5 years progression-free compared with sunitinib. The response to treatment occurred in more than half of the patients receiving the combination, which was twice as high as in the sunitinib group.

Therefore, the improvement in OS is definitely not due to first-line sunitinib. The similarity in OS curves is most likely because patients in both groups received effective subsequent therapies that improved OS, as demonstrated in the CheckMate 025 and METEOR studies [6,7].

In the Javelin Renal 101 trial, half of the patients treated with sunitinib received checkpoint inhibitors and the other half received targeted agents. When disease progressed on the combination of avelumab and axitinib, VEGF(R) inhibitors were prescribed in half of the cases, and subsequent immunotherapy was prescribed in only 19%. When comparing groups of patients for subsequent anti-PD-1(L1) therapy, Kaplan-Meier curves diverge in favor of avelumab and axitinib (HR=0.76).

Moreover, this idea is supported by the results in the poor risk subgroup, where the risk of death was significantly reduced by 43% (p=0.0076), and the OS was doubled in the combination group compared to the sunitinib alone. It can be assumed that patients with an initially poor risk are less likely to receive subsequent lines of therapy, which highlights the substantial impact of the first-line treatment.

While it is certainly beneficial to have effective options for subsequent therapy in routine practice, their influence in randomized trials of first-line therapy cannot be ignored. Thus, OS may not be an adequate primary endpoint in such trials.

I personally strongly believe that OS should be a secondary endpoint in an era of effective subsequent treatment lines. However, if we aim to demonstrate a difference in OS as a primary endpoint in a first-line therapy study, we should design the study with preplanned subsequent lines of therapy.

Examples include the SWITCH study, the RECORD-3 study, or the DremSeq study for melanoma [8-10]. This approach ensures that the cohorts are well balanced and provides a clearer understanding of the impact of the each line of treatment.

In conclusion, do not panic and continue to use first-line immuno-targeted therapy with switch to effective subsequent therapies in case of progressive disease in routine practice. This approach will ultimately result in more patients remaining progression-free and surviving beyond five years.”

Provided by Ilya Tsimafeyeu, Director at Bureau for Cancer Re­search.

References:

1. Motzer RJ, Penkov K, Uemura H, et al. Avelumab + axitinib vs sunitinib in patients (pts) with advanced renal cell carcinoma (aRCC): Final overall survival (OS) analysis from the JAVELIN Renal 101 phase 3 trial. 2024 ASCO Annual Meeting, abstract 4508.

2. Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus axitinib versus sunitinib as first-line therapy for advanced clear cell renal cell carcinoma: 5-year analysis of KEYNOTE-426. J Clin Oncol 41, 2023 (suppl 17; abstr LBA4501).

3. Motzer RJ, Porta C, Eto M, et al. Lenvatinib Plus Pembrolizumab Versus Sunitinib in First-Line Treatment of Advanced Renal Cell Carcinoma: Final Prespecified Overall Survival Analysis of CLEAR, a Phase III Study. J Clin Oncol. 2024 Apr 10;42(11):1222-1228.

4. Powles T, Burotto M, Escudier B, et al. Nivolumab plus cabozantinib versus sunitinib for first-line treatment of advanced renal cell carcinoma: extended follow-up from the phase III randomised CheckMate 9ER trial. ESMO Open. 2024 Apr 19;9(5):102994.

5. Naci H, Zhang Y, Woloshin S, et al. Overall survival benefits of cancer drugs initially approved by the US Food and Drug Administration on the basis of immature survival data: a retrospective analysis. Lancet Oncol. 2024 May 13:S1470-2045(24)00152-9.

6. Motzer RJ, Escudier B, George S, et al. Nivolumab versus everolimus in patients with advanced renal cell carcinoma: Updated results with long-term follow-up of the randomized, open-label, phase 3 CheckMate 025 trial. Cancer. 2020 Sep 15;126(18):4156-4167.

7. Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial. Lancet Oncol. 2016 Jul;17(7):917-927. doi: 10.1016/S1470-2045(16)30107-3.

8. Eichelberg C, Vervenne WL, De Santis M, et al. SWITCH: A Randomised, Sequential, Open-label Study to Evaluate the Efficacy and Safety of Sorafenib-sunitinib Versus Sunitinib-sorafenib in the Treatment of Metastatic Renal Cell Cancer. Eur Urol. 2015 Nov;68(5):837-47.

9. Knox JJ, Barrios CH, Kim TM, et al. Final overall survival analysis for the phase II RECORD-3 study of first-line everolimus followed by sunitinib versus first-line sunitinib followed by everolimus in metastatic RCC. Ann Oncol. 2018 Nov 1;29(11):2269.

10. Atkins MB, Lee SJ, Chmielowski B, et al. Combination Dabrafenib and Trametinib Versus Combination Nivolumab and Ipilimumab for Patients With Advanced BRAF-Mutant Melanoma: The DREAMseq Trial-ECOG-ACRIN EA6134. J Clin Oncol. 2023 Jan 10;41(2):186-197.