EAU Guidelines Endorse Frontline Immunotherapy-Based Combinations in Advanced RCC

Jens Bedke, MD

Positive findings from the phase 3 CLEAR (NCT02811861), CheckMate 9ER (NCT03141177), CheckMate 214 (NCT02231749), and KEYNOTE-426 (NCT02853331) trials have led to the swift adoption of combination immunotherapy as the preferred frontline standard of care for the treatment of patients with advanced clear cell renal cell carcinoma (RCC), which has been further enforced by a recommendation from the European Association of Urology RCC Guidelines Panel that was published in European Urology.¹

The guidelines recommend the combinations of axitinib (Inlyta) plus pembrolizumab (Keytruda), cabozantinib (Cabometyx) plus nivolumab (Opdivo), and lenvatinib (Lenvima) plus pembrolizumab across all International Metastatic RCC Database Consortium (IMDC) risk groups and that of ipilimumab (Yervoy) plus nivolumab in IMDC intermediate- and poor-risk groups.

“New data from combination trials with immune checkpoint inhibitors for advanced kidney cancer confirm a survival benefit for lenvatinib plus pembrolizumab, cabozantinib plus nivolumab with improved quality of life [QOL], axitinib plus pembrolizumab, and ipilimumab plus nivolumab. Collectively, four immune checkpoint inhibitor combinations with proven OS [overall survival] benefit form the new standard of care for first-line clear cell metastatic RCC patients,” lead study author Jens Bedke, MD, professor and vice chairman in the Department of Urology at the University of Tüebingen in Tübingen, Germany, and coauthors wrote in the study publication.

The most recently reported trial with proven survival benefit, CLEAR, demonstrated improved progression-free survival (PFS), OS, and objective response rate (ORR) with the combination of lenvatinib plus pembrolizumab vs sunitinib (Sutent). In the study, patients with treatment-naïve advanced RCC were randomized 1:1:1 to receive lenvatinib plus pembrolizumab (n = 355), lenvatinib plus everolimus (Afinitor; n = 357), or sunitinib (n = 357).

The results showed that the median PFS was 23.9 months with lenvatinib plus pembrolizumab vs 9.2 months with sunitinib, meeting the primary endpoint of independently assessed PFS (HR, 0.39; 95% CI, 0.32-0.49; P < .001). At a median follow-up of 26.6 months, OS was not reached in either arm but favored lenvatinib plus pembrolizumab vs sunitinib (HR, 0.66; 95% CI, 0.49-0.88; P = .005). Moreover, the ORR was 71% with lenvatinib plus pembrolizumab vs 36.1% with sunitinib. Notably, the combination demonstrated activity irrespective of IMDC risk groups and PD-L1 status.

In terms of safety, grade 3 or greater treatment-related adverse effects (TRAEs) with lenvatinib plus pembrolizumab occurred in 72% of patients. Treatment-related deaths occurred in 4 patients in the lenvatinib plus pembrolizumab arm vs in 1 patient in the sunitinib arm.

Similarly, the CheckMate 9ER trial demonstrated improved PFS and OS with the combination of cabozantinib and nivolumab, as well as improved QOL vs sunitinib. In the study, treatment-naïve patients with advanced RCC were randomized to nivolumab plus a reduced dose of cabozantinib (n = 323) or sunitinib (n = 328).

At a median follow-up of 23.5 months, the median PFS was 17 months with the combination vs 8.3 months with sunitinib, meeting the primary endpoint of independently assessed PFS in the intention-to-treat (ITT) population (HR, 0.52; 95% CI, 0.43-0.64; P < .0001). Moreover, OS was not reached with the combination vs 29.5 months with sunitinib (HR, 0.66; 95% CI, 0.50-0.87; P = .0034). The ORR was 54.8% vs 28.4%, respectively. Here too, the combination demonstrated an advantage independent of IMDC risk group and PD-L1 status.

Furthermore, the combination led to improved QOL compared with sunitinib.

Regarding safety, grade 3 or greater TRAEs occurred in 61% of patients in the combination arm vs 51% of patients in the sunitinib arm. Treatment-related deaths occurred in 1 patient in the combination arm vs in 2 patients in the sunitinib arm.

In KEYNOTE-426, treatment-naïve patients with advanced RCC were randomized to pembrolizumab plus axitinib (n = 432) or sunitinib (n = 429). Independently assessed OS and PFS in the ITT population served as the primary end points.

At a median follow-up 30.6 months, the median OS was not reached with pembrolizumab plus axitinib vs 35.7 months with sunitinib in the ITT population (HR, 0.68; 95% CI, 0.55-0.85; P < .001). Moreover, the median PFS was 15.4 months vs 11.1 months, respectively, and was improved across all IMDC subgroups (HR, 0.71; 95% CI, 0.60-0.84; P < .0001). In the favorable-risk group, OS was comparable between treatment arms. Additionally, patients who completed 2 years of the combination had a 36-month OS rate of 95% and a 36-month PFS rate of 75%.

Additional results showed that the ORR in the ITT population was 60.2% with pembrolizumab plus axitinib vs 39.9% with sunitinib.

“Pembrolizumab plus lenvatinib, nivolumab plus cabozantinib, and pembrolizumab plus axitinib show benefit irrespective of IMDC risk group and PD-L1 status. These combinations achieved all three endpoints of PFS, OS, and ORR. In addition, the 32% to 34% reductions in the risk of death in CLEAR, KEYNOTE-426, and CheckMate 9ER, together with acceptable safety profiles, are reasons for recommending these three combinations as the new standard of care in all IMDC risk groups,” wrote the authors.

In CheckMate 214, treatment-naïve patients with advanced RCC were randomized to ipilimumab plus nivolumab (n = 550) or sunitinib (n = 546). At a median follow-up of 48 months, the median OS was 48.1 months with the combination vs 26.6 months with sunitinib in patients with intermediate- and poor-risk disease (HR, 0.65; 95% CI, 0.54-0.78; P < .001). Additionally, the ORR was higher in intermediate- and poor-risk patients who received the combination vs sunitinib, at 65% vs 50%, respectively.

In the favorable-risk group, sunitinib demonstrated improved outcomes vs the combination. Despite the HR moving toward improved OS with the combination at a median follow-up of 48 months (HR, 0.93; 95% CI, 0.62-1.40), PFS continued to favor sunitinib (HR, 1.84; 95% CI, 1.29-2.62).

“For treatment-naïve IMDC intermediate- and poor-risk patients, nivolumab and ipilimumab is a fourth option, with favorable response rates and OS end points. The reduction in risk of death by 35%, and impressive long-term PFS plateauing at approximately 35% after 30 months as well as superior QOL data vs sunitinib make this combination attractive,” wrote the authors.

The panel also discussed the results of the phase 3 JAVELIN Renal 101 (NCT02684006) and IMmotion151 (NCT02420821) trials, which demonstrated an improvement in PFS in the PD-L1–positive population with axitinib plus avelumab (Bavencio) and atezolizumab (Tecentriq) plus bevacizumab (Avastin), respectively, vs sunitinib.

However, the panel withheld their recommendation of either combination given the absence of a robust OS improvement in both trials in the primary population of PD-L1–positive patients.

In conclusion the authors wrote, “In patients who cannot receive or tolerate immune checkpoint inhibition, monotherapies with sunitinib, pazopanib [Votrient], and cabozantinib in intermediate- and poor-risk disease are alternative treatment options in this setting.”

Reference

1. Bedke J, Albiges L, Capitanio U, et al. The 2021 updated European Association of Urology Guidelines on renal cell carcinoma: immune checkpoint inhibitor–based combination therapies for treatment-naive metastatic clear-cell renal cell carcinoma are standard of care. Eur Urol. 2021;80(4):393-397. doi:10.1016/j.eururo.2021.04.042