Immunotherapy/TKI frontline combo lowers need for subsequent therapy in advanced renal cell carcinoma

Findings from the phase 3 CLEAR trial (NCT02811861) shared during the 2022 International Kidney Cancer Symposium showed that patients with advanced renal cell carcinoma (RCC) treated upfront with the immunotherapy pembrolizumab (Keytruda) plus the TKI lenvatinib (Lenvima) were far less likely to need second-line therapy vs patients receiving first-line sunitinib (Sutent).1

The results showed that 33.0% of patients assigned to the combination (n = 355) received subsequent systemic therapy compared with 57.7% of the sunitinib group (n = 357). Among those who progressed to subsequent systemic therapy, the median time from randomization to next line of therapy was 12.68 months (range, 1.45-37.36) in the combination arm vs 6.62 months (range, 0.39-28.52) in the sunitinib arm. The median duration of first subsequent anticancer therapy was 5.16 months (range, 0.10-30.23) in the combination arm and 6.82 months (range, 0.03-30.72) in the sunitinib arm.

Furthermore, patients in the combination arm received fewer subsequent PD-L1/PD-1 checkpoint inhibitor therapies than patients in the control arm (8.2% vs 43.1%, respectively). Patients in the combination group were also less likely to receive mTOR inhibitors (1.7% vs 4.8%) and CTLA-4 inhibitors (1.7% vs 5.0%). Patients received anti-VEGF (30.4% vs 33.6%) and other (3.4% vs 5.6%) therapies at similar rates.

The most common subsequent systemic therapy in combination arm was cabozantinib (Cabometyx; 14.9%). The most common subsequent therapy in the sunitinib arm was nivolumab (Opdivo; 39.8%).

In the open-label, randomized study, investigators assigned treatment-naïve patients to 20 mg once-daily oral Lenvatinib plus 200 mg IV pembrolizumab once every 3 weeks or 50 mg once-daily oral sunitinib in a 4-weeks-on/2-weeks-off cycle. Eligible patients had untreated, histologically or cytologically confirmed RCC with a clear-cell component and proof of advanced disease. Patients were also required to have a Karnofsky performance score of 70 or better.

The combination conferred a benefit in progression on first subsequent systemic cancer therapy or death (PFS2), irrespective of International Metastatic RCC Database (IMDC) or Memorial Sloan Kettering Cancer Center (MSKCC) risk group. The median PFS2 was not reached [NR] in the experimental arm vs 28.7 months in the experimental arm (HR, 0.50; 95% CI 0.39-0.65; nominal P < .0001). PFS2 rates at 12 months (87.6% vs 72.5%) and 24 months (72.7% vs 54.2%) also favored the combination arm.

When investigators analyzed median PFS2 by MSCKCC risk group, the median PFS2 was not reached (NR) for the combination was (95% CI, not evaluable [NE]–NE) compared with 34.7 (95% CI, 28.7-NE) in the favorable-risk group (HR, 0.47; 95% CI, 0.26-0.87). Similarly, outcomes favored the combination in the intermediate- (NR vs 23.7 months; HR, 0.53; 95% CI, 0.39-0.71), and poor- (NR vs 10.2 months; HR, 0.42; 95% CI, 0.20-0.88) risk groups.

Assessing by IMDC risk group, investigators found that the median PFS2 was again NR (95% CI, NE-NE) in the favorable-risk group with the combination compared with 34.7 months (95% CI, 28.8-NE) with sunitinib (HR, 0.57; 95% CI, 0.32-1.00). PFS2 was also NR (95% CI, 31.9-NE) in the intermediate-risk group with the combination vs 23.0 months (95% CI, 17.7-NE) with sunitinib (HR, 0.53; 95% CI, 0.38-0.73). In the poor-risk group, PFS2 was NR (95% CI, 11.8-NE) with the combination compared with 10.2 months (95% CI, 4.2-12.2) with sunitinib (HR, 0.37; 95% CI, 0.19-0.74).

Data from CLEAR previously presented at the 2022 ESMO Congress in September showed that the combination demonstrated continued improvement in overall survival (OS) and PFS compared with sunitinib with an additional 7 months of follow-up.2

At a median follow-up of approximately 33 months, investigators observed a 28% reduction in the risk of death with the combination (HR, 0.72; 95% CI, 0.55-0.93). The 24-month OS rate with the combination was 80.2% (95% CI, 75.5%-84.1%) compared with 69.7% (95% CI, 64.4%-74.3%) for sunitinib. Median OS was not estimable for either treatment. Median PFS was 23.3 months (95% CI, 20.8-27.7) with the combination vs 9.2 months (95% CI, 6.0-11.0) with sunitinib (HR, 0.42; 95% CI, 0.34-0.52).

The objective response rate was 71% with lenvatinib plus pembrolizumab (95% CI, 66.3%-75.7%) compared with 36.1% (95% CI, 31.2%-41.1%) for sunitinib (relative risk, 1.97; 95% CI, 1.69-2.29). The rate of complete responses was 17.2% with the combination compared with 4.2% for sunitinib. The median duration of response was 26.0 months (95% CI, 22.2-41.4) with lenvatinib/pembrolizumab compared with 14.7 months (95% CI, 9.4-16.8) with sunitinib.

References

1. Voss MH, Powles T, McGregor B, et al. Impact of subsequent therapies in patients with advanced renal cell carcinoma receiving lenvatinib plus pembrolizumab or sunitinib in the CLEAR study. Presented at: 2022 International Kidney Cancer Symposium; November 3-5, 2022; Austin, Texas. Abst 36.

2. Porta CG, Eto M, Motzer RJ, et al. Updated efficacy of lenvatinib (LEN) + pembrolizumab (PEMBRO) vs sunitinib (SUN) in patients (pts) with advanced renal cell carcinoma (aRCC) in the CLEAR study. Ann Oncol. 2022;33(suppl 7):S1205-S1206. doi:10.1016/j.annonc.2022.07.1552.