In renal cell carcinoma, lenvatinib/pembrolizumab outperforms first-line standard

Results of a network meta-analysis (NMA) shared during2024 ASCO Genitourinary Symposium showed that in patients with first-line advanced renal cancer (aRCC), lenvatinib/lenvatinib (Lenv First-line treatment with atinib plus pembrolizumab outperformed the global standard of care, showing similar overall survival (OS) and improved progression-free survival (PFS) and response rates. The lenvatinib/pembrolizumab combination provided a greater likelihood of OS benefit of more than 70% compared with 8 of 12 therapies. Likewise, the likelihood of a PFS benefit for lenvatinib/pembrolizumab was greater than 75% compared with all available comparators.

Comparative treatments includeatezolizumab (ateezolizumab)/bevacizumab (bevacizumab), avelumab (Avelumab)/ Axitinib , Nivolumab (Nivolumab)/Cabozantinib (cabozantinib) , Nivolumab/Ipilimumab (I pilimumab) and pembrolizumab/axitinib, and other combinations; as well as single drugs including sunitinib (sunitinib), interferon alpha-2a (IFNα-2a), interleukin-2 (IL-2), etc.

Efficacy in these first-line trials was compared with that of lenvatinib and pembrolizumab in the Phase 3 CLEAR trial (NCT02811861), which was the basis for the combination's approval. Fixed effects (FE) and random effects (RE) HRs or odds ratios (OR) and 95% confidence intervals (CrI) show the likelihood of providing greater benefit. In addition, a subgroup analysis was performed among patients with intermediate/low-risk renal cell carcinoma according to the International Metastatic Renal Cell Carcinoma Database Consortium criteria. Comparison of the intention-to-treat (ITT) and intermediate/low-risk groups showed that the PFS benefit of lenvatinib/pembrolizumab was maintained in subgroups with feasible comparators.

In theITT population, lenvatinib/pembrolizumabprovided greaterThe probability of OS benefit is 23.8%-99.8%. This probability was statistically significant compared with 2 therapies: interferonα-2a (FE HR, 0.65; 95% CrI, 0.48-0.88) and sunitinib (FE HR, 0.79; 95% CrI, 0.63-0.99). In the intermediate/low-risk subgroup, the OS benefit compared with sunitinib alone was statistically significant, with the probability of greater benefit ranging from 20% to 98.8%.

In terms of PFS, lenvatinib/pembrolizumab had a 75.3% to 100% probability of providing greater benefit in the ITT population compared with the comparator group. Thirteen of 18 treatments showed significant PFS benefit, similar in FE and RE models. Compared with placebo, PFS probability benefit was greatest (RE HR, 0.18; 95% CrI, 0.08-0.40), IL-2 (relative risk, 0.25; 95% CrI, 0.12-0.54), and interferon alfa-2a (relative risk, 0.28; 95% CrI, 0.16-0.51).

Lenvatinib/PembrolizumabOther therapies with statistically significantPFS benefits include sunitinib, pazopanib (Votrient), Tevo Tivozanib, sorafenib (Nexavar), atezolizumab/bevacizumab, bevacizumab/IFNα-2a, atezolizumab, everolimus, pembrolizumab/axitinib and bevacizumab/everolimus.

Similarly, lenvatinib/pembrolizumab had a 66.7% to 100% probability of providing a greater PFS benefit compared with comparators in the intermediate/low-risk subgroups. Statistically significant benefit was seen in 6 of 8 comparison groups, with the greatest benefit for temsirolimus (FE HR, 0.31; 95% CrI, 0.17-0.55).

The overall response rate (ORR) in the ITT population had the potential to provide a greater benefit of 93.2% to 100% compared with the control group and was significant in 9 of 12 people. Compared with placebo, lenvatinib/pembrolizumab had the best ORR (FE OR, 38.47; 95% CrI, 11.94-180.19), everolimus (FE OR, 18.25; 95%CrI, 9.80-35.16) and sorafenib (FE OR, 5.29; 95%CrI, 3.38-8.28). Intermediate/low-risk subgroups achieved greater gains with lenvatinib/pembrolizumabThe probability of ORR benefit ranged from 94.5% to 100%, showing statistically significant differences in 5 of the 6 comparison groups.

In theITT group, the probability of complete response benefit of lenvatinib combined withpembrolizumab was 58.5% to 100% higher than that of the comparator therapy. This combination was statistically significant for 9 out of 14 comparators. The greatest benefit was bevacizumab/everolimus, with a FE OR of 103.65 (95% CrI, 2.05-61083.68). The probability of complete response benefit in patients with intermediate/low risk ranged from 28.2% to 100%, and 2 of the 5 comparison regimens had significant benefit.

In terms of safety, lenvatinib/pembrolizumab did not significantly alter grade 3 or higher adverse events (AEs) from any cause compared with most combination therapies. For treatment-emergent AEs, lenvatinib/pembrolizumab was comparable to nivolumab/cabotinib. Compared with the four combinations of atezolizumab/bevacizumab, bevacizumab/interferon alfa-2a, bevacizumab/everolimus, and nivolizumab/ipilizumab, lenvatinib/pembrolizumab also has significant advantages in terms of treatment interruption. Otherwise, the CLEAR trial protocol was noninferior to all other monotherapies and combination therapies evaluated.

The results of the NMA indicate that the combination of lenvatinib plus pembrolizumab provides comparable OS and improved trends in PFS and response outcomes compared with most current SOC therapies for treatment-naïve aRCC patients worldwide.