Network Meta-Analysis Sheds Light on Efficacy of Lenvatinib Plus Pembrolizumab Vs SOC in Advanced RCC

Lenvatinib (Lenvima) plus pembrolizumab (Keytruda) demonstrated a trend of improved progression-free survival (PFS) and overall response rate (ORR) with comparable overall survival (OS) outcomes to that achieved with global standard-of-care (SOC) immunotherapies in patients with advanced renal cell carcinoma (aRCC), according to findings from a network meta-analysis (NMA) that were presented during the 2024 Genitourinary Cancers Symposium.¹

Lenvatinib/pembrolizumab provided over 70% probability of greater OS benefit compared with 8 out of 12 therapies. Similarly, there was more than 75% probability of greater PFS benefit with lenvatinib/pembrolizumab vs all available comparators.

The investigators of this Bayesian NMA found 34 randomly assigned, controlled trials in a systematic literature review, then looked at 24 of those trials with 22 interventions as first-line treatment in patients with newly diagnosed metastatic or aRCC for the NMA. The comparison treatments included combinations such as atezolizumab (Tecentriq)/bevacizumab (Avastin), avelumab (Bavencio)/axitinib (Inlyta), nivolumab (Opdivo)/cabozantinib (Cabometyx), nivolumab/ (Opdivo)/ipilimumab (Yervoy), and pembrolizumab/axitinib; and single agents including sunitinib (Sutent), interferon alfa-2a (IFN alfa-2a), interleukin-2 (IL-2), among others.

Treatment efficacy from these first-line trials were compared with lenvatinib and pembrolizumab’s efficacy in the phase 3 CLEAR trial (NCT02811861), which is what the combination’s’ approval is based on.^2,3 Probability to provide greater benefit was shown by fixed-effect (FE) and random-effect (RE) HR or odds ratio (OR) and 95% credible interval (CrI).

Additionally, subgroup analyses were conducted for patients with intermediate-/poor-risk aRCC according to the International Metastatic RCC Database Consortium criteria.¹ The comparison of the intention-to-treat (ITT) and intermediate-/poor-risk group showed the PFS benefit with lenvatinib/pembrolizumab was maintained in the subgroups with feasible comparators.

In the ITT population, the probability of lenvatinib/pembrolizumab providing greater OS benefit than the comparators ranged from 23.8% to- 99.8%. This probability was statistically significant against 2 therapies: IFN alfa-2a interferon alfa-2a (FE HR, 0.65; 95% CrI, 0.48-0.88) and sunitinib (FE HR, 0.79; 95% CrI, 0.63-0.99). The OS benefit was statistically significant against only sunitinib in the intermediate-/poor-risk subgroup, and probability of greater benefit ranged from 20% to 98.8%.

“While interpreting the findings, it should be noted that indirect comparisons of OS could be influenced by inter-trial differences in proportion of poor prognosis patients, length of trial follow-up, and use of second-line treatments,” the study authors noted in their poster.

There was a 75.3% to 100% probability of providing greater benefit with lenvatinib/pembrolizumab vs comparators for the ITT population in terms of PFS. Significant PFS benefit was shown against 13 out of 18 treatments, and similar in FE and RE models. The most PFS probability benefit was seen compared with placebo (RE HR, 0.18; 95% CrI, 0.08-0.40), IL-2 (RE HR, 0.25; 95% CrI, 0.12-0.54), and IFN alfa-2a (RE HR, 0.28; 95% CrI, 0.16-0.51).

Other therapies that lenvatinib/pembrolizumab had statistically significant PFS benefit over included sunitinib, pazopanib(Votrient), tivozanib (Fotivda), sorafenib (Nexavar), atezolizumab/bevacizumab, bevacizumab/IFN alfa-2a, atezolizumab, everolimus, pembrolizumab/axitinib, and bevacizumab/everolimus.

Similarly, lenvatinib/pembrolizumab had a 66.7% to 100% probability of providing greater PFS benefit over comparators in the intermediate-/poor-risk subgroup. Statistically significant benefit was shown vs 6 out of 8 comparators, with most benefit against temsirolimus (FE HR, 0.31; 95% CrI, 0.17-0.55).

The ORR in the ITT population had a probability of providing greater benefit in 93.2% to 100% over comparators and was significant in 9 out of 12. Lenvatinib/pembrolizumab had the best comparative ORR against placebo (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). The intermediate-/poor-risk subgroup had a 94.5% to 100% probability of greater ORR benefit with lenvatinib/pembrolizumab and showed statistically significant difference in 5 out of 6 comparators.

In the ITT group, complete response benefit with lenvatinib/pembrolizumab was 58.5% to 100% greater probability than comparative therapies. Out of 14 comparators, the combination was statistically significant against 9. The biggest benefit was against bevacizumab/everolimus with an FE OR of 103.65 (95% CrI, 2.05-61083.68). There was a 28.2% to 100% probability of greater complete response benefit in the patients with intermediate/poor risk, and significant benefit of 2 of the 5 comparative regimens.

In terms of safety, lenvatinib/pembrolizumab did not significantly change any-cause grade 3 or higher adverse events (AEs) compared with most of the combination therapies. Lenvatinib/pembrolizumab was comparable with nivolumab/cabozantinib for treatment-emergent AEs. There was also a significant advantage with lenvatinib/pembrolizumab over 4 combinations for treatment discontinuation: atezolizumab/bevacizumab, bevacizumab/IFN alfa-2aIFN alpha-2a, bevacizumab/everolimus, and nivolumab/ipilimumab. Otherwise, the CLEAR trial regimen was non-inferior to all other monotherapies and combinations evaluated.

“The NMA results show that combination therapy with lenvatinib plus pembrolizumab provides a comparable OS, and a trend of improvement in PFS and response outcomes, compared with most current global SOC therapies for treatment-naïve patients with aRCC,” the study authors wrote in their conclusion.

References

1. Grünwald V, Winquist E, Peer A, et al. Network meta-analysis (NMA) to assess comparative efficacy of lenvatinib plus pembrolizumab compared with other first-line treatments for management of advanced renal cell carcinoma (aRCC). J Clin Oncol. 2024;42(suppl 4):482. doi:10.1200/JCO.2024.42.4_suppl.482
2. Motzer R, Alekseev B, Rha SY, et al. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl J Med. 2021;384(14):1289-1300. doi:10.1056/NEJMoa2035716
3. FDA approves lenvatinib plus pembrolizumab for advanced renal cell carcinoma. FDA. News rRelease. FDA. August 11, 2021. Accessed January 27, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-lenvatinib-plus-pembrolizumab-advanced-renal-cell-carcinoma#:~:text=FDA%20approves%20lenvatinib%20plus%20pembrolizumab%20for%20advanced%20renal%20cell%20carcinoma,-Subscribe%20to%20Email&text=On%20August%2010%2C%202021%2C%20the,renal%20cell%20carcinoma%20(RCC).