Lenvatinib Combo Improves Clinical Benefit in Clear Cell RCC Subgroups

Combination of Lenvatinib and Pembrolizumab Improves Clinical Benefits Over Sunitinib in Clear Cell Renal Cell Carcinoma Patients

The phase 3 CLEAR trial has shown that the combination of lenvatinib, marketed as Lenvima, and pembrolizumab, marketed as Keytruda, provides superior clinical benefits compared to sunitinib, marketed as Sutent, in patients with advanced clear cell renal cell carcinoma (RCC) regardless of biomarker subtypes. This was revealed by the progression-free survival (PFS) rate consistently favoring lenvatinib plus pembrolizumab over sunitinib regardless of RCC driver gene mutation status. Patients treated with the combination experienced longer PFS than those treated with sunitinib, with an objective response rate of 71% compared to 37%.

PFS Benefit Regardless of Biomarker Subtypes

The benefit of lenvatinib plus pembrolizumab has been confirmed by PFS data from the CLEAR trial, which showed that the combination is active regardless of PD-L1 immunohistochemistry. Patients experienced a longer PFS regardless of gene signature subgroups or biomarker subtype. Additionally, there was a PFS benefit in patients with mutated VHL, PBRM1, SETD2, BAP1, and KDM5C, which were the most frequently mutated genes. Patients with wild-type disease also experienced a PFS benefit with the combination, including those with wild-type VHL, PBRM1, SETD2, BAP1, and KDM5C. Notably, gene signature scores were not associated with PFS outcomes for the lenvatinib plus pembrolizumab arm.

No Difference in Clinical Benefit Despite Different Biomarker Subsets

Dr. Toni Choueiri, a director of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute and a lead researcher for the CLEAR trial, stated that there wasn’t a major difference in baseline characteristics, risk factor by MSKCC or International Metastatic RCC Database Consortium (IMDC) criteria, or PD-L1 CPS between the total clinical set and the biomarker set. Looking at response rates, PFS, and RCC-specific cluster signature, the combination of lenvatinib plus pembrolizumab remains superior to sunitinib in all the clusters tested.

Lenvatinib Plus Pembrolizumab Superiority Over Sunitinib in All Types of Molecular Subtype Clusters

Across all molecular subtype clusters, lenvatinib plus pembrolizumab showed a median PFS of 24.3 months compared to sunitinib’s 9.4 months. Numerically higher tumor responses and longer PFS were observed across all five molecular subtypes: angiogenesis/stromal, angiogenesis, immune/proliferative, proliferative, and stromal/proliferative. The combination of lenvatinib/pembrolizumab showed clinical benefit over sunitinib in patients with first-line advanced clear cell RCC regardless of all the biomarkers tested, a significant step forward for treating this population.

Biomarkers Are Not Indicative of Treatment of Choice

Although the initial study reported benefit consistently with the PD-L1 immunohistochemistry using the combined positive score (CPS) cutoff of one, examining PD-L1 CPS as a continuous variable in the lenvatinib plus pembrolizumab arm versus the sunitinib arm showed no difference. Therefore, PD-L1 cannot be used to pick one treatment over the other. Similarly, gene signature scores were not indicative of treatment of choice.

Conclusion

The combination of lenvatinib plus pembrolizumab presents clinical benefits that far exceed those of sunitinib in treating first-line advanced clear cell RCC. Dr. Toni Choueiri stated that even though the biomarkers suggest different subtypes, lenvatinib and pembrolizumab still deliver superior clinical benefits compared to sunitinib.

Originally Post From https://www.cancernetwork.com/view/lenvatinib-combo-improves-clinical-benefit-in-clear-cell-rcc-subgroups