Lenvatinib Combo Enhances Clinical Benefit for Clear Cell RCC Subgroups

Combination Therapy with Lenvatinib and Pembrolizumab Improves Clinical Benefits in Clear Cell RCC Patients: Biomarker Analysis from CLEAR Trial

The results of the CLEAR trial, presented at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting, showed that combining lenvatinib (Lenvima) and pembrolizumab (Keytruda) was more effective in treating advanced clear cell renal cell carcinoma (RCC) patients as compared to sunitinib (Sutent) regardless of the subtype of the biomarker. Progression-free survival (PFS) was found to have consistently favored lenvatinib plus pembrolizumab over sunitinib, despite the mutation status of RCC driver genes. This was the first study to evaluate biomarkers as potential predictors of response to treatment.

Details of the Clinical Trial

The CLEAR trial enrolled adult patients with advanced clear cell RCC who had not received prior systemic anticancer therapy for RCC. Patients were divided into two treatment arms; one arm received lenvatinib 20 mg daily plus pembrolizumab 200 mg every three weeks, and the other treated patients with sunitinib 50 mg daily given for four weeks on and two weeks off. A biomarker analysis of the study solely focused on the lenvatinib plus pembrolizumab and sunitinib arms. At baseline, PD-L1 expression was evaluated in 441 patients via the IHC pharmDx assay, gene alteration was evaluated in 380 patients via the whole-exome sequencing ImmunoID NeXT platform, and gene expression was evaluated in 388 patients via the RNA-sequencing ImmunoID NeXT platform.

PFS Benefit Regardless of Gene Mutations

The lenvatinib plus pembrolizumab combination showed a clinical advantage over sunitinib in patients with advanced clear cell RCC, regardless of the subtype of the biomarker used for classification. Patients with mutated VHL, PBRM1, SETD2, BAP1 and KDM5C, which were the most frequently mutated genes, experienced a PFS advantage with the lenvatinib and pembrolizumab combination therapy. Moreover, patients with wild-type disease also experienced a PFS benefit with the combination therapy vs sunitinib.

No Significant Association between PD-L1 and Gene Signature Scores with PFS Outcomes

Gene signature scores and PD-L1 did not predict PFS outcomes for the lenvatinib plus pembrolizumab arm. As per Toni Choueiri, MD, the combination benefitted all patients irrespective of PD-L1 immunohistochemistry or the signature of the gene.

Better ORR with Lenvatinib Plus Pembrolizumab

The objective response rate (ORR) was higher for the lenvatinib plus pembrolizumab combination compared to sunitinib irrespective of the five gene mutations examined and gene signatures across high or low subgroups. The ORRs were found to be higher for lenvatinib plus pembrolizumab in patients with mutated VHL, PBRM1, SETD2, BAP1, and KDM5C. It was also higher in patients with wild-type VHL, PBRM1, SETD2, BAP1, and KDM5C treated with the combination compared to sunitinib.

Superior ORR and PFS across all Molecular Subtype Clusters

Across all molecular subtype clusters, the combination therapy led to higher ORR and PFS as compared to sunitinib. These subtypes include angiogenesis/stromal, angiogenesis, immune/proliferative, proliferative, and stromal/proliferative.

Conclusion

The biomarker analysis of the CLEAR trial confirms the benefit of combining lenvatinib and pembrolizumab for patients with clear cell RCC regardless of PD-L1 IHC and biomarker subtype. This combination showed a clinical benefit over sunitinib in patients with first-line advanced clear cell RCC regardless of all the biomarkers tested, making it a potentially effective first-line treatment option for patients with clear cell RCC.

###long-tail keywords:
– lenvatinib plus pembrolizumab
– CLEAR trial
– RCC driver genes
– PD-L1 IHC
– gene mutations
– signature subgroups
– objective response rate
– mutation status
– advanced clear cell RCC
– first-line therapy

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