Lenvatinib/pembrolizuma shows sustained anti-tumor activity and extends survival in nccRCC

First-line treatment with lenvatinib/Lenvatinib plus pembrolizumab continues to show antitumor activity and improve survival in patients with advanced non-clear cell renal cell carcinoma (RCC) compared with prior control, according to long-term follow-up results from the single-arm Phase 2 KEYNOTE-B61 trial. Published study results showed that with extended follow-up, the updated objective response rate (ORR) in the overall population was 50.6%. The disease control rate (DCR) was 82.3% and the clinical benefit rate (CBR) was 71.5%. Additionally, the median duration of response (DOR) was 19.5 months.

The latest efficacy and safety results continue to support lenvatinib plus pembrolizumab as a first-line treatment option for patients with advanced non-clear cell renal cell carcinoma. Based onPhase 3 CLEAR/KEYNOTE-581/e 7080-g Based on the results of the 0000-307 trial (NCT02811861), the U.S. Food and Drug Administration (FDA) approved the combination of lenvatinib plus pembrolizumab as first-line treatment for patients with advanced clear cell RCC.

In the prospectivePhase 2 KEYNOTE-B61 trial, researchers evaluated treatment options for 158 patients with advanced non-clear cell renal cell carcinoma. Initial data, including a median follow-up of 15 months, showed an ORR of 49.4%, with 74.6% of responders remaining in response at 1 year or longer. The 1-year progression-free survival rate (PFS) and overall survival rate (OS) were 62.8% and 82.2%, respectively. Responses were also observed in the subgroups of papillary renal cell carcinoma (53.8%), chromophobe cell carcinoma (27.6%), unclassified renal cell carcinoma (52.4%), translocated renal cell carcinoma (66.7%), and other histological types of renal cell carcinoma (55.6%). In results published in 2024, data are presented for a median time of 22.8 months from the first dose to the data cutoff date (July 5, 2023).

To be eligible for enrollment, patients must have histologically confirmed locally advanced or metastatic non-clear cell renal cell carcinoma who have not received prior systemic therapy, have measurable disease according to RECIST v1.1 criteria, and have a Karnofsky score of 70% or higher. Tumor tissue samples must also be available.

Every400 mg intravenously every 6 weeksPembrolizumab , for up to 18 cycles or approximately 2 years; lenvatinib 20 mg orally daily. Patients were assessed for disease 12 weeks after allocation, then every 6 weeks for 54 weeks, and then every 12 weeks. The primary endpoint was ORR according to RECIST v1.1 criteria for Blinded Independent Central Review (BICR). Secondary endpoints were CBR, DCR, DOR and PFS according to RECIST v1.1 criteria for BICR, OS and safety. All patients who received at least 1 dose of study treatment were eligible for efficacy and safety assessment, and investigators assessed DOR in those patients who achieved a complete or partial response (PR).

45.6% of patients are receiving treatment. A total of 54.4% of patients experienced disease progression, adverse events (AEs), patient decision, physician decision, and non-study anticancer treatment. Other efficacy findings showed that the complete response (CR) rate was 8.2%, the PR rate was 42.4%, and 31.6% of patients had stable disease (SD); 20.9% of patients had SD lasting at least 6 months. A total of 10.8% of patients experienced disease progression and 7.0% had non-evaluable responses. Response was also assessed histologically. The ORR was 53.8% for papillary renal cell carcinoma (CR rate, 10.8%; PR rate, 43.0%), 34.5% for chromophobe renal cell carcinoma (all PRs), and 50.0% for unclassified histology (all PRs). PRs), translocation renal cell carcinoma 66.7% (CR rate 16.7%; PR rate 50.0%), and other histologies 60.0% (CR rate 20.0%; PR rate 40.0%).

The ORR for lenvatinib/pembrolizumab was similar among prespecified patient subgroups but was lowest among patients with PD-L1 CPS less than 1 (34.0%) and chromophobe renal cell carcinoma (20.0%). The overall reduction in tumor burden was 88.6%; in the papillary, unclassified, chromophobe, and translocated/other subgroups, these rates were 96.6%, 95.0%, 95.0%, 84.0%, and 93.3%, respectively. 148 patients had a baseline assessment and at least one post-baseline assessment. The median PFS and OS for the entire patient population was 17.9 months, which was not reached. The PFS rates at 12 months and 18 months were 63.9% and 48.1% respectively; the OS rates at 12 months and 18 months were 81.6% and 72.5% respectively.

PFS and OS data for papillary and chromophobe histological subgroupsare also included. In the papillary subgroup, the median PFS and OS were 17.5 months and NR, respectively. The PFS rates at 12 and 18 months were 67.1% and 46.0%, respectively; the OS rates at 12 months and 18 months were 82.8% and 71.8%, respectively. In the chromocyte subgroup, the median PFS was 26.2 months, and the median OS was NR. The 12-month PFS rate was 56.5%, and the 18-month PFS rate was 51.4%; the 12-month and 18-month OS rates were 82.8% and 75.9%, respectively.

Regarding safety, almost all patients experienced adverse events;70.9% of patients experienced grade 3 to 5 adverse events. A total of 26.6% of patients discontinued any treatment due to pembrolizumab and/or lenvatinib. Serious adverse events occurred in 42.4% of patients, and 9 patients died due to adverse events.

Any grade andGrade 3/4 treatment-related AEs (TRAEs) occurred in 95.6% and 21.5% of patients, respectively. TRAEs leading to any treatment discontinuation occurred in 21.5% of patients; 15.2% of these patients discontinued pembrolizumab alone, 12.7% of lenvatinib alone, and 4.4% of both drugs. Treatment-related serious adverse events occurred in 24.7% of patients.

Any grade and grade 3-5 immune-mediated AEs were reported in 58.2% and 9.5% of patients, respectively. 13.9% of patients required high-dose (≥40 mg/day prednisone or equivalent) or low-dose (<40 mg/day prednisone or equivalent; 7.0% each). In addition, TRAEs of any grade occurred in at least 10% of patients and included hypertension, diarrhea, hypothyroidism, proteinuria, fatigue, palmar-plantar red blood cell dysesthesia syndrome, dysphonia, decreased appetite, nausea, weight loss, fatigue, stomatitis, arthralgia, pruritus, mucosal inflammation, increased aspartate aminotransferase, increased alanine aminotransferase, vomiting, hyperthyroidism, dry mouth, dysgeusia, and rash.