Pembrolizumab/Lenvatinib Plus Belzutifan or Quavonlimab Under Investigation in Advanced Clear Cell RCC

Pipeline Report | <b>Pipeline Report: December 2021</b>

A phase 3 clinical trial will compare the safety and efficacy of a co-formulation of pembrolizumab and quavonlimab plus lenvatinib, and that of pembrolizumab, belzutifan, and lenvatinib, vs pembrolizumab/lenvatinib alone in the frontline treatment of patients with advanced renal cell carcinoma.

A phase 3 clinical trial (NCT04736706) will compare the safety and efficacy of a co-formulation of pembrolizumab (Keytruda) and quavonlimab (MK-1308; MK-1308A) plus lenvatinib (Lenvima) and that of pembrolizumab, belzutifan (Welireg), and lenvatinib, vs pembrolizumab/lenvatinib alone in the frontline treatment of patients with advanced renal cell carcinoma (RCC).1

Despite significant progress made in the treatment of patients with this disease, most will eventually experience disease progression. One such development has been the combination comprised of the PD-1 inhibitor pembrolizumab and the VEGFR TKI lenvatinib.

In August 2021, the FDA approved the doublet for use in the first-line treatment of adult patients with advanced RCC based on findings from the phase 3 CLEAR/KEYNOTE-581 (Study 307; NCT02811861).2 Pembrolizumab plus lenvatinib resulted in a median progression-free survival (PFS) of 23.9 months (95% CI, 20.8-27.7) vs 9.2 months (95% CI, 6.0-11.0) with sunitinib (Sutent; hazard ratio [HR], 0.39; 95% CI, 0.32-0.49; P < .0001). The doublet also reduced the risk of death by 34% compared with sunitinib (HR, 0.66; 95% CI, 0.49-0.88; P = .0049).

The doublet also induced an objective response rate (ORR) of 71% (95% CI, 66%-76%) compared with 36% (95% CI, 31%-41%) with sunitinib monotherapy. Among those who responded to the combination, 16% achieved a complete response and 55% experienced a partial response; these rates were 4% and 32%, respectively.

“The current study is designed to evaluate whether the addition of a CTLA-4 inhibitor, quavonlimab, or a HIF-2a inhibitor, belzutifan, can improve patient outcomes when added to pembrolizumab plus lenvatinib,” lead study author Toni K. Choueiri, MD, senior physician and director of the Lank Center for Genitourinary Oncology and Kidney Cancer Center at Dana-Farber Cancer Institute, stated in a poster on the trial in progress shared during the 2021 SITC Annual Meeting.

The open-label, multicenter, randomized, active-controlled phase 3 study will enroll those who have locally advanced or metastatic clear cell RCC, with or without sarcomatoid features, and who are at least 18 years of age. To be eligible for enrollment, patients must have measurable disease per RECIST v1.1 criteria and investigator assessment, and a Karnofsky Performance Scale score of 70% or higher. Patients could not have previously received systemic treatment for advanced disease.

Those with a known additional malignancy that is progressing or has required treatment in the past 3 years, and those with central nervous system metastases or carcinomatous meningitis will be excluded. Other exclusion criteria include having received radiotherapy within 2 weeks before the first dose of the study regimen, having hypoxia, or having clinically significant cardiac disease.

Investigators anticipate to enroll a total of 1431 patients to the trial, who will be randomized 1:1:1 to receive either intravenous (IV) quavonlimab at a dose of 25 mg plus IV pembrolizumab at 400 mg every 6 weeks (Q6W) and oral lenvatinib at a daily dose of 20 mg; oral belzutifan at a daily dose of 120 mg plus IV pembrolizumab at 400 mg Q6W, and oral lenvatinib at a daily dose of 20 mg; or IV pembrolizumab at 400 mg Q6W plus oral lenvatinib at a daily dose of 20 mg.

Treatment with pembrolizumab and MK-1308A will be limited to 18 infusions, and treatment with lenvatinib and belzutifan will continue until a treatment discontinuation event occurs.

Patients will be stratified by International Metastatic RCC Database Consortium prognostic scores (0 vs 1 or 2 vs 3 to 6) and geographic region (North America vs Western Europe vs rest of the world).

The primary end points of the study are PFS per RECIST v1.1 criteria and blinded independent central review (BICR), as well as OS. Secondary end points include ORR and duration of response (DOR) per RECIST v1.1 criteria and BICR, as well as safety and tolerability.

Adverse effects (AEs) will be monitored both throughout the study and for 90 days after patients stop receiving the study treatment. Moreover, AEs will be graded using the Common Terminology Criteria for Adverse Events version 5.0.

Tumor imaging will be performed at week 12, and then Q6W up to week 78, followed by every 12 weeks (Q12W) thereafter. If a patient is positive on bone imaging at baseline, subsequent bone imaging will be performed at week 18, Q12W through week 78, and then every 24 weeks until disease progression is verified by BICR. Additionally, after randomization, brain imaging will be done, as clinically indicated, to confirm complete responses in patients with brain metastases at baseline.

A post-treatment safety follow-up visit will occur within 30 days following discontinuation of study treatment, and additional safety follow-ups will be done 60 days and 90 days after discontinuation of the study regimen.

The efficacy analysis population will be comprised of all randomized patients, and the PFS and OS will be evaluated using a stratified log-rank test. The HR will be estimated using stratified Cox proportional hazards models, and event rates over time will be estimated within each treatment group utilizing the Kaplan-Meier method. ORR will be analyzed using the stratified Miettinen and Nurminen method, with strata weighted by sample size.

The safety analysis population will include all randomized patients who received at least 1 dose of the study regimen. Safety results will be analyzed following a tiered approach, and the Miettinen and Nurminen method will be utilized to perform analyses in which 95% confidence intervals will be provided for the between-treatment differences in the percentages of patients who experiences events.

References

  1. Choueiri TK, Pimack E, Powles T, et al. Phase 3 study of pembrolizumab + belzutifan + lenvatinib or pembrolizumab/quavonlimab + lenvatinib versus pembrolizumab + lenvatinib as first-line treatment for advanced renal cell carcinoma. Presented at: 2021 SITC Annual Meeting; November 10-14, 2021; Washington DC. Abstract 417.
  2. FDA approves KEYTRUDA (pembrolizumab) plus LENVIMA (lenvatinib) combination for first-line treatment of adult patients with advanced renal cell carcinoma (RCC). News release. Merck. August 11, 2021. Accessed August 11, 2021. https://bwnews.pr/3fXk8Rj