Safety and Efficacy of Investigational Agents Under Evaluation in Umbrella Study for Advanced RCC

The safety and efficacy of experimental combinations of investigational agents are being analyzed as treatment for advanced clear cell renal cell carcinoma (ccRCC) as part of a phase 1b/2 umbrella platform study, according to data shared during the 2021 American Association for Cancer Research Virtual Annual Meeting.¹

Substudy 03B (NCT04626518) will evaluate patients whose disease progresses after treatment with PD-1/PD-L1 inhibitors and VEGF-tyrosine kinase inhibitors (TKIs).

“PD-1/L1-based combination regimens are the standard of care for first-line treatment of advanced clear cell RCC (ccRCC); however, there is no standard of care in the post–immuno-oncology/post-VEGF patient population, resulting in a high-unmet need,” explained the investigators, led by Hans Hammers, MD, PhD, of the University of Texas Southwestern Medical Center, Dallas.

The treatments to be evaluated in the study include the cytotoxic T-lymphocyte-associated protein 4 quavonlimab (MK-1308), belzutifan (MK-6482), lymphocyte activation gene 3 (MK-4280), immunoglobulin-like transcript 4 (MK-4830), pembrolizumab (Keytruda), and lenvatinib (Lenvima).

“Given the promising results in the RCC cohort of the phase 1b/2 trial (KEYNOTE-146; NCT02501096)² and the recent phase 3 CLEAR study (NCT02811861),³ pembrolizumab in combination with lenvatinib will be used as the reference arm in substudy 03B,” wrote the investigators.

Adults aged 18 years or older with locally advanced or metastatic ccRCC, measurable disease per RECIST v1.1 criteria, disease progression on or after anti-PD-1/PD-L1 treatment, disease progression after VEGF-TKI therapy, and Karnofsky performance status of 70% or higher are eligible for the study.

The study will include a safety lead-in phase followed by an efficacy phase. Treatment arms in the safety lead-in phase will include pembrolizumab plus belzutifan and lenvatinib plus belzutifan cohorts. Patients will be assigned 1:1 to treatment in an experimental arm or the reference arm. Patients will continue treatment until radiographic disease progression, unacceptable toxicity, intercurrent illness that prevents further administration of study treatment, or withdrawal of consent, according to the investigators.

Experimental arms in the efficacy phase will include quavonlimab 25 mg and pembrolizumab 400 mg IV Q6W; MK-4280 800 mg and pembrolizumab 200 mg IV Q3W; pembrolizumab 200 mg IV Q3W plus MK-4830 800 mg IV Q3W; pembrolizumab 400 mg IV Q6W plus belzutifan 120 mg orally QD; and lenvatinib 20 mg orally QD plus belzutifan 120 mg orally QD. The reference arm will evaluate pembrolizumab 400 mg IV Q6W plus lenvatinib 20 mg orally QD.

“Primary end points for safety lead-in phase (if applicable) are safety and tolerability to establish [a recommended phase 2 dose]; co-primary end points for efficacy phase are safety and objective response rate per RECIST v1.1 by blinded independent central review (BICR). Secondary end points during the efficacy phase are duration of response, progression-free survival, and clinical benefit rate per RECIST v1.1 (BICR), and overall survival,” according to the investigators.

Enrollment for the research is taking place at 27 sites in Australia, New Zealand, South Korea, Spain, and the United States.

References

1.Hammers H, Choueiri T, Plimack E, et al. A phase 1b/2 umbrella study of investigational immune and targeted combination therapies for patients with advanced renal cell carcinoma (RCC) who progressed on PD-1/L1 and VEGF inhibitors. Presented at: 2021 AACR Virtual Annual Meeting; April 10-15, 2021; Virtual. Poster CT243

2. Lee C-H, Shah AY, Hsieh JJ, et al. Phase II trial of lenvatinib (LEN) plus pembrolizumab (PEMBRO) for disease progression after PD-1/PD-L1 immune checkpoint inhibitor (ICI) in metastatic clear cell renal cell carcinoma (mccRCC). Journal of Clinical Oncology. 2020;38, no. 15_suppl:5008. doi:10.1200/JCO.2020.38.15_suppl.5008

3. Motzer R, Alekseev B, Rha S-Y, et al. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl J Med. 2021;384(14):1289-1300. doi:0.1056/NEJMoa2035716