Novel Pembrolizumab Combinations Are Active in Frontline Advanced ccRCC

Multiple novel pembrolizumab (Keytruda)–based combination regimens were effective for the first-line treatment of patients with advanced clear cell renal cell carcinoma (ccRCC), according to data from the phase 1b/2 KEYMAKER-U03 substudy 03A (NCT04626479) published in Annals of Oncology.¹

Findings from the study showed that patients who received reference pembrolizumab plus lenvatinib (Lenvima; n = 62), quavonlimab coformulated with pembrolizumab plus lenvatinib (n = 90), favezelimab coformulated with pembrolizumab plus lenvatinib (n = 61), pembrolizumab plus lenvatinib plus belzutifan (Welireg; n = 90), or vibostolimab coformulated with pembrolizumab plus belzutifan (n = 90) experienced respective overall response (ORR) rates of 80.6% (95% CI, 68.6%-89.6%), 71.3% (95% CI, 60.0%-80.8%), 62.7% (95% CI, 48.1%-75.9%), 77.5% (95% CI, 66.8%-86.1%), and 42.5% (95% CI, 31.5%-54.1%). The median overall survival (OS) was not reached (NR) in any of the investigative arms.

“Observed efficacy and safety of pembrolizumab plus lenvatinib were confirmatory of prior observations for this combination,” Cristina Suárez, MD, a medical oncologist and clinical investigator within the Genitourinary, Central Nervous System Tumors, Sarcoma, and Cancer of Unknown Primary Site Group, at Vall d’Hebron University Hospital in Barcelona, Spain, and her coauthors wrote in the publication. “ORR was similar to the reference for pembrolizumab plus lenvatinib plus belzutifan and quavonlimab/pembrolizumab plus lenvatinib, but not the other investigative arms. Further investigation of pembrolizumab plus lenvatinib plus belzutifan and quavonlimab/pembrolizumab plus lenvatinib vs pembrolizumab plus lenvatinib is ongoing in the phase 3 LITESPARK-012 study [NCT04736706].”²

What was the design of the KEYMAKER-U03 substudy 03A?

KEYMAKER-U03 was a rolling-arm, multicenter, open-label trial that enrolled adult patients with histologically confirmed locally advanced or metastatic ccRCC with measurable lesions per RECIST 1.1 criteria. All patients had not received prior systemic therapy for advanced renal cell carcinoma.¹ Patients were also required to have a Karnofsky performance status score of at least 70%, adequate organ function, and adequately controlled blood pressure with or without medication, measuring no higher than 150/90 mmHg within 1 week of random assignment.

In substudy 03A, patients were randomly assigned 2:1 to an investigative regimen or the reference treatment arm. Treatment in the investigative arms was administered as follows: intravenous (IV) coformulated quavonlimab/pembrolizumab at 25 mg/400 mg every 6 weeks plus oral lenvatinib at 20 mg daily; IV coformulated favezelimab/pembrolizumab at 800 mg/200 mg every 3 weeks plus oral lenvatinib at 20 mg daily; IV pembrolizumab at 400 mg every 6 weeks plus oral lenvatinib at 20 mg daily plus oral belzutifan at 120 mg daily; or IV coformulated vibostolimab/pembrolizumab at 200 mg/200 mg every 3 weeks plus oral belzutifan at 120 mg daily. Patients in the reference arm received IV pembrolizumab at 400 mg every 6 weeks plus oral lenvatinib at 20 mg daily.

The primary end points were ORR per RECIST 1.1 criteria by blinded independent central review and safety. Secondary end points included clinical benefit rate (CBR), duration of response (DOR), progression-free survival (PFS), and OS.

At baseline, the median ages in the reference, quavonlimab, favezelimab, pembrolizumab plus lenvatinib and belzutifan, and vibostolimab arms were 61 years (range, 39-81), 60 years (range, 36-81), 60 years (range, 40-82), 61 years (range, 38-84), and 63 years (range, 37-83). Most patients in each arm were less than 65 years old (66.1% vs 65.6% vs 65.6% vs 61.1% vs 55.6%), male (79.0% vs 75.6% vs 62.3% vs 76.7% vs 74.4%), White (85.5% vs 78.9% vs 62.3% vs 86.7% vs 93.3%), and had intermediate-risk disease per the International Metastatic RCC Database Consortium (62.9% vs 66.7% vs 59.0% vs 68.9% vs 58.9%).

What were the additional efficacy and safety data?

Additional findings from substudy 03A demonstrated that the median DOR values in the reference, quavonlimab, favezelimab, pembrolizumab plus lenvatinib and belzutifan, and vibostolimab arms were 25.6 months (range, 1.4+ to 41.2+), 25.0 months (range, 2.4-37.1+), 26.3 months (range, 1.4+ to 34.4+), 33.4 months (range, 2.6-37.6+), and 14.0 months (range, 2.7+ to 18.2+), respectively. The respective CBRs were 88.7% (95% CI, 78.1%-95.3%), 75.0% (95% CI, 64.1%-84.0%), 66.7% (95% CI, 52.1%-79.2%), 83.8% (95% CI, 73.8%-91.1%), and 63.8% (95% CI, 52.2%-74.2%). The median PFS values were 26.3 months (95% CI, 15.3-39.8), 18.0 months (95% CI, 11.6-34.3), 26.0 months (95% CI, 8.2-31.8), 31.8 months (95% CI, 26.3-NR), and 15.2 months (95% CI, 12.4-NR).

In terms of safety, the profiles of the investigative regimens were generally consistent with the profiles of the individual drugs, and with that of the reference treatment. Dose-limiting toxicities (DLTs) were reported in the reference (5.4%), quavonlimab (2.5%), favezelimab (21.1%), and vibostolimab (2.3%) arms; no DLTs occurred in the pembrolizumab plus lenvatinib and belzutifan arm. Treatment-related adverse effects leading to dose reductions occurred in the reference (74.2%), quavonlimab (65.6%), favezelimab (45.9%), pembrolizumab plus lenvatinib and belzutifan (66.7%), and vibostolimab (33.3%) arms.

“In conclusion, these results support the established efficacy and safety of standard-of-care pembrolizumab plus lenvatinib in advanced ccRCC and the feasibility of investigating first-line triplet regimens in a platform design against an active reference,” Suárez and her coauthors wrote.

References

1. Suarez C, Rojas C, Shin SJ, et al. Novel pembrolizumab-based treatments as first-line therapy in advanced clear-cell renal cell carcinoma: substudy 03A of the open-label, umbrella platform, phase I/II KEYMAKER-U03 trial. Ann Oncol. 2026;37(2):229-240. doi:10.1016/j.annonc.2025.10.010
2. A study of pembrolizumab (MK-3475) in combination with belzutifan (MK-6482) and lenvatinib (MK-7902), or pembrolizumab/​quavonlimab (MK-1308A) in combination with lenvatinib, versus pembrolizumab and lenvatinib, for treatment of advanced clear cell renal cell carcinoma (MK-6482-012). ClinicalTrials.gov. Updated November 18, 2024. Accessed February 23, 2026. https://clinicaltrials.gov/study/NCT04736706