The phase 3 LITESPARK-012 study (NCT04736706) evaluated efficacy and safety of 1L pembrolizumab + lenvatinib + belzutifan or MK-1308A (coformulated quavonlimab [anti–CTLA-4]/pembrolizumab) + lenvatinib vs standard-of-care (SOC) pembrolizumab + lenvatinib in clear cell RCC (ccRCC).
Adults with untreated advanced ccRCC were randomized 1:1:1 to Arm A: pembrolizumab (400 mg Q6W, ≤18 cycles) + lenvatinib (20 mg QD) + belzutifan (120 mg QD); Arm B: MK-1308A (quavonlimab/pembrolizumab 25 mg/400 mg Q6W, ≤18 cycles) + lenvatinib; or Control: pembrolizumab + lenvatinib; and treated until progression, unacceptable toxicity, or withdrawal from study (pembrolizumab or MK-1308A treatment for max ∼2 yrs). Dual primary endpoints were PFS by blinded independent central review (BICR) per RECIST 1.1 and OS, tested in all randomized pts for Arm A vs Control, and pts with IMDC intermediate/poor risk or all pts for Arm B vs Control. ORR by BICR and safety were secondary endpoints.
1688 pts were randomized. As of Feb 4, 2026, median follow-up was 43.6 mo (range, 31.8–57.4). Triplet therapy (Arm A, Arm B) did not improve efficacy vs Control (Table). Median duration of each drug therapy was as follows – Arm A: pembrolizumab (14.1 mo) + lenvatinib (18.1 mo) + belzutifan (18.6 mo); Arm B: MK-1308A (11.8 mo) + lenvatinib (15.2 mo); and Control: pembrolizumab (21.2 mo) + lenvatinib (22.2 mo). All cause AEs led to discontinuation of any drug in 51.6% of pts in Arm A, 51.4% in Arm B, and 36.2% in the Control arm. All cause grade ≥3 AEs occurred in 87.2%, 88.7%, and 84.8% of pts, respectively. Table: 3586O
| N | Median PFS, mo | PFS HR (95% CI) and p-value vs control | Median OS, mo | OS HR (95% CI) and p-value vs control | ORR, % (95% CI) | |
| Arm A, all pts | 560 | 20.8 | 1.08 (0.93–1.26); P=.84 | 52.0 | 1.04 (0.87–1.25); P=.66 | 69.1 (65.1–72.9) |
| Arm B, all pts | 562 | 20.7 | 1.07 (0.92–1.25); P=.82 | NR | 1.12 (0.94–1.35); P=.90 | 69.0 (65.0–72.8) |
| Control, all pts | 566 | 23.7 | NR | 76.3 (72.6–79.8) | ||
| Arm B, IMDC intermediate/poor risk | 429 | 20.5 | 1.12 (0.94–1.33); P=.90 | 39.1 | 1.17 (0.96–1.42); P=.94 | 66.9 (62.2–71.3) |
| Control, IMDC intermediate/poor risk | 429 | 23.5 | 46.2 | 75.5 (71.2–79.5) |
NR, not reached.
Neither addition of HIF-2α inhibitor belzutifan nor of CTLA-4 blockade to pembrolizumab + lenvatinib in advanced RCC improved efficacy; pembrolizumab + lenvatinib remains a 1L SOC. Higher discontinuation rate of pembrolizumab, MK-1308A, and lenvatinib due to AEs in the investigational arms may have limited drug exposure and partly impacted efficacy.
NCT04736706; LITESPARK-012.
Writing assistance was provided by Ina Bremer, PhD, an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.
The study was conducted by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.
Funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.