Background
Phase 3, randomized, open-label, three-arm trial. N=1688. Previously untreated advanced clear-cell RCC. Tests adding a HIF-2α inhibitor (belzutifan) or an anti-CTLA-4 (quavonlimab) to pembrolizumab + lenvatinib.
Results
Interventions and follow up: Arm A: pembrolizumab 400 mg IV q6w + lenvatinib 20 mg daily + belzutifan 120 mg daily (n=560)
Arm B: coformulated quavonlimab/pembrolizumab 25 mg/400 mg IV q6w (MK-1308A) + lenvatinib (n=562)
Control: pembrolizumab + lenvatinib (n=566)
Primary endpoints: PFS (BICR) and OS (dual)
mFollow up: 43.6 mo (range 31.8-57.4)
Results: PFS (Arm A vs control): 20.8 vs 23.7 mo; HR 1.08 (0.93-1.26); P=.8408
PFS (Arm B vs control): 20.7 vs 23.7 mo; HR 1.07 (0.92-1.25); nominal P=.8174
OS (Arm A vs control): 52.0 mo vs NR; HR 1.04 (0.87-1.25); P=.6622
OS (Arm B vs control): NR vs NR; HR 1.12 (0.94-1.35); nominal P=.8955
PFS (Arm B vs control, IMDC int/poor): 20.5 vs 23.5 mo; HR 1.12 (0.94-1.33)
OS (Arm B vs control, IMDC int/poor): 39.1 vs 46.2 mo; HR 1.17 (0.96-1.42)
Arm B: coformulated quavonlimab/pembrolizumab 25 mg/400 mg IV q6w (MK-1308A) + lenvatinib (n=562)
Control: pembrolizumab + lenvatinib (n=566)
Primary endpoints: PFS (BICR) and OS (dual)
mFollow up: 43.6 mo (range 31.8-57.4)
Results: PFS (Arm A vs control): 20.8 vs 23.7 mo; HR 1.08 (0.93-1.26); P=.8408
PFS (Arm B vs control): 20.7 vs 23.7 mo; HR 1.07 (0.92-1.25); nominal P=.8174
OS (Arm A vs control): 52.0 mo vs NR; HR 1.04 (0.87-1.25); P=.6622
OS (Arm B vs control): NR vs NR; HR 1.12 (0.94-1.35); nominal P=.8955
PFS (Arm B vs control, IMDC int/poor): 20.5 vs 23.5 mo; HR 1.12 (0.94-1.33)
OS (Arm B vs control, IMDC int/poor): 39.1 vs 46.2 mo; HR 1.17 (0.96-1.42)
Adverse events
Discontinuation of any drug (all-cause AE): 51.6% (A) vs 51.4% (B) vs 36.2% (control)
Grade ≥3 (any): NR in abstract
Control arm safety: consistent with prior reports
Grade ≥3 (any): NR in abstract
Control arm safety: consistent with prior reports
Conclusions
Neither belzutifan nor quavonlimab added to pembrolizumab plus lenvatinib improved PFS or OS in first-line advanced ccRCC, and both increased treatment discontinuations.
Key Limitations
Negative trial; quavonlimab arm results are nominal. Open-label. Control arm PFS (23.7 mo) was strong, leaving little room for improvement; triplet toxicity and dose-intensity issues may have blunted benefit. Grade ≥3 AE detail is not in the abstract.
Clinical Context
Pembrolizumab plus lenvatinib remains a first-line standard for advanced ccRCC alongside other IO-TKI and IO-IO regimens. LITESPARK-012 indicates that triplet intensification with HIF-2α inhibition or CTLA-4 blockade should not be adopted. Belzutifan retains its other roles (e.g., VHL-associated disease and pretreated RCC combinations, per label/trials not discussed here).
