Background
Single-arm, open-label phase 2 trial (non-randomized). 158 patients with previously untreated advanced non-clear cell RCC (nccRCC), including papillary (45%), chromophobe (20%), unclassified (16%), and other histologies. Standard first-line therapies had not been validated in nccRCC; this trial tested pembrolizumab + lenvatinib, a combination approved in clear-cell RCC (CLEAR trial), in the non-clear cell setting.
Interventions and follow up
Arm A: Pembrolizumab 200mg IV q3wk + lenvatinib 20mg/day orally (continuous)
Arm B: Not applicable — single-arm study
Primary endpoint: Objective response rate (ORR) by RECIST 1.1
mFollow up: 14.4 mo
Arm B: Not applicable — single-arm study
Primary endpoint: Objective response rate (ORR) by RECIST 1.1
mFollow up: 14.4 mo
Results
ORR: 49.4% (95% CI 41.3–57.4%)
Complete response rate: 8.9%
mPFS: 17.9 mo
mOS: Not reached at data cutoff (12-mo OS rate: 79.7%)
Complete response rate: 8.9%
mPFS: 17.9 mo
mOS: Not reached at data cutoff (12-mo OS rate: 79.7%)
Adverse events
Overall grade ≥3: 79.1%
Cardiovascular: hypertension grade ≥3 26.6%
GI: diarrhea grade ≥3 8.2%
Constitutional: fatigue grade ≥3 5.7%
Endocrine: hypothyroidism (any grade) 26.6%
Renal: proteinuria grade ≥3 5.1%
Hepatic: hepatotoxicity grade ≥3 8.9%
Discontinuation due to AEs: 12.7% (lenvatinib), 10.1% (pembrolizumab)
Cardiovascular: hypertension grade ≥3 26.6%
GI: diarrhea grade ≥3 8.2%
Constitutional: fatigue grade ≥3 5.7%
Endocrine: hypothyroidism (any grade) 26.6%
Renal: proteinuria grade ≥3 5.1%
Hepatic: hepatotoxicity grade ≥3 8.9%
Discontinuation due to AEs: 12.7% (lenvatinib), 10.1% (pembrolizumab)
Conclusions
Pembrolizumab + lenvatinib demonstrated clinically meaningful efficacy with ORR ~49% and median PFS ~18 months in first-line non-clear cell RCC, establishing this combination as an emerging standard across multiple nccRCC histologies and providing the highest ORR reported to date in this setting.
Key Limitations
Key Limitations: Non-randomized single-arm phase 2 design — no comparator arm and no direct efficacy comparison to sunitinib or other agents. ORR is the primary endpoint, not PFS or OS. Histologic heterogeneity across nccRCC subtypes means responses may vary by histology — chromophobe RCC, which is characteristically PD-L1 negative and immunotherapy-less responsive, may behave differently. The high grade ≥3 AE rate (79%) reflects the intensive nature of the combination. OS immaturity limits long-term benefit assessment. Formal randomized confirmation is lacking.
Clinical Context
KEYNOTE-B61 led to FDA approval of pembrolizumab + lenvatinib for first-line non-clear cell RCC in 2024. Cabozantinib (PAPMET) remains an alternative, particularly for papillary RCC. For collecting duct, translocation RCC, and FH-deficient histologies, data are limited and clinical trial enrollment is recommended. The nccRCC landscape is rapidly evolving — histology-specific genomic selection (MET, FH, TFE3) increasingly guides treatment choice.
References
References: Albiges L et al, Lancet Oncol 2023