ESMO Congress 2026

First-line standard therapy for advanced clear cell renal cell carcinoma (ccRCC) is currently ICI-based doublets, either dual ICI or ICI plus a VEGF-TKI ^[3]. Efforts to build on this backbone took two directions: one is the HIF-2α inhibitor belzutifan, currently the only approved HIF-2α inhibitor, approved in 2021 for RCC associated with VHL disease and in 2023 for advanced sporadic RCC after multiple lines of therapy — with solid biological rationale, since most ccRCC harbors VHL deletion or inactivation driving constitutive HIF-2α activation, angiogenesis and tumor growth ^[5][6]; the other is the CTLA-4 inhibitor quavonlimab ^[1]. The phase 3 LITESPARK-012 (NCT04736706) was designed to test whether adding belzutifan or quavonlimab to pembrolizumab + lenvatinib could establish triplet therapy as a new standard of care ^[1], building on the phase Ib/II KEYMAKER-U03 substudy 03A, which explored regimens including quavonlimab/pembrolizumab + lenvatinib and pembrolizumab + lenvatinib + belzutifan in previously untreated advanced ccRCC, with pembrolizumab + lenvatinib as a concurrent reference and ORR by BICR as the primary endpoint ^[2].

What was reported at ESMO26 is precisely this phase 3 LITESPARK-012 readout: 1688 patients with untreated advanced ccRCC were randomized to pembrolizumab + lenvatinib + belzutifan (Arm A), MK-1308A + lenvatinib (Arm B, the CTLA-4 blockade direction, corresponding to quavonlimab in the protocol ^[1]), or pembrolizumab + lenvatinib as control, with dual primary endpoints of PFS by BICR and OS. Arm A: PFS HR 1.08 (0.93–1.26), OS HR 1.04 (0.87–1.25); Arm B: PFS HR 1.07 (0.92–1.25), OS HR 1.12 (0.94–1.35). Discontinuation due to AEs: 51.6% (A), 51.4% (B), 36.2% (control). The conclusion is clear: neither belzutifan nor CTLA-4 blockade improved efficacy, and pembrolizumab + lenvatinib remains a 1L SOC.

The value of this negative readout is that it delivers a definitive answer against the 'triplet beats doublet' hypothesis under first-line phase 3 conditions: despite the clear pathogenic role of the HIF-2α axis in VHL-inactivated ccRCC ^[6] and the activity shown by triplet regimens in early-phase research ^[2], none of it translated into PFS or OS benefit, while discontinuation rates climbed from 36.2% to above 51% — and belzutifan's known on-target adverse event anemia, along with hypoxia, already requires monitoring during treatment ^[5], making the tolerability burden of triplets an unavoidable practical issue. On-site commentary also pointed to a separate thread: LITESPARK-011 (belzutifan plus lenvatinib after IO) is the cleaner test of HIF-2α, a distinct study that should not be conflated with this readout.

Limitations to note: the study is randomized open-label, and the post explicitly states it was compiled solely from abstracts publicly available on the ESMO website; beyond the dual primary endpoint HRs and discontinuation rates, ORR, detailed safety profile, subgroup analyses and follow-up duration are not disclosed, so final judgment awaits the full data.