Physician reactions to LITESPARK-012
Posts by 21 physicians (29 posts) about LITESPARK-012, from the release of the 3586O abstract (October 20, 2026) through Toni Choueiri’s presentation in Proffered paper 2 at ESMO 2026 on October 25 and the simultaneous Annals of Oncology publication. Each post is shown in full and verbatim, newest first, and linked to the original on X. Slide-verified figures are in At a Glance below.
𝕏My take: LITESPARK-012 and COSMIC-313 remind us that more drugs don’t always mean more survival. I favor proven IO-TKI or IO/IO options until intensification proves its worth. @myESMO @OncoAlert @OpenMedicineHQ #ESMO26 @DrChoueiri @IKCCorg @KidneyCancer @kidneycan @Uromigos
𝕏Agreed, Tobias. LITESPARK-012 tests intensification, not IO/IO vs IO-TKI. But without reliable predictive biomarkers, how do we identify patients who truly need CTLA-4? @myESMO @OncoAlert @OpenMedicineHQ #ESMO26
𝕏Interesting point, but I'm not sure LITESPARK-012 can answer this. It tested CTLA4 on top of IO-TKI, not an IO/IO doublet vs IO-TKI. To me it says more about the limits of treatment intensification than about who benefits from CTLA4.
𝕏Proud to have contributed to LITESPARK-012. A reminder that adding more drugs does not always mean better outcomes. Negative trials help us protect patients from unnecessary toxicity. @myESMO @OncoAlert @OpenMedicineHQ #ESMO26 @Annals_Oncology @tompowles1 @DrChoueiri @curijoey @AnkaraUni @Ankaratip1945
𝕏RCC wrap-up, this morning’s session 🍀 LITESPARK-012: Another triplet that failed in metastatic clear-cell RCC, following COSMIC-313. Adding neither belzutifan nor anti-CTLA-4 to pembrolizumab + lenvatinib showed any benefit. The CPI/anti-VEGF doublet remains the backbone. Stacking yet another existing drug on top doesn't help us better understand the biology of the disease. 🍀 XmAb819 phase 1: Welcoming T-cell engagers to ccRCC. For years we've labeled tumors that don't respond to checkpoint inhibitors as "cold" in daily practice, as if there were only one immunological mechanism. T-cell engagers are challenging that laziness, and not only in immune-excluded tumors. In immunogenic RCC, even in heavily pretreated patients (median 3 prior lines, including CPI), we saw an impressive 27% ORR and 68% DCR. 🍀 Ivonescimab phase 2: After NSCLC and biliary tract cancer, the VEGF/PD-1 bispecific keeps moving forward. In first-line IMDC favorable-risk metastatic RCC, it showed a 57% ORR and 95% DCR, with a side-effect profile quite different from that of TKIs. Patients with advanced cancer are surely the last group in society who care which country a drug comes from. Here's hoping every effective drug becomes globally accessible. #ESMO2026 #kidneycancer #RCC @OncBrothers @OncoAlert @myESMO @DrYukselUrun @dr_yakupergun
𝕏🚨 TRIPLE therapy, DOUBLE disappointment! #ESMO26 | LITESPARK-012 📖 Concomitant publication in Annals of Oncology Phase III | 1,688 patients | 1L advanced ccRCC Adding belzutifan or quavonlimab to pembrolizumab + lenvatinib FAILED to improve PFS or OS! 📊 PFS HR: • Belzutifan triplet: 1.08 • Quavonlimab triplet: 1.12 (IMDC intermediate/poor risk) ⚠️ AE-related drug discontinuation: ~52% vs 36%. 🎯 Verdict: More toxicity, no added survival benefit. The doublet remains a standard! @myesmo @ESMO_open @ASCO @oncoalert #ESMO26 #KidneyCancer
𝕏LITESPARK-012 raises a key question: which RCC patients truly benefit from adding CTLA-4 or should IO-TKI remain our preferred approach in RCC? @myESMO @OncoAlert @OpenMedicineHQ #ESMO26 https://t.co/tErc6E0hlO
𝕏#ESMO26 LITESPARK-012: Can adding HIF-2α or CTLA-4 inhibition improve on 1L pembro+len in advanced ccRCC? Ph 3, n=1,688 3 arms: 🔹 Pembro + len + belzutifan 🔹 Quavonlimab/pembro + len 🔹 Pembro + len control 🚨Neither triplet improved outcomes🚨 Belzutifan triplet vs pembro+len: 🔹 PFS: 20.8 vs 23.7 mo; HR 1.08 🔹 OS: 52.0 mo vs NR; HR 1.04 Quavonlimab triplet: 🔹 No OS benefit in IMDC int/poor-risk pts: HR 1.17 🔹 No PFS benefit overall: HR 1.07 🔹 ORR: 69.1% / 69.0% / 76.3%, respectively 🔹 AE-related discontinuation: 51.6% / 51.4% / 36.2% 🔑 Triplet intensification added toxicity without improving efficacy → pembro+len remains a 1L standard. @urotoday
𝕏🚨 #ESMO26 | #Podium2Screen — LITESPARK-012 @OncoAlert A useful reminder in advanced #RCC: Adding more active drugs does not necessarily create a better first-line regimen. @DrChoueiri presents phase III LITESPARK-012, evaluating whether adding either belzutifan or the CTLA-4 antibody quavonlimab to pembrolizumab + lenvatinib could improve outcomes. 📊 n=1,688 ➡️ No improvement in PFS ➡️ No improvement in OS ➡️ No improvement in ORR ➡️ Higher treatment discontinuation in the triplet arms 🎯 Why this matters: negative trials can be highly informative. They tell us that simply layering another mechanistically attractive agent onto an effective backbone is not enough. Biology, sequencing, toxicity and patient selection still matter. For me, the message is clear: pembrolizumab + lenvatinib remains an established 1L standard — and future intensification needs a stronger biological rationale, not just another drug. Excellent discussion by @DrChoueiri with @tompowles1 @MVossMD @ERPlimackMD @HowardGurney @brian_rini Pinging @DrDanielHeng @TiansterZhang @HHammersMD @AlbigesL @montypal @apolo_andrea @crisbergerot @neerajaiims @DrYukselUrun @nataliagandur #OncoAlert #ESMO26 #KidneyCancer #ccRCC #Immunotherapy #Belzutifan #GUOncology
𝕏The established doublet remains a first-line standard of care.
𝕏LITESPARK-012 | First-Line Advanced ccRCC Adding belzutifan or quavonlimab to pembrolizumab + lenvatinib failed to improve PFS or OS, while increasing treatment discontinuations. @OncoAlert #ESMO26 #ESMOAmbassadors @myESMO #ESMOcommunity https://t.co/mBWHOIPBYl https://t.co/qxANPHF9pj
𝕏LITESPARK-12 tested Len/pem/CTLA4 vs Len/pem in 1st line advanced RCC. This, and the adjuvant nivo vs ipi/nivo trials both add CTLA4 to Nivo. #ESMO26 8Y8 (ipi/nivo vs Nivo) is long awaited. Uncertainty on the role of CTLA4 is increasingly uncertain @brian_rini @DrChoueiri @OncoAlert
𝕏Triplets not always better in 1L mRCC. LITESPARK-012 showed no improvement in efficacy outcomes with len + bel + pembro or MK-1308A (PD-1 + CTLA-4) + len in 1L mRCC. Important practice-informing trial! Congratulations, @DrChoueiri & colleagues! @OncoAlert @nataliagandur @OncHahn @PavlosMsaouel @DrDanielHeng
𝕏Pragmatic overview and RCC discussion with #DrNaomiHaas: LITESPARK-012 shows no benefit from intensifying 1L Pembro/Len, LITESPARK-011 supports Bel/Len after IO progression, and PE-PE explores Pembro + MDT in oligometastatic RCC. Right drugs, right setting, right patients? #RCC @myESMO @OncoAlert #ESMO26
𝕏A negative trial, and an important one! LITESPARK-012: adding belzutifan or CTLA-4 blockade to pembro + lenvatinib in 1L ccRCC didn’t improve PFS, OS or ORR, with more discontinuations. For patients, pembro + lenvatinib stays the standard. Great breakdown by @DrChoueiri 👇 #ESMO26 #RCC . .
𝕏1/2 Research moves metastatic kidney cancer care forward, but every gain must be weighed against toxicity. At #ESMO26, adding belzutifan or quavonlimab to standard therapy may improve disease control. Patients deserve a clear discussion of benefits, risks, and uncertainty. https://t.co/tNHPxaZpQp
𝕏Sunday morning GU session: 2 phase III published in @Annals_Oncology —congrats Annals team, @myESMO and EIC @tompowles1 ! #ESMO26 @DanaFarber_GU @DanaFarber @OncoAlert https://t.co/NgkflRDUZr
𝕏@DrChoueiri 1st up w #LITESPARK012 - Len/bel/pembro vs Len/quavonlimab/pembro vs Len/pembro for #kidneycancer. No diff in PFS or OS - likely from strong control cohort. Still no triplet for 1st line metastatic RCC. @oncoalert #ESMO26 @myESMO https://t.co/08j4zrxYuS
𝕏More is not always better in 1L RCC! Presenting LITESPARK-012 Ph.III: adding belzutifan or CTLA-4 blockade to Pembro/Len failed to improve PFS or OS. PFS HR 1.08/1.07; OS HR 1.04/1.12. ORR 69%/69% vs 76% SOC. #ESMO26 #RCC @myESMO @OncoAlert https://t.co/6yL8CsELLj
𝕏IO-based doublets have been hard to beat in 1L mRCC. Triplets don't seem to be the answer whether by adding a HIF2i or CTLA4i! Drug exposure and tox may be the issue here @DrChoueiri continues to push for better SOC! What other strategies could be attempted to improve outcomes for pts in this setting? #ESMO26 @OncoAlert
𝕏LITESPARK-12 tested Len/pem/bel (VEGF/PD1/HIF) vs Len/pem in 1st line RCC #ESMO26 (supported by a RII +ve PFS R2 @AlbigesL @crisuarez08). In the R3 both PFS and OS hasd HRs~1 with ⬆️ tox for triplets. Belzutifan doublets seem active so why do the triplets fail. It’s likely due to the increased toxic compromising dose intensity of the extremely active Len/pem (2 yr PFS). There seems a limit to tolerable drug intensity- triplets (COSMIC313 too) maybe a step too far. @OncoAlert @DrChoueiri
𝕏Interesting data from @DrChoueiri @DanaFarber from #LITESPARK12. Seems as though we have reached the max in what we can do with combining current classes of tx frontline. Need to see if we can incorporate novel tx upfront! #ESMO26 @brian_rini @tompowles1 @AlbigesL @OncoAlert https://t.co/KGNrgz1wcF
𝕏LITESPARK-012: triplet therapy for 1L mRCC fails to improve survival. More is not always better. And it is usually, like in this case, more toxic. #ESMO26 https://t.co/RfUSy61csq
𝕏LITESPARK-012: Adding belzutifan to pembrolizumab + lenvatinib failed to improve PFS in 1L mRCC (HR 1.08). What is the optimal setting and combination partner for belzutifan? #ESMO26 https://t.co/vZmU9MwvoO
𝕏Negative LITESPARK-012 at #ESMO26. Adding belzutifan to pembrolizumab + lenvatinib in 1L advanced RCC failed to improve PFS (HR 1.08; p=0.84), with no OS benefit (HR 1.04). More treatment ≠ better outcomes. @SCUColombia @achoHematoYOnco @myESMO @ASCO @OncoAlert @oncodaily https://t.co/XU9ANCyFLg
𝕏Neither addition of HIF-2α inhibitor belzutifan nor of CTLA-4 blockade to pembrolizumab + lenvatinib in advanced #RCC improved efficacy; pembro + lenv remains a 1L SOC. By @DrChoueiri #ESMO26 @myESMO https://t.co/tyqGvBD3pa
𝕏腎癌の注目すべきNegative trial レンペンの2剤で十分？ LITESPARK-012（Phase III、n=1688） 未治療進行ccRCCに対し、標準治療レンペンへのBelzutifan or Quavonlimab追加 PFSのHR 1.08／1.07で、改善せず OSも有意差なし 奏効率も約69% vs 76%と標準2剤が上回り、毒性による治療中止は増加 https://t.co/CvijSYArp8
𝕏Triplets don’t always beat doublets! LITESPARK-012: no PFS or OS gain with belzutifan or MK-1308A, just more discontinuations. An important negative phase 3 for 1L RCC. #ESMO26 #KidneyCancer
𝕏🧬 LITESPARK-012 | ESMO 2026 More Drugs ≠ Better Outcomes! Two triplets failed to outperform pembrolizumab + lenvatinib in first-line advanced ccRCC. ❌ PFS HR: Belzutifan triplet 1.08 | CTLA-4 triplet 1.07 ❌ No OS benefit with either triplet. 📉 ORR: 69.1% | 69.0% vs 76.3% (control) ⚠️ Treatment discontinuation: ~51% vs 36% — could reduced drug exposure partly explain the failure? 💡 Take-home: Treatment intensification is not always better. Pembrolizumab + lenvatinib remains an established first-line standard. 📚 Reference: Choueiri TK et al. LITESPARK-012. ESMO 2026; Abstract 3586O. #ESMO2026 #LITESPARK012 #RCC #KidneyCancer #MVOnco
LITESPARK-012 Key Takeaways
Belzutifan triplet vs pembrolizumab + lenvatinib: dual primary endpoints not met (all randomized)
Adding belzutifan to pembrolizumab plus lenvatinib did not improve progression-free survival by blinded independent central review (median 20.8 vs 23.7 months; HR 1.08, 95% CI 0.93–1.26; one-sided P=0.8408) or overall survival (median 52.0 months vs not reached; HR 1.04, 95% CI 0.87–1.25; one-sided P=0.6622). (data cutoff Feb 4, 2026; median follow-up 43.6 months; ESMO 2026 3586O slides, abstract and Annals of Oncology.)
| Belzutifan triplet vs control, all randomized (ITT) | Pembro + len + belz (N=560) | Pembro + len (N=566) |
|---|---|---|
| PFS by BICR (dual primary): events, n (%) | 337 (60.2) | 345 (61.0) |
| Median PFS, months (95% CI) | 20.8 (17.9–23.7) | 23.7 (20.7–26.6) |
| PFS at 12 / 24 / 36 months | 66.3% / 45.3% / 34.7% | 69.1% / 49.6% / 36.7% |
| PFS HR (95% CI); 1-sided P | 1.08 (0.93–1.26); P=0.8408 | |
| OS (dual primary): events, n (%) | 229 (40.9) | 227 (40.1) |
| Median OS, months (95% CI) | 52.0 (48.0–NR) | NR (48.0–NR) |
| OS at 12 / 24 / 36 months | 88.7% / 76.4% / 64.5% | 89.9% / 78.2% / 66.3% |
| OS HR (95% CI); 1-sided P | 1.04 (0.87–1.25); P=0.6622 |
Landmark rates are the values printed on the Kaplan-Meier slides; NR = not reached. The curves themselves are in Key Slides.
Belzutifan triplet: PFS HR 1.08 · OS HR 1.04ESMO 2026 abstract 3586O (Choueiri et al.), Proffered paper 2 ↗ · Rini et al., Annals of Oncology 2026 ↗ · OS slide (posted by @tompowles1) ↗
Quavonlimab triplet (MK-1308A + lenvatinib) vs pembrolizumab + lenvatinib: dual primary endpoints not met
For this comparison the testing strategy started in patients with IMDC intermediate/poor risk (α 0.0035 for PFS and 0.0215 for OS), with the all-randomized population tested only if those were positive. In the intermediate/poor-risk group, PFS was 20.5 vs 23.5 months (HR 1.12, 95% CI 0.94–1.33; one-sided P=0.8954) and OS 39.1 vs 46.2 months (HR 1.17, 95% CI 0.96–1.42; one-sided P=0.9419). (data cutoff Feb 4, 2026; median follow-up 43.6 months; 3586O slides, abstract and Annals of Oncology; alpha allocation from the presented statistical-considerations slide.)
| Quavonlimab triplet vs control, IMDC intermediate/poor risk (tested first) | MK-1308A + len (N=429) | Pembro + len (N=429) |
|---|---|---|
| PFS by BICR: events, n (%) | 259 (60.4) | 261 (60.8) |
| Median PFS, months (95% CI) | 20.5 (16.6–23.5) | 23.5 (20.6–26.3) |
| PFS at 12 / 24 / 36 months | 62.3% / 43.7% / 31.2% | 67.5% / 47.6% / 34.8% |
| PFS HR (95% CI); 1-sided P | 1.12 (0.94–1.33); P=0.8954 | |
| OS: events, n (%) | 214 (49.9) | 191 (44.5) |
| Median OS, months (95% CI) | 39.1 (36.3–NR) | 46.2 (40.7–NR) |
| OS at 12 / 24 / 36 months | 84.1% / 67.3% / 55.3% | 87.4% / 73.1% / 60.8% |
| OS HR (95% CI); 1-sided P | 1.17 (0.96–1.42); P=0.9419 |
In all randomized patients, the Annals of Oncology paper reports the quavonlimab-triplet comparison with nominal P values (Figures 2C and 3C, as shared by @DrRishabhOnco; the same HRs appear in the abstract table). These are the PFS HR 1.07 and OS HR 1.12 figures quoted in several physician posts:
| Quavonlimab triplet vs control, all randomized (ITT) | MK-1308A + len (N=562) | Pembro + len (N=566) |
|---|---|---|
| PFS by BICR: events, n (%) | 334 (59.4) | 345 (61.0) |
| Median PFS, months (95% CI) | 20.7 (18.1–26.0) | 23.7 (20.7–26.6) |
| PFS at 12 / 24 / 36 months | 66.2% / 46.0% / 33.1% | 69.1% / 49.6% / 36.7% |
| PFS HR (95% CI); P | 1.07 (0.92–1.25); nominal P=0.8174 | |
| OS: events, n (%) | 245 (43.6) | 227 (40.1) |
| Median OS, months (95% CI) | NR (45.2–NR) | NR (48.0–NR) |
| OS at 12 / 24 / 36 months | 87.5% / 72.7% / 61.7% | 89.9% / 78.2% / 66.3% |
| OS HR (95% CI); P | 1.12 (0.94–1.35); nominal P=0.8955 |
ESMO 2026 abstract 3586O (Choueiri et al.), Proffered paper 2 ↗ · Rini et al., Annals of Oncology 2026 ↗ · OS int/poor slide (posted by @tompowles1) ↗
Objective response (secondary endpoint)
Response rates were numerically lower with both triplets than with pembrolizumab plus lenvatinib (69.1% and 69.0% vs 76.3% in all randomized patients); complete responses were 19.1%, 14.8% and 14.8%. (data cutoff Feb 4, 2026; median follow-up 43.6 months; ORR slide and abstract.)
| ORR by BICR (RECIST 1.1) | Pembro + len + belz (N=560) | MK-1308A + len (N=562) | Pembro + len (N=566) | MK-1308A + len, int/poor (n=429) | Pembro + len, int/poor (n=429) |
|---|---|---|---|---|---|
| ORR, % (95% CI) | 69.1 (65.1–72.9) | 69.0 (65.0–72.8) | 76.3 (72.6–79.8) | 66.9 (62.2–71.3) | 75.5 (71.2–79.5) |
| Complete response, n (%) | 107 (19.1) | 83 (14.8) | 84 (14.8) | 59 (13.8) | 56 (13.1) |
| Partial response, n (%) | 280 (50.0) | 305 (54.3) | 348 (61.5) | 228 (53.1) | 268 (62.5) |
| Progressive disease, n (%) | 28 (5.0) | 27 (4.8) | 19 (3.4) | 24 (5.6) | 18 (4.2) |
| Median DOR, months (range) | 26.4 (1.2+–52.5+) | 26.3 (1.4+–51.9+) | 27.7 (1.1+–51.3+) | 25.1 (1.4+–51.9+) | 27.2 (1.1+–51.3+) |
ORR slide (posted by @montypal) ↗ · ESMO 2026 abstract 3586O (Choueiri et al.), Proffered paper 2 ↗
Safety and drug exposure
Grade ≥3 all-cause adverse events occurred in 87.2%, 88.7% and 84.8%, and adverse events led to discontinuation of any drug in 51.6%, 51.4% and 36.2% of the belzutifan-triplet, quavonlimab-triplet and control arms. Grade 3–5 anemia and hypoxia, known belzutifan effects, were more frequent with the belzutifan triplet. Median time on pembrolizumab or MK-1308A was 14.1 and 11.8 months in the triplet arms vs 21.2 months in the control arm; the investigators said the higher discontinuation rate may have limited drug exposure and partly affected efficacy. (data cutoff Feb 4, 2026; median follow-up 43.6 months; safety and drug-exposure slides, abstract.)
| All-cause AEs, as-treated, n (%) | Pembro + len + belz (N=556) | MK-1308A + len (N=558) | Pembro + len (N=564) |
|---|---|---|---|
| Any grade | 554 (99.6) | 557 (99.8) | 562 (99.6) |
| Grade ≥3 | 485 (87.2) | 495 (88.7) | 478 (84.8) |
| Led to discontinuation of any drug | 287 (51.6) | 287 (51.4) | 204 (36.2) |
| of belzutifan | 166 (29.9) | – | – |
| of pembrolizumab / of MK-1308A | 181 (32.6) | 198 (35.5) | 111 (19.7) |
| of lenvatinib | 176 (31.7) | 208 (37.3) | 158 (28.0) |
| Led to death | 42 (7.6) | 53 (9.5) | 44 (7.8) |
| Grade ≥3 treatment-related | 431 (77.5) | 437 (78.3) | 390 (69.1) |
| Grade 3–5 anemia, % | 23.4 | 4.1 | 3.7 |
| Grade 3–5 hypoxia, % | 13.5 | 0.2 | 0.4 |
| Grade 3–5 hypertension, % | 25.0 | 28.7 | 30.7 |
| Grade 3–5 ALT increased, % | 11.2 | 8.6 | 5.5 |
| Grade 3–5 lipase increased, % | 8.8 | 13.6 | 6.9 |
| Drug exposure, as-treated, median (range) | Pembro + len + belz | MK-1308A + len | Pembro + len |
|---|---|---|---|
| Pembrolizumab or MK-1308A, duration (months) | 14.1 (0.03–31.8) | 11.8 (0.03–37.2) | 21.2 (0.03–29.5) |
| Pembrolizumab or MK-1308A, cycles | 11.0 (1.0–18.0) | 9.0 (1.0–18.0) | 16.0 (1.0–18.0) |
| Lenvatinib, duration (months) | 18.1 (0.03–56.6) | 15.2 (0.1–56.8) | 22.2 (0.1–57.3) |
| Lenvatinib dose intensity (mg/day) | 12.6 (2.1–20.0) | 12.0 (1.6–20.0) | 12.8 (2.4–20.0) |
| Belzutifan, duration (months) | 18.6 (0.03–56.6) | – | – |
| Belzutifan dose intensity (mg/day) | 106.8 (16.6–120.0) | – | – |
Dose intensity = total dose divided by duration on therapy. 21 patients in the quavonlimab arm continued on pembrolizumab alone after stopping MK-1308A (drug-exposure slide footnote).
AE-related discontinuation 51.6% / 51.4% vs 36.2%AE slide (posted by @DrChoueiri) ↗ · drug-exposure slide (posted by @tompowles1) ↗ · ESMO 2026 abstract 3586O (Choueiri et al.), Proffered paper 2 ↗
OS subgroups, belzutifan triplet (exploratory)
OS hazard ratios on the presented forest plot were close to 1 across key subgroups: IMDC favorable 0.95 (0.60–1.52), intermediate 1.07 (0.85–1.36), poor 1.03 (0.70–1.51); sarcomatoid features 1.29 (0.75–2.22) vs none 1.01 (0.83–1.23); North America 0.72 (0.35–1.49), Western Europe 0.92 (0.65–1.29), rest of world 1.15 (0.91–1.44). (data cutoff Feb 4, 2026; median follow-up 43.6 months; OS key-subgroups slide.)
OS subgroup slide (posted by @zapatalaguadomd) ↗Regulatory status
⚠️ Investigational: neither LITESPARK-012 triplet (pembrolizumab + lenvatinib + belzutifan; MK-1308A + lenvatinib) is FDA approved, and quavonlimab (MK-1308) and the coformulation MK-1308A are investigational. ✅ Control arm approved: KEYTRUDA (pembrolizumab) plus LENVIMA (lenvatinib) is FDA approved for first-line treatment of adults with advanced RCC. ✅ Belzutifan’s own approvals are separate indications (WELIREG, Merck): von Hippel-Lindau disease-associated tumors; monotherapy for advanced ccRCC after a PD-1/PD-L1 inhibitor and a VEGF-TKI (LITESPARK-005); adjuvant ccRCC with pembrolizumab; with lenvatinib for advanced RCC with a clear cell component after a PD-1/PD-L1 inhibitor (FDA, September 24, 2026, LITESPARK-011); and pheochromocytoma/paraganglioma. None of these covers first-line combination with pembrolizumab plus lenvatinib.
FDA: belzutifan + lenvatinib approval (Sept 24, 2026) ↗ · Merck/Eisai press release (Apr 21, 2026) ↗ · KEYTRUDA US prescribing information ↗KOL pulse
Physicians reacting to the presentation largely read LITESPARK-012 as an informative negative trial: many wrote that pembrolizumab plus lenvatinib remains a first-line standard. Tom Powles, an author, suggested that added toxicity compromised the dose intensity of the doublet, Tian Zhang pointed to a strong control arm, and Sumanta Pal wrote that the field may have reached the limit of combining current drug classes. The invited discussant, Naomi Balzer-Haas, concluded on her slides that the findings are not practice changing.
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Top KOLs Discussing LITESPARK-012
LITESPARK-012 Key Slides & Visuals
ESMO 2026 slides
LITESPARK-012 Trial Design
LITESPARK-012 (NCT04736706; MK-6482-012) is a randomized, open-label phase 3 trial sponsored by Merck Sharp & Dohme LLC in collaboration with Eisai. It asked whether adding a third drug to first-line pembrolizumab plus lenvatinib, either the HIF-2α inhibitor belzutifan or the anti-CTLA-4 antibody quavonlimab (given as MK-1308A, coformulated with pembrolizumab), improves outcomes in previously untreated advanced clear-cell renal cell carcinoma.
Toni K. Choueiri, MD (Dana-Farber Cancer Institute and Harvard Medical School) presented the results as abstract 3586O in Proffered paper 2 (Genitourinary tumours, renal and urothelial) at ESMO 2026 on October 25, 2026, with simultaneous publication in Annals of Oncology (first author Brian I. Rini, MD, Vanderbilt-Ingram Cancer Center). Naomi Balzer-Haas (Philadelphia) was the invited discussant. Merck and Eisai had announced on April 21, 2026 that, at a pre-specified interim analysis, neither combination met the dual primary endpoints.
Study Design
Randomized 1:1:1, open-label phase 3; 1,688 patients (560 belzutifan triplet, 562 quavonlimab triplet, 566 control). Stratified by IMDC risk (favorable vs intermediate vs poor), region (North America vs Western Europe vs rest of world) and sarcomatoid features. (Study-design slide; abstract)
Population
Adults with advanced clear-cell RCC (stage IV per AJCC), KPS ≥70%, measurable disease per RECIST 1.1 and no prior systemic therapy for advanced RCC. Median age 61 years; IMDC favorable 23.7–25.9%, intermediate 58.8–60.8%, poor 15.0–17.3%; prior nephrectomy 62.2–66.7%; sarcomatoid features 9.5–11.9% across arms. (Study-design and baseline slides)
Interventions
Arm A: pembrolizumab 400 mg IV Q6W (up to 18 cycles) + lenvatinib 20 mg daily + belzutifan 120 mg daily. Arm B: MK-1308A (quavonlimab/pembrolizumab 25 mg/400 mg IV Q6W, up to 18 cycles) + lenvatinib 20 mg daily. Control: pembrolizumab 400 mg IV Q6W (up to 18 cycles) + lenvatinib 20 mg daily. (Abstract; study-design slide)
Endpoints
Dual primary: PFS by blinded independent central review per RECIST 1.1 and OS, tested in all randomized patients for Arm A vs control and in IMDC intermediate/poor-risk patients, then all patients, for Arm B vs control. Secondary: ORR and duration of response by BICR, safety. (Abstract; Annals of Oncology)
Statistics
One-sided type I error controlled at 2.5% within each comparison, with a pre-specified hierarchical (graphical) strategy. Arm A vs control: α 0.005 for PFS and 0.02 for OS (ITT). Arm B vs control: α 0.0035 for PFS and 0.0215 for OS in intermediate/poor risk; 0 initially for the ITT tests. Stratified Cox model and log-rank test. (Statistical-considerations slide)
Data cut
Data cutoff February 4, 2026 (also the actual primary completion date on ClinicalTrials.gov); median follow-up 43.6 months (range 31.8–57.4). ClinicalTrials.gov status: active, not recruiting (start April 14, 2021). (Abstract; ClinicalTrials.gov)
LITESPARK-012 in the News
LITESPARK-012 FAQ
What is the LITESPARK-012 trial?
LITESPARK-012 (NCT04736706) is Merck’s randomized, open-label phase 3 trial in 1,688 patients with previously untreated advanced clear-cell renal cell carcinoma. It compared pembrolizumab + lenvatinib + belzutifan, and quavonlimab/pembrolizumab (MK-1308A) + lenvatinib, with pembrolizumab + lenvatinib. See Trial Design.
What did LITESPARK-012 show at ESMO 2026?
Neither triplet improved the dual primary endpoints. The belzutifan triplet had a PFS HR of 1.08 and an OS HR of 1.04 versus pembrolizumab + lenvatinib; the quavonlimab triplet, tested first in IMDC intermediate/poor-risk patients, had a PFS HR of 1.12 and an OS HR of 1.17. Figures and the data cut are in At a Glance.
Why might the triplets have failed?
Adverse events led to discontinuation of any drug in about 51% of patients on either triplet vs 36% on the doublet, and patients on the triplets spent less time on pembrolizumab or MK-1308A. The investigators said this may have limited drug exposure and partly affected efficacy; the abstract describes this as a possible contributor, not a proven cause. See At a Glance.
Is belzutifan approved for first-line advanced RCC?
No. The first-line triplet tested in LITESPARK-012 is investigational. Belzutifan (WELIREG) is FDA approved in other settings, including with lenvatinib after a PD-1/PD-L1 inhibitor (based on LITESPARK-011) and as adjuvant therapy with pembrolizumab. Details are in At a Glance.
Is quavonlimab approved?
No. Quavonlimab and the coformulation MK-1308A are investigational. Pembrolizumab plus lenvatinib, the LITESPARK-012 control arm, is FDA approved for first-line advanced RCC.
What did physicians say about LITESPARK-012?
Most physicians called it an informative negative trial that keeps pembrolizumab + lenvatinib as a first-line standard, and several discussed toxicity and reduced drug exposure. Their full posts are in Physician Reactions.
Key KOL Sentiments - LITESPARK-012
Compiled and reviewed by the KOL Pulse research team, led by Brian Shields, Founder, KOL Pulse. Last updated October 25, 2026. Statistics carry their source and data-cut label in place; every quote is verbatim from the physician’s own post.