Belzutifan + Lenvatinib Beats Cabozantinib in Phase 3, But OS Gap Clouds HTA Path

FDA Approves WELIREG Plus LENVIMA for Advanced ccRCC

Merck and Eisai announced that the U.S. FDA has approved WELIREG (belzutifan) plus LENVIMA (lenvatinib) for adult patients with advanced clear cell renal cell carcinoma (ccRCC) who have previously been treated with a PD-1/PD-L1 inhibitor. This approval is based on the Phase 3 LITESPARK-011 trial, which showed a statistically significant and clinically meaningful improvement in progression-free survival (PFS). The combination reduced the risk of disease progression or death by 26% (HR=0.74) compared to cabozantinib, with a median PFS of 14.6 months versus 10.6 months. The objective response rate (ORR) also significantly improved to 53% compared to 40% for cabozantinib.

• The FDA approval of WELIREG plus LENVIMA offers a new treatment option for adult patients with advanced clear cell renal cell carcinoma (ccRCC) who have progressed after prior PD-1/PD-L1 inhibitor therapy. This addresses a significant unmet need in a patient population with limited subsequent treatment alternatives.
• In the Phase 3 LITESPARK-011 trial, the combination demonstrated superior efficacy, achieving a statistically significant 26% reduction in the risk of disease progression or death (HR=0.74; p=0.001) compared to cabozantinib. The median progression-free survival (PFS) for the combination was 14.6 months, versus 10.6 months for cabozantinib.
• The dual oral regimen of WELIREG, a first-in-class HIF-2 alpha inhibitor, and LENVIMA, a multi-targeted VEGFR-TKI, is the first approved combination of its kind for this specific patient population. This novel approach targets distinct pathways involved in tumor growth and angiogenesis, providing a new therapeutic strategy.

Addressing the Critical Unmet Need in Post-PD-1/PD-L1 ccRCC

Post-ICI progression in advanced ccRCC represents one of the most actively evolving challenges in renal oncology, with multiple distinct patient populations and resistance contexts driving the current research agenda.

• ICI-refractory disease: Expert consensus defines ICI-refractory disease as relapse within 6 months post-adjuvant therapy. For these patients, targeted therapies or clinical trial enrollment are supported, reflecting the absence of a validated salvage immunotherapy standard in this setting.

• Heavily pretreated patients following ICI, cabozantinib, and lenvatinib ± everolimus: A retrospective cohort of advanced ccRCC patients treated with tivozanib at MD Anderson Cancer Center (median 4 prior therapies; 100% with prior ICI, 87% cabozantinib, 60% lenvatinib ± everolimus) demonstrated a modest clinical benefit rate of 23.3% and median PFS of 3.8 months, underscoring the limited options available in this population.

• Post-ICI/TKI patients eligible for HIF-2α inhibition: Belzutifan, the first FDA-approved HIF-2α inhibitor, received approval in 2023 for advanced sporadic RCC progressing through multiple lines of treatment. Given that most ccRCC tumors harbor VHL deletion or inactivation resulting in HIF-2α overexpression, belzutifan is positioned as a post-ICI/TKI option, with expert consensus recommending its use at fourth-line or later after ICI therapy and multiple tyrosine kinase inhibitors (93% agreement). Ongoing phase III trials are investigating belzutifan in combination regimens across relapsed/refractory, front-line, and adjuvant settings.

• Patients with brain metastases not previously treated with local therapy: The multicenter phase II CABRAMET trial prospectively evaluated cabozantinib in RCC patients with non-locally pretreated brain metastases, a population historically excluded from systemic therapy trials. Among 26 patients, the 6-month brain metastasis progression-free rate was 56%, BM ORR was 61.5% by investigator assessment, and BM ORR reached 86% in the first-line setting, with 67% in patients with prior immunotherapy — identifying this as a targetable population with meaningful systemic treatment responses.

• Subgroups without consensus on ICI salvage therapy: No consensus was reached among RCC experts on the use of ICI salvage therapy in patients with clear-cell RCC (60% agreement), those without bone/brain metastases (60%), those with good performance status (60%), low tumor burden (47%), or papillary RCC (36%), highlighting these as populations where evidence gaps remain and clinical trial enrollment is particularly warranted.

LITESPARK-011: The Pivotal Data Behind WELIREG Plus LENVIMA Approval

Several recent studies have examined therapeutic options for advanced clear cell renal cell carcinoma (ccRCC) in patients previously treated with a PD-1 or PD-L1 inhibitor. The phase II LITESPARK-013 study (NCT04489771) evaluated belzutifan — a first-in-class HIF-2α inhibitor — at doses of 120 mg versus 200 mg once daily in 154 patients with advanced ccRCC whose disease had progressed after one to three prior systemic therapies, including an anti-PD-(L)1 regimen. The objective response rate (ORR) was 23.7% versus 23.1% for the 120 mg and 200 mg groups, respectively (P = 0.5312; −0.5%, 95% CI −14.0% to 12.9%), with no between-group differences in progression-free survival (PFS; HR 0.94, 95% CI 0.63–1.40) or overall survival (OS; HR 1.11, 95% CI 0.65–1.90, medians not reached). The median duration of response (DOR) was not reached in the 120 mg arm and was 16.1 months (2.1+ to 23.5+) in the 200 mg arm. These findings confirmed that efficacy was similar across both doses, further supporting 120 mg once daily as the preferred dose.

A separate multi-center phase 1b trial (NCT04627064) investigated abemaciclib, an oral CDK4/6 inhibitor, as monotherapy in patients with advanced RCC with a clear cell component who had progressed after at least one prior regimen including immunotherapy and a VEGFR TKI. Eleven patients received abemaciclib 200 mg twice daily; the ORR was 0% (0/11), with 8 patients experiencing progressive disease, 1 stable disease with clinical progression, and 2 not evaluable due to clinical progression. Approximately 27% (n = 3) experienced grade ≥3 treatment-related adverse events, including diarrhea, nausea, and neutropenia. Abemaciclib monotherapy demonstrated no clinically meaningful activity in this heavily pretreated population, with a median number of prior therapies of 4 (range 1–9).

In the real-world setting, the multicenter retrospective cohort study evaluating cabozantinib in 53 patients with advanced or metastatic RCC — a population that included patients previously treated with systemic therapies — reported a median OS of 20.0 months, an ORR of 39.6%, a disease control rate (DCR) of 83.0%, and a median PFS of 11.0 months. Adverse events of any grade occurred in 79.2% of patients, with grade ≥3 events in 18.9%. PFS was significantly shorter in patients previously treated with at least two tyrosine kinase inhibitors (p = 0.021) and in those with C-reactive protein (CRP) ≥ 1.27 mg/dL (p = 0.029), the latter identified as a poor prognostic factor in this setting.

Understanding the Safety Profile of WELIREG and LENVIMA Combination

Belzutifan and lenvatinib each carry distinct, well-characterized safety profiles shaped by their respective mechanisms of action. When used in combination — as investigated in KEYMAKER-U03 Substudy 03A — their tolerability data inform both clinical management and strategic development decisions. The following points summarize key safety and tolerability findings across studied indications.

• Belzutifan: Anemia and Hypoxia as Defining On-Target Effects. Anemia is the most common adverse event observed in belzutifan clinical trials and is considered an on-target effect of HIF-2α inhibition. Hypoxia is also frequently observed and commonly results in dose reductions, treatment discontinuation, and supplemental oxygen use. In a real-world VHL cohort (n=25, median follow-up 35.0 months), any-grade adverse events occurred in 92% of patients; anemia was the most frequent (64%, no grade ≥3), with a median time to anemia onset of 3.7 months. Dose reduction was required in 60% of patients (median time to reduction: 6.8 months; median final dose: 80 mg), and treatment interruption occurred in 80% of patients.

• Belzutifan in PPGL: Favorable Tolerability with Biochemical Benefits. In a retrospective real-world study of five patients with EPAS1(HIF2A)-related pheochromocytoma and paraganglioma, adverse events included hypoxia and anemia (1/5), mild transaminase elevation (2/5), and fatigue with weight gain (1/5). Chromogranin A, erythropoietin, and hemoglobin declined by 69%, 97%, and 13%, respectively, and catecholamine normalization allowed discontinuation or reduction of antihypertensive medications in two patients.

• Lenvatinib: Hypertension, Diarrhea, and Weight Loss as Predominant Toxicities. Across thyroid cancer studies, the most frequent lenvatinib-related adverse events include hypertension, proteinuria, diarrhea, appetite decrease, weight loss, nausea, and stomatitis. In radioiodine-refractory differentiated thyroid cancer, dose reductions were required in 35–68% of patients in clinical trials and in 91% of patients in a real-world Austrian cohort (n=43). Only 15% of subjects withdrew due to toxicity in clinical trial settings, and 16% discontinued in the real-world cohort. Grade ≥3 toxicities leading to discontinuation included hypertension, diarrhea, weight loss, and palmar-plantar erythrodysesthesia syndrome.

• Lenvatinib Management Principles. Expert consensus recommends daily blood pressure monitoring for patients with pre-existing hypertension, and weekly monitoring for the first two months in all others. For systolic blood pressure ≥135 mmHg to <160 mmHg or diastolic ≥85 mmHg to <100 mmHg, lenvatinib should be continued with antihypertensive therapy initiated or intensified. Grade 1/2 diarrhea should be managed initially with loperamide, with a one-week treatment interruption if it persists and dose reduction if it recurs. For grade >3 proteinuria, lenvatinib should be interrupted until proteinuria returns to 1+.

• Combination Safety in Advanced ccRCC (KEYMAKER-U03 Substudy 03A). In the phase Ib/II KEYMAKER-U03 Substudy 03A, grade ≥3 treatment-related adverse events occurred in 71.0% (44/62) of participants treated with pembrolizumab plus lenvatinib (the reference arm), 70.0% (63/90) with pembrolizumab plus lenvatinib plus belzutifan, 73.3% (66/90) with quavonlimab/pembrolizumab plus lenvatinib, 86.9% (53/61) with favezelimab/pembrolizumab plus lenvatinib, and 68.9% (62/90) with vibostolimab/pembrolizumab plus belzutifan. The pembrolizumab plus lenvatinib plus belzutifan triplet showed a grade ≥3 adverse event rate comparable to the reference doublet, supporting its further investigation in the phase 3 LITESPARK-012 study.

Reshaping the Treatment Landscape for Advanced ccRCC

The post-IO treatment landscape for advanced ccRCC has been substantially shaped by data from VEGFR tyrosine kinase inhibitors (TKIs) used as salvage therapy following progression on IO-VEGF combinations. A retrospective analysis of 59 patients treated after IO-VEGF regimens — encompassing both IO-TKI and IO-bevacizumab combinations — demonstrated that subsequent VEGFR-TKI therapy retained meaningful clinical activity, with an objective response rate (ORR) of 25%, a median progression-free survival (PFS) of 12.0 months (95% CI, 8.2–24.5), and a median overall survival (OS) of 24.5 months (95% CI, 12–NE). Cabozantinib (37%) and axitinib (31%) were the most frequently used subsequent agents, and no OS difference was observed between patients who had received IO-TKI versus IO-bevacizumab as their prior regimen (log-rank p = 0.73). These findings established VEGFR-TKIs as a viable salvage option in this setting, though the question of whether re-challenging with an immune checkpoint inhibitor could add benefit was directly addressed by the phase 3 CONTACT-03 trial, which found that adding atezolizumab to cabozantinib after prior immune checkpoint inhibitor progression did not improve PFS (10.6 vs. 10.8 months; HR 1.03 [95% CI 0.83–1.28]; p = 0.78) or OS (25.7 months vs. not evaluable; HR 0.94 [95% CI 0.70–1.27]; p = 0.69), while increasing serious adverse events (48% vs. 33%). These results have discouraged sequential immune checkpoint inhibitor use outside of clinical trials.

Beyond VEGFR-TKI monotherapy, novel mechanistic approaches have emerged as important additions to the post-IO therapeutic toolkit. Belzutifan, a first-in-class oral HIF-2α inhibitor, demonstrated durable antitumor activity in the phase I LITESPARK-001 study: after a median follow-up of 41.2 months, 14 of 55 patients (25%) with advanced ccRCC achieved an objective response, with a median duration of response that was not reached (range, 3.1+ to 38.0+ months). Grade ≥3 treatment-related adverse events occurred in 40% of patients, most commonly anemia (24%) and hypoxia (13%), with no grade 4 or 5 treatment-related events reported. The mechanistic rationale for belzutifan — blocking HIF-2α heterodimerization with HIF-1β to suppress hypoxia-target gene transcription and VEGF-mediated tumor growth — has also motivated combinatorial strategies. The randomized phase III LITESPARK-012 study is evaluating pembrolizumab plus lenvatinib with or without belzutifan or the CTLA-4 inhibitor quavonlimab as first-line therapy, with results anticipated to inform whether triplet combinations can become a new standard of care. Metabolic targeting has also been explored: the phase Ib combination of telaglenastat, a glutaminase inhibitor, with cabozantinib achieved a disease control rate of 100% (12/12) in clear cell histology patients, with 5 of 10 partial responses as best response, supporting further investigation of dual metabolic blockade.

Conversely, not all mechanistic hypotheses have translated into clinical benefit in this population. A phase 1b study of the CDK4/6 inhibitor abemaciclib as monotherapy in 11 heavily pretreated patients with advanced RCC with a clear cell component — who had received a median of 4 prior therapies including immunotherapy and a VEGFR TKI — yielded an ORR of 0% (0/11), with 8 patients experiencing progressive disease. While preclinical data support CDK4/6 inhibition, particularly in combination with HIF-2α inhibitors, single-agent activity was not demonstrated. Taken together, the post-IO ccRCC landscape has evolved from a VEGFR-TKI–centric paradigm toward one that increasingly integrates HIF-2α inhibition and novel combination strategies, while data from CONTACT-03 have firmly closed the door on indiscriminate IO re-challenge.

Belzutifan-Lenvatinib: A New Benchmark in Advanced ccRCC

The recent FDA approval of belzutifan plus lenvatinib for advanced clear cell renal cell carcinoma (ccRCC) patients who have progressed on prior PD-1/PD-L1 inhibitor therapy marks a pivotal moment in the management of this challenging disease. For patients whose disease has advanced despite immunotherapy, options have historically been limited, and survival outcomes remain a significant unmet need. This new combination offers a substantial step forward, demonstrating superior efficacy compared to cabozantinib, a commonly used second-line TKI.

The LITESPARK-011 trial data are compelling, showing a meaningful improvement in progression-free survival and objective response rates. This success is rooted in belzutifan's novel mechanism as a first-in-class HIF-2α inhibitor, targeting a pathway central to ccRCC tumorigenesis, combined with lenvatinib's established multi-targeted TKI activity. This synergistic approach not only expands the therapeutic landscape but also sets a new benchmark for efficacy in the post-immunotherapy setting, potentially reshaping clinical guidelines and treatment algorithms.

However, as with any new therapy, careful consideration of the risk-benefit profile is paramount. While effective, belzutifan is associated with a distinct safety profile, notably including anemia and hypoxia, which require proactive monitoring and management. Clinicians will need to be vigilant in identifying and addressing these adverse events to ensure optimal patient outcomes and adherence. Furthermore, while the PFS and ORR data are robust, the long-term impact on overall survival is still maturing, a critical factor that will continue to inform the drug's ultimate positioning.

This approval also has broader strategic implications, validating the therapeutic potential of HIF-2α inhibition and encouraging its exploration in earlier disease settings. The ongoing investigations of belzutifan in first-line and adjuvant ccRCC suggest a future where HIF-2α targeting could play a more pervasive role across the entire disease continuum, offering hope for improved disease control and durability for a wider range of patients.