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  • Belzutifan Plus Pembrolizumab and Lenvatinib Demonstrates Potential in Advanced Clear Cell RCC

    Belzutifan Plus Pembrolizumab and Lenvatinib Demonstrates Potential in Advanced Clear Cell RCC

    Treatment with belzutifan (Welireg) plus pembrolizumab (Keytruda) and lenvatinib (Lenvima) improved efficacy outcomes compared with multiple other pembrolizumab-based triplet regimens in patients with advanced clear cell renal cell carcinoma (ccRCC), according to findings from substudy 3A of the phase 1/2 KEYMAKER-U03 trial (NCT04626479) presented at the 2025 ESMO Congress.

    Providing the background for the study, Cristina Suarez Rodriguez, MD, PhD, of Vall d’Hebron University Hospital, Barcelona, Spain, said, “First-line triplet regimens adding novel mechanisms of action to standard doublet therapy may be a promising approach for advanced clear cell renal cell carcinoma…The potent and selective HIF-2α inhibitor belzutifan is a treatment for advanced RCC following prior anti-PD-(L1) and VEGFR-TKI therapy, and may be a highly suitable candidate for novel triplet therapy in the first-line setting.”

    For substudy 3A (NCT04626479) of the umbrella phase 1/2 KEYMAKER-U03 trial, investigators sought to evaluate novel pembrolizumab-based regimens as first-line treatment for advanced ccRCC.

    “The study employed an adaptive design in which experimental arms were added and/or inactivated on a rolling basis with a continuous enrolling reference arm. Experimental arms each had a safety lead-in phase of 10 patients,” Suarez Rodriguez explained.

    Patients with histologically confirmed locally advanced or metastatic ccRCC as measurable by RECIST v1.1, no prior systemic therapy for advanced RCC, and a KPS score of at least 70% were eligible for the study. Following the safety lead-in phase, the study entered the randomized phase. In this phase, patients were randomly assigned to 2:1 to 1 of 5 arms. Arm 1 included coformulated favezelimab/pembrolizumab 800mg/200 mg intravenously every 3 weeks, and lenvatinib 20 mg orally once daily. Arm 2 included coformulated vibostolimab/pembrolizumab 200/200 mg IV every 3 weeks plus belzutifan 120 mg orally once daily. Arm 3 included coformulated quavonlimab/pembrolizumab 25 mg/400 mg IV every 6 weeks plus lenvatinib 20 mg orally once daily. Arm 4 included belzutifan 120 mg orally once daily plus pembrolizumab 400 mg IV every 6 weeks, plus lenvatinib 20 mg orally once daily. A concurrent reference arm included pembrolizumab 400 IV every 6 weeks plus lenvatinib 20 mg orally once daily.

    Primary end points were overall responsive rate (ORR) as measured by RECIST v1.1 by blinded independent central review (BICR), as well as safety. Secondary end points included duration of response (DOR) and progression-free survival by RECIST v1.1 by BICR, as well as overall survival (OS).

    Suarez Rodriguez reported ORR for the arms as follows:

    • Arm 1: At a median follow-up of 39.2 months (range, 28.8-44.6 months), ORR was 62.7% (95% CI: 48.1-75.9).

    • Arm 2: At a median follow-up of 16.4 months (range, 11.8-23.4 months), ORR was 42.5% (95% CI: 31.5-54.1).

    • Arm 3: At a median follow-up of 22.1 months (range, 13.5-40.6 months), ORR was 71.3% (95% CI: 60.0-80.8).

    • Arm 4: At a median follow-up of 23.4 months (range, 14.1-41.0 months), ORR was 77.5% (95% CI: 66.8-86.1).

    • Reference arm: At a median follow-up of 21.2 months (range, 11.9-44.4 months), ORR was 80.6% (95% CI: 68.6-89.6).

    Complete response was observed in 5 (9.8%), 4 (5.0%), 5 (6.3%), 10 (12.5%), and 4 (6.5%) patients across the respective arms.

    In arm 1, DOR and PFS were found to be numerically similar to the reference arm, Suarez Rodriguez reported. The treatment regimen of arm 2 was found to be not superior to the reference arm. For arm 3, median DOR was 25.0 months (range, 2.4-37.1+ months) in arm 3 and 25.6 months (range, 1.4+-27.6 months) in the reference arm.

    Arm 4 “showed a median duration of response of 33 months vs 26 months in the reference arm,” Suarez Rodriguez said. Median PFS was 31.8 months (95% CI: 26.3-NR) in arm 4 vs 20.8 months (95% CI: 12.4-29.0) in the reference arm (HR, 0.45, 95% CI: 0.25-0.83). OS was not reached in either arm.

    Suarez Rodriguez also discussed safety across the regimens. Arm 1 had the highest incidence of grade 3 or higher adverse events (AEs) (86.9%), followed by arm 3 (73.3%), the reference arm (71.0%), arm 4 (70.0%), and arm 2 (68.9%). Arm 1 had the highest rate of treatment-related AEs (37.7%), followed by arm 3 (34.4%), arm 2 (31.1%), the reference arm (30.6%), and arm 4 (24.4%). Serious treatment-related AEs were highest in arm 1 (36.1%) followed by arm 3 (34.4%), the reference arm (30.6%), arm 2 (27.8%), and arm 4 (22.2%).

    “As expected, the most common adverse event observed in the combination arms containing lenvatinib was hypertension. The most common adverse event in the combinations containing belzutifan was anemia,” Suarez Rodriguez said.

    “In conclusion, observed efficacy of pembrolizumab plus lenvatinib were confirmatory of prior observations for this combination. Belzutifan/pembrolizumab plus lenvatinib and the anti-CTLA-4 combination had similar overall response rate compared to pembrolizumab/lenvatinib as first-line therapy in patients with previously untreated advanced clear cell renal cell carcinoma. Responses were potentially less favorable in the anti-LAG-3 and anti-TIGIT arms. Belzutifan plus pembrolizumab plus lenvatinib, but not the other investigative arms, may have been associated with a higher proportion of complete response, prolonged duration of response, and prolonged progression-free survival compared to pembrolizumab plus lenvatinib,” Suarez Rodriguez said in her concluding remarks.

    Suarez Rodriguez also noted that belzutifan plus pembrolizumab plus lenvatinib and quavonlimab/pembrolizumab plus pembrolizumab are being evaluated in the phase 3 LITESPARK-012 study (NCT047367706).

    DISCLOSURES: Suarez Rodriguez noted research funding and medical writing support from Merck Sharp & Dohme (MSD) LLC; research funding from Bristol Myers Squibb, Ipsen, Pfizer, and Roche; advisory board membership with Astellas, AstraZeneca, Bristol Myers Squibb, and MSD; travel accommodations from Bayer, speakers’ bureau membership with AstraZeneca, Astellas, Bristol Myers Squibb, Ipsen, and MSD; an invited speaker for Bristol Myers Squibb and MSD; and expert testimony for Bristol Myers Squibb and MSD.

    Reference

    1. Suarez Rodriguez C, Rojas CI, Shin SJ, et al. First-line pembrolizumab-based regimens for advanced clear cell renal cell carcinoma: KEYMAKER-U03 substudy 03A. Presented at: European Society for Medical Oncology Congress. October 17-21, 2025. Berlin, Germany. Abstract LBA96. https://s3.eu-central-1.amazonaws.com/m-anage.com.storage.esmo/static/esmo2025_abstracts/LBA96.html.pdf

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  • Single Gene Swap Transfers Courtship Behavior Between Two Species For The First Time

    Single Gene Swap Transfers Courtship Behavior Between Two Species For The First Time

    Researchers have engineered a courtship ritual from one species of fruit fly into another using genetic modification. 

    A Japanese research team tweaked a single gene in the fly Drosophila melanogaster, causing it to display a courtship ritual…

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  • Lilah Fear/Lewis Gibson take spicy route to rhythm dance lead; Guillaume Cizeron finds “magic” on comeback

    Lilah Fear/Lewis Gibson take spicy route to rhythm dance lead; Guillaume Cizeron finds “magic” on comeback

    Cizeron not flawless but finds “magic” in comeback

    France’s Guillaume Cizeron is no stranger to feeling victorious on Grand Prix de France ice, having won this Grand Prix stage a record six times with his former partner Gabriella…

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  • Lenvatinib/Everolimus Beats Cabozantinib in Phase 2 RCC Study

    Lenvatinib/Everolimus Beats Cabozantinib in Phase 2 RCC Study

    The combination of lenvatinib (Lenvima) and everolimus (Afinitor) reduced the risk of progression or death by 49% compared with cabozantinib (Cabometyx) for patients with metastatic clear cell renal cell carcinoma (ccRCC) following progression on a PD-1 inhibitor, according to findings from a phase 2 study presented at the European Society for Medical Oncology Congress 2025 and simultaneously published in the Annals of Oncology.1,2

    In the multicenter phase 2 study, the median progression-free survival (PFS), which was the primary end point of the study, was 15.7 months with the combination of lenvatinib plus everolimus compared with 10.2 months with cabozantinib (HR, 0.51; 95% CI, 0.29-0.89; P = .02). There were more adverse events (AEs) observed with the combination, but these differences were not deemed statistically significant. Grade 3/4 AEs were experienced by 67.5% of those treated with lenvatinib plus everolimus compared with 50% of those receiving cabozantinib (odds ratio [OR], 2.08; 95% CI, 0.86-5.02).

    “Lenvatinib plus everolimus significantly prolonged progression-free survival over cabozantinib,” Andrew W. Hahn, MD, Department of Genitourinary Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, said during a presentation of the results. “As the first head-to-head randomized comparison of contemporary second-line or later treatments after immune checkpoint inhibition, these results are relevant to treatment sequencing and inform oncology practice.”

    The study enrolled 86 patients, with 40 receiving the combination and 46 receiving cabozantinib. For the combination arm, lenvatinib was administered at 18 mg per day and everolimus was given at 5 mg per day. Cabozantinib was administered at 60 mg per day. The most common prior treatment was the combination of nivolumab (Opdivo) and ipilimumab (Yervoy), which was received by 70.9% of patients enrolled in the study. This was followed by the combination of pembrolizumab (Keytruda) and axitinib (Inlyta) for 16.3%, adjuvant pembrolizumab for 4.7%, and any other checkpoint inhibitor for 8.1%.

    Baseline characteristics were well balanced between the groups with most patients (69.8%) in each group having received 1 prior line of therapy and 30.2% having received 2 prior lines of therapy. Nearly half of patients had received prior VEGF-targeted therapy (45% for the combination arm and 41.3% for the single agent group). The IMDC risk was primarily intermediate in both groups (80% for combination and 73.9% for single agent). The IMDC risk was poor for 7.5% of those in the combination arm and for 8.7% of those in the control arm.

    The objective response rate was 52.6% with lenvatinib plus everolimus compared with 38.6% with cabozantinib. Although numerically higher, this rate did not pass the bar for statistical significance (OR, 1.87; 95% CI, 0.75-4.6; P = .17). In addition to responses, stable disease was observed in 39.5% of those receiving the combination and for 54.5% of those in the single-agent arm.

    The study was not designed to assess differences in overall survival (OS) and findings for this end point were still immature, Hahn noted. After a median of 20 months of follow-up, there had been 11 events in the combination arm and 13 in the control group. The 1-year OS probability was 87.0% with lenvatinib plus everolimus compared with 84.6% with cabozantinib (HR, 1.05; 95% CI, 0.47-2.38; P = .86).

    Serious AEs were experienced by 27.5% of those treated with lenvatinib plus everolimus compared with 19.6% of those in the cabozantinib arm (OR, 1.56; 95% CI, 0.57-4.24). Dose interruptions were necessary for 70% of those in the combination arm compared with 78.3% of those in the cabozantinib group (OR, 0.65; 0.24-1.73). Dose reductions were necessary for 57% and 60.9% of those in the combination and control arm, respectively (OR, 0.80; 95% CI, 0.33-1.93). Treatment discontinuation was more common in the combination group at 20% compared with the single agent at 10.9% (OR, 2.05; 95% CI, 0.61-6.91).

    “Of the 8 patients who discontinued treatment with lenvatinib plus everolimus, 5 of those were due to proteinuria,” said Hahn.

    The most commonly observed AEs in the study aligned with those historically associated with each agent, Hahn noted. For the combination and single agent arms, respectively, the most common all-grade AEs were diarrhea (70% vs 73.9%), fatigue (72.5% vs 60.9%), proteinuria (65% vs 37%), hypertension (57.5% vs 39.1%), nausea (40% vs 39.1%), palmar-plantar erythrodysesthesia (20% vs 52.2%), vomiting (32.5% vs 34.8%), and oral mucositis (15% vs 43.5%).

    “This is a positive phase 2 trial and demonstrates improved PFS and response compared with cabozantinib, but with higher toxicity,” said invited discussant Lisa M. Pickering, consultant medical oncologist at The Royal Marsden, MD, PhD, FRCP. “So, is it positive enough? I think that depends on you and your patient, but I would say that we can and should consider using lenvatinib/everolimus, particularly in patients for whom the priority is response and to who the toxicity rate is acceptable.”

    The combination of lenvatinib and everolimus was approved by the FDA in 2016 for the treatment of patients with advanced RCC after a prior anti-angiogenic agent.3 The phase 2 study was completed to assess the combination in a more contemporary treatment setting, Hahn noted.

    References

    1. Hahn AW, Chahoud J, Skelton W, et al. LenCabo: A randomized phase II multicenter trial of lenvatinib plus everolimus (len/eve) versus (vs) cabozantinib (cabo) in patients (pts) with metastatic clear cell RCC (ccRCC) that progressed on PD-1 immune checkpoint inhibition (ICI). Presented at: 2025 ESMO Congress; October 17-21, 2025; Berlin, Germany. Abstract LBA94.
    2. Hahn AW, Chahoud J, Skelton WP, et al. A multicenter randomized phase II trial of lenvatinib plus everolimus versus cabozantinib in patients with metastatic clear cell RCC that progressed on PD-1 immune checkpoint inhibition (LenCabo). Ann Oncol. 2025. Doi:10.1016/j.annonc.2025.10.009.
    3. Lenvatinib in combination with Everolimus. FDA. May 16, 2016. Accessed October 18, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/lenvatinib-combination-everolimus

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  • AWS Introduces EC2 Instance Attestation

    AWS Introduces EC2 Instance Attestation

    AWS has introduced EC2 instance attestation, a new security feature that enables customers to verify that their virtual machines are running approved software configurations in a cryptographically secure manner. The capability is powered…

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  • How Dr. Barbara Sturm Turned Glowing Skin Into a Global Empire

    How Dr. Barbara Sturm Turned Glowing Skin Into a Global Empire

    It’s a summery Monday in Gstaad, and Dr. Barbara Sturm has just finished an afternoon of tennis with her younger daughter, Pepper, who recently turned 11. But if the renowned skincare guru is at all worn out from the sun—or from trying to…

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  • Ahead of Doha talks Afganistan pins blame for conflict on Pak

    Ahead of Doha talks Afganistan pins blame for conflict on Pak



    ANI |
     Updated:     Oct 18, 2025 18:31 IST

    Kabul [Afghanistan],…

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  • Update Microsoft Windows Now — New 2 Week Security Deadline Confirmed

    Update Microsoft Windows Now — New 2 Week Security Deadline Confirmed

    Updated October 18 with expert comment regarding CVE-2025-24990, which is now confirmed as residing in “legacy code installed by default on all Microsoft Windows…

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  • Scientists Discover Rogue Star-Eating Black Hole Far From Home

    Scientists Discover Rogue Star-Eating Black Hole Far From Home

    Welcome back to the Abstract! Here are the studies this week that mounted a defense, felt out of place, found new life, and resurrected the gods of yore.

    First, a tale of pregnant stinkbugs, parasitic wasps, and fungi weapons that…

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  • Epomaker Unveils Magcore65 Lite: A Compact, Stable, and Durable Inductive Keyboard

    Epomaker Unveils Magcore65 Lite: A Compact, Stable, and Durable Inductive Keyboard

    Featuring a 65% layout and a high-strength ABS plastic case, the Epomaker Magcore65 Lite is a keyboard designed for those who prioritize stability and durability, offering a hardcore performance experience.

    …

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