Treatment with Lenvima (lenvatinib) in combination with Welireg (belzutifan) exhibited durable antitumor activity and a safety profile consistent with prior reports of each individual agent in patients with histologically confirmed locally advanced or metastatic clear cell renal cell carcinoma (ccRCC) whose disease progressed on or following PD-L1 inhibitor or VEGF-tyrosine kinase inhibitor treatment, according to cohort analysis findings from the phase 1/2 KEYMAKER-U03 substudy 03B presented at the 2025 ASCO Genitourinary Cancers Symposium.
Efficacy data revealed that between three arms — Keytruda (pembrolizumab)/Welireg (62 patients; arm B4), Lenvima/Welireg (64 patients; arm B5) and Keytruda/Lenvima (73 patients; reference arm) –– Lenvima/Welireg elicited the greatest number of responses. The objective response rate (ORR) in arms B4, B5, and the reference arm, respectively, were 19.4%, 46.9% and 39.7%. In each respective arm, two, one and zero patients attained complete responses and 10, 29 and 29 attained partial responses.
Further data exhibited a clinical benefit rate (CBR) of 32% in arm B4, 59% in arm B5 and 58% in the reference arm. In the respective arms, the median duration of response (DOR) was not reached, 22.1 months and 8.3 months.
In arm B4, arm B5, and the reference arm, the median progression-free survival (PFS) was 5.4 months, 12.5 months and 9.4 months, respectively. The six-month PFS rates in the respective arms were 41.8%, 63.1% and 66.7%, and the 12-month rates were 28.6%, 51.8% and 34.5%.
The median overall survival (OS) was 27.4 months in arm B4, 32.3 months in arm B5 and not reached in the reference arm. The 12-month OS rates were 67.9%, 79.5% and 81.7% in the respective arms, with 18-month rates of 57.6%, 74.4% and 73.2%.
In arm B4, 66.1% of evaluable patients experienced a target lesion size reduction, 28.8% of whom had a reduction of 30% or greater. In arm B5, it was 88.3% and 60.0%, respectively, as well as 91.8% and 49.3% in the reference arm.
“In KEYMAKER-U03 Substudy 03B, in a patient population with many prior treatment lines, we see that Lenvima plus Welireg showed an ORR of [46.9%] with a median PFS of 12.5 months,” Dr. Katy Beckermann, medical oncologist and medical director of Genitourinary Clinical Research at Tennessee Oncology, stated in the presentation. “We saw results from the Keytruda plus Welireg arm were similar to those observed in the Welireg monotherapy arm in the phase 3 LITESPARK-005 study. ... Results from Substudy 03B showed promising clinical activity in the Lenvima plus Welireg arm, and we recognized that the phase 3 LITESPARK-011 trial was ongoing and was testing this combination compared [with] Cabometyx [cabozantinib].”
In the LITESPARK-005 study, patients with advanced ccRCC who received previous immune checkpoint and antiangiogenic therapies were randomly assigned to receive either 120 mg of oral Welireg or 10 mg of oral Afinitor (everolimus) until disease progression or unacceptable toxicity. At the first interim analysis, the median PFS in the Welireg arm was 5.6 months, with an 18-month PFS rate of 24%. Additionally, the confirmed ORR was 21.9%, and at a second interim analysis, the median OS was 21.4 months with an 18-month OS rate of 55.2%.
The LITESPARK-011 trial is currently ongoing and randomly assigning patients with advanced RCC who experienced progression after prior anti–PD-L1 therapy to receive either Welireg/Lenvima or Cabometyx (cabozantinib). The primary study end points are PFS and OS.
Patients enrolled in KEYMAKER-U03 substudy 03B were randomly assigned to receive Keytruda/Welireg or Lenvima/Welireg. Arms B4 (10 patients) and B5 (12 patients) had a safety lead-in phase wherein approximately 10 patients were enrolled before random assignment. Afterwards, patients were assigned to arm B4 (52 patients), arm B5 (52 patients) or the reference arm (73 patients) during the efficacy phase.
Patients were stratified by International Metastatic RCC Database Consortium (IMDC) risk factors and prior treatment with CTLA-4 inhibition. Additionally, patients were required to have measurable disease criteria by blinded independent review committee (BICR) and a Karnofsky performance status score of 70% or greater for enrollment.
Those in arm B4 were treated with 400 mg of intravenous Keytruda every six weeks plus 120 mg of daily oral Welireg. Patients in arm B5 were treated with 20 mg of daily oral lenvatinib plus 120 mg of daily oral Welireg. Patients in the reference arm were treated with 400 mg of intravenous Keytruda every six weeks plus 20 mg of daily oral lenvatinib.
Across all cohorts, 100% of patients experienced any-grade side events. In arms B4, B5 and the reference arm, grade 3 (severe) to 5 (fatal) side effects occurred in 64.5%, 77.8% and 76.7% of the respective arms. Side effects leading to dose interruption occurred in 54.8%, 71.4%, and 58.9% of each respective arm, with side effect-related discontinuations occurring in 16.1%, 14.3% and 16.4%, and side effect-related deaths occurring in 3.2%, 4.8% and 2.7% of patients.
Treatment-related side effects occurred in 95.2%, 95.2% and 98.6% of the respective arms. Grade 3 to 5 treatment-related side effects occurred in 41.9%, 60.3% and 49.3%, respectively, with treatment-related side effects leading to treatment continuation occurring in 11.3%, 9.5% and 12.3% of the respective arms. Treatment-related side effects resulting in death occurred in 0%, 3.2% and 1.4%, respectively.
The most common treatment-related side effects in the respective arms included anemia (69.4%, 65.1%, 4.1%), diarrhea (4.8%, 42.9%, 56.2%), hypertension (0%, 36.5%, 52.1%), fatigue (24.2%, 46.0%, 34.2%) and nausea (12.9%, 38.1%, 24.7%).
Reference:“KEYMAKER-U03 Substudy 03B: pembrolizumab (pembro) and targeted therapy combinations for advanced clear cell renal cell carcinoma (ccRCC).” By Dr Laurence Albiges. Journal of Clinical Oncology.
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