Welireg Plus Lenvima Has ‘Promising Antitumor Activity’ in Kidney Cancer Subset

The combination of Welireg (belzutifan) and Lenvima (lenvatinib) showed promising clinical activity with manageable toxicity in patients with advanced clear cell renal cell carcinoma (ccRCC) and disease progression after receiving a PD-1/L1 inhibitor and a VEGF-TKI, according to initial results from arm B5 of the phase 1/2 KEYMAKER-U03B study.

Results presented at the 2023 ASCO Annual Meeting showed that at a median follow-up of 6.9 months, a regimen combining Welireg and the VEGF-TKI Lenvima elicited an objective response rate (percentage of patients whose disease shrunk or disappeared as a result of treatent) of 50% among 24 patients who had received at least two follow-up scans after enrolling in the trial. All of the responses were partial responses, meaning that the disease got smaller, but did not disappear entirely.

The clinical benefit rate (patients whose disease responded and was stable for six or more months) was 54% and the median duration of response was not reached. Nearly three-fourths (74%) of responders remained in response for 12 months or longer. One patient had progressive disease.

Among all enrolled patients, the median progression-free survival (average time from treatment until disease worsened) was 11.2 months and at six months, 55% of patients did not experience disease progression.

“Preliminary results…from arm B5 of KEYMAKER-U03B showed promising antitumor activity with (Welireg) plus (Lenvima) in patients with (clear cell renal cell carcinoma) that progressed on PD-1/L1 inhibitors and VEGF-TKIs, a population that has limited efficacious treatment options,” said first study author Dr. Laurence Albiges, from the Institut Gustave Roussy, Villejuif, France.

Overall, the multicenter, multi-arm, open-label, adaptive, phase 1/2 KEYMAKER-U03B study is exploring various treatment combinations in patients with heavily pretreated clear cell renal cell carcinoma who have progressed after receiving a PD-1/L1 inhibitor and a VEGF-TKI, either in combination or given in sequence. As of the cutoff date of Sept. 29, 2022, 32 patients had been enrolled in arm B5, 30 had been treated and 23 remained on treatment.

The median patient age was 60.5 years, 78% of patients were male, and 78% of patients had intermediate/poor IMDC risk disease. The ECOG performance status was 0 for 17 patients and 1 for 15 patients. Seventy-eight percent of patients had prior nephrectomy, which is the surgical removal of one or both of the kidneys.

Patients in arm B5 were treated with Welireg at 120 mg orally each day and Lenvima at 20 mg orally each day. Patients received a median of 3.5 treatment cycles (range, 1.0-13.0)

There were no new side effects compared with the safety profiles of Welireg and Lenvima reported in previous research.In the safety lead-in phase of the trial, only 1 of 10 evaluable patients had a dose-limiting toxicity, which was difficult or labored breathing (grade 1).

In the overall safety analysis, which included all 30 treated patients, 93% (28 patients) of patients experienced at least one treatment-related side effect. The side effects that occurred in at least 30% of patients were anemia (43%), fatigue (43%), hypertension (43%), proteinuria (33%), diarrhea (33%), nausea (33%) and decreased appetite (30%).

Moderate or severe (grade 3/4) side effects occurred in half (15) of the patients. The most common grade 3/4 side effects were hypertension (27%) and anemia (17%). Side effects led to one patient discontinuing both study drugs, two patients discontinuing Lenvima and two patients discontinuing Welireg. There were no deaths due to side effects.

The combination is being further examined in the phase 3 LITESPARK-011 study, which is evaluating Welireg plus Lenvima compared with Cabometyx (cabozantinib) in patients with advanced kidney cancer and disease progression after treatment with a PD-1/L1 inhibitor.

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