First-in-Class Oral MK-6482 Shows Exciting Results in Clear-Cell Renal-Cell Carcinoma

Treatment with the novel agent MK-6482 led to promising results in a phase 1/2 clinical trial of patients with metastatic clear-cell renal-cell carcinoma (RCC). In heavily pretreated patients, the objective response rate (ORR) with single-agent MK-6482 was 24%, and a response was consistently seen across patients with favorable-, intermediate-, and poor-risk disease. These results were greeted with optimism at the 2020 Genitourinary Cancers Symposium.

“This is probably the most promising drug we have in kidney cancer,” said ASCO Expert Sumanta K. Pal, MD, Co-Director, Kidney Cancer Program, City of Hope, Duarte, CA. “The mechanism of action is compelling, and we have not seen the response rates we are seeing so far with this drug.”

Lead investigator Toni K. Choueiri, MD, Director, Kidney Cancer Center, Dana-Farber Cancer Institute, Boston, MA, said, “A new drug as a single agent showing an overall response rate of 24% across all risk categories and in a heavily refractory population is quite promising.”

MK-6482 is a first-in-class oral drug that selectively targets hypoxia-inducible factor (HIF)-2a, enabling the body to adjust to hypoxia and grow more red blood cells and new blood vessels in response to the shortage of oxygen.

Promising Results

A dose-finding phase 1 study identified MK-6482 120 mg daily as the dose going forward. The results from the dose-expansion cohort presented by Dr Choueiri were based on 55 patients (median age, 62 years; 62% received ≥3 previous therapies) with advanced clear-cell RCC who received MK-6482 120 mg daily until progressive disease or unacceptable toxicity. Of these patients, 39 (71%) discontinued treatment, most often for disease progression (55%). At the time of Dr Choueiri’s presentation, 16 (25%) patients were still receiving treatment, with a median follow-up of 13 months. A total of 67% of patients had previously received anti–PD-1 and anti-VEGF agents.

“Anemia and hypoxia are on-target effects of this drug,” Dr Choueiri noted.

A total of 75% of patients had all-grade anemia, including 6% grade 3 and 49% grade 1 or 2 anemia. The rates of hypoxia were 15% grade 3 and 11% grade 1 or 2.

Two patients had 4 grade 4 adverse events (hypercalcemia, sepsis, cardiac arrest, and respiratory failure); 4 patients had grade 5 adverse events, secondary to progressive disease. Two patients discontinued treatment after hypoxia. Five patients required dose reductions. No deaths were reported.

The best confirmed ORR was 24%, with responses observed across all risk categories. The disease control rate was 80%, and high disease control rates were seen across all risk categories, including 100% in favorable-risk patients, 80% in intermediate-risk patients, and 70% in poor-risk patients. The median duration of response was not reached. In all, 81% of patients had a response lasting ≥6 months at the cutoff time of May 15, 2019.

At a median follow-up of 13 months, the median progression-free survival was 11 months among all patients, 16.5 months among favorable-risk patients, 11 months among intermediate-risk patients, and 6.9 months among poor-risk patients.

“MK-6482 is well-tolerated and has a favorable safety profile. After 13 months, promising clinical activity was observed in heavily pretreated advanced ccRCC, with clinical activity across all risk groups,” Dr Choueiri said.

Single-agent MK-6482 will be compared with everolimus (Afinitor) in a randomized phase 3 clinical trial in patients with advanced clear-cell RCC who have received treatment with checkpoint inhibitors.

Expert Comments

Daniel M. Geynisman, MD, Assistant Professor, Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA, discussed these results. “The response rates were fabulous in this group of heavily pretreated patients. Sixty-nine percent had some tumor shrinkage, 24% had an objective response, and the disease control rate was 80%. The drug helped all risk groups. The toxicity data were favorable, and the side effects seen with other tyrosine kinase inhibitors were not prominent,” he said.

“The question is why use a VEGFR inhibitor if you can inhibit tumor growth more proximally with an agent like MK-6482,” Dr Geynisman noted. “This study will not change my practice on Monday morning, but HIF-2a is clearly a new target in clear-cell RCC.”

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