Merck's HIF-2α Inhibitor MK-6482 Demonstrates 80% Disease Control Rate in Advanced Clear Cell Renal Cell Carcinoma

February 17, 2020 /BioValleyBIOON/ -- Researchers from the Dana-Farber Cancer Institute in the United States recently presented findings at the 2020 American Society of Clinical Oncology (ASCO) Annual Meeting held in San Francisco.TumorAt the American Society of Clinical Oncology Genitourinary Cancers Symposium (ASCO-GU 2020), results from a Phase I/II study of the anticancer drug MK-6482 for the treatment of advanced clear cell renal cell carcinoma (ccRCC) were presented.Clinical Trials(NCT02974738) results. This study was conducted in 55 patients who had received a median of 3 prior systemic therapy regimens, with the vast majority having received VEGF inhibitors (93%) and immune checkpoint inhibitors (73%); two-thirds of the patients had previously received both anti-PD-1 and anti-VEGF therapies. The results demonstrated that monotherapy with MK-6482 yielded highly promising efficacy data in this refractory patient population:Among patients in all risk categories, the overall response rate (ORR) was 24%, and the disease control rate was 80%.

In most (approximately 90%) patients with clear cell renal cell carcinoma (ccRCC), the tumor suppressor protein Von Hippel-Lindau (VHL) is nonfunctional, leading to the accumulation and activation of hypoxia-inducible factor (HIF) proteins within cancer cells. This erroneously signals a state of hypoxia, thereby activating angiogenesis and stimulatingTumorGrowth.

MK-6482 (formerly PT2977) is a drug that selectively inhibits hypoxia-inducible factor-2α (HIF-2α), blocking cell growth and proliferation and preventing abnormal angiogenesis.MK-6482 was developed by Peloton Therapeutics, which was acquired by Merck & Co., Inc. (MSD) in May 2019 for an upfront payment of $1.05 billion and milestone payments totaling $1.15 billion.

At the conference, this study was presented with a median follow-up of 13 months. Thirteen patients achieved disease remission, resulting in an overall response rate (ORR) of 24% (n=13/55), while 31 patients had stable disease. The disease control rate (DCR = complete response + partial response + stable disease) was 80% (n=44/55). Among the 55 patients, 38 (69%) experiencedTumorReduction. Responses were observed across low-, intermediate-, and high-risk patients: 2 out of 5 low-risk patients, 10 out of 40 intermediate-risk patients, and 1 out of 10 high-risk patients achieved partial response following treatment with MK-6482. The median duration of response (DOR) was not reached; 81% of responding patients had a DOR ≥6 months, and 16 patients (29%) continued treatment for more than 12 months. Overall, the median progression-free survival (PFS) with MK-6482 treatment was 11 months, and the 12-month PFS rate was 49%. The median PFS for the low-, intermediate-, and high-risk patient groups was 16.5 months, 11.0 months, and 6.9 months, respectively. In the study, MK-6482 was well tolerated with a favorable safety profile and demonstrated promising single-agent activity.

These findings support the initiation of the planned Phase III trial (NCT04195750). This trial will be conducted in patients with metastatic clear cell renal cell carcinoma (ccRCC) who have previously received PD-1/PD-L1 inhibitors and VEGF-targeted therapies, with no more than three prior systemic treatment regimens. The study plans to enroll 736 patients, who will be randomized in a 1:1 ratio to receive either MK-6842 monotherapy or everolimus (Afinitor) monotherapy. The co-primary endpoints of the study are overall survival (OS) and progression-free survival (PFS).

The first author of the study abstract, from the Lank Center for Genitourinary Oncology at Dana-Farber Cancer InstituteTumorToni Choueiri, Director of the Center and Jerome and Nancy Kohlberg Professor of Medicine at Harvard Medical School, stated, “An overall response rate of 24% with a novel agent as monotherapy across all risk categories—whether low, intermediate, or high risk, as well as in the heavily pretreated population—is highly promising.”

Choueiri’s mentor and collaborator, William G. Kaelin Jr., shared the 2019 Nobel Prize in Physiology or Medicine with two other researchers for their discovery of the mechanisms by which cells sense oxygen levels and activate relevant genes to enable the body to adapt to hypoxia.

Clear cell renal cell carcinoma (ccRCC) is characterized by malignant epithelial cellsTumor, with clear cytoplasm, tightly packed nested growth pattern, and accompanied by complex arborizing vasculature. According to Medscape, the incidence of RCC has been rising in Europe and the United States over the past 30 years, with a higher incidence in males than in females. The typical features of ccRCCDiagnosisThe age range is 60-64 years, but 7% of sporadic ccRCC cases are diagnosed in individuals under the age of 40. The most common risk factors are smoking, obesity, andHypertension. (Bioon.com）

Original Source: Dana-Farber Researchers Present Promising Kidney Cancer Trial Results