Novel small-molecule inhibitor ‘quite promising’ in advanced kidney cancer
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MK-6482 appeared well-tolerated and showed promising single-agent activity among heavily pretreated patients with clear cell renal cell carcinoma, according to results of a first-in-human phase 1/phase 2 study presented at Genitourinary Cancers Symposium.
“A new drug as a single agent showing an overall response rate of 24% across all risk categories — poor, intermediate and good — and in a heavily refractory population is quite promising,” Tony K. Choueiri, MD, director of the Lank Center for Genitourinary Oncology and of the Kidney Cancer Center at Dana-Farber Cancer Institute, and Jerome and Nancy Kohlberg professor of medicine at Harvard Medical School, said in a press release.
Most patients with clear cell renal cell carcinoma lack a functional tumor suppressor gene known as von Hippel-Lindau, according to the press release. Consequently, hypoxia-inducible factor proteins gather in the tumor cell and wrongly signal there is a shortage of oxygen, which activates the formation of blood vessels and fuels tumor growth.
MK-6482 (Merck) targets hypoxia-inducible factor 2-alpha and blocks cancer cell growth, proliferation and abnormal blood vessel formation.
Choueiri and colleagues studied the oral small-molecule inhibitor among a dose-expansion cohort of 55 patients with advanced clear cell kidney cancer who received a median three (range, 1-9) prior lines of therapy. Two-thirds (67%) of patients had been treated with anti-PD-1 and anti-VEGF agents. Seventy-three percent were considered intermediate risk, 18% poor risk and 9% favorable risk according to International Metastatic Renal Cell Carcinoma Database guidelines.
Researchers assigned the patients 120 mg once-daily oral MK-6482.
Safety served as the primary endpoint. Secondary endpoints included ORR, duration of response and PFS.
At median follow-up of 13 months, results showed an ORR of 24%, with 13 confirmed partial responses. Most patients (56%) had stable disease, for a disease control rate of 80%.
Researchers observed partial responses among two of five patients considered favorable risk, 10 of 40 considered intermediate risk and one of 10 considered poor risk. The disease control rate was 100% for favorable risk, 80% for intermediate risk and 70% for poor risk.
Median duration of response had not been attained, but 81% of patients experienced an estimated response of longer than 6 months and 29% remained on treatment beyond 12 months.
Investigators reported median PFS of 11 months among all patients, with a 12-month PFS rate of 49%. Median PFS was 16.5 months for those considered favorable risk, 11 months for intermediate risk and 6.9 months for poor risk.
The most common adverse events of any grade and cause included anemia (75%), fatigue (67%), dyspnea (47%), nausea (33%) and cough (31%). Common grade 3 adverse events included anemia (26%) and hypoxia (15%). Researchers observed no grade 4 or grade 5 adverse events.
A future phase 3 trial with a similar patient population is planned, according to the researchers. – by Jennifer Southall
Reference:
Choueiri TK, et al. Abstract 611. Presented at: Genitourinary Cancers Symposium; Feb. 13-15, 2020; San Francisco.
Disclosure: The study was funded by Merck Sharp & Dohme. Choueiri reports pending patents for biomarkers of immune checkpoint blockers; stock or other ownership in Pionyr Immunotherapeutics and Tempest Therapeutics; and honoraria from, consultant/advisory roles with and/or research funding from Agensys, Alexion Pharmaceuticals, Alligent, Analysis Group, ASCO, AstraZeneca, Bayer, Bristol-Myers Squibb, Calithera Biosciences, Celldex, Cerulean Pharma, Clinical Care Options, Corvus Pharmaceuticals, Eli Lilly, Eisai, EMD Serono, European Society for Medical Oncology, Exelixis, Foundation Medicine Inc., Gateway for Cancer Research, Genentech/Roche, GlaxoSmithKline, Harborside Press, Heron Therapeutics, Ipsen, Kidney Cancer Journal, Lpath, Merck, Michael J. Hennessy Associates, National Comprehensive Cancer Network, Navinata Healthcare, NCI, Novartis, Peloton Therapeutics, Pfizer, Platform Q Health, Prometheus Labs, Roche, Sanofi/Aventis, Seattle Genetics/Astellas, Takeda, Tracon Pharma, The Lancet Oncology, The New England Journal of Medicine, Up-to-Date and U.S. Department of Defense. Please see the abstract for all other authors’ relevant financial disclosures.
Perspective
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Sumanta K. Pal, MD
This study showed an agent produced outstanding response rates in a population of patients who had received up to nine prior lines of treatment. These findings introduce a potential new paradigm for treating advanced kidney cancer. In particular, combinations of this particular agent with either an immune treatment or targeted treatment could potentially move it into earlier treatment settings. Future research should really see whether we can potentially apply this therapy in other settings. I am very interested in seeing whether this agent would have benefit in an adjuvant trial or even a first-line metastatic trial.
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