1. Fuerst, Mark L.

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SAN FRANCISCO-Targeting an essential transcription factor in renal cell carcinoma (RCC) demonstrates effectiveness as a potential treatment for clear-cell RCC in early studies.

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Hypoxia-inducible factor (HIF)-2[alpha], an important protein in the development and maintenance of RCC, is an attractive therapeutic target. MK-6482 is a first-in-class small molecule inhibitor that helps block RCC tumor growth. This drug could potentially be combined with other therapies to provide an alternative approach to treating RCC, particularly given that most side effects from single-agent MK-6482 are minor, lead author Toni K. Choueiri, MD, Director of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute, told attendees of the 2020 Genitourinary Cancers Symposium hosted by ASCO.


The therapeutic approach for RCC is guided by the probability of cure, which is related directly to the stage or degree of tumor dissemination. More than half of patients with early-stage disease are cured, but the outcome for stage IV disease is poor. Patients with clear-cell RCC tend to have a worse prognosis than patients with other histologic subtypes of RCC, with 5-year disease-specific survival rates of 50-69 percent compared with 67-87 percent for papillary RCC and 78-87 percent for chronic RCC.


At the ASCO meeting, Choueiri reported on a study of 55 patients with advanced clear-cell RCC who had received at least one prior therapy (an average of three therapies) who were enrolled in an expansion cohort of the first-in-human phase I/II study of the novel drug MK-6482 against advanced solid tumors (Abstract 611). Patients received 120 mg of MK-6482 orally once daily. The primary endpoint was safety.


With a median follow-up of 13 months, the overall response rate was 24 percent with 13 confirmed partial responses (PR). Another 31 patients (56%) had stable disease, leading to a disease control rate of 80 percent. Two-thirds of patients with baseline and post-baseline assessments had tumor shrinkage.


Median duration of response was not reached; 81 percent of patients had a response of 6 or more months. Sixteen (29%) patients continued treatment beyond 12 months. By IMDC risk, 2 of 5 patients with favorable risk had PR, 10 of 40 patients with intermediate risk had PR, and 1 of 10 patients with poor risk had PR; disease control rate was 100 percent, 80 percent, and 70 percent, respectively, he reported.


"Median progression-free survival (PFS) for the total population was 11 months; the 12-month PFS rate was 49 percent," said Choueiri. Median PFS for favorable, intermediate, and poor IMDC risk was 16.5, 11, and 6.9 months, respectively.


As of May 15, 2019, 30 (55%) patients discontinued due to progressive disease. Only 4 percent of patients discontinued therapy due to side effects. Sixteen (29%) patients had treatment ongoing.


The most common all-grade, all-cause adverse events more than 30 percent were anemia (75%), fatigue (67%), dyspnea (47%), nausea (33%), and cough (31%). Anemia (26%) and hypoxia (15%) were the most common grade 3 adverse events. No grade 4/5 drug-related adverse events were observed.


In conclusion, Choueiri noted: "MK-6482 is well-tolerated with a favorable safety profile and demonstrated promising single-agent activity in heavily pretreated patients with clear-cell RCC across IMDC risk groups."


A phase III trial in a similar population is planned.


Mark L. Fuerst is a contributing writer.


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