A New Kidney Cancer Drug Inspired by the 2019 Nobel Prize Generates Excitement: HIF2A Inhibitor

The 2019 Nobel Prize in Medicinewas awarded for work on how cells sense oxygen availability and adapt to hypoxia (oxygen deficiency). To grow rapidly, tumors also need to make effective use of cellular mechanisms for adapting to hypoxia. This gave rise to the idea that drugs targeting tumor cells' hypoxia-adaptation mechanisms could be effective in cancer treatment, and drug development began in this area. A new, first-in-class small molecule, a hypoxia-inducible factor 2 alpha (HIF2A) inhibitor, metastatic (stage 4) clear cell kidney cancer patients previously treated with multiple lines of therapy showed significant anticancer activity with this drug as a single agent. Results from the phase I / II study of this HIF2A inhibitor were presented at the 2020 Genitourinary Cancers Symposiumby Dr. Toni Choueiri. Researchers reported that patients treated with this inhibitor, code-named MK-6482 , had, with this HIF2A inhibitor across all risk categories, a % 24 response rate . Based on these findings, a phase III trial was initiated. The HIF2A inhibitor is an anti-angiogenic agent that blocks the growth of new blood vessels feeding kidney tumors. MK-6482 as a single agent demonstrates an overall response rate of % 24 across all risk categories (poor, intermediate, and favorable, including heavily treatment-resistant patient groups) and is highly promising.

What Is the HIF2A Inhibitor's Mechanism of Action?

Implications of the 2019 Nobel Prize in Medicine... The drug targets a component of the mechanism that senses the body's oxygen levels and switches on genes allowing adaptation to hypoxia by producing more red blood cells and forming new blood vessels. The 2019 Nobel Prize in Medicinewas awarded for the discovery that revealed this complex mechanism, which cancer can exploit to help tumors survive and grow.

In most patients with clear cell kidney cancer, the protein known as von Hippel-Lindau, a tumor suppressor protein , is not functional. As a result, hypoxia-related factor proteins accumulate inside the tumor cell, falsely signal oxygen deficiency, and trigger tumor growth by activating blood vessel formation. Understanding this abnormal process opened the way to new cancer drugs, of which MK-6482 is one. Its distinct feature is directly targeting HIF2A, leading to inhibition of cancer cell growth, proliferation, and abnormal blood vessel formation.

Phase I / II Study Results

• The MK-6482 study included patients who had previously received an average of three lines of treatment for advanced clear cell kidney cancer: 55 patients.
• After an average follow-up of 13 months, the overall response rate was % 24, with 13 confirmed partial responses.
• In 41 patients, the disease control rate was % 80 with stable disease. Among high-risk patients, 5 included 2 with partial responses; among 40 intermediate-risk patients, 10; and among 10 low-risk patients, 1.
• Median response duration had not been reached: % 81 of patients had an estimated response exceeding 6 months, and 16 patients continued treatment beyond 12 months.
• Median progression-free survival was 11 months.
• The most common (>% 30) all-grade, all-cause adverse effects were anemia (% 75), fatigue (% 67), dyspnea (% 47), nausea (% 33), and cough (% 31). Anemia (% 26) and hypoxia (% 15) were the most common severe (grade 3) adverse effects. No drug-related grade 4 or 5 adverse effects were observed.

Conclusion MK-6482 is well tolerated, with a favorable safety profile, and demonstrated promising single-agent activity in heavily pretreated patients with clear cell renal cell carcinoma across International Metastatic RCC Database risk groups.