FDA Grants Breakthrough Status to MK-6482 for Select VHL Disease–Associated RCC

The FDA has granted a breakthrough therapy designation to MK-6482 for the treatment of patients with von Hippel-Lindau (VHL) disease–associated renal cell carcinoma (RCC) who have nonmetastatic tumors of less than 3 centimeters, unless immediate surgery is necessitated, according to an announcement from Merck.¹

The regulatory agency also granted the HIF-2α inhibitor an orphan drug designation for patients with VHL disease.

“Merck’s diverse and expansive oncology pipeline is focused on bringing forward innovative new treatments to patients in need and continues to show important progress," Scot W. Ebbinghaus, MD, vice president of clinical research a Merck Research Laboratories, stated in a press release. “These designations for MK-6482 support the potential of targeting HIF-2α in certain patients with VHL disease, who currently have limited treatment options and face an increased risk for benign tumors as well as several types of cancer, including RCC.”

Both designations are based on data from an open-label phase 2 trial (NCT03401788) recently presented during the 2020 ASCO Virtual Scientific Program, which indicated that MK-6482 had favorable efficacy and tolerability in patients with VHL disease–associated RCC, a population known to have a poor prognosis.²

Results revealed that the agent elicited a confirmed objective response rate (ORR) of 27.9% (95% CI, 17.1-40.8); this was comprised of 17 partial responses (PRs; 27.9%). Forty-three patients (70.5%) achieved stable disease with the HIF-2α inhibitor and 8 patients (13%) achieved an unconfirmed PR. Additionally, the median duration of response (DOR) with MK-6482 had not yet been reached at the time of the presentation; the majority of participants, or 95%, remained on study treatment at the time of the report. Notably, most of the patients on the trial (86.9%) experienced a reduction in the size of their target lesions.

To be eligible for the trial, patients had to have a diagnosis of VHL disease based on germline mutation, have had greater than or equal to 1 measurable RCC tumor, have received no previous systemic anticancer treatment, no metastatic disease, and an ECOG performance status of 0 or 1. A total of 61 adult patients were given a 120-mg dose of the HIF-2α inhibitor once daily until either disease progression or unacceptable toxicity. Tumor evaluation was done at the time of screening and every 12 weeks thereafter.

The primary end point of the trial was ORR in VHL-associated RCC tumors via RECIST v1.1 criteria and independent central review. Key secondary end points of the trial included ORR in non-RCC lesions, DOR in RCC and non-RCC lesions, and safety.

Additional results revealed that MK-6482 also had clinical activity in patients with non-RCC tumors.

Regarding safety, 96.7% of patients experienced treatment-related adverse effects (TRAEs); these effects mostly ranged from grade 1 to 2 in severity (83.6%) and included anemia (83.6%), fatigue (52.5%), and headache (36.1%). Grade 3 TRAEs occurred in 9.8% of the participants and included fatigue (4.9%) and anemia (3.3%).

“[This research] provides hope for patients with VHL disease; these are individuals who literally, in some cases, have had dozens of surgeries throughout their lives to help deal with their central nervous system (CNS), as well as renal and adrenal manifestations of the disease,” lead study author Eric Jonasch, MD, of The University of Texas MD Anderson Cancer Center, told OncLive in a recent interview. “[The results of this study] have brought joy to some of our patients; they’re finally seeing a light at the end of the tunnel. This has really been amazing and beautiful to see.”

Previous data were reported during the 2020 Genitourinary Cancers Symposium from a phase 1/2 trial (NCT02974738), which showed encouraging single-agent activity with MK-6482 in patients with heavily pretreated clear cell RCC, a benefit that was observed across all International Metastatic RCC Database IMDCC) risk groups analyzed.³

In 55 patients enrolled to the dose escalation/expansion cohort of the trial, the ORR was 24% with the agent, while the disease control rate was 80%. The ORR was comprised of 13 confirmed PRs. Moreover, the median progression-free survival (PFS) reported with MK-6482 in the overall patient population studied was 11.0 months. Notably, at 1 year, almost half, or 49%, of patients remained progression free.

“Regarding next steps, a pivotal phase 3 clinical trial with MK-6482 as monotherapy versus everolimus (Afinitor) was [recently] launched,” Toni K. Choueiri, MD, of Harvard Medical School and Dana-Farber Cancer Institute, told OncLive in a past interview. “The trial will have PFS and overall survival as its co-primary end points. We are planning to enroll over 700 patients who have progressed on prior PD-1 and VEGF inhibitors and have had up to 3 prior lines of therapy.”

The phase 3 trial (NCT04195750) has started to recruit patients.⁴ In the trial, patients will either receive 120 mg of oral MK-6482 once daily or 10 mg of oral everolimus once daily. To be eligible to participate, patients must have unresectable, locally advanced, or metastatic clear cell RCC, have progressed on or after systemic treatment for locally advanced or metastatic disease with both a PD-1 inhibitor and a VEGF TKI in sequence or in combination, have received no more than 3 previous systemic regimens, and have adequate organ function.

If patients have an additional known malignancy that is progressing or has required active treatment within the past 3 years, they are not eligible for enrollment. Those with known CNS metastases and/or carcinomatous meningitis, clinically significant cardiac disease, poorly controlled hypertension, and moderate to severe hepatic impairment, among other criteria, are not eligible for inclusion.

References

1. FDA grants breakthrough therapy designation to Merck’s novel HIF-2α inhibitor MK-6482 for treatment of certain patients with Von Hippel-Lindau disease-associated renal cell carcinoma. News release. Merck. July 29, 2020. Accessed July 29, 2020. https://bit.ly/2BKVbHW.
2. Jonasch E, Donskov F, Iliopoulos O, et al. Phase II study of the oral HIF-α for Von Hippel-Lindau disease–associated renal cell carcinoma. J Clin Oncol. 2020;38(suppl 15):5003. doi:10.1200/JCO.2020.38.15_suppl.5003
3. Choueiri TK, Plimack ER, Bauer TM, et al. Phase I/II of the oral HIF-2α inhibitor MK-6482 in patients with advanced clear cell carcinoma (RCC). J Clin Oncol. 2020;38(suppl 6):611. doi:10.1200/JCO.2020.38.6_suppl.611
4. A study of MK-6482 versus everolimus in participants with advanced renal cell carcinoma (MK-6482-005). ClinicalTrials.gov. Updated July 23, 2020. Accessed July 29, 2020. https://clinicaltrials.gov/ct2/show/NCT04195750.