FDA Grants Fast Track Designation to KIN-2787 for Select Stage IIB to IV Malignant Melanoma

The FDA has granted a fast track designation to KIN-2787 for use as a potential therapeutic option in patients with BRAF class II or III alteration–positive and/or NRAS mutation–positive, metastatic or unresectable, stage IIB to IV malignant melanoma.¹

Approximately 6% of patients with cancer harbor oncogenic BRAF alterations, which are known to result in activated BRAF monomers (class I), homodimers (class II), and heterodimers (class III).² Although some BRAF inhibitors have received regulatory approval for use in those with class I BRAF mutation–driven cancers, these agents are not effective in those with class II or III BRAF mutations.

“The interesting thing about [KIN-2787] is that it was developed also to try to target the other 2 classes of BRAF mutations; that was not the case for the drugs that we have available on the market. [Those agents] were always developed to try to target the class I mutation,” Cesar Augusto Perez, MD, director of drug development at Florida Cancer Specialists & Research Institute, told OncLive® in a past interview. “It is important that we have been able to classify these mutations and recognize the mechanisms of how they promote proliferation and survival. We can now actually target these mutations. One of the most exciting things is that after we classified and understood how the class II and class III mutations can promote survival, we were able to develop drugs to target [them].”

In a phase 1 trial (NCT04913285), investigators are examining the safety, tolerability, pharmacokinetics, and preliminary efficacy of KIN-2787 in adult patients with BRAF-mutated, advanced or metastatic solid tumors (n = 155).3 To be eligible for enrollment, patients were required to have measurable disease per RECIST v1.1 criteria, an ECOG performance status of 0 to 2, and acceptable organ function. Patients needed to have the ability to swallow, retain, and absorb oral medications.

Those in the dose-escalation portion of the trial had solid tumors with class I, II, or III mutations, and they were administered KIN-2787 monotherapy. In this portion of the research, investigators sought to determine the recommended phase 2 dose of the agent.

The dose-expansion portion of the research is comprised of 3 cohorts, each planned to enroll 25 patients. The first cohort includes patients with melanoma with class II or III BRAF alterations. These patients were to receive KIN-2787 at a twice-daily dose of 25 mg/kg as part of 28-day treatment cycles. The second cohort includes patients with non–small cell lung cancer and class II or III BRAF alterations, and the third cohort is comprised of those with other solid tumors with class II or III BRAF alterations. These cohorts also received the agent at 25 mg/kg twice daily.

Primary end points of the trial include incidence of dose-limiting toxicities, treatment-emergent adverse effects (AEs), treatment-related AEs, and incidence of clinically significant changes in vital signs, physical examinations, electrocardiograms, and clinical laboratory tests.

For the dose-expansion portion of the research, primary end points include examining the objective response rate, disease control rate, duration of response, and duration of stable disease in each cohort. Key secondary end points include maximum observed plasma concentration (Cmax) of the agent, time to achieve Cmax, and area under the plasma concentration time curve.

In January 2022, the trial was expanded to include a dose-escalation cohort of patients with NRAS-mutant melanoma who would receive the investigative agent in combination with binimetinib (Mektovi). The decision was supported by findings from a phase 1 study (NCT03284502), which indicated that the combination of a pan-RAF inhibitor and a MEK inhibitor could produce a 26.3% partial response rate in this patient population (n = 19); 41.2% of patients achieved stable disease with the doublet.⁴

For the trial, investigators are examining KIN-2787 at 10 mg/kg twice daily plus binimetinib at 3 mg/kg twice daily in up to 36 patients with NRAS-mutant melanoma.

Previously, KIN-2787 has been granted an orphan drug designation from the FDA for the treatment of patients with stage IIB-IV melanoma.⁵

References

1. Kinnate Biopharma Inc. receives fast track designation from the US Food and Drug Administration for KIN-2787, an investigational pan-RAF inhibitor. News release. Kinnate Biopharma, Inc. September 21, 2022. Accessed September 26, 2022. https://bit.ly/3Rg11BB
2. Franovic A, Miller N, Severson P, et al. The next-generation pan-RAF inhibitor, KIN-2787, is active in class II and class III BRAF mutant models. J Clin Oncol. 2021;39(suppl 15):3116. doi:10.1200/JCO.2021.39.15_suppl.3116
3. A study to evaluate KIN-2787 in participants with BRAF and/or NRAS mutation positive solid tumors. ClinicalTrials.gov. Updated January 28, 2022. Accessed September 26, 2022. https://www.clinicaltrials.gov/ct2/show/NCT04913285
4. Kim TW, Lee J, Kim TM, et al. A phase Ib trial of belvarafenib in combination with cobimetinib in patients (pts) with RAS- or RAF- mutated (m) solid tumors: updated safety data and indication-specific efficacy results. Ann Oncol. 2021;32(suppl 5):S595. doi:10.1016/j.annonc.2021.08.1051
5. Kinnate Biopharma Inc. announces second quarter 2022 financial results and recent corporate updates. News release. Kinnate Biopharma, Inc. August 11, 2022. Accessed September 26, 2022. https://bit.ly/3r6KPbt