Investigators hope to address the need for additional treatment options for patients with class II or class III BRAF-altered disease with KIN-2787, a next-generation, orally available, potent, and selective small molecule inhibitor.
Patients with solid tumors harboring class I BRAF alterations, such asBRAF V600, have gained substantial clinical benefit from first-generation BRAF inhibitors. However, currently approved BRAF inhibitors have not been proven as effective in patients with class II or class III BRAF alterations, which account for approximately 34% of BRAF mutations.1
BRAF mutations are observed in up to 8% of patients with cancerand are known to behave differently across tumor types.2,3 For example, approximately 50% of patients with melanoma harbor a class I BRAF V600 mutation, whereas approximately 50% to 80% of BRAF mutations in non–small cell lung cancer (NSCLC) and 22% to 30% in colorectal cancer are class II or class III.3 Because of the increasing use of next-generation sequencing in clinical oncology practice, BRAF mutations beyond V600 are being identified at a greater rate. However, patients with diseases harboring these alterations lack approved treatment options for targeting them.3
Three BRAF-targeted therapies are approved by the FDA, each of which is engineered to target class I alterations:vemurafenib (Zelboraf), dabrafenib (Tafinlar), and encorafenib (Braftovi). All 3 agents are approved in combination with MEK inhibitors for patients with BRAF V600–positive melanoma.4-7 Vemurafenib and dabrafenib are also approved as a single-agent therapy for patients with BRAF V600–positive unresectable or metastatic melanoma.4,5 There are no approved systemic therapies targeting class II or class III BRAF alterations.
“BRAF as a driving genomic abnormality is very well recognized in the oncology community,” Cesar Augusto Perez, MD, said in an interview with OncologyLive®. “Initial success [with BRAF inhibitors] has been seen in patients with BRAF mutations with melanoma, NSCLC, and colorectal cancer. But we [must] acknowledge that in many of the diseases where we see a BRAF mutation, it is not the typical BRAF V600 mutation for which the current drugs have been found to be effective,” added Perez, who is director of drug development at Florida Cancer Specialists & Research Institute.
“As an oncologist, when you get a next-generation sequencing report and you see a BRAF mutation, there is some excitement initially because you always want to offer something that is effective for your patient,” Perez said. “But right after that when you see it is a non-V600 or a class II or class III, then the general [reaction] is disappointment because we know that for class II, class III mutations [agents such as] dabrafenib are not going to work for this population.”
Investigators hope to address the need for additional treatment options for patients with class II or class III BRAF-altered disease with KIN-2787, a next-generation, orally available, potent, and selective small molecule inhibitor. The pan-RAF inhibitor is specifically designed to inhibit class II and class III BRAF dimers while still inhibiting class I monomers. Investigators will evaluate the agent in the phase 1/1b KN-8701 trial (NCT04913285) of adult patients with solid tumors harboring class I, class II, or class III BRAF alterations.1
In vitro and in vivo activity with KIN-2787 laid the foundation for investigators to pursue the agent as a viable option. Specifically, KIN-2787 had activity against human cancers driven by class I, class II, and class III BRAF mutations and treatment with the agent led to time-dependent and exposure-dependent inhibition of MEK-ERK phosphorylation. This activity was accompanied by suppression of MAPK transcriptional targets at the RNA and protein level. Investigators also evaluated the dosing tumor response in the human cancer models and reported that twice-daily oral dosing was found to be well tolerated and had prolonged target coverage/inhibition with a trend in the direction of more frequent and deeper tumor responses in vivo.1
“The interesting thing about [KN-2787] is that it was developed also to try to target the other 2 classes of BRAF mutations,” Perez said. “That was not the case for the drugs that we have available on the market. They were always developed to try to target the class I mutation. I think 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 and 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].”
The pan-RAF approach in the development of KIN-2787 optimized the agent’s ability to cover the heterogenous nature of class II and III alteration as well as narrow the concentration levels at which paradoxical activation occurs, such as in BRAF-BRAF or BRAF-CRAF conformations.8 Perez added that distinguishing factors in genomic abnormalities of BRAF are displayed in several diseases and that although these mutated cancers may represent only 1% to 2% of cancer cases, it is important to develop drugs to address this patient population. Despite uncertainty as to how effective pan-RAF inhibitors will be against any of the classes in clinical practice, investigators hope initiation of trials such as KN-8701 will shed some light on their role for patients with these mutations.
The KN-8701 multicenter study will evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of KIN-2787 in approximately 115 adult patients with BRAF-mutated advanced or metastatic solid tumors (FIGURE).9 The study will be divided into dose escalation and dose expansion portions. The dose escalation group will consist of patients withsolid tumors harboring class I, class II, or class III BRAF alterations and will determine therecommended phase 2 dose (RP2D). The RP2D will then be evaluated in patients with NSCLC, melanoma, and other solid tumors harboring class II or class III BRAF alterations in the dose expansion segment. KIN-2787 will be administered orally twice daily in 28-day cycles in both phases.
BRAF alteration will be confirmed by previous genomic analysis of tumor tissue or circulating tumor DNA. Patients must have received prior standard therapy appropriate for the tumor type and disease stage or be unlikely to tolerate or derive clinically meaningful benefit from appropriate standard of care therapy. An ECOG performance status of 2 or less, adequate organ function, and the ability to swallow, retain, and absorb oral medications are also required.
“Patients with class I mutations who have been previously treated with an approved BRAF inhibitor—for example, patients with melanoma who have had disease progression—will [be included in the trial],” Perez explained. If patients have previously received BRAF-directed, MEK-directed, or MAPK-directed inhibitor therapy for tumor types and indications not approved by the FDA, they will not be able to participate. Further, those with known active brain metastases from nonbrain tumors will be excluded from the trial, along with those who are seropositive for hepatitis B or hepatitis C.
The primary end points of the trial are the incidence of dose-limiting toxicities, treatment-emergent adverse events, treatment-related adverse events, and incidence of clinically significant changes in vital signs, physical examinations, electrocardiograms, and clinical laboratory tests. In the dose expansion portion, primary outcome measures include objective response rate, disease control rate, duration of overall response, and duration of stable disease. Secondary end points of the study consist of maximum observed plasma concentration (Cmax) of KIN-2787, time to achieve Cmax, and area under the plasma concentration-time curve.
Perez noted that any signaling on activity patients with class I, class II, or class III BRAF genomic abnormalities will also be monitored. The first patient in the study was dosed in August 2021. The study is estimated to be completed in June 2024.9,10
In January 2022, investigators expanded the KN-8701 trial to include a dose-escalation cohort of patients with NRAS-mutant melanoma who will receive KIN-2787 in combination with binimetinib (Mektovi). “Patients with NRAS mutations are another population with a high unmet need in metastatic melanoma,” Meredith McKean, MD, MPH, said in an interview. “There are a couple of different targeted therapies under development, but the fact is that there are no approved therapies for these patients and data show that [this population] has worse outcomes than patients without NRAS mutations.” McKean is the associate director of melanoma and skin cancer research at Sarah Cannon Research Institute in Nashville, Tennessee.
Somatic mutations of NRAS occur in approximately 25% of melanomas with signaling shown to be highly CRAF-dependent.11,12 Data from a phase 1 study (NCT03284502) showed that treatment using a pan-RAF inhibitor in combination with a MEK inhibitor elicited a partial response rate of 26.3% among 19 patients, with 41.2% achieving stable disease.13
Investigators leveraged these findings as rationale to combine KIN-2787 administered at the clinical dosing strategy (10 mg/kg twice daily) with binimetinib (3 mg/kg twice daily) in patients with NRAS-mutant melanoma. The 2 agents had a synergistic effect with meaningful tumor reductions compared with monotherapy. Specifically, preclinical findings demonstrated a 122% tumor growth inhibition with the combination.8
The dose expansion cohort will evaluate up to 36 patients with NRAS-mutant melanoma. “There is a lot of excitement about opportunities in this trial and trying to find new avenues of treatment for these patients,” McKean said. “[We need to] highlight the importance of molecular profiling. The days of testing for BRAF V600 mutations are over and we really should be doing full, comprehensive profiling for all patients with metastatic melanoma to make sure that we are identifying other actionable driver mutations and [to help us] identify clinical trial opportunities for these mutations.”