A Phase 1/1b Open-label, Multicenter Study to Investigate the Safety, Tolerability, Pharmacokinetics, and Antitumor Activity of KIN-2787 in Participants With BRAF and/or NRAS Mutation-positive Solid Tumors.

More details:

Overview

Exarafenib (KIN-2787) is an investigational, orally administered, selective pan-RAF inhibitor developed to target cancers driven by BRAF and NRAS mutations. (kinnate.com)

Mechanism of Action

Exarafenib inhibits RAF kinases, including BRAF, RAF1, and ARAF, with high potency and selectivity. It is designed to effectively target BRAF Class I, II, and III mutations, as well as NRAS mutations, by inhibiting aberrant MAPK pathway signaling. (ascopubs.org)

Efficacy

In a Phase 1 clinical trial (KN-8701), exarafenib demonstrated preliminary efficacy in patients with advanced solid tumors harboring BRAF alterations and NRAS-mutant melanoma. Among 34 patients with at least one post-baseline tumor assessment, 6 (17.6%) achieved partial responses, and 16 (47.1%) had stable disease. Notably, at the maximum tolerated dose (MTD) of 300 mg twice daily, the response rate was 33% (4 out of 12 patients), including responses in patients with BRAF Class I, II, III, and NRAS mutations. (onclive.com)

Safety

Exarafenib was generally well-tolerated. Treatment-related adverse events (TRAEs) of any grade occurred in 69.2% of patients, with 13.5% experiencing Grade 3 or higher events. The most common TRAEs were skin-related, observed in 48.1% of patients, with 7.7% experiencing Grade 3 or higher skin events. Gastrointestinal TRAEs occurred in 19.2% of patients, all Grade 1-2. Reversible, asymptomatic Grade 3 increases in ALT and/or AST were reported in 3 patients. (onclive.com)

Further Reading

• A Phase 1 Clinical Trial Evaluating Monotherapy With Exarafenib (KIN-2787), a Highly Selective Pan-RAF Inhibitor, in BRAF‑Altered Solid Tumors and NRAS-Mutant Melanoma
• The next-generation pan-RAF inhibitor, KIN-2787, is active in class II and class III BRAF mutant models

Last updated: Apr 2025

Overview

Exarafenib (KIN-2787) is an investigational, orally administered, selective pan-RAF inhibitor developed to target cancers driven by BRAF and NRAS mutations. (kinnate.com)

Mechanism of Action

Exarafenib inhibits RAF kinases, including BRAF, RAF1, and ARAF, with high potency and selectivity. It is designed to effectively target BRAF Class I, II, and III mutations, as well as NRAS mutations, by inhibiting aberrant MAPK pathway signaling. (ascopubs.org)

Efficacy

In a Phase 1 clinical trial (KN-8701), exarafenib demonstrated preliminary efficacy in patients with advanced solid tumors harboring BRAF alterations and NRAS-mutant melanoma. Among 34 patients with at least one post-baseline tumor assessment, 6 (17.6%) achieved partial responses, and 16 (47.1%) had stable disease. Notably, at the maximum tolerated dose (MTD) of 300 mg twice daily, the response rate was 33% (4 out of 12 patients), including responses in patients with BRAF Class I, II, III, and NRAS mutations. (onclive.com)

Safety

Exarafenib was generally well-tolerated. Treatment-related adverse events (TRAEs) of any grade occurred in 69.2% of patients, with 13.5% experiencing Grade 3 or higher events. The most common TRAEs were skin-related, observed in 48.1% of patients, with 7.7% experiencing Grade 3 or higher skin events. Gastrointestinal TRAEs occurred in 19.2% of patients, all Grade 1-2. Reversible, asymptomatic Grade 3 increases in ALT and/or AST were reported in 3 patients. (onclive.com)

Further Reading

• A Phase 1 Clinical Trial Evaluating Monotherapy With Exarafenib (KIN-2787), a Highly Selective Pan-RAF Inhibitor, in BRAF‑Altered Solid Tumors and NRAS-Mutant Melanoma
• The next-generation pan-RAF inhibitor, KIN-2787, is active in class II and class III BRAF mutant models

Last updated: Apr 2025

The Phase 1/1b clinical trial NCT04913285, known as KN-8701, is evaluating exarafenib (KIN-2787), a selective pan-RAF inhibitor, in patients with BRAF and/or NRAS mutation-positive solid tumors.

Early Clinical Results

As of December 13, 2022, preliminary data from 52 patients indicated that exarafenib achieved dose-proportional exposure and demonstrated pathway inhibition across various BRAF classes and tumor types. The maximum tolerated dose was established at 300 mg twice daily. Among 34 patients with at least one post-baseline tumor assessment, 17.6% experienced partial responses, and 47.1% had stable disease. Notably, responses were observed in patients with BRAF Class I, II, III alterations, and NRAS mutations. (aacrjournals.org)

In a subset of 16 efficacy-evaluable patients with NRAS mutant melanoma who had not received prior RAF, MEK, or ERK inhibitors, a 38% overall response rate was reported, with 69% achieving disease control. These findings suggest promising activity of exarafenib in this patient population. (delta.larvol.com)

Trial Status and Future Directions

As of September 2023, Kinnate Biopharma announced a strategic reprioritization, deciding not to proceed with further clinical development of exarafenib as a monotherapy agent. The company is exploring strategic alternatives for the program. (delta.larvol.com)

Key References

• (aacrjournals.org)
• (delta.larvol.com)

Last updated: Apr 2025

Inclusion Criteria:

* Provide written informed consent prior to initiation of any study-specific procedures.

* Metastatic or advanced stage solid tumor

* Known BRAF Class I, Class II, or Class III alteration or melanoma with an NRAS mutation as confirmed by previous genomic analysis of tumor tissue or ctDNA.

* Measurable (Part A and B) or evaluable (Part A only) disease by RECIST v1.1.

* ECOG performance status 0-1

* Adequate organ function, as measured by laboratory values (criteria listed in protocol).

* Able to swallow, retain, and absorb oral medications.

Exclusion Criteria:

* Known participants who have received local therapy with either surgery and/or radiation therapy (participants with asymptomatic untreated brain metastasis may be eligible if met with certain criteria)

* In Part B Dose Expansion, previous treatment with any approved or in-development small molecule BRAF-, MEK-, or MAPK-directed inhibitor therapy.

* GI tract disease causing an inability to take oral medication, malabsorption syndrome, requirement for intravenous alimentation, or uncontrolled inflammatory GI disease.

* Active, uncontrolled bacterial, fungal, or viral infection.

* Participant with a positive test result for SARS-CoV2 infection, is known to have asymptomatic infection or is suspected of having SARS-CoV2, is excluded

* Women who are lactating or breastfeeding, or pregnant.

* Participants with any other active treated malignancy within 3 years prior to enrollment

Complete inclusion and exclusion criteria are listed in the clinical study protocol.