A phase 2 basket trial of an ERK1/2 inhibitor (LY3214996) in combination with abemaciclib for patients whose tumors harbor pathogenic alterations in BRAF, RAF1, MAP2K1/2 ERK1/2, and NF1.

Abstract

e15088 Background: LY3214996 (L) is a potent inhibitor of ERK1/2 kinases that can potentially obviate resistance mechanisms in cancers that harbor BRAF, RAS, NF1, MAP2K1/2, and other MAPK alterations. Abemaciclib (A) is a CDK 4/6 inhibitor. Studies have shown that concomitant inhibition of the MAPK pathway exemplified by ERK inhibitors may augment the antitumor activity of CDK4/6 inhibitors. In this biomarker-informed phase 2 study, we assess the clinical efficacy of L in combination with A. Methods: The study enrolled patients with advanced unresectable or metastatic cancer with no other standard of care options available. The malignancy must harbor pathogenic alterations in BRAF, RAF1, MAP2K1/2, ERK1/2, or NF1, in whom standard treatments failed to provide clinical benefit. L was administered at a dose of 200 mg orally QD in combination with A at 150 mg BID hours on Days 1 through 28 of a 28-day cycle until progression, toxicity, or withdrawal. The primary endpoint is the objective response rate. Secondary outcomes include evaluation of safety and tolerability, progression-free survival (PFS), and duration of the overall response. Additionally, tumor samples were collected for organoid development. Results: Between September 1, 2020, and February 1, 2023, 12 patients were enrolled. Primary malignancies included colorectal (6), lung (1), breast (2), pancreas (1), uterus (1), and thyroid (1). The pathogenic alterations included NF1 (4), BRAF (6), and MAP2K1/2 (2). There were no CR or PR observed. Stable disease was achieved in 4 patients (33%) with a median disease control rate of 6.5 months. Pathogenic alterations in patients with stable disease included BRAF, MAP2K1/2, and NF1. Most common treatment-related adverse events of any grade included fatigue (41%), rash (41%), nausea (33%), vomiting (33%), anemia (25%), anorexia (25%), and increased creatinine (25%). There were no grade 4 or 5 adverse events. Conclusions: The combination of L+A is safe and promising in patients whose tumors harbor pathogenic alterations in BRAF, MAP2K1/2, and NF1. Enrollment is ongoing, and efficacy and toxicity outcomes continue to be assessed. (NCT04534283). Clinical trial information: NCT04534283 .