Reference Detail

Ref Type

Abstract

PMID

Authors

Benjamin Solomon; Bo Gao; Vivek Subbiah; Michael Millward; Lee Rosen; Jayesh Desai; Eric I. Sbar; Neal Collins; Thuy Hoang; Xi Song; Wenlin Shao; Jaspreet Jaggi; Badreddin Edris; Paraneedharan Ramachandran; Lusong Luo; Michael Friedlander

Title

Abstract CT033: Safety, pharmacokinetics, and antitumor activity findings from a phase 1b, open-label, dose-escalation and expansion study investigating RAF dimer inhibitor lifirafenib in combination with MEK inhibitor mirdametinib in patients with advanced or refractory solid tumors

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer Research	83	8_Supplement	April 14 2023

URL

https://aacrjournals.org/cancerres/article/83/8_Supplement/CT033/725420/Abstract-CT033-Safety-pharmacokinetics-and

Abstract Text

Background: RAF dimer inhibition can suppress RAF-dependent MEK reactivation leading to sustained MAPK pathway inhibition. RAF dimer inhibitor lifirafenib (L) synergized with MEK inhibitor mirdametinib (M) in RAS-mutated cancer models. In this ongoing Phase 1b study of L+M in patients (pts) with advanced/refractory solid tumors harboring MAPK pathway aberrations, we investigate preliminary safety, PK, and efficacy. Methods: Pts were enrolled by a 3+3 design and treated with L (15-20 mg QD) + M (2-4 mg QD or BID) across 9 dose levels (DLs). Primary objectives were to evaluate safety/tolerability, estimate MTD, and identify recommended Phase 2 dose (RP2D). Tumor responses were investigator assessed using RECIST v1.1. AEs were graded per NCI CTCAE v5.0. Results: Table 1 presents demographic, efficacy, and safety results as of 01 Sep 2022. Objective responses (1 CR, 14 PRs) were achieved in 15/54 (27.8%) efficacy-evaluable pts, including 10/17 low-grade serous ovarian cancer (LGSOC) (58.8%; median exposure ~23 mo), 2 NSCLC (1 NRAS Q61K, 1 BRAF-V600E), 2 endometrial cancer (1 BRAF ZC3HAv1 fusion, 1 KRAS G12A), and 1 LG serous adenocarcinoma of Mullerian origin (KRAS G12V). For L and M, plasma maximum drug concentration (Cmax) and exposure (AUC) were comparable to that of each compound at same DL in monotherapy studies, suggesting low likelihood of drug-drug interaction. L+M was generally well tolerated, with limited DLTs and discontinuations. There were 2 deaths due to TEAEs considered unrelated to L+M. The MTD/RP2D were not yet determined. Conclusions: L+M demonstrated a favorable safety profile and showed antitumor activity in pts with various KRAS, NRAS, and BRAF mutations across several solid tumor types, including LGSOC, NSCLC, and endometrial cancer. The combination warrants further clinical investigation.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
NRAS Q61K	lung non-small cell carcinoma	sensitive	Lifirafenib + PD-0325901	Phase I	Actionable	In a Phase Ib trial, Lifirafenib (BGB-283) and PD-0325901 combination treatment demonstrated safety and activity in patients with advanced solid tumors harboring MAPK pathway alterations, resulting in an objective response rate of 27.8% (15/54, 1 complete and 14 partial responses), including an objective response in a patient with non-small cell lung cancer harboring NRAS Q61K (Cancer Res (2023) 83 (8_Supplement): CT033).	detail...
BRAF V600E	lung non-small cell carcinoma	predicted - sensitive	Lifirafenib + PD-0325901	Phase I	Actionable	In a Phase Ib trial, Lifirafenib (BGB-283) and PD-0325901 combination treatment demonstrated safety and activity in patients with advanced solid tumors harboring MAPK pathway alterations, resulting in an objective response rate of 27.8% (15/54, 1 complete and 14 partial responses), including an objective response in a patient with non-small cell lung cancer harboring BRAF V600E (Cancer Res (2023) 83 (8_Supplement): CT033).	detail...