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
Authors: Solomon Benjamin , Gao Bo , Subbiah Vivek , Millward Michael , Rosen Lee , Desai Jayesh , Sbar Eric I. , Collins Neal , Hoang Thuy , Song Xi , Shao Wenlin , Jaggi Jaspreet , Edris Badreddin , Ramachandran Paraneedharan , Luo Lusong , Friedlander Michael 
Published: April 2023

Abstract
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.
(Acknowledgements: We thank patients/their families, investigators, and site staff for participating in this study, which is sponsored by BeiGene. Support for abstract preparation was funded by BeiGene and provided by Traci Ginnona, inSeption Group, Lansdale, PA, USA)
Table 1. Demographics (N=56) Age (y), median (range) 59.5 (29-78) ECOG PS 0/1, n (%) 56 (100.0) Prior lines of therapy, median (range) 1 (1-6) Efficacy Set (N=54), n (%) LGSOC (n=17) Other than LGSOC (n=37) All malignancies (n=54) ORR (CR+PR) 10 (58.8) 5 (13.5) 15 (27.8) CR 1 (5.9) 0 1 (1.9) PR 9 (52.9) 5 (13.5) 14 (25.9) SD 6 (35.3) 18 (48.6) 24 (44.4) DCR (CR+PR+SD) 16 (94.1) 23 (62.2) 39 (72.2) Safety Set (N=56), n (%) TEAEa 55 (98.2) SAE 23 (41.1) Grade 3 TEAE 24 (42.9) TEAE leading to treatment discontinuation 3 (5.4) DLT 6 (10.7) CR, complete response; DCR, disease control rate; DLT, dose-limiting toxicity; ECOG PS, Eastern Cooperative Oncology Group performance status; LGSOC, low-grade serous ovarian cancer; ORR, objective response rate; PR, partial response; SAE, serious adverse event; SD, stable disease; TEAE, treatment-emergent adverse event. a Commonly reported (&gt;40%): fatigue (55.4%), dermatitis acneiform (46.4%), and diarrhea (44.6%).
Citation Format: 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. 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 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT033.