Efficacy and Safety of Avutometinib ± Defactinib in Recurrent Low-Grade Serous Ovarian Cancer: Primary Analysis of ENGOT-OV60/GOG-3052/RAMP 201

Abstract

Purpose: This study evaluated the efficacy and safety of avutometinib (rapidly accelerated fibrosarcoma/mitogen-activated extracellular signal-regulated kinase [MEK] clamp) alone or in combination with defactinib (focal adhesion kinase inhibitor) in patients with recurrent low-grade serous ovarian cancer (LGSOC).

Methods: In this phase II, open-label study, patients with recurrent, measurable LGSOC after ≥1 line of platinum chemotherapy were stratified by tumor Kirsten rat sarcoma virus homolog (KRAS) mutation status and randomly assigned to oral avutometinib 4.0 mg two times per week monotherapy or avutometinib 3.2 mg two times per week in combination with oral defactinib 200 mg two times per day. The combination was selected as the go-forward regimen for expansion. The primary end point was objective response rate (ORR) by blinded independent central review.

Results: A total of 115 patients received the go-forward combination regimen. Patients had a median of 3 (range, 1-9) prior lines of therapy, including hormonal (86%), bevacizumab (51%), and MEK inhibitor (22%). Confirmed ORR was 31% (95% CI, 23% to 41%) with a median duration of response of 31.1 months (95% CI, 14.8 to 31.1). ORR was 44% in KRAS-mutant and 17% in KRAS wild-type cohorts. The median progression-free survival was 12.9 months (95% CI, 10.9 to 20.2) overall and 22.0 months (95% CI, 11.1 to 36.6) and 12.8 months (95% CI, 7.4 to 18.4) in KRAS-mutant and wild-type cohorts, respectively. The most frequent grade ≥3 treatment-related adverse events (AEs) were elevated creatine phosphokinase (24%), diarrhea (8%), and anemia (5%). Ten percent of patients discontinued because of AEs.

Conclusion: The efficacy and safety profile of avutometinib in combination with defactinib support this combination as a potential standard of care for recurrent LGSOC. A randomized phase 3 study of avutometinib and defactinib versus investigator's choice of therapy for women with recurrent LGSOC is currently enrolling (RAMP301; ClinicalTrials.gov identifier: NCT06072781).

Trial registration: ClinicalTrials.gov NCT04625270 NCT06072781 NCT04625270.

FIG 1.

Study design. n values represent patients treated in the study. BICR, blinded independent central review; BID, two times per day; BIW, two times per week; LGSOC, low-grade serous ovarian cancer; KRAS, Kirsten rat sarcoma virus; MEKi, mitogen-activated extracellular signal-regulated kinase inhibitor; mt, mutant; ORR, objective response rate; wt, wild-type.

FIG 2.

Patient disposition is depicted by a CONSORT diagram for Parts A, B, C, and is summarized by KRAS mutation status and treatment group. ^aDisease progression measured by RECIST v1.1. ^bOther reasons include clinical progression, patient noncompliance, physician decision, debulking surgery, patient withdrawal, and disease progression. KRAS, Kirsten rat sarcoma virus; mt, mutant; wt, wild-type.

FIG 3.

(A) DOR as assessed by the BIRC was calculated for patients with a complete response or partial response from the time of first response to progressive disease using Kaplan-Meier methods and (B) PFS as assessed by the BIRC is summarized by KRAS mutation status, phase, and treatment group for the efficacy-evaluable population. (C) Best response (percent change from baseline) of the sum of target lesions as assessed by the BIRC for the efficacy evaluable population for the avutometinib 3.2 mg BIW + defactinib 200 mg BID combination therapy group. BID, two times per day; BIRC, blinded independent central review; BIW, two times per week; DOR, duration of response; KRAS, Kirsten rat sarcoma virus homolog; MEKi, mitogen-activated extracellular signal-regulated kinase inhibitor; mt, mutant; NE, not evaluable or unknown; PFS, progression-free survival; wt, wild type.

FIG A1.

Confirmed ORR in subgroups by prior therapies: Parts A, B, and C. Error bars represent 95% CI. MEKi, mitogen-activated extracellular signal-regulated kinase inhibitor; ORR, objective response rate.