[en] 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).
Disciplines :
Oncology
Author, co-author :
Banerjee, Susana N ; The Royal Marsden NHS Foundation Trust and Institute of Cancer Research, GTG-UK, London, United Kingdom
Van Nieuwenhuysen, Els; University Hospitals Leuven, Leuven Cancer Institute, BGOG, Leuven, Belgium
Aghajanian, Carol; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY ; Weill Cornell Medical College, New York, NY
D'Hondt, Véronique ; Institut du Cancer de Montpellier (ICM) Val d'Aurelle Parc Euromedecine, Oncologie Médicale, GINECO, Montpellier, France
Monk, Bradley J ; Florida Cancer Specialists, West Palm Beach, FL
Clamp, Andrew; Medical Oncology, The Christie NHS Foundation Trust and University of Manchester, GTG-UK, Manchester, United Kingdom
Oaknin, Ana ; Medical Oncology Service, Vall d'Hebron Institute of Oncology, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
Ring, Kari; Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Virginia, Charlottesville, VA
Colombo, Nicoletta ; Università degli Studi di Milano Bicocca, Bicocca, Italy ; European Institute of Oncology, Milan, Italy
Holloway, Robert W ; AdventHealth Cancer Institute, Orlando, FL
Rodrigues, Manuel ; Department of Medical Oncology, Institut Curie, Paris, France ; DRUM Team, INSERM U830, Institut Curie, Paris, France
Chon, Hye Sook; Department of Gynecologic Oncology, H. Lee Moffitt Cancer Center, Tampa, FL
Gourley, Charlie ; CRUK Scotland Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom
Santin, Alessandro D ; Department of Obstetrics, Gynecology, and Reproductive Sciences, Division of Gynecologic Oncology, Yale School of Medicine, New Haven, CT
Thaker, Premal H ; Division of Gynecologic Oncology, Washington University School of Medicine and Siteman Cancer Center, St Louis, MO
Gennigens, Christine ; Université de Liège - ULiège > Département des sciences cliniques > Oncologie
Newman, Gregg; Sansum Clinic Healthcare, USO, Santa Barbara, CA
Salinas, Erin; Northwest Cancer Specialists, P.C., USO, Portland, OR
Youssoufian, Hagop; Verastem Oncology, Boston, MA
Moore, Kathleen N ; Stephenson Oklahoma Cancer Center at the University of Oklahoma Health Sciences Center, Oklahoma City, OK
Lustgarten, Stephanie; Verastem Oncology, Boston, MA
O'Malley, David M ; The Ohio State University, James Comprehensive Cancer Center, Columbus, OH
Van Gorp, Toon ; University Hospitals Leuven, Leuven Cancer Institute, BGOG, Leuven, Belgium
Grisham, Rachel N; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY ; Weill Cornell Medical College, New York, NY
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