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

Author(s): Susana N. Banerjee, PhD, MBBS, MA, FRCP¹; Els Van Nieuwenhuysen, MD²; Carol Aghajanian, MD^3,4; Véronique D’Hondt, MD, PhD⁵; Bradley J. Monk, MD, FACS, FACOG⁶; Andrew Clamp, PhD, MSc, BMBCh, MRCP⁷; Emily Prendergast, MD⁸; Ana Oaknin, MD, PhD⁹; Kari Ring, MD¹⁰; Nicoletta Colombo, MD, PhD^11,12; Robert W. Holloway, MD¹³; Manuel Rodrigues, MD^14,15; Hye Sook Chon, MD¹⁶; Charlie Gourley, PhD, FRCP¹⁷; Alessandro D. Santin, MD¹⁸; Premal H. Thaker, MD¹⁹; Christine Gennigens, MD, PhD²⁰; Gregg Newman, MD²¹; Erin Salinas, MD²²; Hagop Youssoufian, MD²³; Kathleen N. Moore, MD, MS, FASCO²⁴; Stephanie Lustgarten, PhD²³; David M. O’Malley, MD²⁵; Toon Van Gorp, MD, PhD²; Rachel N. Grisham, MD^3,4;

Source: doi.org/10.1200/JCO-25-00112

Dr. Anjan Patel's Thoughts

The ENGOT-OV60/GOG-3052/RAMP 201 phase II trial evaluated avutometinib (a RAF/MEK clamp) plus defactinib (FAK inhibitor) in recurrent low-grade serous ovarian cancer (LGSOC), showing a confirmed objective response rate (ORR) of 31% (44% in KRAS-mutant, 17% in KRAS wild-type) and a median progression-free survival (PFS) of 12.9 months (22.0 vs 12.8 months for KRAS-mutant vs wild-type). The median duration of response was notably long at 31.1 months, and the disease control rate was 88%. The most common grade ≥3 AEs were elevated creatine phosphokinase (CPK) (24%), diarrhea (8%), and anemia (5%), with a 10% discontinuation rate due to adverse events (AEs); so management of AE’s is key for using this new drug combo. This combination looks like a real contender for a new standard in recurrent LGSOC, especially for KRAS-mutant patients.

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).

Author Affiliations

¹The Royal Marsden NHS Foundation Trust and Institute of Cancer Research, GTG-UK, London, United Kingdom; ²University Hospitals Leuven, Leuven Cancer Institute, BGOG, Leuven, Belgium; ³Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY; ⁴Weill Cornell Medical College, New York, NY; ⁵Institut du Cancer de Montpellier (ICM) Val d’Aurelle Parc Euromedecine, Oncologie Médicale, GINECO, Montpellier, France; ⁶Florida Cancer Specialists, West Palm Beach, FL; ⁷Medical Oncology, The Christie NHS Foundation Trust and University of Manchester, GTG-UK, Manchester, United Kingdom; ⁸Gynecologic Oncology, Minnesota Oncology, Minneapolis, MN; ⁹Medical Oncology Service, Vall d’Hebron Institute of Oncology, Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain; ¹⁰Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Virginia, Charlottesville, VA; ¹¹Università degli Studi di Milano Bicocca, Bicocca, Italy; ¹²European Institute of Oncology, Milan, Italy; ¹³AdventHealth Cancer Institute, Orlando, FL; ¹⁴Department of Medical Oncology, Institut Curie, Paris, France; ¹⁵DRUM Team, INSERM U830, Institut Curie, Paris, France; ¹⁶Department of Gynecologic Oncology, H. Lee Moffitt Cancer Center, Tampa, FL; ¹⁷CRUK Scotland Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom; ¹⁸Department of Obstetrics, Gynecology, and Reproductive Sciences, Division of Gynecologic Oncology, Yale School of Medicine, New Haven, CT; ¹⁹Division of Gynecologic Oncology, Washington University School of Medicine and Siteman Cancer Center, St Louis, MO; ²⁰Department of Medical Oncology, University Hospital of Liège, CHU of Liège, Liège, Belgium; ²¹Sansum Clinic Healthcare, USO, Santa Barbara, CA; ²²Northwest Cancer Specialists, P.C., USO, Portland, OR; ²³Verastem Oncology, Boston, MA; ²⁴Stephenson Oklahoma Cancer Center the University of Oklahoma Health Sciences Center, Oklahoma City, OK; ²⁵The Ohio State University, James Comprehensive Cancer Center, Columbus, OH

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