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Efficacy and safety of avutometinib ± defactinib in recurrent low-grade serous ovarian cancer: primary analysis of ENGOT-OV60/GOG-3052/RAMP 201
Banerjee, S. N. Van Nieuwenhuysen, E. Aghajanian, C. D'Hondt, V. Monk, B. J. Clamp, A. Prendergast, E. Oaknin, A. Ring, K. Colombo, N.
Banerjee, S. N.
Van Nieuwenhuysen, E.
Aghajanian, C.
D'Hondt, V.
Monk, B. J.
Clamp, A.
Prendergast, E.
Oaknin, A.
Ring, K.
Colombo, N.
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).
Authors
Banerjee, S. N.
Van Nieuwenhuysen, E.
Aghajanian, C.
D'Hondt, V.
Monk, B. J.
Clamp, A.
Prendergast, E.
Oaknin, A.
Ring, K.
Colombo, N.
Holloway, R. W.
Rodrigues, M.
Chon, H. S.
Gourley, C.
Santin, A. D.
Thaker, P. H.
Gennigens, C.
Newman, G.
Salinas, E.
Youssoufian, H.
Moore, K. N.
Lustgarten, S.
O'Malley, D. M.
Van Gorp, T.
Grisham, R. N.
Van Nieuwenhuysen, E.
Aghajanian, C.
D'Hondt, V.
Monk, B. J.
Clamp, A.
Prendergast, E.
Oaknin, A.
Ring, K.
Colombo, N.
Holloway, R. W.
Rodrigues, M.
Chon, H. S.
Gourley, C.
Santin, A. D.
Thaker, P. H.
Gennigens, C.
Newman, G.
Salinas, E.
Youssoufian, H.
Moore, K. N.
Lustgarten, S.
O'Malley, D. M.
Van Gorp, T.
Grisham, R. N.
Description
Date
2025
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Citation
Banerjee SN, Van Nieuwenhuysen E, Aghajanian C, D'Hondt V, Monk BJ, Clamp A, et al. Efficacy and Safety of Avutometinib ± Defactinib in Recurrent Low-Grade Serous Ovarian Cancer: Primary Analysis of ENGOT-OV60/GOG-3052/RAMP 201. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2025 Sep;43(25):2782-92. PubMed PMID: 40644648. Pubmed Central PMCID: PMC12393057 manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center. Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments). Susana N. Banerjee Stock and Other Ownership Interests: Perci Health, Innovative Diagnostics Honoraria: AstraZeneca, GlaxoSmithKline, Immunogen, MSD Oncology, AbbVie, Eisai, Pharma&, Verastem Consulting or Advisory Role: GlaxoSmithKline, MSD Oncology, AstraZeneca, Seagen, Immunogen, Myriad Genetics, Verastem, Zymeworks, Abbvie, BioNTech SE, Eisai, Gilead Sciences, Gray Wolf Therapeutics, Incyte, ITM Oncologics, TORL Biotherapeutics, Genmab, Biogene, Lilly Research Funding: GlaxoSmithKline (Inst), AstraZeneca (Inst) Travel, Accommodations, Expenses: GlaxoSmithKline, AstraZeneca, Verastem, Zymeworks Uncompensated Relationships: Royal Society of Medicine President Oncology Section, International Cancer Foundation Board Els Van Nieuwenhuysen Consulting or Advisory Role: Regeneron (Inst), Oncoinvent, AstraZeneca (Inst), Merck Serono (Inst) Speakers' Bureau: GlaxoSmithKline (Inst), AstraZeneca (Inst), MSD Research Funding: AstraZeneca (Inst), Lilly (Inst), Merck (Inst), Seagen (Inst), Roche (Inst), Novartis (Inst), Regeneron (Inst), Oncoinvent (Inst) Travel, Accommodations, Expenses: Regeneron (Inst), GlaxoSmithKline (Inst) Carol Aghajanian Leadership: GOG Foundation, NRG Oncology Consulting or Advisory Role: Merck, AstraZeneca, WCG Research Funding: Genentech/Roche (Inst), AbbVie (Inst), Clovis Oncology (Inst), AstraZeneca (Inst), Artios (Inst) Véronique D'Hondt Travel, Accommodations, Expenses: Lilly, Pfizer, MSD, Novartis Bradley J. Monk Honoraria: AstraZeneca, BioNTech SE, Corcept Therapeutics, DSI, Eisai, Lilly, Genmab/Seagen, GOG Foundation, GlaxoSmithKline, Immunogen, AbbVie, Incyte, Karyopharm Therapeutics, Merck, Mersana, Mural, Myriad Genetics, Natera, Novartis, Novocure, Onco4, Panavance Therapeutics, Pharma&, ProfoundBio, Genmab, Regeneron, Roche/Genentech, Sutro Biopharma, Tubulis GmbH, Verastem, Zentalis, Zymeworks Consulting or Advisory Role: AstraZeneca, Eisai, Genmab/Seattle Genetics, GOG Foundation, ImmunoGen, Merck, Mersana, Myriad Pharmaceuticals, Regeneron, Roche/Genentech, Karyopharm Therapeutics, Novocure, Gradalis, Novartis, OncoC4, Panavance Therapeutics, Verastem, Zentalis, Alkermes, BioNTech SE, Tubulis GmbH, Corcept Therapeutics, DSI, Lilly, AbbVie, Incyte, Natera, Pharma&, ProfoundBio, Sutro Biopharma, Zymeworks Speakers' Bureau: AstraZeneca, Eisai, TESARO/GSK, Merck, Lilly, Immunogen/AbbVie Research Funding: Novartis (Inst), Amgen (Inst), Genentech (Inst), Lilly (Inst), Janssen (Inst), Array BioPharma (Inst), Tesaro (Inst), MORPHOTEK (Inst), Pfizer (Inst), Advaxis (Inst), AstraZeneca (Inst), Immunogen (Inst), Regeneron (Inst), NuCana (Inst) Andrew Clamp Consulting or Advisory Role: GlaxoSmithKline Speakers' Bureau: GlaxoSmithKline Research Funding: AstraZeneca (Inst), Clovis Oncology (Inst), Pfizer (Inst), Immunogen (Inst), Merck (Inst), Verastem (Inst), Eisai (Inst), Advenchen Laboratories (Inst), MorphoSys (Inst), Corcept Therapeutics (Inst), Alkermes (Inst) Emily Prendergast Consulting or Advisory Role: AstraZeneca Ana Oaknin Consulting or Advisory Role: AstraZeneca, PharmaMar, Clovis Oncology, Immunogen, Genmab, Mersana, GSK, Deciphera, AGENUS, Corcept Therapeutics, Eisai, Roche, Merck Sharp & Dohme, Novocure, Shattuck Labs, Sutro Biopharma, ITeos Therapeutics, Regeneron, Exelixis, Zentalis, Myriad Genetics, Daiichi Sankyo, Debiopharm International, OncoXerna Therapeutics, Seagen/Pfizer, Zymeworks, TORL Therapeutics, AbbVie Speakers' Bureau: AstraZeneca, GlaxoSmithKline, Roche, MSD, Immunogen Research Funding: AbbVie (Inst), Advaxis (Inst), Aeterna Zentaris (Inst), Aprea Therapeutics (Inst), Clovis Oncology Inc (Inst), Eisai (Inst), Roche (Inst), Regeneron (Inst), Bristol Myers Squibb International Corporation (BMS) (Inst), Immunogen (Inst), Merck Sharp & Dohme (Inst), Tesaro (Inst), Amgen (Inst), Millennium Pharmaceuticals Inc (Inst), PharmaMar (Inst) Travel, Accommodations, Expenses: AstraZeneca, PharmaMar, Roche Nicoletta Colombo Employment: Sarepta Therapeutics (I) Honoraria: Roche/Genentech, AstraZeneca, GlaxoSmithKline, MSD Oncology, Clovis Oncology, Immunogen, Mersana, Eisai, Nuvation Bio, OCXERNA, Pieris Pharmaceuticals, Novocure, BioNTech, Incyte, Gilead Sciences Consulting or Advisory Role: Roche/Genentech, AstraZeneca, Clovis Oncology, MSD Oncology, GlaxoSmithKline, Immunogen, mersana, Eisai, Nuvation Bio, OCXERNA, Pieris Pharmaceuticals, Novocure Speakers' Bureau: AstraZeneca, Clovis Oncology, GlaxoSmithKline, MSD Oncology, Eisai Research Funding: AstraZeneca (Inst), Roche (Inst), GlaxoSmithKline (Inst) Travel, Accommodations, Expenses: GlaxoSmithKline, AstraZeneca, Corcept Therapeutics Robert W. Holloway Consulting or Advisory Role: Genelux, GlaxoSmithKline Speakers' Bureau: AstraZeneca, GlaxoSmithKline, Merck, Natera Uncompensated Relationships: Genelux Manuel Rodrigues Consulting or Advisory Role: AstraZeneca, GlaxoSmithKline, Immunocore, AbbVie Speakers' Bureau: Immunocore, GlaxoSmithKline Research Funding: MSD (Inst), Johnson & Johnson/Janssen (Inst), Daiichi Sankyo/UCB Japan (Inst) Travel, Accommodations, Expenses: Immunocore Hye Sook Chon Honoraria: Curio Science, Envision Communications, MJH Healthcare Holdings, LLC, Guidepoint Global Consulting or Advisory Role: Envision Communications, Eisai, Merck, Envive Biotech Speakers' Bureau: Clinical Care Options Travel, Accommodations, Expenses: Agenus Charlie Gourley Honoraria: AstraZeneca, GlaxoSmithKline, MSD Oncology, Cor2Ed, AbbVie, Pharma& Consulting or Advisory Role: AstraZeneca, GlaxoSmithKline, MSD Oncology, Verastem, Immunogen, AbbVie Research Funding: AstraZeneca (Inst), GlaxoSmithKline (Inst), MSD Oncology (Inst), Novartis (Inst), MedAnnex (Inst), Roche/Genentech (Inst), Verastem (Inst), Artios (Inst) Patents, Royalties, Other Intellectual Property: One patent issued and four pending for a gene expression signature to predict cancer sensitivity to anti-angiogenic therapy (Inst) Travel, Accommodations, Expenses: GlaxoSmithKline Other Relationship: AstraZeneca, MSD Oncology, GlaxoSmithKline Alessandro D. Santin Consulting or Advisory Role: Merck, Tesaro, R-Pharm, Eisai, Daiichi Sankyo/Astra Zeneca Research Funding: Tesaro (Inst), Merck (Inst), Boehringer Ingelheim (Inst), Gilead Sciences (Inst), Puma Biotechnology (Inst), Genentech/Roche (Inst), R-Pharm (Inst), Immunomedics (Inst), Verastem (Inst) Premal H. Thaker Stock and Other Ownership Interests: Immunon Consulting or Advisory Role: Iovance Biotherapeutics, Novocure, GlaxoSmithKline, Eisai, Merck, AstraZeneca, Immunogen, Zentalis, Verastem/Pharmacyclics, Immunon, Corcept Therapeutics, BioNTech SE, Mural Oncology, Caris Life Sciences Research Funding: Merck (Inst), GlaxoSmithKline (Inst) Christine Gennigens Honoraria: MSD Oncology, Ipsen, Pfizer, PharmaMar, AstraZeneca, GlaxoSmithKline, Bristol Myers Squibb/Celgene Consulting or Advisory Role: MSD Oncology, Bristol Myers Squibb/Celgene, Ipsen, AstraZeneca, GlaxoSmithKline, Eisai, Genmab, Pharma& GmBH Research Funding: AstraZeneca, Lilly (Inst), Bristol Myers Squibb/Celgene (Inst), MSD (Inst), Novartis (Inst), Gilead/Forty Seven (Inst), AstraZeneca (Inst), GlaxoSmithKline (Inst), Pfizer (Inst) Travel, Accommodations, Expenses: Ipsen, PharmaMar, Pfizer, MSD Oncology, AstraZeneca, GlaxoSmithKline Hagop Youssoufian Employment: Deciphera (I), Pfizer (I) Stock and Other Ownership Interests: Verastem, Treos Bio, OnCusp Therapeutics Consulting or Advisory Role: Treos Bio, Verastem, Beam Therapeutics, Cothera Kathleen N. Moore Leadership: GOG Partners, NRG Oncology (Inst) Honoraria: Astellas Medivation, Clinical Education Alliance, The Clearity Foundation, Haymarket Medical Education, IDEOlogy Health, Medscape Consulting or Advisory Role: Genentech/Roche, Immunogen, AstraZeneca, Merck, Eisai, Mersana (Inst), Blueprint Medicines (Inst), GlaxoSmithKline/Tesaro (Inst), Verastem/Pharmacyclics, AADi, Caris Life Sciences, Iovance Biotherapeutics, Duality Biologics (Inst), Janssen Oncology, Regeneron, Zentalis, Daiichi Sankyo Europe GmbH, Novocure, BioNTech SE, Immunocore, Sanofi/Aventis, Seagen, Takeda Science Foundation, Zymeworks, ProfoundBio, Schrodinger (Inst), ADC Therapeutics, Corcept Therapeutics, Third Arc, Loxo/Lilly, Bristol Myers Squibb Foundation, Tango Therapeutics, AbbVie, T knife, Roche, Exelixis, Xencor, Elucida Oncology, Tubulis GmbH, Clovis Oncology Research Funding: Merck (Inst), Regeneron (Inst), Verastem (Inst), AstraZeneca (Inst), Immunogen (Inst), Artios (Inst), Amgen (Inst), Daiichi Sankyo/Lilly (Inst), Immunocore (Inst) Other Relationship: GOG Partners (Inst) Stephanie Lustgarten Employment: Verastem Stock and Other Ownership Interests: Verastem David M. O'Malley Consulting or Advisory Role: AstraZeneca, Novocure, GOG Foundation, GlaxoSmithKline, Regeneron, Sutro Biopharma, Corcept Therapeutics, Merck, Verastem, DualityBio, Pfizer, AbbVie, Zentalis Research Funding: Amgen (Inst), AstraZeneca (Inst), Genentech/Roche (Inst), Regeneron (Inst), Immunogen (Inst), Clovis Oncology (Inst), EMD Serono (Inst), Ergomed (Inst), Immunogen (Inst), Cerulean Pharma (Inst), PharmaMar (Inst), Array BioPharma (Inst), Bristol Myers Squibb (Inst), Tesaro (Inst), Genmab (Inst), Seagen (Inst), Iovance Biotherapeutics (Inst), Leap Therapeutics (Inst), Merck (Inst), Abbvie/Stemcentrx (Inst), AbbVie (Inst), Mersana (Inst), Eisai (Inst), BBI Healthcare (Inst), Sumitomo Dainippon Pharma Oncology, Inc (Inst), Acerta Pharma (Inst), Advaxis (Inst), Ajinomoto (Inst), Arcus Biosciences (Inst), Deciphera (Inst), EMD Serono (Inst), Exelixis (Inst), Roche (Inst), Incyte (Inst), Karyopharm Therapeutics (Inst), Ludwig Institute for Cancer Research (Inst), Novartis (Inst), NovoCure (Inst), OncoQuest (Inst), BeiGene (Inst), Pfizer (Inst), Precision Therapeutics (Inst), Sanofi (Inst), Seagen (Inst), Sutro Biopharma (Inst), GlaxoSmithKline (Inst), Verastem (Inst), Zentalis (Inst), Pfizer (Inst) Toon Van Gorp Consulting or Advisory Role: Immunogen (Inst), Eisai Europe (Inst), OncXerna Therapeutics (Inst), GlaxoSmithKline (Inst), MSD/Merck (Inst), Seagen (Inst), Tubulis GmbH (Inst), Incyte (Inst), Zentalis (Inst), Karyopharm Therapeutics (Inst), BioNTech SE (Inst), AbbVie (Inst), BeiGene (Inst), AstraZeneca (Inst), Pharma& (Inst), Daiichi Sankyo (Inst), Genmab (Inst), Lilly (Inst), TORL Biotherapeutics (Inst), Verastem (Inst) Speakers' Bureau: AbbVie (Inst), AstraZeneca (Inst), Eisai (Inst), GlaxoSmithKline (Inst), MSD (Inst) Research Funding: Amgen (Inst), Roche (Inst), AstraZeneca (Inst) Travel, Accommodations, Expenses: MSD/Merck (Inst), Immunogen (Inst), GlaxoSmithKline (Inst), PharmaMar (Inst), AstraZeneca (Inst) Rachel N. Grisham Employment: Memorial Sloan-Kettering Cancer Center Consulting or Advisory Role: GlaxoSmithKline, AstraZeneca, Signatera, Corcept Therapeutics, Intellisphere, SpringWorks Therapeutics, Verastem Research Funding: Context Therapeutics (Inst), Verastem (Inst), SpringWorks Therapeutics (Inst), Bayer (Inst), Novartis (Inst) Travel, Accommodations, Expenses: EMD Serono Other Relationship: Prime Oncology, MCM Education, OncLive, Aptitude Health, Cardinal Health Uncompensated Relationships: Verastem No other potential conflicts of interest were reported. Epub 2025/07/11. eng.