TY - JOUR
T1 - Efficacy and Safety of Avutometinib ± Defactinib in Recurrent Low-Grade Serous Ovarian Cancer
T2 - Primary Analysis of ENGOT-OV60/GOG-3052/RAMP 201
AU - Banerjee, Susana N.
AU - Van Nieuwenhuysen, Els
AU - Aghajanian, Carol
AU - D'Hondt, Véronique
AU - Monk, Bradley J.
AU - Clamp, Andrew
AU - Prendergast, Emily
AU - Oaknin, Ana
AU - Ring, Kari
AU - Colombo, Nicoletta
AU - Holloway, Robert W.
AU - Rodrigues, Manuel
AU - Chon, Hye Sook
AU - Gourley, Charlie
AU - Santin, Alessandro D.
AU - Thaker, Premal H.
AU - Gennigens, Christine
AU - Newman, Gregg
AU - Salinas, Erin
AU - Youssoufian, Hagop
AU - Moore, Kathleen N.
AU - Lustgarten, Stephanie
AU - O'Malley, David M.
AU - Van Gorp, Toon
AU - Grisham, Rachel N.
N1 - Publisher Copyright:
© 2025 American Society of Clinical Oncology.
PY - 2025/9/1
Y1 - 2025/9/1
N2 - PURPOSEThis 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).METHODSIn 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.RESULTSA 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.CONCLUSIONThe 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).
AB - PURPOSEThis 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).METHODSIn 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.RESULTSA 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.CONCLUSIONThe 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).
UR - https://www.scopus.com/pages/publications/105011150283
U2 - 10.1200/JCO-25-00112
DO - 10.1200/JCO-25-00112
M3 - Article
C2 - 40644648
AN - SCOPUS:105011150283
SN - 0732-183X
VL - 43
SP - 2782
EP - 2792
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
IS - 25
ER -