• Nicholas C Turner, Seock-Ah Im, Cristina Saura, Dejan Juric, Sibylle Loibl, Kevin Kalinsky, Peter Schmid, Sherene Loi, Patrapim Sunpaweravong, Antonino Musolino, Huiping Li, Qingyuan Zhang, Zbigniew Nowecki, Roland Leung, Eirini Thanopoulou, Noopur Shankar, Guiyuan Lei, Thomas J Stout, Katherine E Hutchinson, Jennifer L Schutzman, Chunyan Song, and Komal L Jhaveri.
• From the Royal Marsden Hospital and Institute of Cancer Research (N.C.T.) and the Centre for Experimental Cancer Medicine, Barts Cancer Institute, Queen Mary University of London (P. Schmid), London, and Roche, Welwyn Garden City (E.T., G.L.) - all in the United Kingdom; Seoul National University Hospital, Seoul National University College of Medicine, Cancer Research Institute, Seoul National University, Seoul, South Korea (S.-A.I.); Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology, Barcelona (C. Saura); Mass General Cancer Center, Department of Medicine, Harvard Medical School, Boston (D.J.); Winship Cancer Institute at Emory University, Atlanta (K.K.); Genentech, San Francisco (N.S., T.J.S., K.E.H., J.L.S., C. Song); the Breast and Early Drug Development Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, and Weill Cornell Medical College - both in New York (K.L.J.); the German Breast Group, Neu-Isenburg, and the Center for Hematology and Oncology Bethanien, Goethe University, Frankfurt - both in Germany (S. Loibl); the Division of Cancer Research and Clinical Medicine, Peter MacCallum Cancer Centre, Melbourne, VIC, and the Sir Peter MacCallum Department of Medical Oncology, University of Melbourne, Parkville, VIC - both in Australia (S. Loi); the Division of Medical Oncology, Department of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand (P. Sunpaweravong); the Department of Medicine, University of Parma, Parma, and the Medical Oncology and Breast Unit, IRCCS Istituto Romagnolo per lo Studio dei Tumori "Dino Amadori," Meldola - both in Italy (A.M.); the Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Department of Breast Oncology, Peking University Cancer Hospital and Institute, Beijing (H.L.), Harbin Medical University, Harbin (Q.Z.), and the University Department of Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong (R.L.) - all in China; and Maria Skłodowska-Curie Institute of Oncology, Warsaw, Poland (Z.N.).
• N. Engl. J. Med. 2024 Oct 31; 391 (17): 158415961584-1596.

BackgroundInavolisib is a highly potent and selective inhibitor of the alpha isoform of the p110 catalytic subunit of the phosphatidylinositol 3-kinase complex (encoded by PIK3CA) that also promotes the degradation of mutated p110α. Inavolisib plus palbociclib-fulvestrant has shown synergistic activity in preclinical models and promising antitumor activity in early-phase trials.MethodsIn a phase 3, double-blind, randomized trial, we compared first-line inavolisib (at an oral dose of 9 mg once daily) plus palbociclib-fulvestrant (inavolisib group) with placebo plus palbociclib-fulvestrant (placebo group) in patients with PIK3CA-mutated, hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer who had had relapse during or within 12 months after the completion of adjuvant endocrine therapy. The primary end point was progression-free survival as assessed by the investigator.ResultsA total of 161 patients were assigned to the inavolisib group and 164 to the placebo group; the median follow-up was 21.3 months and 21.5 months, respectively. The median progression-free survival was 15.0 months (95% confidence interval [CI], 11.3 to 20.5) in the inavolisib group and 7.3 months (95% CI, 5.6 to 9.3) in the placebo group (hazard ratio for disease progression or death, 0.43; 95% CI, 0.32 to 0.59; P<0.001). An objective response occurred in 58.4% of the patients in the inavolisib group and in 25.0% of those in the placebo group. The incidence of grade 3 or 4 neutropenia was 80.2% in the inavolisib group and 78.4% in the placebo group; grade 3 or 4 hyperglycemia, 5.6% and 0%, respectively; grade 3 or 4 stomatitis or mucosal inflammation, 5.6% and 0%; and grade 3 or 4 diarrhea, 3.7% and 0%. No grade 3 or 4 rash was observed. Discontinuation of any trial agent because of adverse events occurred in 6.8% of the patients in the inavolisib group and in 0.6% of those in the placebo group.ConclusionsIn patients with PIK3CA-mutated, hormone receptor-positive, HER2-negative locally advanced or metastatic breast cancer, inavolisib plus palbociclib-fulvestrant led to significantly longer progression-free survival than placebo plus palbociclib-fulvestrant, with a greater incidence of toxic effects. The percentage of patients who discontinued any trial agent because of adverse events was low. (Funded by F. Hoffmann-La Roche; INAVO120 ClinicalTrials.gov number, NCT04191499.).Copyright © 2024 Massachusetts Medical Society.

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