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N Engl J Med. 2019 May 16;380(20):1929-1940. doi: 10.1056/NEJMoa1813904.

Alpelisib for PIK3CA-Mutated, Hormone Receptor-Positive Advanced Breast Cancer.

Collaborators (197)

Rubovszky G, Kaufman B, Yamashita T, Lu YS, Ciruelos Gil EM, Inoue K, Takahashi M, Pápai Z, Arnedos M, Stemmer S, Cerda H, Campone M, Tesch H, Jurado JC, Toledano I, Rodriguez W, Delgado Mingorance JI, Safra T, Park YH, Krivorotko P, Forget F, Levy C, Masuda N, Lee KH, Melisko M, Huober J, Singer C, Mouret Reynier MA, Iwata H, Iwase H, Sohn J, Yamauchi T, Tomova A, Schenker M, Niikura N, Ungureanu A, Sriuranpong V, Kaen D, Henning JW, Borrego MR, Kurteva G, Deleu GFI, Popov V, Garcia Saenz JA, Timar-David M, Kim J, Lopez Lopez R, Perello Martorell A, Takano T, Kattan J, Wright G, Yañez E, Mundhenke C, Aggarwal L, Nakayama T, Airoldi M, Ludmila L, Alonso Romero JL, Arnaud A, Bianchi GV, Denduluri N, Shtivelband M, Kowalyszyn R, Chouinard E, Farhat F, Sevillano Fernandez E, Bermejo de Las Heras B, Perez Garcia JM, De Toro Salas R, Tseng LM, Sandri I, Barbeaux A, Brust L, Provencher L, Leheurteur M, Nusch A, Yousuf AF, Conte P, Gonzalez Cortijo L, Awada A, Schmidt M, Gopichand M, Lee KS, Vallejos C, Villman K, Aieta M, Rocca A, Takashima S, Van Dijk M, Martinez de Duenas E, Yardley D, Grossi M, Spazzapan S, Reinoso Toledo JG, Ahmed S, Volkov N, Dieterich M, Chiu J, Kaklamani V, Cuff K, Sagara Y, Casalnuovo M, Huizing M, Kohoutek M, Dalenc F, Figueroa Martinez P, Ponce Lorenzo J, Donev I, Brezden-Masley C, Derbel O, Welslau M, Berardi R, Akewanlop C, Dimopoulos M, Gupta S, Tonini G, Natoli C, van de Wouw A, Neciosup S, Margeli Vila M, Nilsson C, Toppmeyer D, Marx G, Holeckova P, Kisro J, Park-Simon TW, Erfan J, Matsumoto K, Kim SB, Overton L, Fontaine C, Campone M, Priou F, Langanke D, Riseberg D, Juric D, Chap L, Dent S, Polikoff J, Varela M, Silva Melo Cruz FJ, Fernandez Abad M, Silverman P, Colangiovanni Girotto G, Fischer D, Allegrini G, Cunha Souza S, Karanikiotis H, Borrega Garcia P, Vukelja S, Northfelt D, Beck JT, Kozevnikovova R, Juhasz-Boess I, Geffen D, Karak FE, Zamora Aunon P, Hart L, Adams J, Santucci Alves da Silva B, Acevedo A, Christodoulou C, Mehta A, Pazzola A, Edlund P, Panwar U, Torrey M, Meyer A, Petzer A, Tournigand C, Heflik L, Mayer F, Gori S, Clement D, Shomova M, Law T, Horenkamp E, Rao R, Poncin R, Priester P, Baciuchka-Palmaro M, Mayeur D, Toledano A, Benasso M, Blasi L, Fujii T, Krie A, Pluard T, Cobb P, Kash J, Sanchez-Rivera I, McIntyre K, O'Rourke M, Mahmood T, Onwere I, Patel N, Zarwan C.

Author information

1
From Institut Gustave Roussy, INSERM Unité 981, Université Paris-Sud, Villejuif (F.A.), Institut de Cancérologie de l'Ouest, St. Herblain (M.C.), and Novartis Pharma, Paris (A.-S.L.) - all in France; Hospital Universitario 12 de Octubre, Madrid (E.C.); National Institute of Oncology (G.R.) and Duna Medical Center (Z.P.), Budapest, Hungary; German Breast Group, Neu-Isenburg, and Center for Hematology and Oncology Bethanien, Frankfurt - both in Germany (S.L.); UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco (H.S.R.); Aichi Cancer Center, Nagoya (H.I.), Kanagawa Cancer Center, Yokohama (T.Y.), Saitama Cancer Center, Saitama (K.I.), and National Hospital Organization Hokkaido Cancer Center, Sapporo (M.T.) - all in Japan; Istituto Oncologico Veneto and the Departments of Surgery, Oncology, and Gastroenterology, University of Padua, Padua, Italy (P.C.); Vanderbilt University, Nashville (I.A.M.); Chaim Sheba Medical Center, Tel Hashomer, Israel (B.K.); National Taiwan University Hospital, Taipei (Y.-S.L.); Novartis Pharma, Basel, Switzerland (D.M., C.W.); Novartis Pharmaceuticals, East Hanover, NJ (S.H.); and Massachusetts General Hospital Cancer Center, Boston (D.J.).

Abstract

BACKGROUND:

PIK3CA mutations occur in approximately 40% of patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer. The PI3Kα-specific inhibitor alpelisib has shown antitumor activity in early studies.

METHODS:

In a randomized, phase 3 trial, we compared alpelisib (at a dose of 300 mg per day) plus fulvestrant (at a dose of 500 mg every 28 days and once on day 15) with placebo plus fulvestrant in patients with HR-positive, HER2-negative advanced breast cancer who had received endocrine therapy previously. Patients were enrolled into two cohorts on the basis of tumor-tissue PIK3CA mutation status. The primary end point was progression-free survival, as assessed by the investigator, in the cohort with PIK3CA-mutated cancer; progression-free survival was also analyzed in the cohort without PIK3CA-mutated cancer. Secondary end points included overall response and safety.

RESULTS:

A total of 572 patients underwent randomization, including 341 patients with confirmed tumor-tissue PIK3CA mutations. In the cohort of patients with PIK3CA-mutated cancer, progression-free survival at a median follow-up of 20 months was 11.0 months (95% confidence interval [CI], 7.5 to 14.5) in the alpelisib-fulvestrant group, as compared with 5.7 months (95% CI, 3.7 to 7.4) in the placebo-fulvestrant group (hazard ratio for progression or death, 0.65; 95% CI, 0.50 to 0.85; P<0.001); in the cohort without PIK3CA-mutated cancer, the hazard ratio was 0.85 (95% CI, 0.58 to 1.25; posterior probability of hazard ratio <1.00, 79.4%). Overall response among all the patients in the cohort without PIK3CA-mutated cancer was greater with alpelisib-fulvestrant than with placebo-fulvestrant (26.6% vs. 12.8%); among patients with measurable disease in this cohort, the percentages were 35.7% and 16.2%, respectively. In the overall population, the most frequent adverse events of grade 3 or 4 were hyperglycemia (36.6% in the alpelisib-fulvestrant group vs. 0.7% in the placebo-fulvestrant group) and rash (9.9% vs. 0.3%). Diarrhea of grade 3 occurred in 6.7% of patients in the alpelisib-fulvestrant group, as compared with 0.3% of those in the placebo-fulvestrant group; no diarrhea of grade 4 was reported. The percentages of patients who discontinued alpelisib and placebo owing to adverse events were 25.0% and 4.2%, respectively.

CONCLUSIONS:

Treatment with alpelisib-fulvestrant prolonged progression-free survival among patients with PIK3CA-mutated, HR-positive, HER2-negative advanced breast cancer who had received endocrine therapy previously. (Funded by Novartis Pharmaceuticals; SOLAR-1 ClinicalTrials.gov number, NCT02437318.).

PMID:
31091374
DOI:
10.1056/NEJMoa1813904
[Indexed for MEDLINE]

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