Inavolisib-based therapy in PIK3CA-mutated advanced breast cancer Journal Article


Authors: Turner, N. C.; Im, S. A.; Saura, C.; Juric, D.; Loibl, S.; Kalinsky, K.; Schmid, P.; Loi, S.; Sunpaweravong, P.; Musolino, A.; Li, H.; Zhang, Q.; Nowecki, Z.; Leung, R.; Thanopoulou, E.; Shankar, N.; Lei, G.; Stout, T. J.; Hutchinson, K. E.; Schutzman, J. L.; Song, C.; Jhaveri, K. L.
Article Title: Inavolisib-based therapy in PIK3CA-mutated advanced breast cancer
Abstract: Background Inavolisib 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. Methods In 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. Results A 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. Conclusions In 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.). © 2024 Massachusetts Medical Society.
Keywords: adult; controlled study; aged; middle aged; survival analysis; unclassified drug; major clinical study; genetics; mutation; clinical trial; mortality; neutropenia; placebo; diarrhea; drug dose reduction; drug withdrawal; pyridines; comparative study; follow up; antineoplastic agent; polymerase chain reaction; gene; progression free survival; multiple cycle treatment; phase 2 clinical trial; breast cancer; randomized controlled trial; stomatitis; antineoplastic combined chemotherapy protocols; epidermal growth factor receptor 2; hemoglobin; pathology; breast neoplasms; risk factor; hyperglycemia; liver metastasis; lung metastasis; body mass; death; multicenter study; adjuvant chemotherapy; breast tumor; tamoxifen; visceral metastasis; glucose; hormonal therapy; phase 3 clinical trial; piperazines; kaplan meier method; premenopause; drug therapy; piperazine derivative; double blind procedure; double-blind method; metastatic breast cancer; brain hemorrhage; disease exacerbation; climacterium; imidazoles; bronchitis; cerebrovascular accident; fulvestrant; imidazole derivative; breast neoplasms, male; pyridine derivative; phosphatidylinositol 3 kinase inhibitor; progression-free survival; kaplan-meier estimate; luteinizing hormone; acute coronary syndrome; pik3ca; hematology/oncology; high throughput sequencing; oxazoles; pik3ca protein, human; phosphatidylinositol 4,5 bisphosphate 3 kinase; humans; human; male; female; article; circulating tumor dna; palbociclib; oxazole derivative; cdk4/6 inhibitor; coronavirus disease 2019; class i phosphatidylinositol 3-kinases; phosphoinositide-3 kinase inhibitors; treatments in oncology; inavolisib
Journal Title: New England Journal of Medicine
Volume: 391
Issue: 17
ISSN: 0028-4793
Publisher: Massachusetts Medical Society  
Date Published: 2024-10-31
Start Page: 1584
End Page: 1596
Language: English
DOI: 10.1056/NEJMoa2404625
PUBMED: 39476340
PROVIDER: scopus
DOI/URL:
Notes: Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PDF -- Source: Scopus
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  1. Komal Lachhman Jhaveri
    201 Jhaveri