Safety overview and management of inavolisib alone and in combination therapies in PIK3CA-mutated, HR-positive, HER2-negative advanced breast cancer (GO39374) Journal Article
| Authors: | Gambardella, V.; Accordino, M. K.; Bedard, P. L.; Cervantes, A.; Hamilton, E.; Italiano, A.; Kalinsky, K.; Krop, I. E.; Oliveira, M.; Saura, C.; Schmid, P.; Turner, N. C.; Varga, A.; Fernandez-Saranillo, A.; Jin, Y.; Royer-Joo, S.; Peters, U.; Shankar, N.; Schutzman, J. L.; Juric, D.; Jhaveri, K. L. |
| Article Title: | Safety overview and management of inavolisib alone and in combination therapies in PIK3CA-mutated, HR-positive, HER2-negative advanced breast cancer (GO39374) |
| Abstract: | Background: Inavolisib is a potent and selective PI3Kα inhibitor that promotes degradation of mutated p110α. We report safety from a phase I/Ib dose-escalation/-expansion study (GO39374; NCT03006172) of inavolisib alone or in combination therapies in PIK3CA-mutated, hormone receptor (HR)-positive, HER2-negative advanced breast cancer. Patients and methods: Patients received inavolisib [oral once daily (od)] alone, with letrozole (2.5 mg od) or fulvestrant (500 mg intramuscularly 4 weekly) ± palbociclib (125 mg od for 21/28 days); metformin was included in one arm. Primary endpoint: safety and tolerability. Results: At data cutoff (1 January 2024), 190 patients had been treated, of which 179 (94.2%) had discontinued study treatment, mainly due to progressive disease [146 (76.8%)]. Treatment-related any-grade and grade 3-5 adverse events (AEs) occurred in 181 (95.3%) and 107 (56.3%) patients, respectively. Inavolisib-related AEs led to inavolisib withdrawal in 5 (2.6%) and dose reductions/interruptions in 103 (54.2%) patients. Hyperglycemia, diarrhea, stomatitis (grouped terms), and rash (grouped terms) occurred in 129 (67.9%), 124 (65.3%), 93 (48.9%), and 47 (24.7%) patients, respectively. Hyperglycemia, diarrhea, and stomatitis mainly occurred early in treatment, and were manageable with supportive measures (including oral antihyperglycemic agents, common antidiarrheal medications, and dexamethasone mouthwash, respectively) and/or inavolisib dose modifications (dose interruptions with or without dose reductions). Hyperglycemia remained frequent in patients with risk factors, despite early metformin treatment. Rash was mostly grade 1 and required no treatment. Patients treated for ≥1 year [n = 65 (34.2%)] demonstrated encouraging long-term tolerability. Conclusions: Inavolisib alone or in combination with HR-positive breast cancer therapies demonstrated a manageable safety and tolerability profile, which supports its ongoing development. © 2025 The Author(s) |
| Keywords: | signal transduction; adult; controlled study; aged; gene mutation; major clinical study; constipation; drug tolerability; fatigue; neutropenia; cancer combination chemotherapy; diarrhea; drug dose reduction; drug safety; drug withdrawal; monotherapy; side effect; treatment duration; gene; multiple cycle treatment; breast cancer; anemia; mucosa inflammation; nausea; stomatitis; vomiting; cohort analysis; dexamethasone; phosphatidylinositol 3 kinase; risk factor; abdominal pain; arthralgia; cancer hormone therapy; coughing; drug dose escalation; hyperglycemia; pruritus; rash; aspartate aminotransferase; maculopapular rash; patient care; acne; erythema; insulin; oral antidiabetic agent; safety; dermatitis; headache; letrozole; maximum tolerated dose; phase 1 clinical trial; trastuzumab; drug dose increase; glossodynia; alopecia; metformin; pik3ca gene; ulcer; fulvestrant; dysgeusia; antidiarrheal agent; mouthwash; hand disease; mouth ulcer; decreased appetite; lip disease; pioglitazone; palate disease; tongue ulcer; advanced breast cancer; human epidermal growth factor receptor 2 positive breast cancer; hormone receptor-positive; human; male; female; article; palbociclib; glossitis; pi3k inhibitor; sitagliptin; hormone receptor-positive, her2-negative breast cancer; inavolisib; pik3ca-mutated |
| Journal Title: | ESMO Open |
| Volume: | 10 |
| Issue: | 7 |
| ISSN: | 2059-7029 |
| Publisher: | European Society for Medical Oncology |
| Date Published: | 2025-07-01 |
| Start Page: | 105303 |
| Language: | English |
| DOI: | 10.1016/j.esmoop.2025.105303 |
| PUBMED: | 40513140 |
| PROVIDER: | scopus |
| PMCID: | PMC12205636 |
| DOI/URL: | |
| Notes: | Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PDF -- Source: Scopus |
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