| Abstract: |
PURPOSE To investigate the safety, tolerability, pharmacokinetics (PK), and preliminary antitumor activity of inavolisib, a potent and selective small-molecule inhibitor of p110a that promotes the degradation of mutated p110a, in combination with palbociclib and endocrine therapy (ET), in a phase I/Ib study in patients with PIK3CA-mutated, hormone receptor–positive/human epidermal growth factor receptor 2–negative locally advanced/metastatic breast cancer (ClinicalTrials.gov identifier: NCT03006172). METHODS Women ≥18 years of age received inavolisib, palbociclib, and letrozole (Inavo 1 Palbo 1 Letro arm) or fulvestrant (Inavo 1 Palbo 1 Fulv arm) until unacceptable toxicity or disease progression. The primary objective was to evaluate safety or tolerability. RESULTS Fifty-three patients were included, 33 in the Inavo 1 Palbo 1 Letro arm and 20 in the Inavo 1 Palbo 1 Fulv arm. Median duration of inavolisib treatment was 15.7 and 20.8 months (cutoff: March 27, 2023), respectively. Treatment-related adverse events (TRAEs) occurred in all patients; the most frequent were stomatitis, hyperglycemia, and diarrhea; grade ≥3 any TRAE rates were 87.9% and 85.0%; 6.1% and 10.0% discontinued any treatment due to TRAEs in the Inavo 1 Palbo 1 Letro and Inavo 1 Palbo 1 Fulv arms, respectively. No PK drug–drug interactions (DDIs) were observed among the study treatments when administered. Confirmed objective response rates were 52.0% and 40.0% in patients with measurable disease, and median progression-free survival was 23.3 and 35.0 months in the Inavo 1 Palbo 1 Letro and Inavo 1 Palbo 1 Fulv arms, respectively. Available paired pre- and on-treatment tumor tissue and circulating tumor DNA analyses confirmed the effects of study treatment on pharmacodynamic and pathophysiologic biomarkers of response. CONCLUSION Inavolisib plus palbociclib and ET demonstrated a manageable safety profile, lack of DDIs, and promising preliminary antitumor activity. © 2024 by American Society of Clinical Oncology. |
| Keywords: |
adult; aged; aged, 80 and over; middle aged; genetics; mutation; clinical trial; pyridines; antineoplastic agent; metabolism; antineoplastic combined chemotherapy protocols; epidermal growth factor receptor 2; pathology; breast neoplasms; multicenter study; breast tumor; receptor, erbb-2; receptors, estrogen; receptors, progesterone; letrozole; phase 1 clinical trial; piperazines; estrogen receptor; progesterone receptor; drug therapy; piperazine derivative; fulvestrant; pyridine derivative; erbb2 protein, human; very elderly; pik3ca protein, human; phosphatidylinositol 4,5 bisphosphate 3 kinase; humans; human; female; palbociclib; class i phosphatidylinositol 3-kinases
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