| Autor: |
Johann S. de Bono, Yvette Drew, Juanita S. Lopez, Bristi Basu, Ruth Plummer, Udai Banerji, Christopher J. Lord, Andrew Foxley, Justin P.O. Lindemann, Paul Rugman, Emma Hall, Laura Finneran, Karen E. Swales, Shaun Decordova, Florence I. Raynaud, Ruth Ruddle, Nicholas C. Turner, Heidrun Gevensleben, Neha Chopra, Nina Tunariu, Alison Turner, Mona Parmar, Ruth Matthews, Sarah Ward, Daniel Nava Rodrigues, Ines Figueiredo, Susana Miranda, Ruth Riisnaes, Rowan Miller, Desamparados Roda, Suzanne Carreira, Joline S.J. Lim, Stephen J. Pettitt, Vasiliki Michalarea, Rebecca Kristeleit, Timothy A. Yap |
| Rok vydání: |
2023 |
| Popis: |
Preclinical studies have demonstrated synergy between PARP and PI3K/AKT pathway inhibitors in BRCA1 and BRCA2 (BRCA1/2)–deficient and BRCA1/2-proficient tumors. We conducted an investigator-initiated phase I trial utilizing a prospective intrapatient dose- escalation design to assess two schedules of capivasertib (AKT inhibitor) with olaparib (PARP inhibitor) in 64 patients with advanced solid tumors. Dose expansions enrolled germline BRCA1/2-mutant tumors, or BRCA1/2 wild-type cancers harboring somatic DNA damage response (DDR) or PI3K–AKT pathway alterations. The combination was well tolerated. Recommended phase II doses for the two schedules were: olaparib 300 mg twice a day with either capivasertib 400 mg twice a day 4 days on, 3 days off, or capivasertib 640 mg twice a day 2 days on, 5 days off. Pharmacokinetics were dose proportional. Pharmacodynamic studies confirmed phosphorylated (p) GSK3β suppression, increased pERK, and decreased BRCA1 expression. Twenty-five (44.6%) of 56 evaluable patients achieved clinical benefit (RECIST complete response/partial response or stable disease ≥ 4 months), including patients with tumors harboring germline BRCA1/2 mutations and BRCA1/2 wild-type cancers with or without DDR and PI3K–AKT pathway alterations.Significance:In the first trial to combine PARP and AKT inhibitors, a prospective intrapatient dose- escalation design demonstrated safety, tolerability, and pharmacokinetic–pharmacodynamic activity and assessed predictive biomarkers of response/resistance. Antitumor activity was observed in patients harboring tumors with germline BRCA1/2 mutations and BRCA1/2 wild-type cancers with or without somatic DDR and/or PI3K–AKT pathway alterations.This article is highlighted in the In This Issue feature, p. 1426 |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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