Details

Autor(en) / Beteiligte

• Keenan, Tanya E
• Li, Tianyu
• Vallius, Tuulia
• Guerriero, Jennifer L
• Tayob, Nabihah
• Kochupurakkal, Bose
• Davis, Janae
• Pastorello, Ricardo
• Tahara, Rie K
• Anderson, Leilani
• Conway, Jake
• He, Meng X
• Shannon, Erin
• Godin, Robert E
• Sorger, Peter K
• D'Andrea, Alan
• Overmoyer, Beth
• Winer, Eric P
• Mittendorf, Elizabeth A
• Van Allen, Eliezer M
• Shapiro, Geoffrey I
• Tolaney, Sara M

Titel

Clinical Efficacy and Molecular Response Correlates of the WEE1 Inhibitor Adavosertib Combined with Cisplatin in Patients with Metastatic Triple-Negative Breast Cancer

Ist Teil von

• Clinical cancer research, 2021-02, Vol.27 (4), p.983-991

Ort / Verlag

United States

Erscheinungsjahr

2021

Quelle

MEDLINE

Beschreibungen/Notizen

• We report results from a phase II study assessing the efficacy of the WEE1 inhibitor adavosertib with cisplatin in metastatic triple-negative breast cancer (mTNBC). Patients with mTNBC treated with 0-1 prior lines of chemotherapy received cisplatin 75 mg/m i.v. followed 21 days later by cisplatin plus adavosertib 200 mg oral twice daily for five doses every 21 days. The study had 90% power to detect the difference between null (20%) and alternative (40%) objective response rates (ORR) with a one-sided type I error of 0.1: an ORR >30% was predefined as making the regimen worthy of further study. RNA sequencing and multiplex cyclic immunofluorescence on pre- and post-adavosertib tumor biopsies, as well as targeted next-generation sequencing on archival tissue, were correlated with clinical benefit, defined as stable disease ≥6 months or complete or partial response. A total of 34 patients initiated protocol therapy; median age was 56 years, 2 patients (6%) had mutations, and 14 (41%) had one prior chemotherapy. ORR was 26% [95% confidence interval (CI), 13-44], and median progression-free survival was 4.9 months (95% CI, 2.3-5.7). Treatment-related grade 3-5 adverse events occurred in 53% of patients, most commonly diarrhea in 21%. One death occurred because of sepsis, possibly related to study therapy. Tumors from patients with clinical benefit demonstrated enriched immune gene expression and T-cell infiltration. Among patients with mTNBC treated with 0-1 prior lines, adavosertib combined with cisplatin missed the prespecified ORR cutoff of >30%. The finding of immune-infiltrated tumors in patients with clinical benefit warrants validation.