Clinical efficacy and molecular response correlates of the WEE1 inhibitor adavosertib combined with cisplatin in patients with metastatic triple-negative breast cancer (mTNBC).
2020
Purpose 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). Experimental design Patients with mTNBC treated with 0-1 prior lines of chemotherapy received cisplatin 75 mg/m2 IV followed 21 days later by cisplatin plus adavosertib 200 mg oral twice daily for 5 doses every 21 days. The study had 90% power to detect the difference between null (20%) and alternative (40%) objective response rates (ORRs) 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. Results 34 patients initiated protocol therapy; median age was 56 years, 2 patients (6%) had BRCA2 mutations, and 14 (41%) had one prior chemotherapy. ORR was 26% (95%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 due to sepsis, possibly related to study therapy. Tumors from patients with clinical benefit demonstrated enriched immune gene expression and T cell infiltration. Conclusions 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.
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