PURPOSE: Napabucasin is an investigational, orally administered reactive oxygen species generator bioactivated by intracellular antioxidant NAD(P)H:quinone oxidoreductase 1 that has been evaluated in various solid tumors, including metastatic colorectal cancer (mCRC). Phosphorylated signal transducer and activator of transcription 3 (pSTAT3) is hypothesized to predict response in napabucasin-treated patients with mCRC. PATIENT AND METHODS: In the multi-center, open-label, phase III CanStem303C (NCT02753127) study, adults with histologically confirmed mCRC that progressed on first-line fluoropyrimidine plus oxaliplatin ± bevacizumab were randomized to twice-daily napabucasin plus FOLFIRI (napabucasin) or FOLFIRI alone (control). The primary endpoint was overall survival (OS) in the general study population and in patients with pSTAT3-positive tumors (biomarker-positive). RESULTS: In the general study population (napabucasin, n = 624; control, n = 629), median OS was 14.3 months for napabucasin and 13.8 months for control (hazard ratio [HR], 0.976, one-sided P = .74). Overall, 44% of patients were biomarker-positive (napabucasin, n = 275; control, n = 272). In the biomarker-positive population, median OS was 13.2 months for napabucasin and 12.1 months for control (HR, 0.969; one-sided P > .99). In the control arm, median OS was shorter for biomarker-positive versus biomarker negative patients (12.1 vs. 18.5 months; HR, 1.518; nominal 2-sided P = .0002). The most common treatment-emergent adverse events (TEAEs) were diarrhea (napabucasin, 84.6%; control, 53.9%), nausea (60.5%, 50.5%), vomiting (41.2%, 29.3%), and abdominal pain (41.0%, 25.2%). Grade ≥3 TEAEs occurred in 73.8% of napabucasin-treated and 66.7% of control-treated patients, most commonly diarrhea (21.2%, 7.0%), neutrophil count decreased (13.7%, 19.2%), and neutropenia (13.3%, 15.2%). Safety was similar in biomarker-positive patients. CONCLUSION: In patients with previously treated mCRC, adding napabucasin to FOLFIRI did not improve OS. Results from the control arm indicate that pSTAT3 is an adverse prognostic factor in mCRC.

Cancer Institute Hospital of Japanese Foundation for Cancer Research Tokyo Japan

City of Hope Comprehensive Cancer Center Duarte CA

Department of Medical Oncology Austin Health Melbourne Australia; University of Melbourne Melbourne Australia

Hôpital Europeen Georges Pompidou APHP Paris France; Université de Paris Paris France; CARPEM Cancer Institute Paris France

Incliva Biomedical Research Institute Valencia Spain; University of Valencia Valencia Spain

Korea University College of Medicine Seoul South Korea

Masaryk Memorial Cancer Institute Brno Czech Republic

National Cancer Center Hospital East Kashiwa Japan

Sarah Cannon Research Institute Tennessee Oncology Nashville TN

Sumitomo Dainippon Pharma Oncology Inc Cambridge MA

Sun Yat sen University Cancer Center Guangzhou China

The Angeles Clinic and Research Institute a Cedars Sinai affiliate Los Angeles CA

University Hospitals Gasthuisberg Leuven and KULeuven Leuven Belgium

University of Pisa Pisa Italy; Department of Translational Research University of Pisa Pisa Italy

Vall d'Hebron Hospital Campus and Institute of Oncology IOB Quiron UVic UCC Barcelona Spain

Weill Cornell Medicine New York NY; New York Presbyterian Hospital New York NY

West Cancer Center and Research Institute Germantown TN

Winship Cancer Institute Emory University Atlanta GA

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