Napabucasin Plus FOLFIRI in Patients With Previously Treated Metastatic Colorectal Cancer: Results From the Open-Label, Randomized Phase III CanStem303C Study

Napabucasin is an investigational, orally administered reactive oxygen species generator that has been evalu-ated in solid tumors, including metastatic colorectal cancer (mCRC). In the multi-center, open-label, phase III CanStem303C (NCT02753127) study, 1253 adults with mCRC that progressed on first-line fluoropyrimi-dine + oxaliplatin +/- bevacizumab were randomized to FOLFIRI +/- twice-daily napabucasin. Adding napabucasin to FOLFIRI did not improve overall survivalPurpose: 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, includ-ing 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 popula-tion and in patients with pSTAT3-positive tumors (biomarker-positive). Results: In the general study population (napabu-casin, 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.

Automated summary

In this study, patients with colorectal cancer were divided into two groups, one receiving combination therapy of napabucasin and FOLFIRI, and the other receiving FOLFIRI alone. The results showed that the addition of napabucasin to FOLFIRI did not significantly improve overall survival compared to the control group.