Napabucasin Clinically Active in Both Pancreatic and Colon Cancer

Tanios Bekaii-Saab, MD

The novel stemness inhibitor napabucasin in combination with different standard chemotherapy backbones demonstrated promising activity in metastatic pancreatic adenocarcinoma and metastatic colorectal cancer, according to findings from 2 separate studies presented during the 2017 ESMO World Gastrointestinal Cancer conference.¹

Napabucasin is a first-in-class cancer stemness inhibitor that blocks STAT3-driven gene transcription and spherogenesis of cancer stem cells, which are highly tumorigenic and fundamental in the development of resistance to therapy, disease recurrence, and metastasis.

Results from preclinical studies suggest that napabucasin also has the ability to sensitize heterogeneous cancer cells to chemotherapy and targeted agents, prompting investigators to evaluate napabucasin in combination with standard of care chemotherapy regimens.

Tanios S. Bekaii-Saab, MD, medical oncologist at the Mayo Clinic Cancer Center in Phoenix, and colleagues evaluated the anticancer activity of napabucasin combined with gemcitabine and nab-paclitaxel in patients with metastatic pancreatic adenocarcinoma (mPDAC) in a phase Ib/II multicenter study.

Of 66 patients with histologic or cytologic evidence of pancreatic adenocarcinoma in the intent to treat (ITT) population, 49 (74%) were treatment-naïve and 17 (26%) had received neoadjuvant treatment. All patients were treated with oral napabucasin at 240 mg twice daily plus weekly nab-paclitaxel at 125 mg/m² and gemcitabine at 1000 mg/m² for 3 of 4 weeks until disease progression.

The study’s primary endpoint was safety and tolerability and the determination of the recommended phase II dose to be taken forward for further evaluation. The patients’ median age was 64.5 years (range, 47 to 82), 53% were male, and the majority (59%) had an ECOG performance status of 1.

Of the 55 evaluable patients, 51 patients demonstrated a response, yielding a 93% disease control rate that included 1 complete response (CR), 26 patients showed partial response (PR), and 24 patients had stable disease. The objective response rate (CR + PR) was 55%. Four patients in the evaluable group had progressive disease (PD); 3 progressed while on treatment and 1 patient experienced PD after going off treatment due to toxicity.

“This response is highly promising, as there is little response rate regularly seen in this disease,” commented Bekaii-Saab.

The 1-year overall survival rate was 56% and the maturing progression-free survival was 7.1 months. All but 10 patients showed tumor reduction. In addition, the majority of patients showed decreased CA 19-9 levels from baseline; 73% of patients showed a ≥20% reduction, 73% showed ≥50%, and 37% of patients demonstrated ≥90% decrease in CA 19-9 levels.

“No evident difference was observed between the safety profiles with nabpaclitaxel/gemcitabine and nabpaclitaxel/gemcitabine plus napabucasin,” said Bekaii-Saab.

In another presentation at the World GI Congress, Bert O’Neil, MD, director of the Phase I and Gastrointestinal Oncology Programs at Indiana University, shared findings on napabucasin combined with FOLFIRI, with or without bevacizumab in patients with metastatic colorectal cancer.²

“STAT3 plays a role in the survival and proliferation of colorectal cancer stem cells, and napabucasin has demonstrated the ability to block colorectal stem cell self-renewal and to kill colorectal stem cells and cancer cells,” according to O’Neil.

Oral napabucasin was administered twice daily at 240 mg continuously and standard FOLFIRI was given on days 1 and 15 of a 28-day cycle; bevacizumab 5 mg/kg was allowed at investigator discretion. The primary endpoint of the study was safety and tolerability.

No dose-limiting, unexpected toxicity or significant pharmacokinetic interactions occurred with napabucasin and FOLFIRI. The most commonly reported adverse events (AEs) included grades 1/2 diarrhea, nausea, vomiting, and fatigue. Grade 3 AEs included neutropenia in 23.2% of patients, diarrhea in 18%, and fatigue in 7.3% of patients. Grade 4 neutropenia occurred at a frequency of 11%, and diarrhea and thrombocytopenia each occurred at 1.2%.

Disease control lasting 6 months or greater (range, 24.3 to 78.4 weeks) was seen in 30 (37%) of patients in the ITT population. Disease control with napabucasin plus FOLFIRI was observed in 19 of the 32 patients who had progressed on prior FOLFIRI. The majority of patients showed tumor reduction.

Both authors commented that napabucasin can be safely combined with these standard therapies.

“These encouraging signs of efficacy in metastatic pancreatic adenocarcinoma are now being confirmed in a phase III study, said Bekaii-Saab.

O’Neil described a phase III study of napabucasin plus FOLFIRI (bevacizumab by investigator discretion) that is now enrolling patients with metastatic colorectal cancer who had received prior FOLFOX or XELOX. The primary endpoint is OS. “The response rate and disease control associated with napabucasin and FOLFIRI in metastatic colorectal cancer is very promising,” he concluded.

References

1. Bekaii-Saab, et al. A phase Ib/II study of cancer stemness inhibitor napabucasin in combination with gemcitabine (gem) & nab-paclitaxel (nabPTX) in metastatic pancreatic adenocarcinoma (mPDAC) patients (pts). Ann Oncol. 2017;28(suppl 3); LBA-002.
2. BH O’Neil, et al. Phase 1b/II study of cancer stemness inhibitor napabucasin in combination with FOLFIRI +/- Bevacizumab (bev) in metastatic colorectal cancer (mCRC) Patients (pts). Ann Oncol. 2017;28(suppl 3); LBA-003.

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View more from the 2017 World Congress on GI Cancer

He discussed early findings from an ongoing phase Ib/II multicenter study that enrolled 82 pretreated patients with colorectal cancer who had failed an average of >2 prior lines of therapy. The median age of the patients was 59 years (range, 24 to 89), 59% of patients were male, and 32 patients had failed prior FOLFOX. Thirty-three percent of patients had KRAS wild-type tumors, 38% had mutated K-Ras and 29% had not been tested.