Novel Drug Targets Stem Cell Activity in Pancreatic Cancer

Tanios Bekaii-Saab, MD

Napabucasin, a novel therapy that targets cancer stem cell (CSC) pathways, is being investigated in a phase III clinical trial that is believed to be the largest study ever conducted in pancreatic ductal adenocarcinoma (PDAC) in the metastatic setting, according to Tanios S. Bekaii-Saab, MD.

Nearly 1200 patients have enrolled in the CanStem111P trial, which recruited participants at approximately 300 study sites, Bekaii-Saab, a key investigator in the trial, said in an interview with OncologyLive^®. Findings are expected late this year or early next year, depending on there being enough events to analyze outcomes, said Bekaii-Saab, a senior associate consultant in the Division of Hematology/Oncology and a professor of medicine at Mayo Clinic in Phoenix, Arizona.

CanStem111P (NCT02993731)1 is evaluating nab-paclitaxel (Abraxane) plus gemcitabine with and without napabucasin in patients with ≥1 metastatic tumors who have not received chemotherapy for PDAC. Patients in the experimental arm are administered 240-mg napabucasin orally twice daily in combination with weekly nab-paclitaxel at 125 mg/m² plus gemcitabine at 1000 mg/m2 intravenously once weekly, in 3 of every 4 weeks (Figure).¹ Those in the active comparator arm receive nab-paclitaxel plus gemcitabine, which is the current standard of care for PDAC. The primary endpoint is overall survival (OS).

Napabucasin, formerly called BBI-608, is designed to target CSCs via STAT3 signaling. CSCs are “fundamentally responsible for continued malignant growth,” according to a poster Bekaii-Saab and colleagues presented at the 2018 American Society of Clinical Oncology Annual Meeting.2 CSCs are resistant to chemotherapy and radiotherapy; exposure to conventional cytotoxic therapy can result in the conversion of non-CSCs to CSCs.³

STAT3 signaling helps promote cell cycle progression and stemness, which allows cells to renew and proliferate.⁴ A small molecule, napabucasin is aimed at inhibiting STAT3.

“Essentially what it does is prohibit those cancer cells from acquiring a stemness-like feature, which would make them very resistant to chemotherapy,” Bekaii-Saab said. “When [cancer cells] acquire these stemness-like features, it not only makes them incredibly resistant to chemotherapy and radiation therapy, but they also become a harbor for future cells that will also be very resistant.”

Early Study Findings

This pathway is an important target for the treatment of many cancers, he said, but it is the primary target for pancreatic cancer.The rationale for pursuing the study of napabucasin was established in a phase IB/II BBI608-118 study in which the drug was administered in combination with nab-paclitaxel plus gemcitabine in patients with metastatic PDAC who had been treated with ≤2 prior lines of systemic therapy.

Among 59 patients treated during the study, the objective response rate was 47.5%, including 2 (3.4%) participants with a complete response (CR) and 26 (44.1%) with a partial response (PR). The disease control rate (DCR), which includes patients with stable disease, was 78%.²

The outcomes were better among 50 patients evaluated with on-study tumor assessment procedures; the DCR in this group was 92%, including 2 (4%) CRs and 26 (52%) PRs.²

In terms of safety, the most frequently reported (≥20%) adverse events of any grade were diarrhea (69.5%), fatigue (66.1%), nausea (45.8%), and peripheral neuropathy (39.0%).²

Notably, Bekaii-Saab said, the phase IB trial was conducted at a mix of academic centers and community practices. “That representation from the community puts a real-world characterization to this study, unlike what you would see with studies that are either single institution or 3 to 4 academic institutions,” Bekaii-Saab said.

Potential Implications

“For most of these patients, we will have tissue samples taken prior to treatment,” he noted. “The tissue is going to be looked at in terms of trying to find predictors for those patients who will be the best responders and those [who] will have the highest likelihood of achieving favorable outcomes.”If napabucasin combination therapy demonstrates a positive effect on OS in this patient population, Bekaii-Saab said the regimen could become the primary option for metastatic PDAC. “It would change the landscape of how we treat pancreatic cancer,” he said.

The development of novel agents for PDAC correlates with the increased understanding of the tumor microenvironment and its involvement in chemotherapy resistance. Several therapeutic approaches are targeting different aspects of the tumor microenvironment including genomic alterations, mast cells, stromal depleting agents, and CSCs.³

Meanwhile, further exploration of napabucasin’s mechanism of action might reveal more extensive activity. “Because [napabucasin] targets STAT, the agent may also target some of the immune cells in the microenvironment of pancreatic cancer cells, which may be a favorable aspect of this agent as well,” Bekaii-Saab said.

Napabucasin is being developed by Boston Biomedical, a company headquartered in Cambridge, Massachusetts.

References

1. The CanStem111P trial. Boston Biomedical website. bostonbiomedical.com/pipeline/canstem-111p-trial/. Accessed March 4, 2019.
2. Bekaii-Saab T, Starodub A, El-Rayes B, et al. Phase 1b/2 trial of cancer stemness inhibitor napabucasin (NAPA) + nab-paclitaxel (nPTX) and gemcitabine (Gem) in metastatic pancreatic adenocarcinoma (mPDAC). J Clin Oncol. 2018;36(suppl; abstr 4110). meetinglibrary.asco.org/record/160098/abstract.
3. Ahn DH, Ramanathan RK, Bekaii-Saab T. Emerging therapies and future directions in targeting the tumor stroma and immune system in the treatment of pancreatic adenocarcinoma. Cancers (Basel). 2018;10(6). doi: 10.3390/cancers10060193.
4. Yuan J, Zhang F, Niu R. Multiple regulation pathways and pivotal biological functions of STAT3 in cancer. Sci Rep. 2015;5:17663. doi: 10.1038/srep17663.