Napabucasin plus nab-paclitaxel with gemcitabine versus nab-paclitaxel with gemcitabine in previously untreated metastatic pancreatic adenocarcinoma: an adaptive multicentre, randomised, open-label, phase 3, superiority trial.

Background: Compared with normal cells, tumour cells contain elevated levels of reactive oxygen species (ROS). Increased levels of the antioxidant protein NAD(P)H:quinone oxidoreductase 1 (NQO1) and phosphorylated signal transducer and activator of transcription 3 (pSTAT3) correlate negatively with the survival of patients with pancreatic cancer. Napabucasin is an investigational, orally administered ROS generator bioactivated by NQO1.
Methods: In the open-label, phase 3 CanStem111P study (NCT02993731), adults with previously untreated metastatic pancreatic adenocarcinoma (mPDAC) were randomised (1:1) to napabucasin plus nab-paclitaxel with gemcitabine or nab-paclitaxel with gemcitabine alone. The primary endpoint was overall survival (OS). In exploratory analyses, OS was evaluated in the subgroup of patients with tumours positive for pSTAT3 (biomarker-positive).
Findings: Between 30 January 2017 and 20 February 2019, a total of 1779 patients were screened across 165 study sites in Austria, Australia, Belgium, Canada, China, Czech Republic, France, Germany, Italy, Japan, Korea, Netherlands, Poland, Portugal, Russia, Singapore, Spain, Taiwan, Ukraine, and the US. Of the 565 and 569 patients randomised to the napabucasin and control treatment arms, respectively, 206 and 176 were biomarker-positive. Median (95% confidence interval [CI]) OS in the napabucasin and control treatment arms was 11.4 (10.5-12.2) and 11.7 (10.7-12.7) months, respectively (hazard ratio, 1.07; 95% CI, 0.93-1.23). Due to the lack of OS improvement in the napabucasin arm, CanStem111P was terminated due to futility. In the biomarker-positive subgroup, no difference between treatment arms was found for OS. Grade ≥3 adverse events were reported in 85.4% and 83.9% of napabucasin-treated and control-treated patients, respectively. The incidence of gastrointestinal-related grade ≥3 events was higher with napabucasin (diarrhoea: 11.6% vs 4.9%; abdominal pain: 10.0% vs 4.8%).
Interpretation: Our findings suggested that although the addition of napabucasin to nab-paclitaxel with gemcitabine did not improve efficacy in patients with previously untreated mPDAC, the safety profile of napabucasin was consistent with previous reports. CanStem111P represents the largest cohort of patients with mPDAC administered nab-paclitaxel with gemcitabine in the clinical trial setting. Our data reinforce the value of nab-paclitaxel plus gemcitabine as a platform for novel therapeutics approaches in mPDAC.
Funding: The Sumitomo Pharma Oncology, Inc.
Competing Interests: Tanios Bekaii-Saab has received research funding (paid to institution) from Agios, Arys, Arcus, Atreca, Boston Biomedical, Bayer, Amgen, Merck, Celgene, Lilly, Ipsen, Clovis, Seattle Genetics, Genentech, Novartis, Mirati, Merus, Abgenomics, Incyte, Pfizer, and Bristol Myers Squibb; served as a consultant (paid to institution) to Ipsen, Array, Pfizer, Seattle Genetics, Bayer, Genentech, Incyte, and Merck; served as a consultant (paid to self) to AbbVie, Boehringer Ingelheim, Janssen, Eisai, Daichii Sankyo, Natera, TreosBio, Celularity, Exact Science, Sobi, Beigene, Xilis, AstraZeneca, and Foundation Medicine; served on independent data monitoring committees/data and safety monitoring boards (paid to self) for AstraZeneca, Exelixis, Lilly, PanCan, and 1Globe; participated in advisory boards for Imugene, Immuneering, and Sun Biopharma; and holds the following inventions/patents: WO/2018/183488 and WO/2019/055687. Takuji Okusaka has received research grants (paid to self and institution) from Eisai, Eli Lilly, Sumitomo Dainippon Pharma Oncology, AstraZeneca, Chugai, Bristol Myers Squibb, Merck Sharp & Dohme, Baxter, and Taiho; participates in advisory boards for Sumitomo Pharma Oncology, Bristol Myers Squibb, and Nihon Servier; and has been a member of speakers' bureaus at Eisai, Novartis, Eli Lilly, Sumitomo Pharma Oncology, AstraZeneca, Chugai, Bristol Myers Squibb, Merck Sharp & Dohme, Taiho, Nihon Servier, Ono, Yakult Honsha, Daiichi Sankyo, Nippon Shinyaku, Pfizer, and Mundipharma. Do-Youn Oh participates in advisory boards (paid to self) for AstraZeneca, Novartis, Genentech/Roche, 13 Merck Serono, Bayer, Taiho, ASLAN, Halozyme, Zymeworks, Bristol Myers Squibb/Celgene, BeiGene, Basilea, Turning Point, Yuhan, Arcus Biosciences and IQVIA and has received research grants (paid to institution) from AstraZeneca, Novartis, Array, Eli Lilly, 15 Servier, BeiGene, Merck Sharp & Dohme, and Handok. Makoto Ueno has been an invited speaker (paid to self) for Taiho, Yakult Honsha, AstraZeneca, Merck, Eisai, Merck Sharp & Dohme, Servier, and Chugai and has received research grants (paid to institution) from Astellas, Taiho, Eisai, AstraZeneca, Ono, Merck Sharp & Dohme, Merck, Incyte, and Chugai. Tatsuya Ioka is a member of speakers’ bureaus at and serves as an advisor to Taiho (paid to self), is on the advisory board (paid to self) at Incyte, and has received research grants (paid to institution) from AstraZeneca, Incyte, Eisai, and Astellas. Michele Reni has participated in advisory boards (paid to self) for Eli Lilly, Celgene, AstraZeneca, Shire, Baxter, Servier, SOTIO, Viatris, and Merck Sharp & Dohme. Hye Jin Choi has received consulting fees (paid to self) from AstraZeneca and Roche. Josep Tabernero has participated in advisory boards (paid to self) for Array, AstraZeneca, Avvinity, Bayer, Boehringer, Chugai, Daiichi Sankyo, F. Hoffman La Roche, Genentech, HalioDx, Hutinson, Ikena Oncology, IQVIA, Lily, Menarini, Merck Serono, Merus, Merck Sharp & Dohme, Mirati, Neophore, Novartis, Orion, Peptomyc, Pfizer, Pierre Fabre, Samsung Biologics, Sanofi, Seattle Genomics, Servier, Taiho, Tessa, and Theramyc. Jian Li is a salaried employee of Sumitomo Pharma Oncology. Emma Foos was a salaried employee of Sumitomo Pharma Oncology at the time that these analyses were undertaken. Cindy Oh was a salaried employee of Sumitomo Pharma Oncology at the time that these analyses were undertaken. Eric Van Cutsem has participated in advisory boards Abbvie, ALX, Amgen, Array, Astellas, Astrazeneca, Bayer, Beigene, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi, GSK, Incyte, Ipsen, Lilly, Merck Sharp & Dohme, Merck KGaA, Mirati, Novartis, Nordic, Pierre Fabre, Pfizer, Roche, Seattle Genetics, Servier, Takeda, Terumo, Taiho, Zymeworks. His institution has also received research grants from Amgen, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Ipsen, Lilly, Merck Sharp & Dohme, Merck KGaA, Novartis, Roche, Servier. Weijia Fang, Eric C. Anderson, Jonathan S. Goldberg, Sang Cheul Oh, David Goldstein, Marcus Noel, and Chung-Pin Li have nothing to disclose.
(© 2023 The Author(s).)