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 trialResearch in context
Summary: 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 negati...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-04-01
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| Series: | EClinicalMedicine |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589537023000743 |
| _version_ | 1827987854582611968 |
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| author | Tanios Bekaii-Saab Takuji Okusaka David Goldstein Do-Youn Oh Makoto Ueno Tatsuya Ioka Weijia Fang Eric C. Anderson Marcus S. Noel Michele Reni Hye Jin Choi Jonathan S. Goldberg Sang Cheul Oh Chung-Pin Li Josep Tabernero Jian Li Emma Foos Cindy Oh Eric Van Cutsem |
| author_facet | Tanios Bekaii-Saab Takuji Okusaka David Goldstein Do-Youn Oh Makoto Ueno Tatsuya Ioka Weijia Fang Eric C. Anderson Marcus S. Noel Michele Reni Hye Jin Choi Jonathan S. Goldberg Sang Cheul Oh Chung-Pin Li Josep Tabernero Jian Li Emma Foos Cindy Oh Eric Van Cutsem |
| author_sort | Tanios Bekaii-Saab |
| collection | DOAJ |
| description | Summary: 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. |
| first_indexed | 2024-04-09T23:53:28Z |
| format | Article |
| id | doaj.art-5dbeea00320a4570827b5add5de5eb9c |
| institution | Directory Open Access Journal |
| issn | 2589-5370 |
| language | English |
| last_indexed | 2024-04-09T23:53:28Z |
| publishDate | 2023-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EClinicalMedicine |
| spelling | doaj.art-5dbeea00320a4570827b5add5de5eb9c2023-03-17T04:33:44ZengElsevierEClinicalMedicine2589-53702023-04-0158101897Napabucasin 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 trialResearch in contextTanios Bekaii-Saab0Takuji Okusaka1David Goldstein2Do-Youn Oh3Makoto Ueno4Tatsuya Ioka5Weijia Fang6Eric C. Anderson7Marcus S. Noel8Michele Reni9Hye Jin Choi10Jonathan S. Goldberg11Sang Cheul Oh12Chung-Pin Li13Josep Tabernero14Jian Li15Emma Foos16Cindy Oh17Eric Van Cutsem18Division of Hematology and Medical Oncology, Mayo Clinic Arizona, Scottsdale, AZ, USA; Corresponding author. Medical Oncology, Mayo Clinic Cancer Center, 5777 East Mayo Boulevard, Phoenix, AZ, 85054, USA.Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, JapanDepartment of Medical Oncology, Prince of Wales Hospital, Randwick, NSW, AustraliaDepartment of Internal Medicine, Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Integrated Major in Innovative Medical Science, Seoul National University Graduate School, Seoul, Republic of KoreaDepartment of Gastroenterology, Hepatobiliary and Pancreatic Medical Oncology Division, Kanagawa Cancer Center, Kanagawa, JapanOncology Center, Yamaguchi University Hospital, Yamaguchi, JapanMedical Oncology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, ChinaDivision of Hematology/Medical Oncology, Oregon Health and Science University, Knight Cancer Institute, Portland, OR, USADepartment of Medicine, Division of Medical Oncology, MedStar Georgetown University Hospital, Washington, DC, USADepartment of Oncology, Pancreas Center, IRCCS Ospedale, San Raffaele Scientific Institute, Milan, ItalyInternal Medicine, Yonsei University College of Medicine, Seoul, Republic of KoreaHematology/Oncology, CareMount Medical, Mount Kisco, NY, USADepartment of Medical Oncology, Korea University College of Medicine, Seoul, Republic of KoreaDivision of Clinical Skills Training, Department of Medical Education, Taipei Veterans General Hospital, Taipei, Taiwan; Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, TaiwanMedical Oncology Department, Vall d'Hebron Hospital Campus and Institute of Oncology (VHIO), IOB-Quiron, UVic-UCC, Barcelona, SpainClinical Development, Sumitomo Pharma Oncology, Inc., Cambridge, MA, USABiostatistics, Sumitomo Pharma Oncology, Inc., Cambridge, MA, USAClinical Operations, Sumitomo Pharma Oncology, Inc., Cambridge, MA, USADigestive Oncology, University Hospitals Gasthuisberg, Leuven & KULeuven, Leuven, BelgiumSummary: 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.http://www.sciencedirect.com/science/article/pii/S2589537023000743NapabucasinPancreatic cancerAdenocarcinomaMetastatic pancreatic adenocarcinomaPhosphorylated signal transducer and activator of transcription 3 |
| spellingShingle | Tanios Bekaii-Saab Takuji Okusaka David Goldstein Do-Youn Oh Makoto Ueno Tatsuya Ioka Weijia Fang Eric C. Anderson Marcus S. Noel Michele Reni Hye Jin Choi Jonathan S. Goldberg Sang Cheul Oh Chung-Pin Li Josep Tabernero Jian Li Emma Foos Cindy Oh Eric Van Cutsem 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 trialResearch in context EClinicalMedicine Napabucasin Pancreatic cancer Adenocarcinoma Metastatic pancreatic adenocarcinoma Phosphorylated signal transducer and activator of transcription 3 |
| title | 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 trialResearch in context |
| title_full | 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 trialResearch in context |
| title_fullStr | 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 trialResearch in context |
| title_full_unstemmed | 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 trialResearch in context |
| title_short | 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 trialResearch in context |
| title_sort | 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 trialresearch in context |
| topic | Napabucasin Pancreatic cancer Adenocarcinoma Metastatic pancreatic adenocarcinoma Phosphorylated signal transducer and activator of transcription 3 |
| url | http://www.sciencedirect.com/science/article/pii/S2589537023000743 |
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