First-line regorafenib with nivolumab and chemotherapy in advanced oesophageal, gastric, or gastro-oesophageal junction cancer in the USA: A single-arm, single-centre, phase 2 trial Journal Article
| Authors: | Cytryn, S. L.; Moy, R. H.; Cowzer, D.; Shah, R. H.; Chou, J. F.; Joshi, S. S.; Ku, G. Y.; Maron, S. B.; Desai, A.; Yang, J.; Sugarman, R.; Rao, D.; Goldberg, Z.; Charalambous, C.; Lapshina, M.; Antoine, A.; Socolow, F.; Trivedi, N.; Capanu, M.; Gerdes, H.; Schattner, M. A.; Simmons, M.; Lacouture, M. E.; Paroder, V.; Tang, L. H.; Shia, J.; Ilson, D. H.; Solit, D. B.; Berger, M. F.; Janjigian, Y. Y. |
| Article Title: | First-line regorafenib with nivolumab and chemotherapy in advanced oesophageal, gastric, or gastro-oesophageal junction cancer in the USA: A single-arm, single-centre, phase 2 trial |
| Abstract: | Background: The addition of nivolumab to chemotherapy improves survival in patients with advanced oesophagogastric (oesophageal, gastric, or gastro-oesophageal junction) adenocarcinoma; however, outcomes remain poor. We assessed the safety and activity of regorafenib in combination with nivolumab and chemotherapy in the first-line treatment of advanced oesophagogastric adenocarcinoma. Methods: This investigator-initiated, single-arm, phase 2 trial in adult patients (aged ≥18 years) with previously untreated, HER2-negative, metastatic oesophagogastric adenocarcinoma was done at the Memorial Sloan Kettering Cancer Center (New York, NY, USA). Eligible patients had measurable disease or non-measurable disease that was evaluable (defined by Response Evaluation Criteria in Solid Tumours [RECIST] version 1.1) and Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received FOLFOX chemotherapy (fluorouracil [400 mg/m2 bolus followed by 2400 mg/m2 over 48 h], leucovorin [400 mg/m2], and oxaliplatin [85 mg/m2]) and nivolumab (240 mg) intravenously on days 1 and 15, and oral regorafenib (80 mg) on days 1–21 of a 28-day cycle. Treatment was continued until disease progression (defined by RECIST version 1.1), unacceptable toxicity, or withdrawal of consent. The primary endpoint was 6-month progression-free survival in the per-protocol population (ie, all participants who received a dose of all study treatments). The regimen would be considered worthy of further investigation if at least 24 of 35 patients were progression free at 6 months. Safety was assessed in all participants who received at least one dose of any study treatment. This trial is registered with ClinicalTrials.gov, NCT04757363, and is now complete. Findings: Between Feb 11, 2021, and May 4, 2022, 39 patients were enrolled, received at least one dose of study drug, and were included in safety analyses. 35 patients were evaluable for 6-month progression-free survival. Median age was 57 years (IQR 52–66), nine (26%) patients were women, 26 (74%) were men, 28 (80%) were White, and seven (20%) were Asian. At data cutoff (March 3, 2023), median follow-up was 18·1 months (IQR 12·7–20·4). The primary endpoint was reached, with 25 (71%; 95% CI 54–85) of 35 patients progression free at 6 months. Nine (26%) of 35 patients had disease progression and one (3%) patient died; the death was unrelated to treatment. The most common adverse event of any grade was fatigue (36 [92%] of 39). The most common grade 3 or 4 adverse events were decreased neutrophil count (18 [46%]), hypertension (six [15%]), dry skin, pruritus, or rash (five [13%]), and anaemia (four [10%]). Serious treatment-related adverse events occurred in ten (26%) patients, which were acute kidney injury (three [8%]), hepatotoxicity (two [5%]), sepsis (two [5%]), dry skin, pruritus, or rash (one [3%]), nausea (one [3%]), and gastric perforation (one [3%]). There were no treatment-related deaths. Interpretation: Regorafenib can be safely combined with nivolumab and chemotherapy and showed promising activity in HER2-negative metastatic oesophagogastric cancer. A randomised, phase 3 clinical trial is planned. Funding: Bristol Myers Squibb, Bayer and National Institutes of Health/National Cancer Institute. © 2023 Elsevier Ltd |
| Keywords: | adolescent; adult; cancer survival; clinical article; controlled study; middle aged; clinical trial; constipation; drug tolerability; fatigue; paresthesia; fluorouracil; advanced cancer; cancer growth; diarrhea; drug efficacy; drug safety; hypertension; united states; follow up; antineoplastic agent; anorexia; adenocarcinoma; progression free survival; liver toxicity; multiple cycle treatment; neutrophil count; phase 2 clinical trial; anemia; nausea; randomized controlled trial; vomiting; antineoplastic combined chemotherapy protocols; myalgia; peripheral neuropathy; clinical protocol; pathology; risk assessment; abdominal pain; arthralgia; coughing; dyspnea; febrile neutropenia; fever; pruritus; rash; acute kidney failure; dysphagia; hypokalemia; hyponatremia; disease progression; thromboembolism; folinic acid; urinary tract infection; peripheral edema; sepsis; stomach cancer; headache; phase 3 clinical trial; oxaliplatin; esophagus cancer; hand foot syndrome; dry skin; hematoma; alopecia; stomach neoplasms; cholecystitis; disease exacerbation; esophagus tumor; esophageal neoplasms; stomach tumor; caucasian; oral mucositis; dysgeusia; muscle cramp; respiratory failure; exanthema; asian; stomach perforation; gastroesophageal junction; faintness; nivolumab; infusion related reaction; regorafenib; humans; human; male; female; article; esophagogastric adenocarcinoma |
| Journal Title: | Lancet Oncology |
| Volume: | 24 |
| Issue: | 10 |
| ISSN: | 1470-2045 |
| Publisher: | Elsevier Science, Inc. |
| Date Published: | 2023-10-01 |
| Start Page: | 1073 |
| End Page: | 1082 |
| Language: | English |
| DOI: | 10.1016/s1470-2045(23)00358-3 |
| PUBMED: | 37666264 |
| PROVIDER: | scopus |
| PMCID: | PMC11208000 |
| DOI/URL: | |
| Notes: | Article -- MSK author Karmelina Charalambous's first name is misspelled on the original publication -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PubMed and PDF -- MSK corresponding author is Yelena Janjigian -- Source: Scopus |
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