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Regorafenib combination explored in untreated metastatic oesophagogastric cancer

An early, first-in-setting study suggests adding investigational regorafenib to nivolumab and chemotherapy may be safe and active; a randomised phase 3 trial is planned to confirm these preliminary findings.

  • Samuel L Cytryn, MD; Ryan H Moy, MD; Darren Cowzer, MBBCh; Ronak H Shah, MS; Joanne F Chou, MPH; Smita S Joshi, MD; et al.

  • September 1, 2023

  • The Lancet Oncology
  • The Lancet Oncology, Volume 24, Issue 10, Pages 1073–1082
  • 10.1016/S1470-2045(23)00358-3

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Evidence before this study

We searched PubMed for published studies from database inception until April 1, 2023, using the search terms (“gastric cancer” OR “gastroesophageal cancer” OR “esophageal cancer”) AND (“regorafenib” OR “PD-1 inhibitor” OR “PD-L1 inhibitor”). The search was restricted to clinical trials with no language restrictions. We found several trials evaluating PD-1 or PD-L1 inhibitors in combination with chemotherapy for patients with previously untreated metastatic oesophagogastric adenocarcinoma. The CheckMate 649 trial reported significantly improved overall survival with nivolumab plus chemotherapy compared with chemotherapy alone in patients with a PD-L1 combined positive score of at least 5 and in all randomised patients. Following the results of the CheckMate 649 trial in 2021, nivolumab plus fluoropyrimidine and platinum chemotherapy became standard of care for HER2-negative advanced oesophagogastric cancer. The multi-targeted tyrosine-kinase inhibitor, regorafenib, has improved outcomes in refractory, advanced oesophagogastric cancer and when administered in combination with nivolumab in the phase 1b REGONIVO trial, was found to be safe and lead to significant anti-tumour activity in heavily pre-treated patients.

Added value of this study

To our knowledge, this is the first study to evaluate the activity of regorafenib, nivolumab, and chemotherapy in patients with previously untreated metastatic oesophagogastric cancer. We also explored potential molecular determinants of response to inform future studies and identify subsets of patients most likely to benefit from this combination.

Implications of all the available evidence

The results of this study suggest that the addition of regorafenib to nivolumab and chemotherapy is safe and active in treating metastatic oesophagogastric cancer. A randomised phase 3 clinical trial of regorafenib in combination with first-line nivolumab and chemotherapy is planned.

Source: The Lancet Oncology

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