Discussion
INTEGRATE IIa and INTEGRATE IIb address the clinically important question of exploring later line therapies that can improve overall survival in participants with refractory AGOC. INTEGRATE IIa and INTEGRATE IIb have similar inclusion/exclusion criteria and primary/secondary endpoints. The use of one previous line of immune checkpoint inhibitor is allowed in INTEGRATE IIb. The rationale for this is that some participants may have had immunotherapy in combination with chemotherapy as first line treatment for their AGOC as per the CheckMate 649 study [There are a few major differences between INTEGRATE IIa and INTEGRATE IIb. INTEGRATE IIa compares regorafenib to placebo whilst INTEGRATE IIb compares regorafenib and nivolumab to chemotherapy. INTEGRATE IIa uses placebo as the control arm as there was minimal evidence at the time of protocol development to support third line chemotherapy as the standard of care. However, a systematic review and meta-analysis by Zheng et al. from 19 studies subsequently showed that third-line chemotherapy compared to placebo was associated with a better median OS (HR 0.68, 95% CI 0.57–0.82, Another difference between INTEGRATE IIa and INTEGRATE IIb is the starting dose of regorafenib. In INTEGRATE IIa, the starting dose of regorafenib is 160 mg (4 × 40 mg) whilst the starting dose of regorafenib is lower in INTEGRATE IIb 90 mg (3 × 30 mg). In the REGONIVO phase I study, the optimal dose of regorafenib when combined with nivolumab in terms of efficacy and safety is 80 mg [In summary, INTEGRATE II provides a platform to evaluate the clinical utility of regorafenib alone, as well as regorafenib in combination with nivolumab in the treatment of participants with AGOC who have failed two or more lines of treatment. The results of this study will hopefully improve the current standard of care in the treatment of AGOC.