Background
cancer, RET, colorectal cancers
CANCER, RECRUITMENT, DISEASE PROGRESSION, COLORECTAL CANCERS
Gastro-oesophageal cancer is the seventh most common cancer globally with an estimated 500,000 new cases diagnosed annually [Chemotherapy is a well-established first- and second-line treatment option for patients with AGOC. The combination of fluoropyrimidine and platinum-based chemotherapy is commonly used in the first line setting in patients with human epidermal growth factor receptor 2 (HER2) negative AGOC [Regorafenib (BAY 73–4506) is a promising treatment option in AGOC. Regorafenib is an oral multikinase inhibitor (TKI) that targets angiogenic (VEGF, TIE-2), stromal (PDGF-β), and oncogenic (RAF, RET and KIT) receptor tyrosine kinases [The results of INTEGRATE formed the basis for launching the original INTEGRATE II phase III RCT with the aim of investigating whether regorafenib at a dose of 160 mg daily given on days 1 to 21 of a 28-day cycle is better than placebo in prolonging OS in participants with refractory AGOC who have failed two or more lines of chemotherapy. Both arms received best supportive care and crossover of placebo participants to receive regorafenib at disease progression was not allowed.After INTEGRATE II opened for recruitment, standard practice in the management of AGOC shifted with increasing evidence through phase II [The INTEGRATE II research plan was consequently expanded to become a platform protocol that included a new second trial comparing regorafenib in combination with nivolumab (experimental treatment) against chemotherapy (control treatment). This new study was called INTEGRATE IIb and the original study was renamed INTEGRATE IIa.INTEGRATE IIb is a phase III RCT that investigates whether regorafenib 90 mg daily on day 1 to 21 of a 28-day cycle in combination with nivolumab 240 mg every 2 weeks is superior to chemotherapy alone in prolonging OS in the overall and Asian sub-population of participants with AGOC who have progressed following two or more lines of treatment. The rationale behind INTEGRATE IIb is the REGONIVO phase Ib trial, a dose-finding/dose expansion Japanese study which assessed the combination of regorafenib and nivolumab in 50 participants with previously treated gastric and colorectal cancers [INTEGRATE IIa and INTEGRATE IIb are two relevant trials that will further clarify the role of regorafenib in the treatment of AGOC. INTEGRATE IIa will answer the important question of whether regorafenib monotherapy is better than placebo in participants with chemotherapy refractory AGOC. INTEGRATE IIa will also provide information on the role of regorafenib monotherapy in participants who cannot have further chemotherapy or immune checkpoint inhibitors. INTEGRATE IIb seeks to evaluate the efficacy of regorafenib in combination with immune checkpoint inhibitors in comparison to standard of care chemotherapy in the third or later line setting.