PD-7 Cabozantinib plus atezolizumab in previously untreated advanced hepatocellular carcinoma (aHCC) and previously treated gastric cancer (GC) and gastroesophageal junction adenocarcinoma (GEJ): Results of the COSMIC-021 study

Cabozantinib may enhance response to immune checkpoint inhibitors by promoting an immune-permissive microenvironment. COSMIC-021 (NCT03170960), a multinational phase 1b study, is evaluating cabozantinib plus atezolizumab in various solid tumors. Efficacy and safety results in previously untreated aHCC (cohort 14) and previously treated GEJ/GC (cohort 15) are presented. Patients had measurable disease and ECOG PS of 0 or 1. Patients with aHCC, Child-Pugh A status, and no prior systemic anticancer therapy were eligible for cohort 14. Patients with GC, GEJ, or lower one-third esophageal adenocarcinoma who radiographically progressed during or following platinum- or fluoropyrimidine-containing chemotherapy and had ≤2 prior lines of therapy were eligible for cohort 15. Patients received cabozantinib 40 mg PO QD and atezolizumab 1200 mg IV Q3W. CT/MRI scans were performed Q6W for 52W and Q12W thereafter. The primary endpoint was ORR by investigator per RECIST 1.1. Other endpoints included safety, PFS, and OS. As of the data cutoff of 21 Dec 2021, 30 patients with aHCC and 31 with GEJ/GC (22 with GEJ, 8 with GC, and 1 other) were enrolled with a median (range) follow-up of 31.2 mo (23.0, 34.2) and 30.4 mo (19.5, 33.6), respectively. For aHCC, median age was 71 y, 12 (40%) had ECOG PS 0; disease etiology was 6 (20%) HBV, 11 (37%) HCV, and 13 (43%) non-viral. Extrahepatic invasion was present/absent in 13 (43%)/16 (53%), macrovascular invasion in 2 (7%)/20 (67%), and portal vein invasion in 10 (33%)/13 (43%). For GEJ/GC, median age was 61 y, 11 (35%) had ECOG PS 0, and 16 (52%), 14 (45%), and 1 (3%) received 1, 2, or 3 prior lines of systemic therapy. ORR per RECIST 1.1 was 13% (all confirmed PRs) for aHCC and 0 for GEJ/GC. Median DOR was 22.1 mo for aHCC. DCR (CR + PR + SD) was 83% for aHCC and 48% for GEJ/GC. Median PFS per RECIST 1.1 was 5.7 mo in aHCC and 2.4 mo in for GEJ/GC; median OS was 19.0 mo and 6.4 mo, respectively. Frequent treatment-related adverse events (TRAEs) for aHCC and GEJ/GC were PPE (47% and 13%), diarrhea (37% and 26%), AST increased (33% and 13%), and fatigue (23% both). Grade 3/4 TRAEs occurred in 40% for aHCC and 35% for GEJ/GC. No grade 5 TRAEs occurred in either cohort. Cabozantinib plus atezolizumab had clinical activity with a manageable safety profile in previously untreated aHCC, consistent with the recently presented phase 3 results in this indication (NCT03755791). Clinical activity of cabozantinib plus atezolizumab was minimal in previously treated GEJ/GC.