Multicenter randomized phase II trial of atezolizumab with or without cobimetinib in biliary tract cancers Journal Article
| Authors: | Yarchoan, M.; Cope, L.; Ruggieri, A. N.; Anders, R. A.; Noonan, A. M.; Goff, L. W.; Goyal, L.; Lacy, J.; Li, D.; Patel, A. K.; He, A. R.; Abou-Alfa, G. K.; Spencer, K.; Kim, E. J.; Davis, S. L.; McRee, A. J.; Kunk, P. R.; Goyal, S.; Liu, Y.; Dennison, L.; Xavier, S.; Mohan, A. A.; Zhu, Q.; Wang-Gillam, A.; Poklepovic, A.; Chen, H. X.; Sharon, E.; Lesinski, G. B.; Azad, N. S. |
| Article Title: | Multicenter randomized phase II trial of atezolizumab with or without cobimetinib in biliary tract cancers |
| Abstract: | BACKGROUND. MEK inhibitors have limited activity in biliary tract cancers (BTCs) as monotherapy but are hypothesized to enhance responses to programmed death ligand 1 (PD-L1) inhibition. METHODS. This open-label phase II study randomized patients with BTC to atezolizumab (anti–PD-L1) as monotherapy or in combination with cobimetinib (MEK inhibitor). Eligible patients had unresectable BTC with 1 to 2 lines of prior therapy in the metastatic setting, measurable disease, and Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 1. The primary endpoint was progression-free survival (PFS). RESULTS. Seventy-seven patients were randomized and received study therapy. The trial met its primary endpoint, with a median PFS of 3.65 months in the combination arm versus 1.87 months in the monotherapy arm (HR 0.58, 90% CI 0.35–0.93, 1-tail P = 0.027). One patient in the combination arm (3.3%) and 1 patient in the monotherapy arm (2.8%) had a partial response. Combination therapy was associated with more rash, gastrointestinal events, CPK elevations, and thrombocytopenia. Exploratory analysis of tumor biopsies revealed enhanced expression of antigen processing and presentation genes and an increase in CD8/FoxP3 ratios with combination treatment. Patients with higher baseline or lower fold changes in expression of certain inhibitory ligands (LAG3, BTLA, VISTA) on circulating T cells had evidence of greater clinical benefit from the combination. CONCLUSION. The combination of atezolizumab plus cobimetinib prolonged PFS as compared with atezolizumab monotherapy, but the low response rate in both arms highlights the immune-resistant nature of BTCs. © 2021, American Society for Clinical Investigation. |
| Keywords: | adult; cancer survival; controlled study; human tissue; treatment response; aged; disease-free survival; middle aged; major clinical study; clinical trial; fatigue; mortality; neutropenia; cancer combination chemotherapy; diarrhea; hypertension; monotherapy; side effect; disease free survival; antineoplastic agent; anorexia; cd8 antigen; transcription factor foxp3; edema; progression free survival; phase 2 clinical trial; gene expression; anemia; esophagitis; gastrointestinal symptom; nausea; randomized controlled trial; thrombocytopenia; vomiting; antineoplastic combined chemotherapy protocols; dehydration; hypercalcemia; tumor biopsy; monoclonal antibody; abdominal pain; dizziness; febrile neutropenia; fever; hyperglycemia; lymphocytopenia; pruritus; rash; hypokalemia; hyponatremia; antigen presentation; multicenter study; xerostomia; colitis; open study; creatine kinase; piperidines; headache; meningitis; biliary tract cancer; biliary tract neoplasms; small intestine obstruction; biliary tract tumor; progression-free survival; thyroid disease; piperidine derivative; exploratory research; myocarditis; antibodies, monoclonal, humanized; faintness; noncardiac chest pain; humans; human; male; female; article; cobimetinib; atezolizumab; non st segment elevation myocardial infarction; ecog performance status; azetidine derivative; azetidines |
| Journal Title: | Journal of Clinical Investigation |
| Volume: | 131 |
| Issue: | 24 |
| ISSN: | 0021-9738 |
| Publisher: | American Society for Clinical Investigation |
| Date Published: | 2021-12-15 |
| Start Page: | e152670 |
| Language: | English |
| DOI: | 10.1172/jci152670 |
| PUBMED: | 34907910 |
| PROVIDER: | scopus |
| PMCID: | PMC8670844 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 February 2022 -- Source: Scopus |
