Atezolizumab Plus Cobimetinib Improves Cancer Control for Patients with Biliary Tract Cancer

Research presented at the American Association for Cancer Research (AACR) Virtual Annual Meeting, held April 27-28, 2020, found that the combination of atezolizumab (Tecentriq) plus cobimetinib (Cotellic) improved cancer control in some patients with biliary tract cancer.¹

“We wanted to see if combining the 2 drugs resulted in improved anticancer activity in biliary tract cancer,” Mark Yarchoan, MD, assistant professor of oncology at Johns Hopkins Kimmel Cancer, said in a press release.² To find out if the combination was effective, Yarchoan and his colleagues decided to compare the benefit of atezolizumab alone vs atezolizumab plus cobimetinib in a randomized study.

Currently, the standard therapy for patients who have advanced disease is a combination of gemcitabine (Gemzar) and cisplatin, however the survival of patients receiving standard treatment is less than 1 year. 

Cobimetinib blocks mitogen-activated extracellular signal-regulated kinase (MEK), which is part of a signaling pathway known to be overactive in biliary tract cancers.³ Though drugs that block MEK do not generally demonstrate much activity when used alone in biliary tract cancer, they have been found to modify the tumor environment, making it more favorable for treatment with monotherapy. Previous research has shown that the 2-drug combination of cobimetinib and anti-PD-L1 immunotherapy may act synergistically.

The multicenter, randomized phase II trial enrolled 86 patients with advanced biliary tract cancer and randomly assigned them to receive either atezolizumab alone or atezolizumab in combination with cobimetinib. Participants were age 44 to 86, 62% (48) were female, and could have received 1 or 2 prior treatments for biliary tract cancer. Of the total cohort, 77 completed at least 1 dose of therapy, including 39 patients in the single-treatment arm and 38 in the combination treatment arm. 

The primary end point for the study was progression-free survival (PFS) using the Kaplan-Meier method and compared between groups under the assumption of Cox proportional hazards, stratified for primary tumor site. Secondary endpoints included objective response rate (ORR), safety and tolerability, and overall survival (OS). 

Median PFS in the combination therapy group was found to be nearly double (111 days) that seen in the single treatment arm (57 days; P = 0.027). Moreover, this difference in PFS met the study’s primary endpoint and was deemed statistically significant. In the combination arm, there was 1 patient with partial response (PR; 3.2%), 13 with stable disease (SD; 41.9%), and 17 with progressive disease (PD); in the atezolizumab monotherapy arm, there was 1 PR (2.9%), 10 patients with SD (29.4%), and 23 with PD (67.6%). OS data were not mature at the time of analysis. 

Overall, the disease control rate was 14 of 31 patients whose treatment could be measured (45.2%) in the combination treatment arm, and 11 of 34 patients (32.4%) in the single-treatment arm. Further, 2 patients who both received combination treatment remained in the study more than 15 months from study enrollment. In addition, 1 patient in each treatment arm had known mismatch repair deficiency (MMRd), of whom 1 had PD as a best response and the other withdrew prior to response evaluation.

Adverse events (AEs) observed in patients administered the combination were manageable, and included nausea, vomiting, rash, and low blood and platelet counts. Additionally, there were no treatment-related deaths, however 12 patients (4 receiving atezolizumab alone and 8 receiving the combination) halted treatment due to various treatment-related AEs. 

“The low response rates in both treatment groups highlights the challenge of immunotherapy in biliary tract cancer,” Yarchoan explained. “However, the combination of atezolizumab with cobimetinib met its primary outcome and significantly prolonged progression free survival as compared to atezolizumab. This combination warrants further clinical investigation.”

References:

1. AACR. A multicenter randomized phase II trial of atezolizumab as monotherapy or in combination with cobimetinib in biliary tract cancers (BTCs): A NCI Experimental Therapeutics Clinical Trials (ETCTN) study. AACR website. Published April 28, 2020. abstractsonline.com/pp8/#!/9045/presentation/10752. Accessed May 8, 2020. 

2. ASCO. AACR 2020: Atezolizumab Alone or in Combination With Cobimetinib for Biliary Tract Cancer. ASCO website. Published May 5, 2020. ascopost.com/news/may-2020/atezolizumab-alone-or-in-combination-with-cobimetinib-for-biliary-tract-cancer/. Accessed May 8, 2020. 

3. Johns Hopkins Medicine. Novel Immunotherapy/Targeted Therapy Combination Extended Survival in Some Patients With Lethal Biliary Tract Cancers. Johns Hopkins Medicine website. Published May 1, 2020. hopkinsmedicine.org/news/newsroom/news-releases/novel-immunotherapytargeted-therapy-combination-extended-survival-in-some-patients-with-lethal-biliary-tract-cancers. Accessed May 8, 2020.