Atezolizumab plus cobimetinib improves PFS in biliary tract cancer
Atezolizumab plus cobimetinib significantly prolonged PFS compared with atezolizumab alone among a cohort of patients with advanced biliary tract cancer, according to results of a phase 2 study presented at the virtual American Association for Cancer Research Annual Meeting.
The combination also demonstrated manageable toxicity in what researchers described as the first randomized trial of immunotherapy in this patient population.
“Biliary tract cancers are uncommon cancers, accounting for approximately 3% of all gastrointestinal malignancies. However, incidence is increasing, which may be related to the rising incidence of obesity in many parts of the world,” Mark Yarchoan, MD, assistant professor of oncology at Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, said during the presentation. “In preclinical and clinical studies, it has been suggested that MEK inhibition may be immunomodulatory, having both direct effects on tumor cells as well as on immune populations.”
Yarchoan and colleagues compared the safety and efficacy of the PD-L1 inhibitor atezolizumab (Tecentriq, Genentech) plus the MEK inhibitor cobimetinib (Cotellic, Genentech) vs. atezolizumab alone among 77 patients (median age, 63 years; range, 44-86; 62% women) with advanced biliary tract cancer whose disease progressed despite one to two lines of previous treatment in the metastatic setting. Most patients (n = 43) had intrahepatic cholangiocarcinoma, whereas 15 had extrahepatic cholangiocarcinoma and 19 had gallbladder cancer. All had an ECOG performance status of 0 to 1 and measurable disease by RECIST v1.1.
Researchers randomly assigned patients to 840 mg IV atezolizumab every 2 weeks (n = 39) or 840 mg IV atezolizumab every 2 weeks plus 60 mg oral cobimetinib daily in a 21-days-on, 7-days-off schedule (n = 38).
PFS, calculated using the Kaplan-Meier method and compared between groups under the assumption of Cox proportional hazards, stratified for primary tumor site, served as the primary endpoint. Objective response rate, safety and tolerability, and OS served as secondary endpoints.
Results showed median PFS of 111 days in the combination group and 57 days in the atezolizumab monotherapy group (P = .0268).
“We also observed a benefit of combination therapy driven by the intrahepatic cholangiocarcinoma subgroup in an unplanned post-hoc analysis,” Yarchoan said.
OS data were immature at the time of data cutoff.
In the combination group, one patient achieved partial response, 13 had stable disease and 17 experienced disease progression. In the monotherapy group, one patient achieved partial response, 10 had stable disease and 23 had disease progression.
Two patients assigned the combination remained on treatment for more than 15 months. One patient in each group had known mismatch repair deficiency, including one patient who experienced disease progression and another who withdrew before evaluation of response.
Common grade 3 to grade 4 treatment-related adverse events appeared similar between the groups. No treatment-related deaths were reported; however, four patients in the monotherapy group and eight patients in the combination group discontinued treatment due to adverse events.
Results of paired tumor biopsies showed changes in tumor CD8, CD4, forkhead box P3 (FoxP3), PD-L1 and major histocompatibility complex (MHC) expression.
“These results are preliminary. Data cleanup is ongoing and OS data will be presented at a later date,” Yarchoan said. "Although this was a positive study, the low response rates observed in both treatment arms highlight the challenge of developing immunotherapy for biliary tract cancer. Additional research is certainly needed to understand the impact of MEK inhibition on the tumor immune microenvironment in cholangiocarcinomas.” – by Jennifer Southall
Reference:
Yarchoan M, et al. Abstract CT043. Presented at: AACR Annual Meeting; April 27-28, 2020 (virtual meeting).
Disclosures: Yarchoan reports financial relationships with Bristol-Myers Squibb, Eisai, Exelixis, Genentech/Roche, Geneos, Incyte Corp. and Merck & Co. Please see the abstract for all other researchers’ relevant financial disclosures.
Perspective
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Biliary tract cancers represent a heterogenous group of malignancies — both genomically and anatomically — that are often categorized into intrahepatic, extrahepatic and gallbladder cancer. For the better part of 10 years, standard of care has been front-line gemcitabine and cisplatin chemotherapy with no real standard second-line treatment. Single-agent PD-L1 inhibitors have been disappointing, among others.
We all know that a targeted therapy era in biliary tract cancer has arrived and that among all gastrointestinal malignancies this may, in fact, be the best one in which to have next generation sequencing because there are many opportunities for targeted therapeutics. In fact, just this past week, a watershed moment occurred in which the first targeted therapy was approved, pemigatinib (Pemazyre, Incyte), which will probably be the first of several targeted therapeutics approved within the next few years for this malignancy.
This study is an incredible effort by Yarchoan and colleagues showing doubling of PFS, meeting its primary endpoint. However, many questions remain. First, it is hard to stratify for three subsets of a rare disease, so we must interpret the data with caution. Second, we have to take the adverse events reported in the study with caution and think about how to minimize them. Finally, whether this study should be pursued into a randomized phase 3 trial is not certain as this phase 2 trial did not give guidance for a phase 3 trial. Randomized phase 3 trials are a big challenge in biliary tract cancers, for which without a biomarker select population, may be difficult with respect to efficacy. Our obligation is that if we are going to perform a randomized phase 3 trial in second-line malignancies, we may have to have 5FU as a single agent. I commend Yarchoan and colleagues for this incredible study.
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