Understanding Predictive Biomarkers and Resistance to Immunotherapy in Biliary Tract Cancers

Improved understanding of predictive biomarkers is needed in immuno-oncology, and various immunotherapy combinations using different mechanisms of action are being investigated in cholangiocarcinoma (CCA) and other biliary tract cancers, according to presentations delivered at Session IV, “What’s New in Immuno-oncology in BTC? Monotherapy and Combo Therapies,” at the 3rd Annual CCA Summit.

Richard Kim, MD, Moffitt Cancer Center, Tampa, FL, discussed biomarkers for immuno-oncology. Single-agent studies of immunotherapy in biliary cancer led to responses that, although low, were durable. A combination of 2 immunotherapies or an immunotherapy plus a tyrosine kinase inhibitor may improve responses.

Microsatellite instability-high (MSI-H) and tumor mutational burden (TMB) are currently the only biomarkers that show response to immunotherapies. However, only approximately 3% of biliary tract cancers are MSI-H, and the incidence of patients with high TMB is very low.

When stratified by gender and ethnicity, the highest survival probabilities have been observed in Asian women in the United States. Patients with hepatitis B also have better responses to immunotherapy. Overall, Asian patients do not have better outcomes from immunotherapy compared with other ethnic groups. To date, the location of the tumor does not seem to affect the outcomes with immunotherapy.

“I do think that understanding predictive biomarkers of response and resistance to immuno-oncology is important,” said Dr Kim.

Do-Youn Oh, MD, PhD, Seoul National University Hospital, South Korea, discussed strategies for improving response to immunotherapy in patients with biliary tract cancer.

“To improve the efficacy of immunotherapy model, various combination strategies of the different modes of action are being actively investigated,” Dr Oh said.

The combination of durvalumab and tremelimumab had a numerically higher objective response rate (ORR) and overall survival rate compared with durvalumab monotherapy. The combination of nivolumab and ipilimumab led to an ORR of 31% in patients with gallbladder cancer, 31% in intrahepatic CCA, and 0% in extrahepatic CCA.

Dual targeting of TGF-beta and PD ligand 1 (PD-L1) with bintrafusp-alfa led to improved ORR and survival outcomes; however, the study’s predefined threshold was not met. The combination of nivolumab and chemotherapy in the first-line setting had a manageable safety profile and improved response rates.

“Immunotherapy is working in biliary tract cancer—not in all, but in some,” said Dr Oh.

Mark Yarchoan, MD, Johns Hopkins University, Baltimore, MD, described the goal of resensitizing CCA to checkpoint inhibitors using a MEK inhibitor. CCA is characterized by low (4.7%) PD-L1 expression and low TMB (2.2 mut/Mb), according to Dr Yarchoan.

MEK inhibition has demonstrated immunomodulatory effects in preclinical models, including increased CD8 T-cell infiltration, increased expression of the major histocompatibility complex (MHC) protein, and possible synergy with PD-1 or PD-L1 inhibitors.

MEK knockout tumors exhibit increased antigen level and T-cell activation. Systemic treatment with cobimetinib leads to beneficial effects on the tumor but impaired T-cell activation, which can be mitigated by treatment with a stimulatory agent.

MEK inhibition is a double-edged sword, Dr Yarchoan suggested, where MHC expression and CD8 T-cell infiltration are enhanced, but T-cell priming and activation may be impaired. Agonist therapy has been shown to rescue T-cell activation in the setting of MEK inhibition.

He cited the CTEP 10476 study, a phase 2, randomized clinical trial that is investigating the triplet of a PD-L1 inhibitor (atezolizumab), a novel CD27 agonist (varlilumab), and a MEK inhibitor (cobimetinib) in patients with unresectable biliary tract cancers.

“This will be one of the first triplets, I think, to go into cholangiocarcinoma,” said Dr Yarchoan. “We’re really excited about this, the triplet combination of a MEK plus anti–PD-L1, plus a CD27 agonist. So, more to come here.”