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Cholangiocarcinoma News

What’s Next in Immunotherapy in Biliary Tract Cancers?

March 2021, Vol 2, No 1

The rationale for immunotherapy in biliary tract cancers is strong, because these cancers are inflammatory in nature, according to Abby Siegel, MD, MS, Executive Director and PDT Lead, Hepatobiliary Oncology, Global Clinical Development at Merck. Inroads are being made into biomarkers predictive of response to immunotherapy in biliary cancers, Dr Siegel said at the 2020 Annual Cholangiocarcinoma Summit.

Whole-genome sequencing of cholangiocarcinoma (CCA) has demonstrated increased expression of immune cells in clusters 2 and 3. Cluster 3, in particular, shows upregulation of PD-1 and PD-L1. “At least in theory, these are the proportion of patients who may respond better to immune-targeted therapies,” said Dr Siegel.

Predictive Biomarkers: MSI-H, TMB, PD-1/PD-L1

The predictors of a tumor response to immunotherapy include high microsatellite instability (MSI-H). Based on an extension of an investigator-initiated study in patients with noncolorectal cancer,1 the FDA approved a new indication for pembrolizumab (Keytruda) in 2017 for the treatment of patients with any type of MSI-H or mismatch repair-deficient cancers.

The study included many types of tumors. In that pivotal study, the overall response rate (ORR) to pembrolizumab in patients with biliary cancers was 40.9%, the median duration of response was not reached, and the median overall survival (OS) was 24 months.1

High tumor mutational burden (TMB)—defined as ≥10 mutations per megabase—is another predictive biomarker for immunotherapy response. In 2020, pembrolizumab received FDA approval for the treatment of solid tumors with high TMB, but few patients with biliary cancers have high TMB.

“Response rates to single-agent immune checkpoint inhibitors in patients with biliary cancers have not been compelling,” said Dr Siegel, with the rate of partial responses ranging from 5% to 13% overall. Nevertheless, several studies have shown higher response rates to immunotherapy in patients who have also received other therapies.

Better understanding of predictive biomarkers in biliary cancers is necessary, Dr Siegel said. MSI-H and TMB are predictors of responses as well as resistance to immunotherapy, she suggested.

The KEYNOTE-028 study, a biomarker selected basket clinical trial, and KEYNOTE-158, a phase 2 unselected multicohort clinical trial, included mostly heavily pretreated patients, Dr Siegel said, with good responses. The responses to pembrolizumab among the patients with biliary cancers were durable: all responses lasted more than 6 months, and more than 50% of the responses lasted more than 2 years.2

“Unfortunately, the location of the biliary cancer was not collected in either of these studies,” she said. There were data missing for several patients in these studies, particularly for patients with MSI-H status in KEYNOTE-028, so the exact location of the tumor was not available for those patients.

In a study of the PD-L1 nivolumab (Opdivo), the ORR to nivolumab monotherapy was 22% by investigator review, but only 11% by independent central review, among 46 evaluable patients with biliary cancers.3 The investigators attributed this difference in the way lymph-node status was assessed.

The PD-L1 expression on tumor cells had a proportion score (PS) of ≥1% in 9 of 10 investigator-assessed responding patients and in all 5 responding patients by central review. Of note, all the responders had MSI-H tumors.

“It definitely looks like for single-agents PD-1 or PD-L1 inhibitors, there may be enrichment by [the patient’s] PD-1/PD-L1 status,” Dr Siegel said.

Indeed, PD-1/PD-L1 agents are currently approved for the treatment of the subpopulation of patients with advanced bladder cancer who have received previous therapies or are ineligible for specific chemotherapies. This includes the 2 PD-L1 inhibitors nivolumab and pembrolizumab, as well as the 2 PD-1 inhibitors atezolizumab (Tecentriq) and avelumab (Bavencio).

Chemotherapy as Immunotherapy Adjuvant

“There were a lot of high hopes for chemotherapy as an immune adjuvant, both in theory and in practice,” said Dr Siegel. “There is a reduction in immune suppression…[and] more expression of neoantigens on the surface of cells.”

Chemotherapy as an immunotherapy adjuvant can act as a chaperone to immunogenic cells, moving from the endoplasmic reticulum to the surface of the cell, to attack tumor cells. One caveat is that syngeneic mouse models may not be applicable to humans.

“Many of these studies have been done in animal models,” she said. “For instance, gemcitabine has been shown to reduce T regulatory cells [Tregs] in syngeneic models, but mice have a much higher percentage of Tregs. This may not be seen so much in human models.”

Emerging clinical trial data for chemotherapy plus checkpoint inhibitor combinations are compelling, Dr Siegel emphasized.

In KEYNOTE-189, a pivotal study in lung cancer, pemetrexed and platinum-based chemotherapy plus pembrolizumab improved the median OS compared with pemetrexed plus chemotherapy,4 but the hazard ratios for OS were not as impressive in clinical trials of chemotherapy plus immunotherapy versus chemotherapy alone in bladder cancer, in the KEYNOTE-361 study and in gastric cancer in CheckMate-649 and KEYNOTE-062.

The combinations of gemcitabine, cisplatin, and immunotherapy have produced heterogeneous results in studies of biliary tract cancers, noted Dr Siegel. The response rates to the combination of immunotherapy plus chemotherapy have generally been in the range of 37% to 56%.

One outlier is a Korean study of the combination of gemcitabine and cisplatin chemotherapy plus immunotherapy with durvalumab (Imfinzi), with or without the investigational immunotherapy tremelimumab. In this study, the ORR was 73.4%, and the median OS was 19 months (20.7 months with the addition of tremelimumab).

Two studies evaluating nivolumab immunotherapy in combination with gemcitabine and cisplatin chemotherapy in biliary cancers have been conducted.5,6

In a Chinese study of patients with unresectable or metastatic biliary tract cancers, the ORR was 55%, including 18.6% complete responses, among 27 evaluable patients with newly diagnosed or with refractory disease.5 The median OS was 8.5 months; at 12 months, the OS was 33.3%. The ORR was 37% in patients with tumors expressing PD-L1 with PS ≥1%, which indicated no evidence of enrichment by PD-L1 status.5

In a Japanese study of 30 evaluable patients with unresectable recurrent biliary tract cancers who received first-line chemotherapy with gemcitabine plus cisplatin, none of the patients had MSI-H disease. The ORR was 37% by blinded independent central review and 40% by investigator assessment, with no evidence of enrichment by PD-L1 status.6

“One of the thoughts is that perhaps by adding chemotherapy, you don’t need enrichment [for PD-L1 status], at least in some tumor types,” she said.

Ethnic Differences?

Asian patients with biliary tract cancers appear to do better with immunotherapy, but the reason is unclear. One possibility is the higher rate of TMB in liver fluke–related biliary tract tumors in these patients, because liver fluke infections are a major risk factor for CCA in Asian countries.

A recent analysis of the SEER database, which was presented at the 2020 European Society for Medical Oncology meeting, showed better OS in Asian women with biliary tract cancers compared with patients from other ethnicities in the United States.

The Future

The next steps in the use of combinations with chemotherapy and immunotherapy, according to Dr Siegel, require a better understanding of the specific immune effects of different chemotherapies, their sequencing, and an investigation of different dosing of immunotherapies, in addition to improved understanding of predictive biomarkers of response and resistance to immunotherapy.


  1. Marabelle A, Le DT, Ascierto PA, et al. Efficacy of pembrolizumab in patients with noncolorectal high microsatellite instability/mismatch repair–deficient cancer: results from the phase II KEYNOTE-158 study. J Clin Oncol. 2020;38:1-10.
  2. Piha-Paul SA, Oh DY, Ueno M, et al. Efficacy and safety of pembrolizumab for the treatment of advanced biliary cancer: results from the KEYNOTE-158 and KEYNOTE-028 studies. Int J Cancer. 2020;147:2190-2198.
  3. Kim RD, Chung V, Alese OB, et al. A phase 2 multi-institutional study of nivolumab for patients with advanced refractory biliary tract cancer. JAMA Oncol. 2020;6:888-894.
  4. Gandhi L, Rodríguez-Abreu D, Gadgeel S, et al; for the KEYNOTE-189 investigators. Pembrolizumab plus chemotherapy in metastatic non–small-cell lung cancer. N Engl J Med. 2018;378:2078-2092.
  5. Feng K, Liu Y, Zhao Y, et al. Efficacy and biomarker analysis of nivolumab plus gemcitabine and cisplatin in patients with unresectable or metastatic biliary tract cancers: results from a phase II study. J Immunother Cancer. 2020;8:e000367.
  6. Ueno M, Ikeda M, Morizane C, et al. Nivolumab alone or in combination with cisplatin plus gemcitabine in Japanese patients with unresectable or recurrent biliary tract cancer: a non-randomised, multicentre, open-label, phase 1 study. Lancet Gastroenterol Hepatol. 2019;4:611-621.

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