Adding pieces to immunotherapy puzzle in biliary tract cancer

Gallbladder cancer is an uncommon disease and early detection at a curable stage remains challenging. Most patients are diagnosed in a symptomatic phase, usually with unresectable or metastatic disease. Even though immunotherapy has been incorporated recently, several unmet needs must be addressed to improve gallbladder adenocarcinoma (GBAC) management.

Immunotherapy has been established in biliary tract cancer (BTC) in a first-line setting combined with gemcitabine and cisplatin according to TOPAZ-1 (NCT03875235) and KEYNOTE-966 (NCT04003636) trials (1,2). These trials revealed that durvalumab and pembrolizumab, respectively, modestly improved overall survival (OS) without adding significant toxicity, resulting in Food and Drug Administration (FDA) approval irrespective of any biomarker expression.

Previously, Oh et al. conducted a phase II study adding durvalumab or durvalumab and tremelimumab to chemotherapy backbone and reported an overall response rate (ORR) of 66% in the entire cohort: 50% with dual blockade and 72% with durvalumab plus chemotherapy (3). Actually, the real benefit of anti-cytotoxic T-lymphocyte antigen 4 (anti-CTLA-4) in BTC has not been demonstrated yet and several ongoing trials are investigating immunotherapy combinations, as well as combinations with tyrosine kinase inhibitors, to modulate the tumor microenvironment (Table 1).

In the article accompanying this editorial, Patel et al. (4) investigated the benefit of dual blockade with anti-programmed cell death 1 (anti-PD-1) (nivolumab) plus anti-CTLA-4 (ipilimumab) in GBAC. In this phase II trial, nineteen patients were treated and three of them achieved a confirmed response (one complete and two partial responses). Even though ORR was higher compared to historical control, the absence of available biomarkers is a significant downside of this study. For example, only seven and nine patients had tumor mutational burden (TMB) and mismatch repair (MMR) status reported, respectively: one case was TMB-high (TMB-H; 10 mutations/Mb) and achieved a partial response (one-third of responses presented in the trial).

Despite PD-L1 being present in around one in four BTC patients, this is not a reliable predictive biomarker in this population. However, MMR deficiency (MMRd)/microsatellite instability-high (MSI-H) as well as TMB-H are predictive of benefits with immunotherapy and this led to the agnostic approval of pembrolizumab in this scenario (5,6). Marabelle et al., for example, reported an ORR of 40.9% for MSI-H/dMMR BTC patients included in the KEYNOTE-158 trial (7). Also, a previous systematic review evaluating biomarkers in BTC reported that 4.6% had TMB-H and 2.5% MMRd/MSI-H but less than 20% of prospective trials have assessed these biomarkers (8).

Although a previous immune checkpoint inhibitor exposure was allowed, only one patient received it before being enrolled in the trial. Also, the relevance of these results now that anti-PD-1 is standard in first-line is questionable. ORR presented in this GBAC cohort of the SWOG 1609 trial was similar to previous data with monotherapy and doublet in the second line (Table 2).

Furthermore, toxicity presented in the GBAC cohort of SWOG 1609 was not trivial. Treatment-related adverse events (TRAEs) grade 3 or higher were seen in 47% of patients and 21% had immune-related adverse events (irAEs) grade 3 or higher. Also, 1 (5%) participant discontinued treatment and 1 (5%) had lethal toxicity (hepatic failure). Although this incidence of TRAEs might compare favorably versus chemotherapy-based trials in second-line, the absence of a clear benefit with dual-blockade versus anti-PD-1 monotherapy and the favorable toxicity profile with anti-PD-1 combined with chemotherapy in first-line followed by immunotherapy maintenance makes this a more useful approach.

Finally, the tumor microenvironment plays an important role in the response to immunotherapy and a previous study showed that stroma comprises ~73% of pancreaticobiliary tumors (13). The stromal component can be heterogeneous and a previous study that classified 368 intra-hepatic cholangiocarcinomas in four TME-based subtypes found that 45% of them had an immune-desert tumor (14) This subgroup presents a markedly reduced lymphocyte infiltration within the tumor as well as tumor and stromal immune signaling. In contrast, the immunogenic subtype revealed an inflammatory tumor microenvironment characterized by a substantial infiltration of both innate and adaptive immune cells, alongside an overexpression of major histocompatibility complex molecules and immune checkpoint proteins.

In summary, the GBAC cohort of SWOG 1609 adds another piece to the immunotherapy puzzle in BTCs and ongoing efforts will elucidate the benefit of combination with different targeted therapies and/or tyrosine kinase inhibitors to modulate tumor microenvironment and increase the synergism.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-24-89/prf

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-89/coif). T.B.C. received honorarium from Bristol-Myers Squibb, Merck Sharp & Dohme Corp, Astra-Zeneca, MD Health Brasil and Remedy Health Group, support for attending meetings and travel from Ipsen and A2Bio, and payment for participation in advisory board from Ipsen and Moderna. R.D.K. received honoraria from Incyte, Pfizer and Astra Zeneca, and consulting fees from Astra Zeneca, Bayer, Roche, Pfizer, Abbvie, Eisai, Exelixis, Merck and Ipsen. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Oh DY, Ruth He A, Qin S, et al. Durvalumab plus Gemcitabine and Cisplatin in Advanced Biliary Tract Cancer. NEJM Evid 2022;1:EVIDoa2200015.
2. Kelley RK, Ueno M, Yoo C, et al. Pembrolizumab in combination with gemcitabine and cisplatin compared with gemcitabine and cisplatin alone for patients with advanced biliary tract cancer (KEYNOTE-966): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2023;401:1853-65. Erratum in: Lancet 2023;402:964 Erratum in: Lancet 2024;403:1140. [Crossref] [PubMed]
3. Oh DY, Lee KH, Lee DW, et al. Gemcitabine and cisplatin plus durvalumab with or without tremelimumab in chemotherapy-naive patients with advanced biliary tract cancer: an open-label, single-centre, phase 2 study. Lancet Gastroenterol Hepatol 2022;7:522-32. Erratum in: Lancet Gastroenterol Hepatol 2023;8:e5. [Crossref] [PubMed]
4. Patel SP, Guadarrama E, Chae YK, et al. SWOG 1609 cohort 48: anti-CTLA-4 and anti-PD-1 for advanced gallbladder cancer. Cancer 2024;130:2918-27. [Crossref] [PubMed]
5. FDA. FDA grants accelerated approval to pembrolizumab for first tissue/site agnostic indication. 2017. Accessed May 10, 2024. Available online: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-pembrolizumab-first-tissuesite-agnostic-indication
6. FDA. FDA approves pembrolizumab for adults and children with TMB-H solid tumors. 2020. Accessed May 10, 2024. Available online: https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-pembrolizumab-adults-and-children-tmb-h-solid-tumors
7. 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. [Crossref] [PubMed]
8. Frega G, Cossio FP, Banales JM, et al. Lacking Immunotherapy Biomarkers for Biliary Tract Cancer: A Comprehensive Systematic Literature Review and Meta-Analysis. Cells 2023;12:2098. [Crossref] [PubMed]
9. 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;6:888-94. [Crossref] [PubMed]
10. Klein O, Kee D, Nagrial A, et al. Evaluation of Combination Nivolumab and Ipilimumab Immunotherapy in Patients With Advanced Biliary Tract Cancers: Subgroup Analysis of a Phase 2 Nonrandomized Clinical Trial. JAMA Oncol 2020;6:1405-9. [Crossref] [PubMed]
11. Doki Y, Ueno M, Hsu CH, et al. Tolerability and efficacy of durvalumab, either as monotherapy or in combination with tremelimumab, in patients from Asia with advanced biliary tract, esophageal, or head-and-neck cancer. Cancer Med 2022;11:2550-60. [Crossref] [PubMed]
12. Delaye M, Assenat E, Dahan L, et al. Durvalumab (D) plus tremelimumab (T) immunotherapy in patients (Pts) with advanced biliary tract carcinoma (BTC) after failure of platinum-based chemotherapy (CTx): Interim results of the IMMUNOBIL GERCOR D18-1 PRODIGE-57 study. J Clin Oncol 2022;40:4108. [Crossref]
13. Micke P, Strell C, Mattsson J, et al. The prognostic impact of the tumour stroma fraction: A machine learning-based analysis in 16 human solid tumour types. EBioMedicine 2021;65:103269. [Crossref] [PubMed]
14. Job S, Rapoud D, Dos Santos A, et al. Identification of Four Immune Subtypes Characterized by Distinct Composition and Functions of Tumor Microenvironment in Intrahepatic Cholangiocarcinoma. Hepatology 2020;72:965-81. [Crossref] [PubMed]