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Corresponding author. Address: Department of Oncology – OncoHealth Institute, Fundación Jiménez Díaz University Hospital, Avda Reyes Catolicos 2, 28040, Madrid Spain.
Department of Oncology – OncoHealth Institute, Fundación Jiménez Díaz University Hospital, Madrid SpainDepartment of Medical Oncology, The Christie NHS Foundation, Manchester; Division of Cancer Sciences, University of Manchester, Manchester, United Kingdom
Management of biliary tract cancers (BTCs) is rapidly evolving. The majority of patients are diagnosed with advanced disease. In this setting, chemotherapy with cisplatin and gemcitabine (with durvalumab) followed by second-line FOLFOX is the cornerstone of treatment. Targeted therapies for tumours harbouring FGFR2 fusions, IDH1 mutations, BRAF V600E mutations, NTRK fusions and/or HER2 (ERBB2) amplifications, among others, have brought precision medicine to the forefront of management of advanced BTC. This holds especially true for patients with intrahepatic cholangiocarcinoma. Recently, immunotherapy, especially combined with chemoterapy, has also shown promising activity. The field is now moving forward – management is no longer limited to chemotherapy or targeted therapies alone, with increasing research focused on how combination strategies could enhance therapeutic responses. We are therefore facing a change of paradigm, where immunotherapy, cytotoxic chemotherapy and targeted therapies will be administered concomitantly with the aim of harnessing potential synergies. This review will focus on the rationale behind these combinations and summarise current clinical trial data.
The majority of patients with biliary tract cancer are diagnosed at advanced stages.
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Chemotherapy remains the cornerstone of systemic therapy.
•
Targeted therapies are now part of treatment strategies for biliary tract cancer.
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Immunotherapy has also shown promising activity in biliary tract cancer.
•
Combinations of these strategies are being explored with the aim of enhancing treatment responses.
Introduction
Biliary tract cancers (BTCs) comprise epithelial cancers of the biliary tree, including cholangiocarcinoma (CCA), gallbladder cancer and ampulla of Vater cancer. CCA can be subdivided into intrahepatic cholangiocarcinoma (iCCA) and extrahepatic cholangiocarcinoma (classified as hilar and distal) depending on their location. They are considered rare malignancies, but their incidence is increasing.
Gemcitabine and cisplatin (GemCis) have been accepted as standard of care since 2010, based on the ABC-02 clinical trial findings. This study showed superiority both in terms of progression-free survival (PFS) and OS in favour of GemCis compared to gemcitabine alone.
Estimated median PFS and OS with GemCis in this trial were 8.0 months and 11.7 months, respectively. In recent years, efforts have been made to identify more active strategies, with the aim of improving outcomes in the future.
The first approach explored was the development of triplet cytotoxic combination strategies and the assessment of treatment options beyond first-line treatment. In terms of triplet chemotherapy options, the combination of GemCis with a third cytotoxic compound such as nab-paclitaxel,
Combination gemcitabine plus S-1 versus gemcitabine plus cisplatin for advanced/recurrent biliary tract cancer: the FUGA-BT (JCOG1113) randomized phase III clinical trial.
has shown promising activity. In addition, there is now prospective data suggesting that following progression on GemCis, and in the absence of targetable alterations,
Second-line FOLFOX chemotherapy versus active symptom control for advanced biliary tract cancer (ABC-06): a phase 3, open-label, randomised, controlled trial.
Nal-IRI with 5-fluorouracil (5-FU) and leucovorin or gemcitabine plus cisplatin in advanced biliary tract cancer - the NIFE trial (AIO-YMO HEP-0315) an open label, non-comparative, randomized, multicenter phase II study.
Final results from the NIFTY trial, a phase IIb, randomized, open-label study of liposomal Irinotecan (nal-IRI) plus fluorouracil (5-FU)/leucovorin (LV) in patients (pts) with previously treated metastatic biliary tract cancer (BTC).
Ann Oncol.2022; 33 (101016/annonc/annonc1036. ESMO 2022): S19-S26
Final overall survival efficacy results of ivosidenib for patients with advanced cholangiocarcinoma with IDH1 mutation: the phase 3 randomized clinical ClarIDHy trial.
Updated results of the FOENIX-CCA2 trial: efficacy and safety of futibatinib in intrahepatic cholangiocarcinoma (iCCA) harboring FGFR2 fusions/rearrangements.
Efficacy of RLY-4008, a highly selective FGFR2 inhibitor in patients (pts) with an FGFR2-fusion or rearrangement (f/r), FGFR inhibitor (FGFRi)-naïve cholangiocarcinoma (CCA): ReFocus trial.
Ann Oncol.2022; 33 (101016/annonc/annonc1089. ESMO 2022): S808-S869
Dabrafenib plus trametinib in patients with BRAF(V600E)-mutated biliary tract cancer (ROAR): a phase 2, open-label, single-arm, multicentre basket trial.
Currently, four compounds targeting these alterations have been approved by regulatory agencies: pemigatinib (FDA and EMA approved in 2020 and 2021, respectively), infigratinib (FDA approved in 2021), ivosidenib (FDA approved in 2022), futibatinib (FDA approved in 2022) and dabrafenib/trametinib (FDA approved in 2022).
The third main research stream in this regard has been the development of immunotherapy approaches in CCA. Unfortunately, the CCA population with mismatch repair deficiency, high microsatellite instability or high tumour mutational burden (predictors of response to immunotherapy), for whom there is current FDA approval for immunotherapy approaches,
Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study.
which was the main rationale behind the development of strategies combining immunotherapy and other agents, such as cytotoxic chemotherapy. Durvalumab, comined with GemCis is now FDA and EMA approved in this setting.
It is therefore clear that chemotherapy remains the “go-to” treatment for the majority of patients diagnosed with advanced CCA and that combination strategies are of huge interest. This review article will focus on current evidence and ongoing research on how to integrate cytotoxic chemotherapy, targeted therapies and immunotherapy approaches into treatment strategies for CCA (Fig. 1).
Fig. 1The management of cholangiocarcinoma is rapidly evolving.
Management is no longer limited to chemotherapy or targeted therapies alone, as combination strategies are showing promising activity. We are therefore facing a change of paradigm, where immunotherapy, cytotoxic chemotherapy and targeted therapies will be administered concomitantly to increase responses and improve outcomes.
Combination of cytotoxic agents and targeted therapies
As noted above, five targeted therapeutics have meanwhile been approved for CCA: pemigatinib (targeting FGFR2), infigratinib (targeting FGFR2), futibatinib (targeting FGFR2), ivosidenib (targeting IDH) and dabrafenib/trametinib (targeting BRAF V600E).
The efficacy of these inhibitors as monotherapy is quite remarkable, yet their clinical application remains limited by the altogether low prevalence of the respective mutations and targets in BTCs. Given the limited efficacy of cytotoxic treatment regimens, combining these regimens with novel targeted therapeutics has been a focus of research in recent years. Some studies tried such approach in the absence of a biomarker-selected population. The combination of GemCis plus the small molecule vascular endothelial growth factor (VEGF) inhibitor cediranib was trialled in the phase II ABC-03 trial published in 2015. No improvement of PFS was seen for the combination treatment in this trial, as VEGF remains an ineffective molecular target in CCA.
Cediranib or placebo in combination with cisplatin and gemcitabine chemotherapy for patients with advanced biliary tract cancer (ABC-03): a randomised phase 2 trial.
A randomized, multicenter, phase II study of vandetanib monotherapy versus vandetanib in combination with gemcitabine versus gemcitabine plus placebo in subjects with advanced biliary tract cancer: the VanGogh study.
Addition of ramucirumab or merestinib to standard first-line chemotherapy for locally advanced or metastatic biliary tract cancer: a randomised, double-blind, multicentre, phase 2 study.
Currently, novel targeted therapy approaches (some with, some without a biomarker-selected population) combined with chemotherapy are under way.
LY3410738, a first-in-class covalent inhibitor of mutant IDH1, is currently being investigated in an open label phase I trial in combination with GemCis for CCA and other solid tumours (NCT04521686). The study is estimated to complete in 2023, with no preliminary data available so far.
Silmitasertib (CX-4945), a CK2 (casein kinase II) inhibitor, is currently being investigated in combination with GemCis as first-line treatment for locally advanced or metastatic CCA in a phase Ib/II study (NCT02128282). An interim analysis of 55 evaluable patients shows a median PFS of 11.1 (95% CI 7.6–14.7) months and a median OS of 17.4 (95% CI 13.4–25.7) months with an objective response rate (ORR) of 32%. Based on these data, a phase III trial is planned.
Silmitasertib (CX-4945) in combination with gemcitabine and cisplatin as first-line treatment for patients with locally advanced or metastatic cholangiocarcinoma: a phase Ib/II study.
Varlitinib, a pan-epidermal growth factor receptor (EGFR) inhibitor, was combined with capecitabine in the second-line phase II ‘TreeTopp’ study. One hundred and twenty-seven patients received varlitinib plus capecitabine or placebo plus capecitabine in a 1:1 randomisation. The study did not show improvement of PFS or ORR in patients who received varlitinib compared to those receiving capecitabine alone.
In a prospective feasibility study, HER2-targeted therapy with trastuzumab was combined with GemCis in the first-line setting. Four patients with HER2-positive BTC (two extrahepatic CCA, one iCCA, one gallbladder cancer) were enrolled. Partial response was the best overall response in two patients, with stable disease the best overall response in the other two patients. The median PFS was 6.1 (95% CI 4.0—NE) months, while median OS was not reached.
Feasibility of HER2-targeted therapy in advanced biliary tract cancer: a prospective pilot study of trastuzumab biosimilar in combination with gemcitabine plus cisplatin.
A phase I clinical trial combining GemCis with ivosidenib or pemigatinib for unresectable or metastatic CCA (NCT04088188) is underway. No results are available for this trial yet. Furthermore, a phase II trial combining lenvatinib with gemcitabine and oxaliplatin (GemOx) for advanced iCCA reported initial data in 2021. At the end of last follow-up (February 2021), the ORR was 30.0% (9/30; 95% CI 14.7%-49.4%). The disease control rate was 86.7% (26/30; 95% CI 69.3%-96.2%) while the median PFS and OS had not been reached at the time of interim data analysis.
Owing to the low proportion of patients diagnosed with advanced CCA harbouring one of the molecular characteristics associated with a high response rate to immunotherapy (namely mismatch repair deficiency, high microsatellite instability or high tumour mutational burden), and the limited activity of immunotherapy alone in CCA in the absence of these biomarkers, combinations of immunotherapy with cytotoxic chemotherapy have attracted lots of attention.
There is evidence suggesting the potential role of immunotherapy in BTC.
Sun and colleagues reported improved OS, PFS and ORR in patients with BTC receiving combined immunotherapy (programmed cell death 1 [PD-1] inhibitor) and chemotherapy (38 patients) compared to immunotherapy alone (20 patients) or chemotherapy alone (19 patients), without increased toxicity,
A multicenter randomized phase II study of nivolumab in combination with gemcitabine/cisplatin or ipilimumab as first-line therapy for patients with advanced unresectable biliary tract cancer (BilT-01).
Toripalimab with chemotherapy as first-line treatment for advanced biliary tract tumors: a preliminary analysis of safety and efficacy of an open-label phase II clinical study.
Ann Oncol.2020; 31 (101016/annonc/annonc259. 2020): S260-S273
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.
One of the largest studies included a total of 124 treatment-naïve patients treated with three potential combinations of immunotherapy and chemotherapy: sequential chemotherapy followed by immunotherapy with durvalumab and tremelimumab (n = 30) and concomitant chemotherapy and immunotherapy with durvalumab (n = 47), or with durvalumab and tremelimumab (n = 47).
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.
The highest ORR was reported in the arms where immunotherapy was administered concomitantly with durvalumab (ORRs of 50%, 72% and 70%, respectively), with similar median PFS (12.8, 11.8 and 12.3 months, respectively). Thus, the role of CTLA-4 (CD152) inhibitors (i.e. tremelilumab) in the management of BTC remains unclear.
The TOPAZ-1 phase III study randomised 685 patients diagnosed with advanced treatment-naïve CCA or gallbladder cancer to GemCis with durvalumab or placebo.
Oh D-Y, He AR, Qin S, Chen L-T, Okusaka T, Vogel A, et al. Durvalumab plus gemcitabine and cisplatin in advanced biliary tract cancer. NEJM Evid.0(0):EVIDoa2200015.
The primary endpoint was OS. The study showed an improvement in OS (hazard ratio [HR] 0.80; 95% CI 0.66-0.97; p = 0.021), PFS (HR 0.75; 95% CI 0.63-0.89; p = 0.001) and ORR (26.7% vs. 18.7%). This improved activity was reported without additional toxicity and with a trend towards longer time to deterioration (Global Health status QLQ C30) in favour of the durvalumab arm.
Oh D-Y, He AR, Qin S, Chen L-T, Okusaka T, Vogel A, et al. Durvalumab plus gemcitabine and cisplatin in advanced biliary tract cancer. NEJM Evid.0(0):EVIDoa2200015.
Utcomes by primary tumour location in patients with advanced biliary tract cancer treated with durvalumab or placebo plus gemcitabine and cisplatin in the Phase 3 TOPAZ-1 study.
Outcomes by disease status in patients with advanced biliary tract cancer treated with durvalumab or placebo plus gemcitabine and cisplatin in the Phase 3 TOPAZ-1 study.
Updated overall survival (OS) from the phase III TOPAZ-1 study of durvalumab (D) or placebo (PBO) plus gemcitabine and cisplatin (+ GC) in patients (pts) with advanced biliary tract cancer (BTC).
Ann Oncol.2022; 33 (101016/annonc/annonc1036. ESMO 2022): S19-S26
) state that the combination of GemCis and durvalumab can be considered as a possible first-line treatment option for advanced CCA. In addition, durvalumab was approved for this indication by the FDA and EMA in 2022.
Results from a similar phase III study with pembrolizumab (KEYNOTE-966; NCT04003636) are awaited. If positive, the role of the combination of immunotherapy and chemotherapy in the first-line treatment of advanced biliary tract malignancies is likely to be established.
Multiple other clinical trials are ongoing in this setting, specifically looking into different combinations of checkpoint inhibitors and chemotherapy in the first-line setting.
Overall, the future of immunotherapy in CCA looks bright for the first time in years. Efforts to identify predictive biomarkers for patient selection and to improve our understanding of mechanisms of resistance will be paramount.
Combination of immunotherapy and targeted therapies
Beyond the combination with chemotherapy, the combination of immunotherapy with tyrosine kinase inhibitors (TKIs) has also been tested, especially in a non-biomarker-driven population. Small phase II studies have shown promising activity with immune checkpoint inhibitors,
with some other clinical trials ongoing and exploring this potential alternative (NCT03260712).
In addition, the results of phase II studies assessing the triple combination of chemotherapy (GemOx), with immunotherapy and TKIs have been reported. The first of these studies combined GemOx with toripalib and lenvatinib in 30 patients diagnosed with iCCA.
56P - anti-PD1 antibody toripalimab, lenvatinib and gemox chemotherapy as first-line treatment of advanced and unresectable intrahepatic cholangiocarcinoma: a phase II clinical trial.
Ann Oncol.2020; 31 (101016/annonc/annonc259. 2020): S260-S273
The study reported an impressive response rate of 80% in the second-line setting, with a disease control rate of 93.3% and a tolerable toxicity profile. Two patients with locally metastatic disease were downstaged and subsequently underwent resection.
Dong and colleagues followed a similar approach in another phase II study, testing the combination of GemOx with sintilimab and a TKI (either lenvatinib or by next generation sequencing [NGS]-guided targeted therapy) for local advanced or metastatic BTCs.
The TKI strategy consisted of lenvatinib (no targetable gene alterations) or targeted therapy based on NGS (olaparib for BRCA1/2 [breast cancer 1/2] mutations, dasatinib for IDH1/2 mutations, afatinib for EGFR amplification, lenvatinib for PDGFR [platelet-derived growth factor receptor]/KIT mutations, and lenvatinib for FGFR/KIT mutations). A total of 22 patients were included in the lenvatinib group with ORR and disease control rates of 45.5% and 86.4%, respectively. For 14 patients with NGS data available, five patients received targeted therapy, leading to stable disease in one case and partial response in the other four cases. For four patients with positive PD-L1 expression, the ORR was 100%.
As proposed by Dong and colleagues for the NGS group,
In 2022, the treatment landscape and outcomes in advanced CCA remain far from satisfactory. Many new therapeutics have come into the picture – targeted molecules as well as checkpoint inhibitors. Neither of them has brought about the urgently needed breakthrough in oncological outcome. This is partly due to the nature of CCA, which has proven notoriously difficult to attack because of its heterogeneous biology, its often poor vascularisation and excessive stromal reaction. In addition, immunotherapies, which have been real gamechangers in many cancers, have failed as monotherapies in CCA. Therefore, combining the most promising approaches in a rational way, based on the specifics of CCA tumour biology and mechanisms of malignancy, is the logical next step to push therapy and eventually OS forward. The combination of chemotherapy with targeted molecules and checkpoint inhibitors may take CCA treatment to a new level. This will first require improved characterisation and understanding of the individual patient’s tumour, to identify molecular targets and immunological patterns that can be exploited for combination therapies. The increasingly detailed understanding of CCA makeup and biology will, at the same time, foster the development of future targeted and individualised therapies.
Dr Angela Lamarca received funding from European Union’s Horizon 2020 Research and Innovation Programme [grant number 825510, ESCALON] and the SEOM Return Fellowship Programme.
Conflict of interest
Dr. Angela Lamarca has received travel and educational support from Ipsen, Pfizer, Bayer, AAA, SirtEx, Novartis, Mylan and Delcath; speaker honoraria from Merck, Pfizer, Ipsen, Incyte, AAA, QED, Servier, Astra Zeneca and EISAI; advisory and consultancy honoraria from EISAI, Nutricia Ipsen, QED, Roche, Servier, Boston Scientific, Albireo Pharma, AstraZeneca, Boehringer Ingelheim, GENFIT and TransThera Biosciences; she is member of the Knowledge Network and NETConnect Initiatives funded by Ipsen. Dr. Joachim Mertens has received support and consultation honoraria from Abbvie, Alfasigma, AstraZeneca, Bayer, BMS, Eisai, Gilead, Incyte, Intercept, MSD, Roche, Vifor.
Please refer to the accompanying ICMJE disclosure forms for further details.
Authors' contributions
Both authors were involved in the writing and final approval of the manuscript.
Supplementary data
The following are the supplementary data to this article:
Combination gemcitabine plus S-1 versus gemcitabine plus cisplatin for advanced/recurrent biliary tract cancer: the FUGA-BT (JCOG1113) randomized phase III clinical trial.
Second-line FOLFOX chemotherapy versus active symptom control for advanced biliary tract cancer (ABC-06): a phase 3, open-label, randomised, controlled trial.
Nal-IRI with 5-fluorouracil (5-FU) and leucovorin or gemcitabine plus cisplatin in advanced biliary tract cancer - the NIFE trial (AIO-YMO HEP-0315) an open label, non-comparative, randomized, multicenter phase II study.
Final results from the NIFTY trial, a phase IIb, randomized, open-label study of liposomal Irinotecan (nal-IRI) plus fluorouracil (5-FU)/leucovorin (LV) in patients (pts) with previously treated metastatic biliary tract cancer (BTC).
Ann Oncol.2022; 33 (101016/annonc/annonc1036. ESMO 2022): S19-S26
Final overall survival efficacy results of ivosidenib for patients with advanced cholangiocarcinoma with IDH1 mutation: the phase 3 randomized clinical ClarIDHy trial.
Updated results of the FOENIX-CCA2 trial: efficacy and safety of futibatinib in intrahepatic cholangiocarcinoma (iCCA) harboring FGFR2 fusions/rearrangements.
Efficacy of RLY-4008, a highly selective FGFR2 inhibitor in patients (pts) with an FGFR2-fusion or rearrangement (f/r), FGFR inhibitor (FGFRi)-naïve cholangiocarcinoma (CCA): ReFocus trial.
Ann Oncol.2022; 33 (101016/annonc/annonc1089. ESMO 2022): S808-S869
Dabrafenib plus trametinib in patients with BRAF(V600E)-mutated biliary tract cancer (ROAR): a phase 2, open-label, single-arm, multicentre basket trial.
Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study.
Cediranib or placebo in combination with cisplatin and gemcitabine chemotherapy for patients with advanced biliary tract cancer (ABC-03): a randomised phase 2 trial.
A randomized, multicenter, phase II study of vandetanib monotherapy versus vandetanib in combination with gemcitabine versus gemcitabine plus placebo in subjects with advanced biliary tract cancer: the VanGogh study.
Addition of ramucirumab or merestinib to standard first-line chemotherapy for locally advanced or metastatic biliary tract cancer: a randomised, double-blind, multicentre, phase 2 study.
Silmitasertib (CX-4945) in combination with gemcitabine and cisplatin as first-line treatment for patients with locally advanced or metastatic cholangiocarcinoma: a phase Ib/II study.
Feasibility of HER2-targeted therapy in advanced biliary tract cancer: a prospective pilot study of trastuzumab biosimilar in combination with gemcitabine plus cisplatin.
A multicenter randomized phase II study of nivolumab in combination with gemcitabine/cisplatin or ipilimumab as first-line therapy for patients with advanced unresectable biliary tract cancer (BilT-01).
Toripalimab with chemotherapy as first-line treatment for advanced biliary tract tumors: a preliminary analysis of safety and efficacy of an open-label phase II clinical study.
Ann Oncol.2020; 31 (101016/annonc/annonc259. 2020): S260-S273
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.
Oh D-Y, He AR, Qin S, Chen L-T, Okusaka T, Vogel A, et al. Durvalumab plus gemcitabine and cisplatin in advanced biliary tract cancer. NEJM Evid.0(0):EVIDoa2200015.
Utcomes by primary tumour location in patients with advanced biliary tract cancer treated with durvalumab or placebo plus gemcitabine and cisplatin in the Phase 3 TOPAZ-1 study.
Outcomes by disease status in patients with advanced biliary tract cancer treated with durvalumab or placebo plus gemcitabine and cisplatin in the Phase 3 TOPAZ-1 study.
Updated overall survival (OS) from the phase III TOPAZ-1 study of durvalumab (D) or placebo (PBO) plus gemcitabine and cisplatin (+ GC) in patients (pts) with advanced biliary tract cancer (BTC).
Ann Oncol.2022; 33 (101016/annonc/annonc1036. ESMO 2022): S19-S26
56P - anti-PD1 antibody toripalimab, lenvatinib and gemox chemotherapy as first-line treatment of advanced and unresectable intrahepatic cholangiocarcinoma: a phase II clinical trial.
Ann Oncol.2020; 31 (101016/annonc/annonc259. 2020): S260-S273
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