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Integrating cytotoxic, targeted and immune therapies for cholangiocarcinoma

  • Joachim Merters
    Affiliations
    GastroZentrum Hirslanden – Digestive Diseases Institute, Hirslanden Hospital Zurich, Switzerland
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  • Angela Lamarca
    Correspondence
    Corresponding author. , Department of Oncology – OncoHealth Institute, Fundación Jiménez Díaz University Hospital, Avda Reyes Catolicos 2, 28040, Madrid Spain.
    Affiliations
    Department of Oncology – OncoHealth Institute, Fundación Jiménez Díaz University Hospital, Madrid Spain

    Department of Medical Oncology, The Christie NHS Foundation, Manchester

    Division of Cancer Sciences, University of Manchester, Manchester, United Kingdom
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Published:November 14, 2022DOI:https://doi.org/10.1016/j.jhep.2022.11.005

      Abstract

      Management of BTCs is rapidly evolving. Majority of patients are diagnosed with advanced disease, when chemotherapy with cisplatin and gemcitabine followed by second-line FOLFOX is the cornerstone of treatment in the absence of targetable alterations. Targeted therapies for tumours harbouring fibroblast growth factor receptor-2 (FGFR-2) fusions, isocitrate dehydrogenase-1 (IDH-1) mutations, BRAF V600E mutations, NTRK fusions and/or HER2 amplifications, among others, have brought precision medicine into the treatment landscape of advanced BTC. This holds true especially for patients with intrahepatic cholangiocarcinoma. Recently, immunotherapy has also shown promising activity. The field is now moving forward and management is no longer limited to chemotherapy or targeted therapies alone, but really looking into how combination strategies could enhance response to treatment. We are therefore facing a change of paradigm, where immunotherapy, cytotoxic chemotherapy and targeted therapies will complement each other when administered concomitantly. This review will focus on the rational behind these combinations and summarise current clinical trial data.

      Keywords

      Funding

      No specific funding was received.

      Disclosure

      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.
      • Majority of patients with BTC are diagnosed at advanced stages
      • Chemotherapy remains cornerstone of systemic therapy
      • Targeted therapies are now part of treatment strategies for BTC
      • Immunotherapy has also shown promising activity in BTC
      • Combination of these strategies are explored aiming to enhance response.

      Authors' contributions

      Both authors were involved in the writing and final approval of the manuscript.

      Introduction

      Cholangiocarcinoma (CCA) can be subdivided into intrahepatic cholangiocarcinoma (iCCA) and extrahepatic cholangiocarcinoma (eCCA) (classified as hilar and distal) depending on their location. They are considered rare malignancies, but incidence is increasing
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      ,
      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).
      are options to considered.
      Second, identification of targetable alterations has brought precision medicine into the CCA field
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      and fibroblast growth factor receptor-2 (FGFR-2) fusions
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      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.
      being the main focus of latest research, there are other targets of interest such as B-Raf proto-oncogene serine/threonine kinase (BRAF) V600E mutations
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      and mutations
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      and neurotrophic tyrosine receptor kinase (NTRK) fusions
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      . Currently, four of these compounds have been approved by regulatory agencies: pemigatinib (Food and Drug Administration (FDA) and European Medicines Agency (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) ,

      Agency EM. https://www.ema.europa.eu/en Last accessed June 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 (dMMR), high microsatellite instability (MSI) or high tumour mutational burden (hTMB), known to achieve best response to immunotherapy and for whom there is current FDA approval for immunotherapy approaches , is small (expected to be <5%)
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      , which was the main rationale for combination strategies of immunotherapy and other agents, such as cytotoxic chemotherapy to be developed.
      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 in the field of how to integrate cytotoxic chemotherapy, targeted therapies and immunotherapy approaches (Figure 1).
      Figure thumbnail gr1
      Figure 1The management of cholangiocarcinoma is rapidly evolving. Management is no longer limited to chemotherapy or targeted therapies alone are combination strategies are showing promising activities. We are therefore facing a change of paradigm, where immunotherapy, cytotoxic chemotherapy and targeted therapies with interact more and more and administered concomitantly.

      Combination of cytotoxic agents and targeted therapies

      As noted above, four targeted therapeutics have meanwhile been approved in CCA: pemigatinib (targeting FGFR2), infigratinib (targeting FGFR2), ivosidenib (targeting IDH) and dabrafenib/trametinib (targeting BRAF V600E) ,

      Agency EM. https://www.ema.europa.eu/en Last accessed June 2022 [.

      . 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 therapy regimes, combining these regimes with novel targeted therapeutics has been a recent approach. Already in the phase-2 ABC-03 trial of 2015 CisGem was combined with the small molecule VEGF inhibitor Cediranib
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      . No improvement of PFS was seen for the combination treatment in this trial as VEGF remains an ineffective molecular target in CCA
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      . Similarly, other studies testing similar approaches in combination with CisGem did not show significant benefit
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      . Of the now approved targeted therapeutics named above, none has entered combination trials with cytotoxic agents. Still other targeted therapeutics, so far not approved as monotherapies have or are being studied in such combinations.
      LY3410738, a first-in-class covalent inhibitor of mutant IDH1 is currently being investigated in an open label phase I trial in combination with CisGem 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 inhibitor is currently being investigated in combination with CisGem 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 an median PFS of 11.1 (95% CI 7.6–14.7) months and an median OS of 17.4 (95% CI 13.4–25.7) months with an ORR of 32%. Based on these data a phase III trial is planned
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      .
      Varlitinib a pan-EGFR inhibitor was combined with capecitabine in the second-line phase II ‘TreeTopp’ study. 127 patients received Varlitinib plus Capecitabine or placebo plus Capecitabine in a 1:1 randomization. The study did not show improvement of PFS or ORR in patients who received Varlitinib compared to those with Capecitabine alone
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      .
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      .
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      .

      Combination of cytotoxic agents and immunotherapy

      Due to the low rate of patients diagnosed with advanced CCA who may harbour one of the molecular characteristics associated with high response rate to immunotherapy strategies (dMMR, MSI or hTMB), and the limited activity with immunotherapy-alone strategies in CCA in the absence of these biomarkers, combination of immunotherapy with cytotoxic chemotherapy options has attracted lots of attention.
      There is, however, some evidence suggesting the potential role of immunotherapy in BTC
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      . Sun and colleagues reported improved OS, PFS and objective response rate (ORR) in biliary tract patients with combined immunotherapy (PD-1 inhibitor) and chemotherapy (38 patients) compared to immunotherapy-alone (20 patients) or chemotherapy-alone (19 patients) approaches without increased toxicity
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      , showing that combination of immunotherapy and chemotherapy was active and tolerable in cholangiocarcinoma. This was supported by additional phase II studies
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      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.
      • Oh D.Y.
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      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 largest study 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)
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      . Highest ORR was reported in the arms where immunotherapy was administered concomitantly with durvalumab (ORR of 50%, 72% and 70%, respectively) with similar PFS (12.8, 11.8 and 12.3 months, respectively). Thus, the role of addition of CTLA inhibitors (i.e tremelilumab) in BTC remains unclear.
      The TOPAZ-1 phase III study randomised 685 patients diagnosed with advanced treatment-naïve cholangiocarcinoma or gallbladder cancer to cisplatin and gemcitabine 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 Evidence.0(0):EVIDoa2200015.

      . Primary end-point was overall survival. The study showed an improvement in OS (HR 0.80 (95% CI 0.66-0.97; p-value 0.021), PFS (HR 0.75 (95% CI 0.63-0.89; p-value 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 Durvalumab arm
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      . Interestingly, subgroup analysis did not identify significant changes depending on the PD-1 expression

      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 Evidence.0(0):EVIDoa2200015.

      , primary site

      al He. 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. ESMO GI 2022 (O-1).

      , disease status

      al Oe. 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. ESMO GI 2022 (PD-8).

      , presence of viral hepatitis
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      or the geographic area
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      . Updated results confirmed such benefit
      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).
      . Based on this results, latest NCCN guidelines (v.2022

      NCCN. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Hepatobiliary Cancers Version 1.2022 — March 29, 2022. https://wwwnccnorg/guidelines/guidelines-detail?category=1&id=1438. Last accessed 30th June 2022.

      ) do consider cisplatin gemcitabine and durvalumab as a possible first-line treatment option for advanced cholangiocarcinoma. In addition, durvalumab has been approved in 2022 by FDA in this indication . Results from a similar phase III study with pembrolizumab (KEYNOTE-966; NCT04003636) are awaited. If positive, the role of immunotherapy and chemotherapy combination in first-line treatment for advanced biliary tract malignancies is likely to be stablished.
      Multiple other clinical trials are ongoing in this setting, specially looking into the addition of checkpoint inhibitors and chemotherapy in the first-line setting
      • Valle J.W.
      • Kelley R.K.
      • Nervi B.
      • Oh D.Y.
      • Zhu A.X.
      Biliary tract cancer.
      . Overall, the future of immunotherapy in CCA looks bright for the first time in many years. Efforts towards predictive biomarkers to allow patient selection and understanding of mechanism of resistance will be paramount.

      Combination of immunotherapy and targeted therapies

      Beyond the combination with chemotherapy, combination of immunotherapy with tyrosine kinase inhibitors (TKIs) has also been tested, specially in a non-biomarker driven population. Small phase II studies have shown promising activity with immune checkpoint inhibitors
      • Villanueva L.
      • Lwin Z.
      • Chung H.C.
      • Gomez-Roca C.
      • Longo F.
      • Yanez E.
      • et al.
      Lenvatinib plus pembrolizumab for patients with previously treated biliary tract cancers in the multicohort phase II LEAP-005 study.
      , with some other clinical trials ongoing and exploring this potential alternative (NCT03260712).
      In addition, phase II study results of triple combination of chemotherapy (GemOx (gemcitabine and oxaliplatin)), with immunotherapy and TKIs have been reported.
      The first one of this studies combined GemOx with toripalib and lenvatinib in 30 partients 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.
      . The study and impressive response rate of 80% in the second-line setting, with disease control rate of 93.3% and tolerable toxicity profile. Two pts with locally metastatic disease were down-staged and they subsequently underwent resection.
      Dong and colleagues followed a similar approach in another phase II study, testing combination of GemOx with sintilimab and TKI (either lenvatinib or by NGS-guided targeted therapy) for local advanced or metastatic BTCs
      • Dong X.
      • Zhang Z.
      • Zhang Q.
      • Chen L.
      • Cao G.
      • Liu C.
      • et al.
      Triple therapy in biliary tract cancers: GemOX plus immune checkpoint inhibitor in combination with lenvatinib or NGS-guided targeted therapy.
      . The TKI strategy consisted on lenvatinib (no targetable gene alterations) or targeted therapy based on NGS (olaparib for BRCA1/2 mutation, dasatinib for IDH1/2 mutation, afatinib for EGFR amplification, lenvatinib for PDGFR and KIT mutation, and lenvatinib for FGFR/KIT mutation). Total of 22 patients were included in the lenvatinib group with ORR and DCR of 45.5% and 86.4%, respectively. For 14 patients with NGS, 5 patients were treated by targeted therapy and there were 1 SD and 4 PR cases. For four patients with positive PD-L1 expression, the ORR was 100%.
      Similar to what Dong and colleagues proposed in the NGS group
      • Dong X.
      • Zhang Z.
      • Zhang Q.
      • Chen L.
      • Cao G.
      • Liu C.
      • et al.
      Triple therapy in biliary tract cancers: GemOX plus immune checkpoint inhibitor in combination with lenvatinib or NGS-guided targeted therapy.
      , in the setting of biomarker-driven patients, combination of immunotherapy and targeted therapies is of much interest but there is scarce data as yet
      • Valle J.W.
      • Kelley R.K.
      • Nervi B.
      • Oh D.Y.
      • Zhu A.X.
      Biliary tract cancer.
      .

      Conclusions

      In 2022 the treatment landscape and outcome in advanced cholangiocarcinoma 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 cholangiocarcinoma, which has proven notoriously difficult to attack because of its heterogeneous biology, its often poor vascularization and excessive stromal reaction. In addition immunotherapeutics, which have been real gamechangers in many cancers did not succeed as monotherapies in CCA. Therefore combining the most promising approaches in a rational way, taking into account the specifics of CCA tumour biology and mechanisms of malignancy is the logical next step to push therapy and eventually overall survival forward. Combination of chemotherapy with targeted molecules and checkpoint-inhibitors may take CCA treatment to a new level. This requires first of all improved characterization and understanding of the individual patients 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 development of future targeted and individualized therapies.

      Acknowledgements

      Dr Angela Lamarca received funding from European Union’s Horizon 2020 Research and Innovation Programme [grant number 825510, ESCALON].

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