5th Annual CCA Summit: Keynote Address

Juan Valle, MBChB, MSc, FRCP

At the 2023 CCA Summit, Juan Valle, MBChB, MSc, FRCP, gave the Keynote Address titled “What Has Been Accomplished Over the Past 5 Years and What Promise Does the Future Hold for the CCA Patient?” Dr Valle informed the audience that there is now an International Classification of Diseases (ICD) code for perihilar cholangiocarcinoma (pCCA), in ICD-11, which was introduced in January 2022.¹ Previously, no ICD code was listed for pCCA, which led to the miscoding of pCCA as intrahepatic CCA (iCCA) and misrepresentation of the incidence of CCA subtypes.¹ In addition, the histological classification of iCCA has been updated in the 5th edition of the World Health Organization classification of hematolymphoid tumors.² Updates to the molecular characterization of iCCA include the addition of small duct–type iCCA, which can frequently have genetic alterations in IDH1/2, FGFR2, and BAP1, and large duct–type iCCA, which has frequent genetic alterations in KRAS, SMAD4, and TP53.² In the era of precision medicine, anatomical subgroups matter, and the type of surgery performed depends on the anatomical location of the CCA.³ Dr Valle also said that we now understand that patients with iCCA have a more favorable prognosis compared with patients who do not have iCCA. In a post-hoc analysis of the ABC-01, -02, and -03 studies, patients with liver-only iCCA had a median overall survival of 16.7 months compared with 11.7 months in non-iCCA patients.⁴ Over the past 5 years, advances in precision medicine have emerged, with studies evaluating targeted therapies directed at mutations in FGFR, IDH, BRAF, NTRK, and KRAS, as well as advances in immunotherapy, with studies evaluating gemcitabine/cisplatin (GemCis) plus durvalumab and GemCis plus pembrolizumab.⁵

Dr Valle discussed advances in adjuvant therapy for patients with biliary tract cancer (BTC). Although there is still room for improvement in clinical outcomes, ASCO Guidelines from 2019 recommend that patients with BTC be offered adjuvant capecitabine chemotherapy for 6 months and that patients with extrahepatic CCA or gallbladder cancer and a microscopically positive surgical margin be offered adjuvant chemoradiotherapy.⁶

In advanced disease, clinical trials have demonstrated that little or no benefit is seen from intensifying chemotherapy, as highlighted in the PRODIGE 38 AMEBICA and SWOG 1815 studies.^7,8 In the SWOG 1815 study of gemcitabine, nab-paclitaxel, and cisplatin (GAP) versus GemCis in patients with advanced BTC, the overall survival was 14.0 months versus 12.7 months, respectively (hazard ratio, 0.93; 95% confidence interval, 0.74-1.19, P=.58).⁸

Dr Valle also discussed the rationale for neoadjuvant therapy, which includes a better baseline performance status for patients, early delivery of systemic chemotherapy, and a higher chemotherapy completion rate.¹ Neoadjuvant therapy may also downstage the primary tumor, improve R0 resection, treat micrometastatic disease, allow for the exclusion of unfavorable biology, and prevent futile surgery.¹ The phase 2 NEO-GAP feasibility study evaluated neoadjuvant GAP in patients with high-risk iCCA.⁹ More than 50% of the patients in this study completed chemotherapy and surgery, and patients had a median recurrence-free survival of 7.1 months and a median overall survival of 24 months.⁹

In summarizing the clinical rationale for immunotherapy, Dr Valle highlighted the fact that many risk factors for CCA are inflammation- or immune-related.¹⁰ These risk factors include primary sclerosing cholangitis, infections such as hepatitis B and C and liver fluke, and chronic inflammation, including ulcerative colitis, cholecystitis, cirrhosis, and bile ducts cysts.¹⁰ Data suggest that PD-1 blockade alone does not offer much clinical benefit, and only a small subset of patients respond to treatment with monotherapy.¹¹ CCA tumors tend to be cold, in that they have an immune-resistant microenvironment, so PD-1 blockade alone is likely not the most effective therapy in these patients; however, combination therapy using agents with differing mechanisms of action may be beneficial, such as anti–PD-L1 therapy with anti–CTLA4 agents.¹¹ Other combination strategies include the use of checkpoint inhibition in combination with agents that increase antigen presentation in cancer, such as vaccines, anti-CD40, and Toll-like agonists, and checkpoint inhibitor therapy combined with chemotherapy, radiation therapy, or targeted therapy.¹¹ Guidelines for targeted therapies for BTCs have evolved as more data have become available.¹ Currently, targeted treatments for patients with certain mutations, including those with unresectable and metastatic disease, include the use of entrectinib and larotectinib for NTRK gene fusion–positive tumors, pembrolizumab for microsatellite instability-high/mismatch repair deficient tumors, nivolumab plus ipilimumab for tumor mutational burden–high tumors, and pralsetinib and selpercatinib for RET gene fusion–positive tumors.¹

In summary, updates on classification and pathology will help to further classify CCA, and future studies are needed to improve treatments in the adjuvant and neoadjuvant settings. Additional research is needed to leverage our understanding of molecular biology of novel agents and rational combinations, as well as to understand primary and acquired resistance and reduce the number of patients who do not receive CCA treatment.

References

1. Valle J. Keynote: what has been accomplished over the past 5 years and what promise does the future hold for the CCA patient? Presented at: 5th Anniversary Cholangiocarcinoma Summit, October 19-21, 2023; Scottsdale, Arizona.
2. European Association for the Study of the Liver. EASL-ILCA Clinical Practice Guidelines on the management of intrahepatic cholangiocarcinoma. J Hepatol. 2023;79(1):181-208.
3. Mirallas O, López-Valbuena D, García-Illescas D, et al. Advances in the systemic treatment of therapeutic approaches in biliary tract cancer. ESMO Open. 2022;7(3):100503.
4. Lamarca A, Ross P, Wasan HS, et al. Advanced intrahepatic cholangiocarcinoma: post hoc analysis of the ABC-01, -02, and -03 clinical trials. J Natl Cancer Inst. 2020;112(2):200-210.
5. Cowzer D, Harding JJ. Advanced bile duct cancers: a focused review on current and emerging systemic treatments. Cancers (Basel). 2022;14(7):1800.
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7. Phelip JM, Desrame J, Edeline J, et al. Modified FOLFIRINOX versus CISGEM chemotherapy for patients with advanced biliary tract cancer (PRODIGE 38 AMEBICA): a randomized phase ii study. J Clin Oncol. 2022;40(3):262-271.
8. Shroff RT, Guthrie KA, Scott AJ, et al. SWOG 1815: a phase III randomized trial of gemcitabine, cisplatin, and nab-paclitaxel versus gemcitabine and cisplatin in newly diagnosed, advanced biliary tract cancers. J Clin Oncol. 2023;41(suppl 4):LBA490.
9. Maithel SK, Keilson JM, Cao HST, et al. NEO-GAP: a single-arm, phase ii feasibility trial of neoadjuvant gemcitabine, cisplatin, and nab-paclitaxel for resectable, high-risk intrahepatic cholangiocarcinoma. Ann Surg Oncol. 2023;30(11):6558-6566.
10. Kirstein MM, Vogel A. Epidemiology and risk factors of cholangiocarcinoma. Visc Med. 2016;32(6):395-400.
11. Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity. 2013;39(1):1-10.