Physician Debate: Is Chemotherapy Still the Backbone for CCA Treatment?

Chief of Gastrointestinal Medical Oncology and Director of Clinical Trials Office at the University of Arizona Cancer Center Rachna Shroff, MD, MS.

Rachna Shroff, MD, MS, and Madhulika Eluri, MD, debated whether chemotherapy remains the backbone for cholangiocarcinoma (CCA) treatment or if it is time to move away from this therapeutic strategy. Dr Shroff stated that chemotherapy remains the standard of care and dominant treatment for patients with CCA. She acknowledged that biomarker testing and targeted therapy can transform care; however, they are only applicable to a subset of patients and are not currently a frontline treatment option.¹ For more than a decade, gemcitabine/cisplatin (GemCis) has been the backbone of frontline therapy, and although immunotherapy was recently added as a new standard of care, chemotherapy remains a crucial part of this first-line regimen. She argued that monotherapy with an immune checkpoint inhibitor (ICI) has not been able to demonstrate dramatic efficacy and may rely on synergy between the ICI and chemotherapy to have a clinical benefit. It has been shown that chemotherapy modulates the tumor microenvironment in many ways, including depleting immune-suppressive cells, enhancing antigen presentation, and allowing for immune cell infiltration, which allows for a synergistic effect with immunotherapy agents.¹ Dr Shroff also acknowledged that, although SWOG 1815 was a negative trial and did not demonstrate overall improvement with chemotherapy intensification, it did confer a benefit in certain populations, including patients with locally advanced disease, demonstrating the need for chemotherapy in the perioperative and downstaging space.² The NEO-GAP trial determined that chemotherapy is feasible and safe in patients with resectable, oncologically high-risk intrahepatic CCA, with a disease control rate of 90%.³ Finally, she argued that chemotherapy is here to stay in the second-line setting, especially for patients with no actionable mutations. ABC-06 investigated active symptom control (ASC) alone versus ASC and FOLFOX, and the primary end point was met for overall survival in patients receiving ASC and FOLFOX.^1,4

Dr Eluri argued that although chemotherapy is currently the standard of care, treatment with chemotherapy may have reached a threshold since its discovery in the 1940s. GemCis was established as the standard of care in 2010, and it has been shown that more chemotherapy is not always better.⁵ The phase 2/3 PRODIGE 38 AMEBICA study, which investigated FOLFIRINOX versus GemCis in patients with advanced biliary tract cancer (BTC), did not find a benefit with the 3-drug regimen compared with GemCis.⁶ In addition, the recent SWOG 1815 trial did not confer a survival benefit with the addition of nab-paclitaxel to GemCis in patients with advanced BTC.² Since 2010, there have not been any new approvals solely using chemotherapy, and it has been shown that the benefit of chemotherapy diminishes as a patient’s cancer progresses. Second-line studies with chemotherapy have only shown a progression-free survival benefit of 2.5 to 7 months with significant toxicities.^4,7,8 In addition, less than half of patients with BTC go on to receive second-line therapy, and more than two-thirds do not have durable responses with chemotherapy.⁹ Dr Eluri also argued that next-generation sequencing has changed the landscape for BTC and has allowed for the detection of actionable mutations, including ERBB2 amplifications, FGFR fusions and amplifications, and IDH1/2 substitutions.¹⁰ In the past 5 years, tremendous growth has occurred with targeted therapy in the second line and beyond, with many new approvals and novel therapies in development. Response rates are much improved in the second-line setting compared with chemotherapy, which gives the rationale to move these therapies into the frontline setting. FIGHT-302 and FOENIX-CCA3 are phase 3 clinical trials evaluating the efficacy of targeted therapy versus chemotherapy in the frontline setting in patients with FGFR2 fusions/rearranged advanced BTC.^11,12

Overall, the future of CCA treatment will rely on precision medicine to address patient needs and will include adoptive cellular therapies, targeted therapies, gene therapies, and consolidation/curative opportunities with radiation and surgery.⁵

Sources:

1. Shroff RT. Pro: who run the (biliary) world? Chemo. Presented at: Cholangiocarcinoma Foundation meeting, April 12-14, 2023; Salt Lake City, UT.
2. 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:abstr LBA490.
3. Maithel SK, Javle MM, Mahipal A, et al. NEO-GAP: a phase II single-arm prospective feasibility study of neoadjuvant gemcitabine/cisplatin/nab-paclitaxel for resectable high-risk intrahepatic cholangiocarcinoma. J Clin Oncol. 2022;40(16):4097-4097.
4. Lamarca A, Palmer DH, Wasan HS, et al. Second-line FOLFOX chemotherapy versus active symptom control for advanced biliary tract cancer (ABC-06): a phase 3, open-label, randomised, controlled trial. Lancet Oncol. 2021;22(5):690-701.
5. Eluri M. Contra: is it time to move away from chemotherapy? Presented at: Cholangiocarcinoma Foundation meeting, April 12-14, 2023; Salt Lake City, UT.
6. 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.
7. Yoo C, Kim K-P, Jeong JH, et al. Liposomal irinotecan plus fluorouracil and leucovorin versus fluorouracil and leucovorin for metastatic biliary tract cancer after progression on gemcitabine plus cisplatin (NIFTY): a multicentre, open-label, randomised, phase 2b study. Lancet Oncol. 2021;22(11):1560-1572.
8. Suzuki E, Ikeda M, Okusaka K, et al. A multicenter phase II study of S-1 for gemcitabine-refractory biliary tract cancer. Cancer Chemother Pharmacol. 2013;71(5):1141-1146.
9. Pérez-Valderrama B, Singhal M, Wang L, et al. Treatment patterns and clinical outcomes among patients with biliary tract cancers in a large commercially insured US population. J Clin Oncol. 2022;40(4):398-398.
10. Javle M, Bekaii-Saab T, Jain A, et al. Biliary cancer: utility of next-generation sequencing for clinical management. Cancer. 2016;122(24):3838-3847.
11. Bekaii-Saab TS, Valle JW, Van Cutsem E, et al. FIGHT-302: first-line pemigatinib vs gemcitabine plus cisplatin for advanced cholangiocarcinoma with FGFR2 rearrangements. Future Oncol. 2020;16(30):2385-2399.
12. Broad MJ, Bridgewater JA, Morizane C, et al. A phase III study of futibatinib (TAS-120) versus gemcitabine-cisplatin (gem-cis) chemotherapy as first-line (1L) treatment for patients (pts) with advanced (adv) cholangiocarcinoma (CCA) harboring fibroblast growth factor receptor 2 (FGFR2) gene rearrangements (FOENIX-CCA3). J Clin Oncol. 2020; 38(4):TPS600-TPS600.