Standard Therapy Selection for Cholangiocarcinoma Needs Further Interpretation

Besides standard-of-care chemotherapy in the frontline setting, definitive therapy selection in patients with cholangiocarcinoma in both the adjuvant and second-line settings require data from confirmatory clinical trials for further clarification, says Lorenza Rimassa, MD.

Lorenza Rimassa, MD

Besides standard-of-care chemotherapy in the frontline setting, definitive therapy selection in patients with cholangiocarcinoma in both the adjuvant and second-line settings require data from confirmatory clinical trials for further clarification, said Lorenza Rimassa, MD, of the Medical Oncology Unit at Humanitas Research Hospital-IRCCS in Milan, Italy.

“Selected patients may benefit from liver-directed therapies, and potentially curative resection is possible in 20% of patients. Unfortunately, most of these patients eventually relapse,” Rimassa said to an audience at the Annual European Association for the Study of the Liver 2019 International Liver Congress held in Vienna, Austria.

Although success with immunotherapy in this tumor type has been limited, Rimassa outlined several targeted agents that may improve survival in patients with advanced disease as well as chemotherapy combinations that have proven effective in certain settings.

Adjuvant Therapy

Rimassa cited 2 phase III trials that tested the efficacy of adjuvant chemotherapy versus observation in patients following surgical resection.

“Potentially curative resection is possible in 20% of patients; but unfortunately, recurrence rates are high, up to 60% to 70%, and involved nodes and margins are negative prognostic factors for recurrence.”

In the PRODIGE 12 trial of gemcitabine plus oxaliplatin versus surveillance in patients who had underwent resection of localized disease ≤3 months, the differences in relapse-free survival and time to definitive deterioration of global health-related quality of life—the dual primary endpoints—were not statistically significant between the 2 arms.2

Similarly, the BILCAP study failed to show a statistically significant improvement in median overall survival (OS) with capecitabine versus observation alone in patients following surgery with a curative intent (HR, 0.81; 95% CI, 0.63-1.04;P= .097). However, prespecified sensitivity and per-protocol analyses suggest that capecitabine can improve outcomes. Per the sensitivity analysis in the intention-to-treat (ITT) population, which adjusted for minimization factors and nodal status, grade, and gender, the hazard ratio for OS improved to 0.71 (95% CI, 0.55-0.92;P= .01).3

Similar improvements were seen in the per-protocol analysis, with a median OS of 53 months with capecitabine versus 36 months with observation (HR, 0.75; 95% CI, 0.58-0.97;P= .028). In the ITT population, median recurrence-free survival (RFS) was 24.4 months versus 17.5 months with capecitabine and observation, respectively (HR, 0.75; 95% CI, 0.58-0.98;P= .033); in the per-protocol analysis, the median RFS was 25.9 months versus 17.4 months, respectively (HR, 0.70; 95% CI, 0.54-0.92;P= .0093).

“Based on these data, the ASCO [American Society for Clinical Oncology] guidelines that were recently published state that patients should be offered adjuvant capecitabine for a duration of 6 months,” Rimassa said.4

Advanced Disease Setting

The standard of care for frontline therapy in patients with advanced or metastatic cholangiocarcinoma was tested in the ABC-02 trial in which patients were randomized to receive gemcitabine alone or in combination with cisplatin. Those taking the combination had improved median OS, 11.7 months for cisplatin/gemcitabine versus 8.1 months for gemcitabine alone (HR, 0.64; 95% CI, 0.52-0.80;P<.001), and the median progression-free survival (PFS) was 8 months versus 5 months, respectively (HR, 0.63; 95% CI, 0.51-0.77;P<.001).5

In a phase III Japanese study that was designed to replicate ABC-02, the combination had a better 1-year OS rate, median OS, median PFS, and radiologic response rates (NCT00380588). Hazard ratios of 0.69 and 0.66 for OS and PFS, respectively, favoring gemcitabine plus cisplatin were also observed. The authors of a meta-analysis of patient-level data from these studies concluded that the results justify the use of gemcitabine plus cisplatin as the standard of care for frontline treatment of this population.6

Moving to second-line therapy, Rimassa said a standard therapy for patients in this setting is lacking, although many drugs have been studied in phase II trials and in retrospective analyses.

“We know there are prognostic factors associated with survival in the second line such as prior resection of the primary tumor, reasons for first-line [therapy] discontinuation, performance score at the beginning of second-line therapy, and the presence of peritoneal carcinomatosis,” she said.

A systematic review of 25 studies that looked at systemic chemotherapy in the second line found a mean OS of 7.2 months, mean PFS of 3.2 months, mean response rate of 7.7%, and mean disease control rate of 49.5%.7

Rimassa mentioned the phase III ABC-06 trial that is being conducted in patients following prior therapy with gemcitabine and cisplatin and comparing the efficacy of active symptom control with oxaliplatin, folinic acid, and fluorouracil (FOLFOX; NCT01926236). The trial is still ongoing, but positive data may result in a new standard of care for this setting, she said.

Another ongoing trial, REACHIN is evaluating the safety and efficacy of regorafenib (Stivarga) in patients who have progressed following standard-of-care chemotherapy. Data from the phase II trial that were presented at the 2019 Gastrointestinal Cancers Symposium showed an improvement in median PFS with regorafenib versus placebo (3 vs 1.5 months; HR, 0.48; 95% CI, 0.29-0.80;P= .004) but no statistically significant improvements were seen in median OS. Rimassa said further analyses are ongoing.8

Targeting Tumors With Genetic Alterations

Rimassa went on to review successes observed with agents targeting genetic alterations such asIDH1,FGFR2, andBRAFin patients with cholangiocarcinoma.

For example, patients withBRAFV600E—mutated cancers were treated with the combination of dabrafenib (Tafinlar) and trametinib (Mekinist) in the ROAR basket trial. In patients with cholangiocarcinoma who had received ≥1 prior line of therapy, the combination showed favorable efficacy and safety and investigators concluded that patients should be considered forBRAFmutation analysis to determine eligibility for the combination.9

In patients withIDH1mutations, which are detected in up to 25% of those with intrahepatic cholangiocarcinoma, the agent ivosidenib (AG-120) induced a disease control rate (DCR) of >60%—with a 5% partial response rate—and a median PFS of 3.8 months in a phase I trials involving patients who had progressive disease or at least a prior gemcitabine-base regimen.10The results of the ongoing, randomized, placebo-controlled phase III trial ClarIDHy (NCT02989857) will determine if this is a viable treatment option for this patient population and will be presented at an upcoming conference, Rimassa said.

She reviewed 5 agents in the setting of patients with cholangiocarcinoma who harborFGFR2gene fusions. Response rates ranged from 20% to 40% and DCRs were ≥75%, which is high for this population. With pemigatinib (INCB054828) and infigratinib (BGJ398), data from phase II trials have revealed a median OS of 15.8 months and 12.5 months, respectively, in patients who had received prior therapy. Based on these data, both agents are being examined in phase III trials in the first line in patients withFGFR2gene fusions versus standard-of-care gemcitabine plus cisplatin (NCT03656536; NCT03773302).1

Rimassa concluded by stating that a better understanding of clinical and molecular characteristics of this disease is needed to identify biomarkers for therapy that will help select patients who are most likely to benefit from new, promising therapies.

“The most promising drugs under development are for intrahepatic cholangiocarcinoma [and include] IDH inhibitors and molecules targetingFGFR2gene fusions,” she said.


  1. Rimassa, L. Global treatment approach: multidisciplinary approach to cholangiocarcinoma from diagnosis to treatment according to patient profile. Presented at: The 2019 International Liver Congress; April 14-10, 2019; Vienna, Austria.
  2. Edeline J, Benabdelghani M, Bertaut A, et al. Gemcitabine and oxaliplatin chemotherapy or surveillance in resected biliary tract cancer (PRODIGE 12-ACCORD 18-UNICANCER GI): a randomized phase III study.J Clin Oncol. 2019;37(8): 658-667. doi: 10.1200/JCO.18.00050.
  3. Primrose JN, Fox RP, Palmer DH, et al. Capecitabine compared with observation in resected biliary tract cancer (BILCAP): a randomised, controlled, multicentre, phase 3 study [published online March 25, 2019].Lancet Oncol.doi: 10.1016/S1470-2045(18)30915-X.
  4. Shroff RT, Kennedy EB, Bachini M, et al. Adjuvant therapy for resected biliary tract cancer: ASCO clinical practice guidelines [published online March 11, 2019].J Clin Oncol. doi: 10.1200/JCO.18.02178.
  5. Valle J, Wasan H, Palmer DH, et al; ABC-02 Trial Investigators. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer.N Engl J Med. 2010;362(14):1273-1281. doi: 10.1056/NEJMoa0908721.
  6. Valle JW, Furuse J, Jitlal M, et al. Cisplatin and gemcitabine for advanced biliary tract cancer: a meta-analysis of two randomised trials.Ann Oncol. 2014;25(2):391-398. doi: 10.1093/annonc/mdt540.
  7. Lamarca A, Hubner RA, David Ryder W, Valle JW. Second-line chemotherapy in advanced biliary cancer: a systemic review.Ann Oncol.2014;25(12):2328-2338. doi: 10.1093/annonc/mdu162.
  8. Demols A, Borbath I, Van Den Eynde M, et al. Regorafenib after failure of gemcitabine and platinum-based chemotherapy for locally advanced (nonresectable) and metastatic biliary tumors: a randomized double-blinded placebo-controlled phase II trial.J Clin Oncol. 2019;37(suppl 4; abstr 345). doi: 10.1200/JCO.2019.37.4_suppl.345.
  9. Wainberg ZA, Lassen UR, Elez E, et al. Efficacy and safety of dabrafenib (D) and trametinib (T) in patients (PTS) withBRAFV600E-mutated biliary tract cancer (BTC): a cohort of the ROARbasket trial. J Clin Oncol. 2019;37(suppl 4; abstr 187). doi: 10.1200/JCO.2019.37.4_suppl.187.
  10. Phase I study of AG-120, and IDH1 mutant enzyme inhibitor: results from the cholangiocarcinoma dose escalation and expansion cohorts.J Clin Oncol. 2017;35(suppl 15; abstr 4015). doi: 10.1200/JCO.2017.35.15_suppl.4015.