New and Emerging Targeted Therapies Show Promise in Biliary Tract Cancer

Molecular profiling has led to a better understanding of biliary tract cancers by revealing new markers that can be targeted by novel therapies, and several are currently under investigation.

Milind Javle, MD

Milind Javle, MD

Molecular profiling has led to a better understanding of biliary tract cancers (BTC) by revealing new markers that can be targeted by novel therapies, Milind Javle, MD, said in a presentation during the 17th Annual Meeting of the International Society of Gastrointestinal Oncology, and immunotherapy is now a promising area of research, although predictive biomarkers remain elusive.1

“[Although] molecular-targeted therapies are no longer fashionable in the age of immunotherapy, these agents have made remarkable progress in BTC,” said Javle, who is a professor of gastrointestinal medical oncology at the University of Texas MD Anderson Cancer Center. “[Studies have demonstrated] that the genetic profiles of intrahepatic cholangiocarcinoma (CCA), extrahepatic cholangiocarcinoma, and gallbladder cancers are diverse; in fact, 50% of patients have actionable mutations such as FGFR, IDH1, HER2, and BRAF.”

Numerous classes of novel therapeutics are currently under investigation that have shown promising responses in patients with BTC, including molecular-targeted agents, liver-directed agents, immunotherapies, and cytotoxics.

IDH1 Inhibitors in IDH1+ Cholangiocarcinoma

In the global, phase 3, randomized, double-blind ClarIDHy trial (NCT02989857), investigators examined the use of the IDH1 inhibitor ivosidenib (Tibsovo) versus placebo in the second-line treatment of patients with advanced IDH1-mutated CCA; crossover was permitted.2

The study met its primary end point of median progression-free survival (PFS). Results showed a median PFS of 2.7 months in the ivosidenib arm versus 1.4 months in the placebo arm (HR, 0.37; CI, 0.25-0.54; P < .001). The 6-month PFS rate was 32% in the ivosidenib arm versus not evaluable (NE) with placebo; the 12-month PFS rates were 22% and NE, respectively. Additionally, the disease control rate DCR, which is comprised of partial response (PR) and stable disease (SD), was 53% in the ivosidenib arm (2% PR, 51% SD) and 28% in the placebo arm (0% PR, 28% SD).

Additionally, the median overall survival (OS) in the intent-to-treat population was 10.8 months in patients who were treated with ivosidenib and 9.7 months in those who received placebo (HR, 0.69; 95% CI, 0.44-1.10; P = .06). The 6- and 12-month OS rates in the ivosidenib arm were 67% and 48%, respectively; these rates were 59% and 38% in the placebo arm, respectively. Final OS data from the trial showed that although there was a trend for improved OS in those who received the IDH1 inhibitor compared with placebo, it was not statistically significant.3

“[ClarIDHy] has led to studies of IDH resistance. [One study] demonstrated in serial biopsies that there’s isoform switching, whereas a percentage of patients who had IDH1 mutations and resistance [may switch] to an IDH2 isoform, which will, perhaps, be targetable,” Javle explained. “However, at the current time, IDH2 targeting remains experimental.”

FGFR Inhibitors in Cholangiocarcinoma

Approximately 15% of CCA, particularly intrahepatic CCA, have mutations in the FGFR pathway, and these mutations are activating; they unleash a downstream of proliferative and resistance mechanisms that can be targeted with small molecule inhibitors, explained Javle.

Patients whose tumors harbor these mutations are often younger, under the age of 40 years. These mutations are also found to be more common in Caucasian patients rather than Asian patients, and there is a distinct pattern of concurrent mutations. Several FGFR inhibitors have been developed across many tumor types including infigratinib, ponatinib (Iclusig), and pemigatinib (Pemazyre), which are being examined in biliary cancers.

The first trial to be conducted in this space was a phase 2 study, in which 71 patients with advanced CCA who received the FGFR inhibitor infigratinib. Patients experienced a DCR of 83.6% with the agent and an overall response rate (ORR) of 31% in patients who received the agent.4 

A key player is pemigatinib, which was examined in the phase 2 FIGHT-202 trial (NCT02924376). Patients with advanced or metastatic CCA who had FGFR fusions and rearrangements (cohort A; n = 102) experienced an ORR of 35.5% (95% CI, 26.5-45.35).5 Additionally, 3 patients in this cohort had a complete response (CR; 2.6%), 35 had a PR (32.7%), 50 achieved SD (46.7%), and 16 had progressive disease (15%). The median duration of response was 7.5 months (95% CI, 5.7-14.5), and the DCR was 82% (95% CI, 74-89).

For patients with FGFR2 fusion–positive CCA, infigratinib and pemigatinib have been shown to yield some of the highest ORR rates compared with other FGFR inhibitors such as futibatinib and deranzantinib (ARQ 087), at 25.0% in 45 patients and 20.7% in 29 patients, respectively. Erdafitinib (Balversa), however, has been shown to elicit an ORR of 57.1%, albeit in a smaller number of patients (n = 7).

“These agents are potent,” said Javle. “We believe the activity of these agents is higher when you give them earlier in the course of therapy.” To this end, several of these agents are being examined in the first-line setting, he added.

“The most common mechanism of resistance is acquired gatekeeper mutations in the ATP-binding pocket of the FGFR,” Javle explained. “However, these mutations can also be targeted.”

Combination Therapies in BRAF V600-Mutated Cholangiocarcinoma

Although BRAF V600E mutations are only found in 5% of CCA tumors, there is still a need for effective therapies following patient progression on a gemcitabine-based chemotherapy. Due to the fact that dabrafenib (Tafinlar) and trametinib (Mekinist) have shown activity in multiple BRAF V600E–mutated tumor types, the safety and efficacy of the combination was evaluated in patients with BTC in the phase 2 ROAR study (NCT02034110).6

Patients who received the combination therapy (n = 43) experienced an investigator-assessed ORR of 51% (n = 22; 95% CI, 36-67). The independent reviewer-assessed ORR was 47% (n = 22; 95% CI, 36-67). The study not only achieved promising activity within this patient population with the use of dabrafenib plus trametinib, but it also indicated a need for more routine testing to identify BRAF V600E mutations in patients with BTC, noted Javle.

“This is quite similar to the data seen in BRAF V600E-mutated malignant melanoma,” Javle said. “Clearly, at this point, every patient who has a BRAF mutation will probably have access to a BRAF plus MEK inhibitor—in this study, dabrafenib and trametinib was examined. This has made it into the National Comprehensive Cancer Network guidelines.”

Additional Pathways Under Investigation

Several other pathways under investigation with additional agents being examined in clinical trials. For example, in a phase 2 trial, 309 patients with untreated advanced or metastatic BTC received frontline treatment for up to 8 cycles with the VEGFR2 inhibitor ramucirumab (Cyramza) plus gemcitabine/cisplatin (n = 106, intravenous [IV]), the MET multikinase inhibitor merestinib (LY2801653) plus gemcitabine/cisplatin (n = 102, oral), or placebo plus gemcitabine/cisplatin (n = 52, IV; n = 49, oral).7

Results showed that patients who were given the ramucirumab regimen experienced a median PFS of 6.47 months (95% CI, 5.65-7.13) and a median OS of 10.45 months (95% CI, 8.48-11.86). Those in the merestinib arm had a median PFS of 6.97 months (95% CI, 6.21-7.13) and a median OS of 14.03 months (11.96-16.36). Neither of the experimental arms were found to vastly improve OS or PFS over the placebo regimen, which had a median PFS of 6.64 (95% CI, 5.59-6.83) and a median OS of 13.04 months (95% CI, 11.40-15.31). As such, investigators concluded that the addition of ramucirumab or merestinib to the gemcitabine/cisplatin backbone did not significantly improve PFS, OS, or radiological response within this patient population.

Agents such as olaparib (Lynparza), along with other PARP inhibitors, are also being examined in patients with BRCA1/2 and DNA damage repair mutations. PI3K inhibitors and ATK inhibitors including copanlisib (Aliqopa) are being evaluated in those who are positive for PIK3CA and ATK, while porcupine inhibitors are being tested in patients with RSPO fusions and RNF43 mutations, said Javle. PD-1 and PD-L1 inhibitors are also under exploration in patients who are microsatellite instability–high and high tumor mutational burden (TMB).

Moreover, 2 ongoing phase 2 trials are assessing the efficacy of crizotinib (Xalkori; NCT02034981) and ceritinib (Zykadia; NCT02374489) in advanced CCA and other gastrointestinal malignancies.8,9

Novel Immunotherapies and Tumor Mutational Load

While PD-1 and PD-L1 are being tested in patients who have a high TMB, TMB tends to be generally low in this patient population, noted Javle. “When we looked at over 1000 patients across several sites of TMB, it is relatively low,” Javle said. “Only 5%-7% of patients have high or intermediate TMB.” Regardless, immunotherapy is an active area of investigation.

In the phase 2 BilT-01 study (NCT03101566), investigators evaluated nivolumab (Opdivo) in combination with either ipilimumab (Yervoy) or gemcitabine/cisplatin in patients with advanced unresectable BTC.10 Here, 36 patients received nivolumab at 360 mg every 3 weeks plus gemcitabine/cisplatin and 32 patients received nivolumab at 240 mg every 2 weeks with ipilimumab at 1 mg/kg every 6 weeks.

Results showed a 6-month PFS of 64.2% in patients who were treated with nivolumab plus gemcitabine and cisplatin versus 23.4% in those who received the dual immunotherapy. While nivolumab plus ipilimumab was not found to be superior to nivolumab plus gemcitabine/cisplatin, the combination was concluded to be as efficacious as standard-of-care chemotherapy in this patient population, concluded Javle.


  1. Javle M. Updates on new and emerging targeted therapies in biliary tract cancer. Presented at: 17th Annual Meeting of the International Society of Gastrointestinal Oncology; October 2-3, 2020; Virtual.
  2. 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. doi:10.1002/cncr.30254
  3. Abou-Alfa GK, Macarulla Mercade T, M Javle , et al. ClarIDHy: A global, phase 3, randomized, double-blind study of ivosidenib (IVO) vs placebo in patients with advanced cholangiocarcinoma (CC) with an isocitrate dehydrogenase 1 (IDH1) mutation. Ann of Oncol. 2019;20(suppl_5):v851-v934. doi:10.1093/annonc/mdz394
  4. Agios announces final overall survival data from phase 3 ClarIDHy study of TIBSOVO (ivosidenib tablets) in previously treated IDH1-mutant cholangiocarcinoma patients. News release. Agios Pharmaceuticals, Inc. September 21, 2020. Accessed September 22, 2020.
  5. Javle M, Kelley RK, Roychowdhury S, et al. Updated results from a phase II study of infigratinib (BGJ398), a selective pan-FGFR kinase inhibitor, in patients with previously treated advanced cholangiocarcinoma containing FGFR2 fusions. Ann Oncol. 2018;29(suppl_8):VIII720. doi:10.1093/annonc/mdy424.030
  6. Vogel A, Sahai V, Hollebecque A, et al. FIGHT-202: a phase 2 study of pemigatinib in patients (pts) with previously treated locally advanced or metastatic cholangiocarcinoma (CCA). Ann Oncol. 2019;30(suppl_5):v851-v934. doi:10.1093/annonc/mdz394.
  7. Subbiah V, Lassen U, Élez E, et al. Dabrafenib plus trametinib in patients with BRAF V600E-mutated biliary tract cancer (ROAR): a phase 2, open-label, single-arm, multicentre basket trial. Lancet Oncol. 2019;21(9):1234-1243. doi:10.1016/S1470-2045(20)30321-1
  8. Valle JW, Bai LY, Orlova R, et al. Ramucirumab (RAM) or merestinib (MER) or placebo (PL) plus gemcitabine (GEM) and cisplatin (CIS) as first-line treatment for advanced or metastatic biliary tract cancer (BTC): a randomized, double-blind, phase II study. J Clin Oncol. 2020;38(suppl 4):477-477. doi:10.1200/JCO.2020.38.4_suppl.477.
  9. Phase 2 study assessing efficacy and safety of crizotinib in patients harboring an alteration on ALK, MET or ROS1 (AcSé). Updated October 21, 2019. Accessed October 2, 2020.
  10. A phase II trial of LDK378 in ROS1 and /or ALK over-expressed advanced intrahepatic or hilar cholangiocarcinoma. Updated April 5, 2018. Accessed October 2, 2020.
  11. Sahai V Griffith KA, Beg MS, et al. 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). J Clin Oncol. 2020;38(suppl 15):4582. doi:10.1200/JCO.2020.38.15_suppl.4582
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