Targeted Therapies Expand Reach on World Cholangiocarcinoma Day

Over the last 10 years, the treatment landscape for biliary tract cancers, specifically intrahepatic cholangiocarcinoma, has evolved and now offers physicians more front- and second-line choices for their patients. For targeted agents in this setting, promising new data have come out for patients with actionable alterations.

Over the last 10 years, the treatment landscape for biliary tract cancers, specifically intrahepatic cholangiocarcinoma, has evolved and now offers physicians more front- and second-line choices for their patients. Before, these patients’ primary option was gemcitabine plus cisplatin. As the setting expands, more chemotherapy combinations, immunotherapies, and targeted therapies are becoming available.

For targeted agents in this setting, promising new data have come out for patients with actionable alterations. These targets include FGFR2 fusions, IBH1 mutations, HER2 amplifications, and alterations in the DNA damage repair pathway, including BRCA1/2. Pemigatinib (Pemazyre) recently became the first approved drug specifically for cholangiocarcinoma for patients with FGFR2 fusions or who are positive for rearrangements.1 Additionally, multiple studies were presented at the American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium for drugs such as ivosidenib (Tibsovo) and infigratinib (BGJ398). These are encouraging developments on World Cholangiocarcinoma Day.

“Previously, cholangiocarcinoma used to be thought of as 2 anatomic subtypes—intrahepatic cholangiocarcinoma and extrahepatic cholangiocarcinoma,” Lipika Goyal, MD, said in an interview with Targeted OncologyTM. “But what we’ve recognized over time is that it’s actually a heterogeneous group of different molecular subsets. So, within intrahepatic cholangiocarcinoma, about 40% to 50% of patients have some sort of actionable target.”

Molecular Testing

Goyal, an oncologist at Massachusetts General Hospital in Boston, noted that the optimal timing for tumor mutational profiling in this patient population is ideally when patients first come in and receive a diagnosis. This allows the option for first-line targeted therapies or clinical trials.

“We recognize that when people first [receive a diagnosis], there’s an urgency to go ahead and get treatment started. Sometimes it can take up to 2 to 3 weeks to get the results of tumor molecular profiling,” Goyal said.

Even if patients are not able to receive molecular testing before starting treatment, getting tested during first-line therapy can still deliver benefit, “because we know that gemcitabine and cisplatin can help people, but it doesn’t generally cure people,” Goyal continued. “Being able to have that information ready to go when people are ready for a plan B always makes the transition to plan B more seamless.”

FGFR2 Fusions

In 2020, pemigatinib was approved for patients with FGFR2 fusion or rearrangement-positive cholangiocarcinoma.1 The approval was based on the FIGHT-202 trial (NCT02924376), which investigated the ATP-competitive FGFR-selective oral inhibitor in patients who had progressed on at least 1 line of therapy. The overall response rate was 36% (95% CI, 27%-45%). According to Goyal, although this was in an unselected population, it was promising because FOLFOX (folinic acid, fluorouracil, and oxaliplatin) in the second line has a response rate of approximately 5%.

“Seeing response rates of greater than 30% is generally unheard of in cholangiocarcinoma, and many of these responses were durable,” Goyal explained. “We have some patients who have been on pemigatinib for more than a year, so we’re excited that this is a well-tolerated oral option for our patients with cholangiocarcinoma.”

Another potential drug for cholangiocarcinoma is infigratinib, for which data were also presented at the ASCO symposium.2 This agent is an oral FGFR inhibitor that is selective for FGFR1-3,and was investigated in a single-arm phase 2 study looking at patients previously treated for cholangiocarcinoma with FGFR fusions or rearrangements. Patients received 125 mg of infigratinib orally for 21 days of each 28-day cycle. The primary end point was objective response rate (ORR) by independent central review per RECIST 1.1 criteria and duration of response (DOR). One of the secondary end points was progression-free survival (PFS).

With a median follow-up of 10.6 months for the 108 patients, there was an ORR of 23.1% (95% CI, 15.6%-32.2%), with 1 complete response and 24 partial responses. The median DOR was 5.0 months (range, 0.9-19.1). Of those who responded, 32% had a DOR of more than 6 months. The median PFS in this trial was 7.3 months (95% CI, 5.6-7.6). In a prespecified subgroup analysis of infigratinib in the second-line setting versus the third line or later (3 to 8 prior treatments), the ORR was 34% and 13.8%, respectively.

“Overall, these data were encouraging and comparable to the data with pemigatinib. We’re excited that, in general, in patients who have FGFR2 fusions or rearrangements, we have multiple options,” Goyal said.

Currently, the PROOF trial, a phase 3 study (NCT03773302), is investigating infigratinib versus gemcitabine plus cisplatin in the front-line setting for patients with unresectable locally advanced or metastatic cholangiocarcinoma with FGFR2 gene fusions or translocations.

IDH1 Mutations

At the symposium, investigators also presented data from one of the studies for a targeted drug for cholangiocarcinoma, the ClarIDHy trial (NCT02989857) of ivosidenib in patients with IDH1-mutated advanced biliary tract cancers who have progressed on 1 or 2 lines of therapy.3 The phase 3 trial randomized patients 2:1 to 500 mg of ivosidenib once a day versus placebo. This study was placebo controlled because when it started there was no standard second-line therapy for these patients, according to Goyal.

“This particular pathway is very critical for many key aspects of cholangiocarcinoma carcinogenesis,” Andrew X. Zhu, MD, PhD, lead investigator of ClarIDHy, said about the IDH1 mutation in an interview with Targeted OncologyTM. “Even though the mechanism still remains to be defined, we know once you have the mutation, the tumor cells can actually produce what we call oncometabolite hydroxyglutarate, [which can] be measured.”

The primary end point for this trial was PFS by independent radiology center, andsecondary end points included overall survival (OS).

Previously, the investigators had presented PFS data showing a median of 2.7 months with ivosidenib compared with 1.4 months with placebo (HR, 0.37; 95% CI, 0.25-0.54;
1-sided P < .0001).4 This positive study also had a median OS of 10.8 and 9.7 months for ivosidenib and placebo, respectively (HR, 0.69; 95% CI, 0.44-1.10; P = .06).

In the final results, patients receiving ivosidenib had a median OS of 10.3 versus 7.5 for those receiving placebo (HR, 0.79; 95% CI, 0.56-1.12; 1-sided P = .093).3 After adjusting for crossover to ivosidenib, the prespecified analysis based on a rank-preserving structural failure time (RPSFT) model demonstrated a median OS of 5.1 months in the placebo arm (HR, 0.49; 95% CI, 0.34-0.70; 1-sided P < .0001).

“Our study demonstrated numerical improvement in OS despite the high rate of the crossover, about 70%, and also further improvement when we used the RPSFT adjustment for crossover,” Zhu said. “We convincingly demonstrated a statistically significant improvement in PFS. I think the efficacy signal that we see with the improvement of OS, as well as PFS, coupled with the more favorable tolerable safety profile and supportive quality of life data…demonstrate that this agent may be a very reasonable treatment option in the future for this particular population.”

Based on these data, Agios Pharmaceuticals, Inc, the developer of ivosidenib, plans to submit a supplemental new drug application to the FDA for the agent’s use in patients with previously treated cholangiocarcinoma and IDH1 mutations.5

HER2 Amplification

Other promising targets are still being explored in this setting, one of which is HER2 amplification. Among the current investigations are zanidatamab (ZW25; NCT02892123), a bispecific HER2-directed antibody, in a phase 1 trial, and neratinib (Nerlynx) monotherapy, in the phase 2 basket trial SUMMIT (NCT01953926).

Zanidatamab at 20 mg/kg every 2 weeks in the expansion cohort of patients with HER2 -overexpressing biliary tract cancers showed promising and durable antitumor activity and tolerability.6 The patients had a median of 2.5 prior therapies (range, 1-8). In the 17 evaluable patients, the confirmed ORR was 47% (95% CI, 23%-72%). The disease control rate was 65% (95% CI, 38%-86%) and the median DOR was 6.6 months (95% CI, 3.2-not estimable).

As a result of these data, there is an ongoing phase 2b study of zanidatamab for patients with HER2-positive biliary tract cancer who have progressed on gemcitabine (NCT04466891). In November 2020, zanidatamab received an FDA breakthrough therapy designation in this setting.7

In SUMMIT, the cohort of 25 patients with biliary tract cancer and HER2 mutations—24% of whom had intrahepatic cholangiocarcinoma—received neratinib at 240 mg orally per day.8 There was a confirmed ORR of 12% (95% CI, 3%-31%). The observed clinical benefit rate was 20% (95% CI, 7%-41%), including 3 partial responses and 2 patients with stable disease for 16 weeks or more. There was a median PFS and OS of 2.8 months (95% CI, 1.1-3.7) and 5.4 months (95% CI, 3.7-11.7), respectively.

“What this shows us [is] that there are some patients with HER2 mutations who are going to benefit from neratinib, and we need to be able to select which…patients are going to benefit the most,” Goyal said.

Upcoming Treatments

“Given that these tumors have an Achilles’ heel or a vulnerability that we can exploit, I’m hoping we can develop even better targeted therapies that can lead to better outcomes for these patients with actionable alterations,” Goyal said.

Beyond targeted agents, investigators are exploring immunotherapies such as PD-1 inhibitors for patients with microsatellite instability or high tumor mutational burden, as well as treatments for patients without targets. According to Goyal, data from the first US randomized phase 3 trial for patients with biliary tract cancer of gemcitabine, cisplatin, and nab paclitaxel compared with gemcitabine and cisplatin in the front line appear encouraging.

“Overall, we have a variety of different options, but we’re always trying to do better. I’m really excited about all the trials that are going on for patients with biliary tract cancer right now, because there are some promising new drugs on the horizon.”


1. FDA grants accelerated approval to pemigatinib for cholangiocarcinoma with an FGFR2 rearrangement or fusion. FDA. Updated April 20, 2020. Accessed February 5, 2021.

2. Javle M, Roychowdhury S, Kelley RK, et al. Final results from a phase II study of infigratinib (BGJ398), a FGFR-selective tyrosine kinase inhibitor, in patients with previously treated advanced cholangiocarcinoma harboring an FGFR2 gene fusion or rearrangement. J Clin Oncol. 2021;39(suppl 3):265. doi:10.1200/JCO.2021.39.3_suppl.265

3. Zhu AX, Macarulla T, Javle MM, et al. Final results from ClarIDHy, a global, phase III, randomized, double-blind study of ivosidenib (IVO) versus placebo (PBO) in patients (pts) with previously treated cholangiocarcinoma (CCA) and an isocitrate dehydrogenase 1 (IDH1) mutation. J Clin Oncol. 2021;39(suppl 3):266. doi:10.1200/JCO.2021.39.3_suppl.266

4. Abou-Alfa GK, Macarulla T, Javle MM, et al. Ivosidenib in IDH1-mutant, chemotherapy-refractory cholangiocarcinoma (ClarIDHy): a multicentre, randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2020;21(6):796-807. doi:10.1016/S1470-2045(20)30157-1

5. Agios presents final data from phase 3 ClarIDHy study of Tibsovo (ivosidenib tablets) in patients with previously treated IDH1-mutant cholangiocarcinoma. News release. Globe Newswire. January 17, 2021. Accessed January 17, 2021.

6. Meric-Bernstam F, Hanna DL, El-Khoueiry AB, et al. Zanidatamab (ZW25) in HER2-positive biliary tract cancers (BTCs): results from a phase I study. J Clin Oncol. 2021;39(suppl 3):299. doi:10.1200/JCO.2021.39.3_suppl.299

7. Zymeworks receives FDA breakthrough therapy designation for HER2-targeted bispecific antibody zanidatamab in patients with biliary tract cancer. News release. Business Wire. November 30, 2020. Accessed February 9, 2021.

8. Harding JJ, Cleary JM, Quinn DI, et al. Targeting HER2 (ERBB2) mutation-positive advanced biliary tract cancers with neratinib: results from the phase II SUMMIT ‘basket’ trial. J Clin Oncol. 2021;39(suppl 3):320. doi:10.1200/JCO.2021.39.3_suppl.320