Targeted Treatment Advances in Cholangiocarcinoma

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For one of the rarest and most aggressive of tumors—cholangiocarcinoma—two novel molecularly targeted agents yielded encouraging outcomes in advanced disease in studies reported at the European Society for Medical Oncology (ESMO) Congress 2019.

Ghassan K. Abou-Alfa, MD

Ghassan K. Abou-Alfa, MD

In the phase III ClarIDHy trial, the risk of disease progression or death was reduced by 63% with ivosidenib, an inhibitor of the isocitrate dehydrogenase 1 (IDH1) mutation.1 The results were reported at a Presidential Symposium during the ESMO Congress by Ghassan K. Abou-Alfa, MD, of Memorial Sloan Kettering Cancer Center, New York.

“A significant improvement in progression-free survival, by central review, and a favorable overall survival trend and tolerable safety profile all support the clinical benefit of ivosidenib in patients with IDH1-mutated advanced cholangiocarcinoma,” Dr. Abou-Alfa said during a press briefing. “This pivotal trial also represents a practice-changing result, where genomic testing would become a standard of care and would open the possibility for more target-specific trials in a tumor where little progress has been made in recent years.”

ESMO commentator Angela Lamarca, MD, PhD, MSc, of The Christie NHS Foundation Trust in Manchester, United Kingdom, agreed, telling journalists, “These results are practice-changing; they represent the first [phase III] trial successfully exploring precision medicine in cholangiocarcinoma.”

Angela Lamarca, MD, PhD, MSc

Angela Lamarca, MD, PhD, MSc

Arndt Vogel, MD, PhD

Arndt Vogel, MD, PhD

Additionally, the phase II FIGHT-202 study evaluated pemigatinib, a selective, potent oral inhibitor of fibroblast growth factor receptor (FGFR) 1, 2, and 3. Pemigatinib yielded durable responses in more than one-third of patients with FGFR2 rearrangements or fusions and led to a progression-free survival of about 7 months, as reported by Arndt Vogel, MD, PhD, of Hannover Medical School in Germany.2

“In many cholangiocarcinomas, you can detect genetic alterations, which allow for targeted therapies,” he said. “Among them are many patients with FGFR2 fusions or rearrangements. They exclusively occur in intrahepatic cholangiocarcinoma and are detectable in about 15% of patients, indicating that this might be an interesting patient population to be treated by an FGFR inhibitor.”

Currently, first-line treatment for locally advanced or metastatic cholangiocarcinoma consists of chemotherapy with gemcitabine and cisplatin. There is no standard second-line treatment, and all regimens have shown limited efficacy, with a median progression-free survival of about 3 months and median overall survival of about 7 months, according to Dr. Vogel.

The novel agents evaluated in the ClarIDHy and FIGHT-202 studies greatly improve upon these historical outcomes, though experts cautioned the results of the two studies should not be compared. The drugs target mutually exclusive mutations, as Dr. Abou-Alfa and his team have demonstrated.

ClarIDHy Details

Ivosidenib (formerly AG-120) is a first-in-class, oral, small-molecule inhibitor of the mutant IDH1 protein, which occurs in up to 20% of patients with cholangiocarcinoma. It is approved for patients with acute myeloid leukemia (AML) and IDH1 mutations who have relapsed or refractory disease or are newly diagnosed but not eligible for intensive chemotherapy. IDH1 and IDH2 are key enzymes whose mutations lead to the conversion of α-ketoglutarate to 2-hydroxyglutarate, an oncometabolite responsible for several oncogenic effects.

In ClarIDHy, ivosidenib was evaluated in 185 patients with advanced, unresectable IDH1-mutated cholangiocarcinoma who had received one or two prior lines of therapy. Patients were randomly assigned 2:1 to receive ivosidenib at 500 mg once daily or placebo.

The primary endpoint was progression-free survival by central review. Crossover from placebo to ivosidenib was permitted upon disease progression, and the crossover-adjusted overall survival was derived using rank-preserving structural failure time analysis.

Progression-Free Survival Improved

Ivosidenib improved progression-free survival from 1.4 months with placebo to 2.7 months (hazard ratio [HR] = 0.37; P < .001). At 6 months and 12 months, 32% and 22% of ivosidenib-treated patients, respectively, were progression-free. In contrast, all patients on the placebo arm had disease progression at data cutoff, Dr. Abou-Alfa reported.

“These pivotal data demonstrate the clinical relevance and benefit of ivosidenib in patients with IDH1-mutated cholangiocarcinoma….”
— Ghassan K. Abou-Alfa, MD

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Although the objective response rate was low (2.4%), stable disease was achieved by 50.8% of patients. No responses were observed with placebo, and 27.9% of this arm had stable disease. “Ivosidenib efficacy was consistent across all subgroups,” he said, citing line of therapy, extent of disease at screening, cancer type at initial diagnosis, region of treatment, and other factors.

According to the intention-to-treat analysis, median overall survival was 10.8 months with ivosidenib vs 9.7 months with placebo (HR = 0.69; one-sided P = .06), which included the 57% of patients who crossed over from placebo. “Using the [rank-preserving structural failure time] method to reconstruct the survival curve as if the placebo subjects had never crossed over to ivosidenib, the median overall survival with placebo was corrected to 6 months (HR = 0.46; P < .001),” he further reported. Beside looking at the absolute median survival times achieved, Dr. Abou-Alfa said it is key to “focus on the continued separation of the Kaplan-Meier curve and the continued spread that carries on to 22% survival at 12 months.”


  • The phase III ClarIDHy trial evaluated the IDH1 inhibitor ivosidenib in 185 previously treated patients with IDH1-mutated advanced cholangiocarcinoma, showing that the drug reduced the risk of disease progression or death by 63%.
  • The phase II FIGHT-202 trial evaluated the FGF/FGFR inhibitor pemigatinib in 147 previously treated patients with FGFR2 fusions or rearrangements, other FGF/FGFR genetic alterations, or no FGF/FGFR genetic alterations.
  • In the cohort with FGF/FGFR fusions or rearrangements, treatment with pemigatinib resulted in a median progression-free survival of 6.9 months and a median overall survival was 21.1 months.

Safety Profile

The most common treatment-related adverse events among all patients who received ivosidenib (including after crossover) included nausea (32.1%), diarrhea (28.8%), fatigue (23.7%), cough (19.2%), abdominal pain (18.6%), ascites (18.6%), decreased appetite (17.3%), anemia (16.0%), and vomiting (16.0%). Grade 3 adverse events were reported in 46% of patients treated with ivosidenib compared to 36% of patients treated with placebo. More of the placebo arm (8.5% vs. 5.8%) discontinued treatment due to toxicity, and ivosidenib was associated with better physical and emotional functioning on quality-of-life measures.

“These pivotal data demonstrate the clinical relevance and benefit of ivosidenib in patients with IDH1-mutated cholangiocarcinoma and establish the role for genomic testing in this rare cancer with a high unmet need,” Dr. Abou-Alfa said. All patients with cholangiocarcinoma should be tested for the IDH1 mutation, he maintained.


FIGHT-202 was a global, open-label, single-arm phase II trial of patients previously treated with at least one line of therapy and with centrally confirmed FGF/FGFR status. All patients received oral pemigatinib (13.5 mg/d) on a 2 weeks on/1 week off schedule.

Of 1,206 patients screened, 146 were enrolled, including 107 with FGFR2 fusions or rearrangements (cohort A), 20 with other FGF/FGFR genetic alterations (cohort B), and 18 with no FGF/FGFR genetic alterations. The primary endpoint was objective response rate in cohort A by independent central review. The study was not designed to make statistical comparisons among the three cohorts.

In cohort A, the investigators identified 92 fusions and 15 rearrangements of the gene. Analysis revealed 56 different partner genes, 42 of which were unique to single patients. The most common partner gene was BICC1 (29%); no fusion partner was identified in 5%.

Primary Endpoint Met

The study met its primary endpoint, showing responses in 35.5% of patients with FGFR2 fusions/rearrangements and a median duration of response of 7.5 months. Response was independent of prior line of treatment or fusion partner. In contrast, there were no responses in cohort B or cohort C. Disease control rates were 82%, 40%, and 22%, for the respective cohorts.

“Most patients in cohort A had some degree of tumor regression. In only a few patients did we see lesions increase in size,” Dr. Vogel observed.

This higher response rate translated into a median progression-free survival in cohort A of 6.9 months. In contrast, the other cohorts had rapid disease progression, he said, with median progression-free survivals of 2.1 months for cohort B and 1.7 months for cohort C.

Overall survival data were not mature, but with a median follow-up time of 15.4 months, the median overall survival was 21.1 months in the cohort with FGFR2 fusions or rearrangements, dropping to 6.7 months for patients with other FGF/FGFR alterations and to 4.0 months for patients lacking FGF/FGFR alterations.

“Overall, I think these data indicate that FGFR inhibition is a meaningful treatment for this genetically defined subgroup of patients with cholangiocarcinoma,” Dr. Vogel concluded.

Safety Profile

Adverse events were manageable and consistent with the known mechanism of action of pemigatinib, the most common being hyperphosphatemia (60% all grades; 0% grade ≥ 3), with dose reductions or interruptions required in only three patients. Hypophosphatemia was also common (23% all grades; 12% grade ≥ 3), but no cases were clinically significant and none led to treatment discontinuation or dose reduction. Dose reductions due to adverse events were required in 14% of patients, and dose interruptions were needed in 42%.

A phase III study of pemigatinib compared with gemcitabine plus cisplatin in the first-line setting in patients with FGFR2 fusions or rearrangements is ongoing ( identifier NCT03656536).

DISCLOSURE: ClarIDHy was funded by Agios Pharmaceuticals. Dr. Abou-Alfa has advised or consulted for Agios and disclosed financial relationships with numerous other pharmaceutical corporations. FIGHT-202 was sponsored by Incyte Corporation. Dr. Vogel has received honoraria from Incyte, as well as from numerous other pharmaceutical corporations. Dr. Lamarca has received honoraria or consulting fees from Eisai, Nutricia, Ipsen, and QED; has been a member of speakers bureaus for Pfizer, Ipsen, Merck, and Incyte; and has received travel or educational funding from Ipsen, Pfizer, Bayer, Advanced Accelerator Applications (AAA), Sirtex, Novartis, Mylan, and Delcath.


1. Abou-Alfa GK, Macarulla Mercade T, Javle M, et al: ClarIDHy: A global, phase III, randomized, double-blind study of ivosidenib vs placebo in patients with advanced cholangiocarcinoma with an isocitrate dehydrogenase 1 (IDH1) mutation. ESMO Congress 2019. Abstract LBA10_PR. Presented September 30, 2019.

2. Vogel A, Sahai V, Hollebecque A, et al: FIGHT-202: A phase 2 study of pemigatinib in patients with previously treated locally advanced or metastatic cholangiocarcinoma (CCA). ESMO Congress 2019. Abstract LBA40. Presented September 27, 2019.