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Targeted Therapy Has Significant Activity as Second-Line Treatment of Cholangiocarcinoma with FGFR Mutations

TOP - February 2019, Vol 12, No 1 - Emerging Therapies

Munich, Germany—Treatment options are few for patients with cholangiocarcinoma whose disease progresses while receiving first-line treatment with gemci­tabine (Gemzar) and cisplatin (Platinol), with no established second-line regimen. The median overall survival (OS) is 7.2 months and the median progression-free survival (PFS) is 3.2 months in the second-line setting.

Fibroblast growth factor receptor (FGFR) translocations are driver mutations in cholangiocarcinoma, and are present in up to 17% of intrahepatic cholangiocarcinomas. These translocations may predict sensitivity to an investigational class of targeted agents known as FGFR inhibitors.

As presented at the ESMO 2018 Congress, 2 phase 2 clinical trials of FGFR inhibitors showed promising antitumor activity in patients with FGFR2 translocations with an acceptable safety profile. The confirmed overall response rate (ORR) in patients with translocation-positive cholangiocarcinoma was 40.4% and 26.9% in the 2 trials.

“Most cholangiocarcinomas are diagnosed at a very advanced stage. OS with gemcitabine plus cisplatin, the current standard of care in the first-line setting, is 11.7 months. After this treatment fails, there is no standard treatment,” said Milind Javle, MD, Pro­fessor, Gastrointestinal (GI) Medical Oncology, M.D. Anderson Cancer Center, Houston, and lead investigator of one of the studies.

“We often use chemotherapy based on our experience with other GI cancers like colon cancer, but the PFS in the second-line setting is only about 3 months. So it was a very dismal disease overall before the advent of targeted therapy,” Dr Javle added.

Infigratinib Demonstrates Disease Control Rate of 83.6%

Infigratinib (BGJ398), an oral FGFR1-­3-selective tyrosine kinase inhibitor, was studied in an open-label multicenter phase 2 clinical trial of 71 patients with intrahepatic cholangiocarcinoma containing FGFR2 fusions that progressed while receiving platinum-based chemotherapy. The patients received infigratinib 125 mg daily for 21 days, followed by 7 days off in a 28-day cycle, until disease progression. Tumor response was assessed per Response Evaluation Criteria in Solid Tumors version 1.1, using computed tomography or magnetic resonance imaging. More than half (54.9%) of the study patients had received at least 2 previous lines of therapy.

Treatment is ongoing in 9 patients. Of the 62 patients in whom infigratinib treatment was ended, 44 (62%) had progressive disease, 6 (8.5%) discontinued the drug because of an adverse event, and 5 (7%) discontinued the treatment at the treating physician’s discretion.

The combined confirmed and unconfirmed ORR was 31%. A total of 18 (25.4%) patients had a partial response and 41 (57%) patients had stable disease as a best response. Among patients with the potential for confirmation, the ORR was 26.9%. Among patients receiving ≤1 previous lines of therapy, the confirmed ORR was 39.3%, and among those receiving ≥2 previous lines, the confirmed ORR was 17.9%. The disease control rate was 83.6%, and the median duration of response was 5.4 months. The median PFS was 6.8 months, and the median OS was 12.5 months.

“The median OS is pretty interesting, given that OS in this population of cholangiocarcinoma itself is about a year,” said Dr Javle. “This was the survival in the second- or third-line setting, so it suggests that this drug [infigratinib] did have a significant impact.”

The most common adverse event of any grade with infigratinib was hyperphosphatemia, which occurred in 73.2% of patients. According to Dr Javle, prophylactic use of sevelamer (Renagel), a phosphate-binding agent, was recommended on days of infigratinib administration to manage hyperphosphatemia. Patients were also instructed to adhere to a low-phosphate diet.

Fatigue (49.3%) and stomatitis (45.1%) were other common adverse events. The most common grade 3/4 adverse events were hypophosphatemia (14.1%), hyperphosphatemia (12.7%), hyponatremia (11.3%), and stomatitis (9.9%).

Dose reduction because of toxicity was possible without loss of efficacy, Dr Javle said. The dose reductions were based on the worst preceding toxicity, with resumption of treatment after resolution or reduction to grade 1 toxicity. Each patient was allowed 2 dose reductions (to 100 mg and to 75 mg) before infigratinib was discontinued.

“In my mind, the question is whether chemotherapy should be used in the first-line setting at all, or whether we can use this type of targeted approach [with infigratinib] in the first-line setting,” said Dr Javle.

Pemigatinib Results in Overall Response Rate of 40.4%

Pemigatinib (INCB 54828), a selective, potent, oral inhibitor of FGFR1, FGFR2, and FGFR3, was studied in the open-label, multicenter phase 2 Fibroblast Growth Factor Receptor Inhibitor in Oncology and Hematology Trials-202. The study enrolled patients with histologically or cytologically confirmed cholangiocarcinoma whose disease progressed despite having received at least 1 previous treatment.

The study population consisted of 3 cohorts: 91 patients with FGFR2 translocations (cohort A), 22 patients with other FGF/FGFR genetic alterations (cohort B), and 18 patients with no FGF/FGFR genetic alterations (cohort C). The analysis presented at the meeting included results for the first 47 patients enrolled in cohort A who were followed for ≥8 months, as well as the patients in cohorts B and C. Approximately half (49%) of the patients received ≥2 previous lines of therapy.

The patients received treatment with pemigatinib 13.5 mg daily for 2 weeks, followed by 1 week off during each 21-day cycle, until radiologic disease progression or unacceptable toxicity.

The median number of treatment cycles was 11 in cohort A (median duration of treatment, 217 days), 2.5 in cohort B (median duration of treatment, 47.5 days), and 2 in cohort C (median duration of treatment, 39 days).

A total of 19 of the 47 (40.4%) patients in cohort A had a response to treatment with pemigatinib; all 19 responses were a partial response. An additional 21 (44.7%) patients had a best response of stable disease, accounting for a disease control rate of 85.1%. The disease control rates in cohorts B and C were 45.5% and 22.2%, respectively.

The median duration of response in cohort A has not been reached, and the probability of maintaining response for ≥6 months was 86.2%.

The median PFS was 9.2 months in cohort A versus 2.1 and 1.7 months in cohorts B and C, respectively. The median OS was 15.8 months in cohort A, 6.8 months in cohort B, and 4 months in cohort C.

The most common treatment-emergent adverse events in the entire study population were hyperphosphatemia (60.7%), alopecia (41.6%), diarrhea (39.3%), decreased appetite (37.1%), fatigue (36%), and dysgeusia (36%). Improvement in symptoms was observed with dose reduction, said lead investigator Antoine Hollebecque, MD, Senior Medical Physician, Institut Gustave Roussy, Villejuif, France. Grade 3 or 4 adverse events reported in >5% of the patients were hypophosphatemia (13.5%), hyponatremia (7.9%), abdominal pain (6.7%), and arthralgia (6.7%).

“Overall, these results support continued development of pemigatinib as a promising treatment for patients with cholangiocarcinoma harboring FGFR2 translocations,” the investigators concluded. Patient recruitment into the study is close to completion, they noted.

Dr Hollebecque said that several phase 3 studies of FGFR inhibition in the first-line setting are planned. “We need to know better the efficacy of first-line gemcitabine-cisplatin among this particular population of patients with intrahepatic cholangiocarcinoma with FGFR2 fusion,” Dr Hollebecque said.

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Last modified: June 4, 2019