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Targeted Therapies in Cholangiocarcinoma

February 2021 Vol 14, Special Issue: Payers' Perspectives in Oncology - Cholangiocarcinoma

The recent FDA approval of the first FGFR inhibitor, pemigatinib (Pemazyre), and the positive results from the phase 3 study of the first IDH1 inhibitor, ivosidenib (Tibsovo), represent major breakthroughs in the treatment of patients with cholangiocarcinoma (CCA), a rare cancer associated with poor outcomes. However, the duration of response with these agents is still relatively short.

At the 2020 Annual Cholangiocarcinoma Summit, Ghassan Abou-Alfa, MD, MBA, Attending Physician, Memorial Sloan Kettering Cancer Center, New York, NY, discussed the growing list of molecular targets for CCA, the role of gatekeeper mutations and FGFR alterations, and strategies for building on recent advances.

“We are all delighted to see these major achievements, which highlight the clinical relevance of tumor mutation profiling in the management of CCA. As we continue to develop molecular targets, genetic testing is going to be very critical,” said Dr Abou-Alfa.

The phase 3 ClarIDHy study showed a 63% reduction in disease progression risk or death with ivosidenib compared with placebo in patients with advanced CCA and IDH1 mutation. Although overall survival data are difficult to interpret because of the study’s crossover design, there was an “evident improvement” in progression-free survival (PFS) with ivosidenib, Dr Abou-Alfa said.

FGFR Inhibition

Ivosidenib joins a treatment armamentarium that remains focused on FGFR fusions, specifically FGFR2. Pemigatinib, the first targeted therapy approved for CCA, demonstrated a 36% response rate and 21-month median overall survival in patients with CCA and FGFR2 mutation.

“We are all amazed by these numbers,” said Dr Abou-Alfa. “These data highlight the importance of genetic alterations in survival.”

Additional FGFR inhibitors are under investigation. In a recent phase 2 single-arm clinical trial, infigratinib, an FGFR2 inhibitor currently under FDA review, outperformed standard chemotherapy as late-line treatment in patients with CCA and FGFR2 fusion, with an overall response rate of 21%. In another study, futibatinib, an FGFR1-4 inhibitor, had a median PFS of 7.2 months, at a median follow-up of 11.4 months.

Derazantinib has also demonstrated a “robust response rate,” according to Dr Abou-Alfa. Another investigative drug, DB1347, showed responses, but these data are still limited.

Clinical Trials

Despite these promising findings, given how rare CCA is and how rare genetic alterations are in patients with CCA, novel clinical trial designs are likely needed to achieve meaningful progress, Dr Abou-Alfa noted.

“Comparing molecular targeted therapies to standard of care in the first-line setting poses big challenges with respect to accrual, because we may be ultimately competing with each other,” said Dr Abou-Alfa. “With anti-FGFR2 agents, I think we should abandon the idea of randomizing against a standard of care.”

More important than the improved survival rates associated with anti-FGFR2 therapy versus gemcitabine plus cisplatin, which may be limited, is the timing of the targeted therapy, he added.

“Is giving anti-FGFR2 in the first line, followed by systemic chemotherapy, better than giving it in the second line, after getting systemic chemotherapy?” Dr Abou-Alfa asked. “We need to study sequencing to get the answers that our patients are in dire need of.”

He noted that cooperative groups should also speak with agencies about obtaining approval based on PFS as a primary end point.

Next-Generation Sequencing

Finally, Dr Abou-Alfa reported “incredible responses” with the combination of dabrafenib (Tafinlar) and trametinib (Mekinist) in patients with biliary tract cancers and BRAF V600E mutation.

“If you have a patient with a BRAF V600E mutation, there’s no doubt that you should offer that therapy,” said Dr Abou-Alfa. “Don’t wait for a phase 3 trial, because it’s not going to happen for a mutation that occurs in less than 5% of patients.”

Dr Abou-Alfa emphasized that the results from studies of CCA and BRAF V600E mutation also underscore the need for next-generation sequencing as early as possible in the disease course.

“When a patient with CCA walks in the door, the first thing you should do is get next-generation sequencing. There is now a minimum 25% chance of being able to treat CCA with a targeted therapy,” Dr Abou-Alfa said.

“Next-generation sequencing is not a choice any longer—it’s a must. If we don’t have data on next-generation sequencing when we read the CCA pathology, we have an incomplete report,” he emphasized.

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Last modified: August 30, 2021
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