Overcoming Resistance to Therapy in Cholangiocarcinoma

TON - February 2021 Vol 14, No 1

In April 2020, the FDA granted accelerated approval to pemigatinib (Pemazyre), the first targeted therapy for cholangiocarcinoma (CCA). The FGFR inhibitor was approved for adults with CCA and FGFR2 fusion.

After decades in which patients with CCA had only chemotherapy treatment options, the FDA approval of pemigatinib represents a major milestone in the treatment of this disease, according to Lipika Goyal, MD, MPhil, Assistant Professor of Medicine, Harvard Medical School, Boston, MA. However, although pemigatinib has demonstrated remarkable clinical efficacy, treatment responses are still short-lived. Only 18% of patients included in the landmark clinical trial that led to the drug’s approval had a response lasting ≥12 months.

At the 2020 Annual Cholangiocarcinoma Summit, Dr Goyal discussed the mechanisms of resistance to FGFR inhibition and strategies for improving the current approaches to treatment.

“CCA is only the third gastrointestinal cancer with a biomarker specific targeted therapy approved, so we’re excited about our [recent progress],” said Dr Goyal. “We’re seeing great responses in many patients; however, they’re not as prolonged as we would like them to be.”

But, she added, “We may not be squeezing as much out of this lemon as we can.”

Overcoming Acquired Resistance

According to Dr Goyal, FGFR2 fusions and rearrangements are seen in approximately 10% to 15% of patients with intrahepatic CCA. The FIGHT-202 study, which led to the approval of pemigatinib, an adenosine triphosphate (ATP)-competitive, reversible selective FGFR inhibitor, demonstrated an overall response rate of 35.5%, a disease control rate of 82%, and a duration of response of 7.5 months.

“Such good response rates and durations of response are great for CCA, and certainly better than what we see with chemotherapy in an unselected population, but it doesn’t quite match up to what we see in other ‘oncogene-addicted’ tumors,” said Dr Goyal. She noted that the response rates can exceed 70% in patients with lung cancer and EGFR mutations who receive treatment with EGFR inhibitors.

A better understanding of acquired resistance could help extend durations of response, she said. Recent studies have shown, for example, that in patients whose disease progressed after receiving treatment with an ATP-competitive inhibitor, such as pemigatinib, 1 or more FGFR2 kinase domain mutations may emerge.

One of the most common alterations is in the FGFR2 V565 residue, the so-called gatekeeper alteration, but researchers have also seen multiple mutations in the “molecular brake.” In fact, Dr Goyal and colleagues believe that polyclonal resistance is one explanation for the short duration of response seen with FGFR inhibition.

“We have found that patients with polyclonal resistance have a lower median progression free survival than those who develop monoclonal resistance,” said Dr Goyal. “The 2 residues that we want to make sure we target with the next generation inhibitors are the gatekeeper and the molecular brake, V565 and V550.”

Improving Treatment Sequencing Through the Use of ctDNA Analysis

Understanding tumor heterogeneity and addressing it up front will be important in preventing resistance in patients with CCA, Dr Goyal explained. One approach to overcoming tumor heterogeneity is sequential treatment with different FGFR inhibitors based on their spectrum of activity and the different genetic alterations that emerge during disease progression. This strategy could potentially prolong the duration of benefit from FGFR inhibition, Dr Goyal suggested.

“Giving futibatinib, a covalent inhibitor, up front is one possibility,” she said. “Because pemigatinib is now approved, however, we should consider doing postprogression analysis for resistance to see if patients might be candidates for a covalent inhibitor.”

Given the different spectrums of activity of FGFR inhibitors, serial circulating tumor DNA (ctDNA) analysis may be instrumental in helping clinicians determine how to sequence these agents more effectively based on which alterations emerge during disease progression. Investigators in several clinical trials are currently using ctDNA to better understand resistance.

“The next generation inhibitors with potency against the FGFR2 kinase domain mutations are going to be key to prolonging response in this disease,” said Dr Goyal. “We also need to think about combination strategies.”

“This is a rare disease,” Dr Goyal added. “The only path forward is if we all work together.”

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