Resistance Mechanisms and Adverse Events Associated with Targeted Therapy in Cholangiocarcinoma

TOP - March 2022 Vol 15, No 2 - Cholangiocarcinoma

Dermatologic and ocular adverse events require appropriate and timely referral, and circulating tumor (ct)DNA analysis may not detect genomic fusions, as discussed in Session VI, “Molecularly Targeted Therapies in CCA,” at the 3rd Annual CCA Summit.

Mario E. Lacouture, MD, Memorial Sloan Kettering Cancer Center, New York City, discussed targeted therapies in cholangiocarcinoma (CCA).

A study evaluating dermatologic immune-related cutaneous adverse events of targeted therapies in CCA revealed several rash phenotypes, including pruritus, maculopapular rash, lichenoid, psoriasiform, and bullous. Of these immune-related adverse events, 60% have been grade ≥2. Approximately 1 of 5 patients with CCA does not derive benefit from steroids, which are the standard first-line approach for many immune-related adverse events.

Patients receiving FGFR inhibitors have alopecia, hair modification, dry skin, calcinosis cutis or calciphylaxis, mucosal dryness, xerostomia, dysgeusia, mucositis, nail changes with onycholysis, and paronychia. Discontinuations because of FGFR inhibitors were reported in less than 15% of patients with CCA.

Hand-foot syndrome associated with FGFR inhibitors is very different from that observed with taxanes. With multikinase inhibitors, lesions appear as blisters with erythematous halo, then hyperkeratosis. The incidence and severity are decreased with the combination of a BRAF inhibitor as a result of the paradoxical action of the pathway.

Acneiform rash occurs in approximately 33% of patients after HER1/HER2 inhibition and can be reduced or prevented with oral antibiotics and topical steroids. The only data available for IDH inhibitors are in patients with leukemia; studies are needed in patients with CCA.

“We expect these toxicities to increase in importance with combined therapies, and thanks to the remarkable things that you are doing for patients, with remarkable and longer survival,” said Dr Lacouture.

Jasmine Francis, MD, Memorial Sloan Kettering Cancer Center, New York City, discussed current targeted therapies being used in CCA and their impact on ocular adverse events.

Traditional chemotherapy, including oxaliplatin and fluorouracil, can lead to dry eyes or keratoconjunctivitis sicca. Progression can lead to keratitis, corneal abrasion, or ulcer. This is a very rare effect that is associated with FGFR inhibitors. Episcleritis or scleritis can be caused by immune checkpoint inhibition.

Uveitis or iritis, characterized by pain, photophobia, blurry vision, and red eye, can result from treatment with immune checkpoint inhibitors and BRAF inhibitors. Optic nerve edema or neuritis can be caused by oxaliplatin, cisplatin, and immune checkpoint inhibition. Ivosidenib very rarely has led to oculomotor disturbance, which is associated with Guillain-Barré syndrome.

Lipika Goyal, MD, Harvard Medical School, Boston, MA, discussed the use of ctDNA for tumor profiling, acquired resistance to FGFR inhibitors, and sequencing strategies for novel FGFR inhibitors.

In a study of 149 samples sent for analysis, 26.8% of tissue samples and 15.4% of ctDNA samples failed, which approximates what is seen in the clinic.

Tumor tissue with IDH1 mutations had an 87% concordance of ctDNA and tissue profiling. Samples with FGFR2 fusions had 18% concordance. The timing of sample collection did not have a significant impact on detection in ctDNA.

“The caution with ctDNA is, it’s going to miss fusions a high percentage of the time,” said Dr Goyal. “We have to always think about tissue profiling if someone does not have a fusion on ctDNA.”

Serial ctDNA and biopsy sampling in patients receiving FGFR inhibitors are critical to the understanding of the mechanism of acquired resistance.—EB

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Last modified: March 30, 2022