The Lynx Group
Cholangiocarcinoma News

Resistance Mechanisms and Adverse Events Associated with Targeted Therapy in Cholangiocarcinoma

December 2021, Vol 2, No 4

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 or higher. 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 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.

Related Items

A Global Perspective on CCA
By Virote Sriuranpong, MD, PhD
Dr Virote Sriuranpong provides a perspective on key issues facing Thailand and other Asian countries in the prevention, screening, and early diagnosis of CCA.
Molecular Targets in iCCA Surgical Candidates
By Keri Lunsford, MD, PhD, FACS; Alice Wei, MD, MSc, FRCSC, FACS
Drs Keri Lunsford and Alice Wei provide their perspectives on how the molecular profile of iCCA patients can help direct surgery and locoregional therapy.
Periadjuvant Therapy in iCCA
By Cristina Ferrone, MD; Shishir Kumar Maithel, MD, FACS
Dr Cristina Ferrone discusses the use of adjuvant therapy, and Dr Shishir Kumar Maithel speaks to the role of neoadjuvant therapy in patients with iCCA.
New Frontiers in Surgery for CCA
By Skye Mayo, MD, MPH, FACS; Alice Wei, MD, MSc, FRCSC, FACS
Drs Alice Wei and Skye Mayo discuss options for induction therapy prior to surgery in iCCA.
Transplantation in iCCA
By Keri Lunsford, MD, PhD, FACS; Maria B. Majella Doyle, MD, MBA, FRCSI, FACS
Drs Keri Lunsford and Maria Majella Doyle explore clinical data on neoadjuvant treatment before transplantation in patients with iCCA.
New Pathways and Molecular Targets in Cholangiocarcinoma
By Erin Burns, PhD
December 2021, Vol 2, No 4
Potential therapeutic targets for cholangiocarcinoma (CCA) include oncogenic pathways and other options, such as epigenetics, posttranslational modifications, and metabolism, according to presentations delivered during Session I, “Advances in Translational/Molecular Targets in CCA: New Molecular Targets/Pathways in CCA,” at the 3rd Annual CCA Summit.
Molecular Epidemiology of Cholangiocarcinoma: Identifying New Inherited Variants
By Erin Burns, PhD
December 2021, Vol 2, No 4
Cholangiocarcinoma (CCA) involves genetic heterogeneity, highlighting the need to identify new inherited variants, as discussed at the 3rd Annual CCA Summit in Session II, “Molecular Epidemiology of CCA.”
The Future of Chemotherapy in Cholangiocarcinoma
By Erin Burns, PhD
December 2021, Vol 2, No 4
Personalization of therapy and novel regimens are needed to improve options for patients with cholangiocarcinoma (CCA).
Understanding Predictive Biomarkers and Resistance to Immunotherapy in Biliary Tract Cancers
By Erin Burns, PhD
December 2021, Vol 2, No 4
Improved understanding of predictive biomarkers is needed in immuno-oncology, and various immunotherapy combinations using different mechanisms of action are being investigated in cholangiocarcinoma (CCA) and other biliary tract cancers, according to presentations delivered at Session IV, “What’s New in Immuno-­oncology in BTC? Monotherapy and Combo Therapies,” at the 3rd Annual CCA Summit.
Biomarker Testing and Imaging in Cholangiocarcinoma
By Erin Burns, PhD
December 2021, Vol 2, No 4
New biomarker technologies may be combined with cholangiocarcinoma (CCA) characteristics to predict patient response to treatment, according to presenters at Session V, “Biomarker Testing in CCA: New Technologies/­Imaging as a Biomarker,” during the 3rd Annual CCA Summit.

Subscribe Today!

To sign up for our newsletter or print publications, please enter your contact information below.

I'd like to receive: