Matched targeted treatment based on ESCAT actionable genomic alterations associates with improved prognosis of cholangiocarcinoma patients

Matched targeted treatment based on ESCAT actionable genomic alterations associates with improved prognosis of cholangiocarcinoma patients

• VHIO led study supports the integration of ESMO’s evidence-based Scale for Clinical Actionability of molecular Targets (ESCAT) into clinical management for the targeted treatment of patients with advanced cholangiocarcinoma.

• Published in Clinical Cancer Research* results show that matched therapy according to ESCAT’s ranking of genomic alterations for cancer precision medicine improves survival of these patients.

• Findings uphold ESMO’s Precision Medicine Working Group’s recommendation of integrating next-generation sequencing into treatment management to improve outcomes for patients with this rare, complex, and therapeutically challenging disease.

Published online ahead of print in Clinical Cancer Research*, a journal of the American Association for Cancer Research (AACR), results of a study directed by Teresa Macarulla, Principal Investigator of VHIO’s Gastrointestinal & Endocrine Tumors Group, evidence the value of applying Next-Generation Sequencing (NGS) in the clinic for the selection of matched targeted therapies in patients with advanced cholangiocarcinoma (CCA).

The investigators, including researchers from other VHIO groups, retrospectively reviewed a total of 327 patients diagnosed with cholangiocarcinoma at the Vall d’Hebron University Hospital (HUVH) between 2011 and 2020. These patients had undergone tumoral molecular analysis to evaluate impact on survival of targeted treatments administered according to the ESMO Scale for Clinical Actionability of molecular Targets (ESCAT) categorization.

This evidence-based tool developed by the European Society for Medical Oncology’s Precision Medicine Working Group, provides a systematic framework for ranking mutations as personalized cancer medicine targets, and helps guide treatment decision making according to identified genomic alterations showing higher impact on clinical outcomes.

Specifically, ESCAT defines six categories for the use of therapies targeting molecular alterations, based on the level of evidence taking into account study and disease context. Genomic alterations are assigned to the tier which best reflects their clinical utility for selecting patients to receive a matched targeted therapy on the strength of evidence from clinical studies. This offers clinicians a means of prioritizing treatment selection.

Based on ESCAT classification, this single institutional study* was designed to compare survival in patients with metastatic CCA harboring alterations matched to targeted agents, with patients bearing non-actionable alterations. Reported data show that patients with alterations classified as ESCAT tier I-II had longer median overall survival than those with alterations classified as ESCAT tier III-IV or without ESCAT alterations, 22.6 months versus 14.3 months, respectively.

 “For the first time in the treatment management of advanced cholangiocarcinoma, our results show that targeted treatment administered based on ESCAT’s classification of alteration actionability improves survival of these patients, particularly in the chemotherapy-refractory setting,” said Teresa Macarulla, Medical Oncologist at the Vall d’Hebron University Hospital’s (HUVH) Medical Oncology Department, headed by Josep Tabernero, VHIO’s Director and a co-first author of this study.

Among patients who received targeted therapy, median progression free survival (PFS) was significantly longer in patients with ESCAT tier I-II alterations compared to those with ESCAT III-IV alterations, 5.0 months versus 1.9 months. These findings support that the implementation of NGS and the application of the ESCAT framework is feasible in routine clinical practice in order to extend matched therapeutic opportunities to CCA patients.

“Cholangiocarcinoma is a highly heterogeneous, therapeutically challenging disease with a notoriously poor prognosis. When patients with advanced disease fail to respond to first-line chemotherapy, second-line treatment options are limited,” observed lead author Helena Verdaguer, a Clinical Investigator of VHIO’s Gastrointestinal & Endocrine Tumors Group and Medical Oncologist at HUVH.

She continued, “Driving personalized, targeted treatments tailored to the molecular specificities of these patients’ tumors must therefore be prioritized.”  

Considering the prevalence of multiple driver alterations that can be matched to standard-of-care therapies or clinical trial recruitment, ESMO’s Precision Medicine Working Group, chaired by Joaquin Mateo, Principal Investigator of VHIO’s Prostate Cancer Translational Research, recommends routine NGS in all cholangiocarcinoma patients. This study shows that NGS and evidence-based scales, such as ESMO’s ESCAT, can be feasibly integrated in the clinic, and thus used to guide patient selection for targeted therapy.

“Moving forward, frameworks that grade genomic alterations as targets for personalized medicine will help clinicians to match optimal treatments to individual patients accordingly. In so doing, we will collectively strive to extend the promise precision oncology to this patient population,” concluded Teresa Macarulla.

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Reference:

*Verdaguer H, Saurí T, Acosta DA, Guardiola M, Sierra A, Hernando J, Nuciforo P, Miquel JM, Molero C, Peiró S, Serra-Camprubi Q, Villacampa G, Aguilar S, Vivancos A, Tabernero J, Dienstmann R, Macarulla T. ESMO Scale for Clinical Actionability of Molecular Targets driving targeted treatment in patients with cholangiocarcinoma. Clin Cancer Res January 18 2022 DOI: 10.1158/1078-0432.CCR-21-2384.