2021 Cholangiocarcinoma Year in Review

Colleagues,

In 2021, the COVID-19 pandemic continues to impact the practice of medicine and dissemination of treatment advances presented in scientific forums. Adapting to the changes, societies such as the American Society of Clinical Oncology (ASCO), Gastrointestinal Cancers Symposium, and European Society for Medical Oncology (ESMO) have adopted virtual formats that delivered cutting-edge research in the advancement of oncology care. Recognizing the challenges of the virtual format in terms of reach and impact, we are bringing the Year in Review series that seeks to disseminate key information on treatment advances to clinicians in a timely and effective manner.

This edition of Year in Review is focused on cholangiocarcinoma (CCA), which is a diverse group of malignancies characterized by genomic heterogeneity that potentially drives its pathogenesis. Below is a quick review of some of the topics discussed in this issue, with a focus on recent advances, potentially practice-changing developments, and ongoing challenges in CCA.

Increased understanding of the CCA genetic landscape has led to identification of actionable alterations such as FGFR and IDH aberrations, for which therapeutic interventions are being developed and actively investigated. Infigratinib is a selective FGFR1-3 tyrosine kinase inhibitor that was approved in 2021 for patients with advanced, metastatic CCA bearing FGFR2 alterations. Final results of the pivotal phase 2 study demonstrated that infigratinib has promising antitumor activity and a manageable adverse event profile in these patients, representing a new therapeutic option in this setting. In terms of the other approved FGFR inhibitor, pemigatinib, updated results of the FIGHT-202 study supported the primary data that second-line pemigatinib treatment resulted in continued and durable responses and sustained tolerability in patients with CCA harboring FGFR2 rearrangements/fusions. In addition, longitudinal evaluation of quality of life in patients with advanced CCA harboring FGFR fusions/rearrangements treated with pemigatinib showed that patients who achieved responses or stable disease had stable overall health status and emotional functioning.

Several investigational FGFR inhibitors, such as futibatinib, RLY-4008, derazantinib, and gunagratinib, are in varying stages of clinical testing in patients with CCA harboring FGFR2 fusions/rearrangements. Initial results of the FOENIX-CCA2 phase 2 clinical trial of futibatinib in patients with intrahepatic CCA and FGFR2 fusions or other genetic alterations, showed that second-line futibatinib was safe and resulted in durable objective responses in this patient population. Patient-reported outcomes from the FOENIX-CCA2 trial indicated that quality of life and overall health status were maintained among futibatinib-treated patients. Safety and tolerability of futibatinib were further supported by results of a pooled safety analysis, while exposure-safety analysis showed a significant relationship between hyperphosphatemia and futibatinib exposure. RLY-4008, which is designed to selectively target acquired resistance mutations in addition to primary oncogenic FGFR2 alterations, showed favorable tolerability in clinical studies and potential to overcome FGFR inhibitor resistance in patients with advanced CCA. The phase 2 FIDES-01 study demonstrated that derazantinib yielded durable objective responses with a manageable safety profile in this patient population.

Novel therapeutic strategies, including HER2 inhibition, immunotherapy, casein kinase 2, and arginase inhibition, are being evaluated in CCA. MyPathway, the phase 2a multibasket study, demonstrated that dual HER inhibition with pertuzumab plus trastuzumab was well-tolerated in patients with previously treated HER2-positive metastatic biliary tract cancers (BTCs), including CCA. First results of the multicenter phase 2 LEAP-005 trial showed potential efficacy with the combination of lenvatinib and pembrolizumab in advanced solid tumors, including CCA.

Research efforts are also focused on improving chemotherapy options following failure of first-line gemcitabine/cisplatin for patients with advanced BTCs. Results of the NIFTY trial demonstrated that liposomal irinotecan in combination with fluorouracil and leucovorin significantly improved efficacy outcomes compared with fluorouracil and leucovorin in patients with BTC who progressed on gemcitabine/cisplatin, with a manageable adverse event profile. The phase 2 NIFE study will compare the liposomal irinotecan plus 5-fluorouracil/leucovorin regimen to standard-of-care gemcitabine/cisplatin treatment in patients with advanced CCA in the first-line setting.

We are pleased to present the highlights of these topics and more!