2022 Year in Review: Cholangiocarcinoma

Colleagues,

In 2022, the COVID-19 pandemic continued 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, Gastrointestinal Cancers Symposium, and European Society for Medical Oncology have adopted virtual and hybrid formats that deliver cutting-edge research in the advancement of oncology care. Recognizing the challenges of the virtual and hybrid formats 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 aberrations, for which therapeutic interventions are being developed and actively investigated. Both pemigatinib and futibatinib are approved for CCA with FGFR2 alterations. Pemigatinib, an FGFR1-3 inhibitor, received expedited approval for second-line treatment of unresectable locally advanced or metastatic CCA harboring FGFR2 fusions/rearrangements based on the pivotal FIGHT-202 trial. Futibatinib, an FGFR1-4 inhibitor, received accelerated approval for second-line treatment of unresectable, locally advanced or metastatic, intrahepatic CCA harboring FGFR2 fusions/rearrangements based on the phase 2 FOENIX-CCA2 trial. Updated data from each of these trials support the continued use of pemigatinib and futibatinib in these patient populations.

Several investigational FGFR inhibitors, such as erdafitinib, RLY-4008, and derazantinib, are in varying stages of clinical testing in patients with CCA harboring FGFR2 fusions/rearrangements. Erdafitinib, an FGFR1-4 inhibitor, is being assessed in the phase 2a LUC2001 study in Asian patients with advanced CCA harboring FGFR alterations. Based on the interim analysis, investigators concluded that erdafitinib is associated with durable efficacy and manageable safety. The FGFR2 inhibitor RLY-4008 is being invested in patients with CCA harboring FGFR2 fusions/rearrangements in the ReFocus trial, and early data indicated promise in this patient population. Derazantinib is being investigated as a second-line treatment for patients with intrahepatic CCA with FGFR2 alterations in the FIDES-01 trial. Preliminary data from the FIDES-01 trial indicate that derazantinib is clinically meaningful as a second-line treatment of intrahepatic CCA with FGFR2 alterations.

Novel therapeutic strategies are also being evaluated in CCA. The addition of PD-L1 inhibitor durvalumab to gemcitabine/cisplatin (GemCis) was evaluated in the phase 3 TOPAZ-1 trial, which found the treatment regimen to have durable efficacy regardless of primary tumor location, as well as a manageable safety profile. Data stemming from subanalyses of the TOPAZ-1 trial continue to support the utilization of durvalumab plus GemCis, as reported throughout this Year in Review. CPI-613, a stable intermediate of a lipoate analogue that inhibits key enzymes of the tricarboxylic cycle within the mitochondria of cancer cells, is being investigated in combination with GemCis in patients with advanced biliary tract cancers (BTCs) through the phase 1b/2 BilT-04 study, which has demonstrated that CPI-613 is well-tolerated with potential activity.

Research efforts are also focused on improving chemotherapy options following failure of first-line GemCis for patients with advanced BTCs. Several trials are exploring treatment options to optimize the management of advanced BTCs, including the ABC-06 trial assessing FOLFOX with or without active symptom control after progression on GemCis. Numerous trials assessing the effect of various adjuvant and neoadjuvant treatment regimens for BTCs, as well as surgical modalities, are being conducted, as outlined in this edition of Year in Review.

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