Rapid Trajectory of Clinical Research in Biliary Tract Cancers

Dear Friends,

The 2022 ASCO GI Cancers Symposium clearly highlighted the rapid trajectory of clinical research in biliary tract cancers. One of the most eagerly anticipated studies, TOPAZ-1, was presented by Do-Youn Oh, MD, PhD, from Seoul National University Hospital in South Korea. This phase 3 clinical trial enrolled 685 patients and investigated the addition of the PD-L1–directed agent durvalumab to gemcitabine and cisplatin chemotherapy backbone versus these chemotherapies alone. The results demonstrated a statistically significant improvement in overall survival (OS), overall response rate (ORR), and progression-free survival (PFS), without dose-limiting toxicities.

PD-L1 expression in this study did not correlate with response, and there appeared to be an advantage for Asian patients with the immunochemotherapy, although this study was not powered for patient distribution by geography. Nevertheless, this study represents a milestone in the treatment of biliary cancers by (finally) bringing immunotherapy to the forefront of therapy.

Along the same lines, Robin Kate Kelley, MD, from the University of California, San Francisco, reported the results of a phase 2 clinical trial with the immunotherapy pembrolizumab combined with granulocyte macrophage colony-stimulating factors for advanced chemorefractory biliary tract cancer. In this study, the ORR was 12%, and interestingly, a numerical superiority in OS and PFS was seen with the immunotherapy in viral-related cholangiocarcinoma (CCA) compared with nonviral CCA.

We continue to learn about molecular targeting in CCA, and 2 studies—one by Mitesh J. Borad, MD, from the Mayo Clinic in Phoenix, and one by Rachna T. Shroff, MD, from the University of Arizona Cancer Center—used innovative retrospective study designs to describe (1) the relative benefit of futibatinib from clinical trials versus chemotherapy, and (2) the natural history of FGFR-altered CCA in the real-world setting. These types of analyses are particularly informative for uncommon subtypes of rare cancers.

In another subset of molecular targets, Madhulika Eluri, MD, Fellow at M.D. Anderson Cancer Center, and Dr Kelley, provided interesting data regarding family history of liver cancer in patients with CCA and the frequency of DNA repair genetic alterations.

Dr Eluri reported a large series of 429 patients and >1000 controls, noting a disproportionately high incidence of primary liver cancer in first-degree relatives of patients with CCA. Dr Kelley reported a 4.6% incidence of germline mutations and a 13% incidence of somatic mutations in DNA-damage repair genes in 804 patients with biliary tract cancer, with the highest incidence (19%) seen in gallbladder cancer. These data certainly make the case for molecular testing, which includes germline profiling for this population, akin to pancreatic cancer.

Pemigatinib and infigratinib are both effective for the treatment of CCA associated with FGFR2 fusions, but the activity of these agents in patients with FGFR2 mutations remains low. The FIDES-1 study (presented by me) demonstrated that derazantinib resulted in clinical benefit, with a disease control rate of 74% and PFS of 7.3 months, with tolerable adverse effects.

Targeted therapies often affect a patient’s quality of life (QOL). Christina X. Chamberlain, PhD, and colleagues from Servier Pharmaceuticals, reported that QOL was maintained with ivosidenib in the ClarIDHy phase 3 clinical trial compared with placebo in the management of patients with CCA and IDH1 mutation.

Finally, although we are excited by novel therapeutics and innovative clinical trials, Jessica M. Keilson, MD, and colleagues from the Cholangiocarcinoma Foundation reported sobering results regarding patients’ financial toxicity associated with clinical trial participation and the cost of targeted therapies, a fact that should be considered when offering an investigational therapy to our patients.

Sincerely,

Milind M. Javle, MD
Hubert L. and Olive Stringer Professor
Department of Gastrointestinal Medical Oncology
Division of Cancer Medicine
The University of Texas
M.D. Anderson Cancer Center
Houston, TX
Chair
NCI Task Force: Hepatobiliary Cancers