The Drug Pipeline for Cholangiocarcinoma

TOP - March 2022 Vol 15, No 2 - Cholangiocarcinoma

At “The Pharma Pipeline” Roundtable during the 3rd Annual CCA Summit, experts from several pharmaceutical companies discussed recent and upcoming drugs in development for cholangiocarcinoma (CCA), emphasizing drug safety and a focus on patients.

Ying Bian, MD, Servier Pharmaceuticals, presented final data on the ClarIDHy phase 3 clinical trial in patients with CCA and IDH1 mutation whose disease progressed after 1 or 2 previous systemic regimens for advanced disease. Progression-free survival was significantly longer in patients randomized to ivosidenib (Tibsovo) compared with placebo (hazard ratio [HR], 0.37; 95% confidence interval [CI], 0.25-0.54; P <.001).

Because crossover was allowed after radiographic progression, the analysis for overall survival was adjusted by rank-preserving structural failure time. Patients receiving ivosidenib had significantly longer overall survival than those receiving a placebo (HR, 0.49; 95% CI, 0.34-0.70; P <.001). These data contributed to the FDA approval of ivosidenib for patients with CCA and IDH1 mutation who have received previous chemotherapy.

Neil Josephson, MD, Zymeworks, discussed HER2-targeted drugs in development. Zanidatamab is a bispecific HER2 antibody that is a cytotoxin-free approach investigated as monotherapy and in combination with standard-of-care therapy. The unique binding geometry of zanidatamab drives multiple mechanisms of action, including complement-dependent cytotoxicity, HER2 downregulation, and antibody-dependent cellular cytotoxicity and phagocytosis.

Results from a phase 1 study demonstrated that zanidatamab monotherapy is well-tolerated in the outpatient setting, with no treatment-related grade ≥3 adverse events. Antitumor responses included 40% confirmed partial responses and a 65% disease control rate.

In November 2020, the FDA granted zanidatamab a breakthrough therapy designation for patients with HER2-amplified biliary tract cancer after previous therapy.

Carl Dambkowski, MD, QED Therapeutics/Helsinn, discussed the development of infigratinib (Truseltiq), a selective, FGFR1-3 kinase inhibitor, for FGFR2-driven CCA. Infigratinib received FDA approval in May 2021 for the treatment of patients with CCA with FGFR2 mutation.

The ongoing phase 3 PROOF clinical trial is comparing infigratinib versus gemcitabine plus cisplatin, with optional crossover to infigratinib. An amendment to the protocol will allow 1 cycle of gemcitabine-based therapy before randomization.

Additional studies with infigratinib are planned for earlier-stage CCA and for adjuvant therapy in urothelial carcinoma. Tissue-agnostic studies will investigate the broader application of FGFR inhibition with this new targeted therapy.

Valerie Jansen, MD, PhD, Elevation Oncology, discussed NRG1 fusions as rare, but potentially actionable, driver alterations across multiple tumor types. Seribantumab, an anti-HER3 monoclonal antibody, has a consistent and well-tolerated safety profile.

In a preclinical lung cancer model, treatment with seribantumab led to diminished tumor growth over time and increased tumor volume change at best response compared with vehicle plus afatinib. In a preclinical high-grade serous ovarian cancer model, complete or near-complete regression of all tumors was seen with clinically relevant doses of seribantumab.

The phase 2 CRESTONE clinical trial includes adults with locally advanced or metastatic solid tumors harboring an NRG1 fusion who have received ≥1 systemic therapies. Patients will receive seribantumab until disease progression or unacceptable adverse events.

Next steps in FGFR inhibitors include appropriate sequencing of patients and moving targeted therapy to earlier lines of treatment. There is a need to work together as a CCA research community. In particular, hybrid models of patient-centered care for early-phase clinical trials are needed. Moving from drug- or company-specific clinical trials to more patient-centric studies may save time and increase productivity.

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Last modified: March 30, 2022