ASCO GI Presentations Show Progress in BTC

March 2024, Vol 5, No 1
Milind M. Javle, MD
Hubert L. and Olive Stringer Professor
GI Medical Oncology
University of Texas MD Anderson
Cancer Center, Houston
Chair, NCI Task Force,
Hepatobiliary Cancers

Dear Readers,

The recent ASCO GI 2024 symposium highlighted several critical biliary tract cancer (BTC) developments. Some of the meeting highlights included novel methods of delivery, targeted therapy for known and novel targets, and preclinical studies highlighting the next frontier.

The clinical spectrum of liver-limited cholangiocarcinoma (CCA) is changing with the advent of liver-directed approaches. Bas Groot Koerkamp, MD, PhD, presented data using the hepatic arterial infusion pump with floxuridine from a multicenter study of 50 patients in the Netherlands. The study demonstrated a 50% response rate, a progression-free survival (PFS) of 10 months, and a median overall survival of 22 months.

This trial demonstrated the feasibility of this technique in a multicenter setting; clearly, randomized prospective clinical trials in this setting are necessary. The fibroblast growth factor receptor (FGFR) pathway continues to be an area of intensive development.

Notably, 2 FGFR inhibitors, pemigatinib and futibatinib, are clinically available. However, acquired resistance is almost universal, and novel inhibitors that target resistant FGFR pathways are required. Tinengotinib is a novel, next-generation FGFR inhibitor that binds the receptor away from the kinase domain and targets vascular endothelial growth factor (VEGF) and macrophage colony-stimulating factor receptor pathways.

A phase 2 trial in the refractory FGFR setting showed a 37% overall response rate for patients with CCA with an acceptable toxicity profile. This agent is now being investigated in a phase 3 randomized trial (FIRST-308) of tinengotinib versus physician choice (FOLFOX or FOLFIRI) with PFS as the primary endpoint. The FIRST-308 study is currently enrolling patients.

In BTC, particularly gallbladder cancer (GBC), murine double minute 2 (MDM2) amplification (with wild type-TP53) is emerging as an essential target; an estimated 10% of GBCs have this genetic aberration.

Teresa Macarulla, MD, PhD, presented interim results for 23 patients with BTC treated with the MDM2-TP53 antagonist brigimadlin as a single agent or combined with the programmed cell death protein 1 inhibitor, ezabenlimab.

Partial responses and prolonged standard deviation occurred in both arms at the expense of nausea and myelosuppression being the most common toxicities. Brigimadlin is being investigated in the pivotal Brightline-2 trial for this patient population worldwide, and the accrual is proceeding rapidly.

Angiogenesis as a target in BTC is experiencing a resurgence, with several agents being developed in this space. CTX-009 is a bispecific antibody that targets VEGF-A and delta-like ligand 4. Combined with paclitaxel in a pilot phase 2 trial conducted by Do-Youn Oh, MD, PhD, it yielded an impressive response rate.

This combination is being investigated in a randomized, phase 2/3, COMPANION-002 trial of paclitaxel versus the combination of paclitaxel and CTX-009 as second-line therapy for BTC. This trial will hopefully open possibilities for BTC patients who lack actionable genetic alterations.

Other antiangiogenic agents being investigated include surufatinib and anlotinib.

Finally, while BTC remains a model for precision/targeted therapy, the identification of targets is limited by the lack of “bistable” lesions in a significant fraction.

In a real-world study conducted using the Guardant360 platform, Amit Mahipal, MD, demonstrated that actionable alterations are identifiable in the first- or second-line setting on liquid biopsy, and the frequency of these mutations is approximately the same as in tumor biopsies. These data are critical to further using liquid biopsies in the clinical setting.

Finally, the 11th Annual Cholangiocarcinoma Foundation Conference will be held in Salt Lake City, Utah, April 17-19, 2024. It will be chaired by Mitesh Borad, MD, Angela LaMarca, MD, MSc, Do-Youn Oh, MD, PhD, Sumera I. Ilyas, MBBS, and Daniela Sia, PhD.

We look forward to your attendance at this important meeting!


Milind M. Javle, MD Signature.

Milind M. Javle, MD

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