Biliary Tract Cancer: Where Are We Headed?

While promising new therapies for the treatment of biliary tract cancers (BTC) have been introduced recently, “We need much better and much more than what we have,” Nilofer Azad, MD, said during her address on immunotherapy at the International Society for Gastrointestinal Oncology meeting in Tempe, Arizona, on October 13.

Dr. Azad is professor of oncology; codirector of the Developmental Therapeutics Clinical Trials Program; and coleader of the Cancer Genetics and Epigenetics Program at the Sidney Kimmel Comprehensive Cancer Center of Johns Hopkins University in Baltimore, Maryland.

She referenced the TOPAZ trial, which combined what had been the standard of care for BTC—chemotherapy with gemcitabine and cisplatin (GEM/CIS)— with the immune checkpoint inhibitor (ICI) durvalumab. The combination regimen significantly improved overall survival in comparison to placebo plus chemotherapy and demonstrated improvements in progression-free survival and objective response rate. These findings have been confirmed in subsequent studies, Dr Azad noted.  

She further observed other therapies, including antivascular endothelial growth factor (VEGF) agents, poly (ADP-ribose) polymerase (PARP) inhibitors, and the ICIs, individually or in combination, are showing promise in improving overall survival, objective response, and progression-free survival among patients with BTC.

“Still, we need better drugs combined in different ways,” Dr Azad stressed. The greatest challenge, she stated, is the relative rarity of BTC and thus the limited population available for clinical trials. “How can we best use our small patient population in well-designed trials?” is a question that the field must investigate and answer to make progress in designing treatment regimens.

Noting that BTC is not a single disease but several, Dr Azad observed that “many BTCs have many targetable mutations,” including isocitrate dehydrogenase 1 (IDH1) variations that are found in approximately 20% of patients with intrahepatic cholangiocarcinoma. Findings of the ClarIDHy trial of ivosidenib, an inhibitor of mutant IDH1, showed a benefit in overall survival even with adjustment for crossover she added.

“We need an immune system for IDH1 inhibition,” Dr Azad stated. IDH1 mutations result in widespread dysregulation in cancer cells, she explained. Mice with deprived immune systems did not benefit from therapies to inhibit IDH1. This complicates the treatment of patients with this mutation who have undergone chemotherapy and other immune suppressing agents.

Other genetic mutations can also impact the efficacy of treatments for BTC, Dr Azad explained, including BRCA. As with IDH1 inhibition, BRCA inhibition also requires an intact immune system, she said. PARP inhibitors are showing potential in treatment of patients with BRCA mutations, and a trial of the PARP inhibitor niraparib and the ICI ipilimumab among patients with pancreatic cancer met the progression-free survival endpoint of 6 months. “This might be an area to explore in BTC as well,” Dr Azad said.

Certain subsets of BTC are KRAS mutated, she continued. “There’s whole slew of KRAS inhibitors coming up,” which synergize with ICIs. Dr Azad posed the question, “Should we try to explore this more in animal models or jump to human studies?” for patients with BTC.

Cell therapy offers an “extraordinarily exciting” field, she said. “Within a few years, this will really come on stage for solid tumors.”

“The time is nigh” for significant progress in therapy for biliary tract cancers, Dr Azad concluded. “Perhaps the biggest benefit from TOPAZ is that pharma companies are now interested in BTC.”