Poster Roundup: Boosting Checkpoint Inhibitors, Resistant Mechanisms in Cholangiocarcinoma

Research presented at the 2021 Cholangiocarcinoma Foundation Annual Meeting focused on precision medicine and therapeutic targets.

For the first time, the 2021 Cholangiocarcinoma Foundation (CCF) Annual Meeting held March 31 through April 2 included a poster competition, with presentations continuing the themes seen elsewhere in the meeting: developing better precision medicine solutions, and building on knowledge gained in treating other cancers. A selection of findings appears below:

Can CD40 improve checkpoint inhibitor response? Laurence Diggs, MD, a former research fellow at the National Cancer Institute who is now at Rutgers Robert Wood Johnson Medical School in New Jersey, presented research that examined whether stimulating CD40 would improve PD-1 inhibition and, when combined with standard-of-care chemotherapy (gemcitabine/cisplatin), would bring improved tumor responses in mice with intrahepatic cholangiocarcinoma (CCA). Researchers treated the ice for 4 weeks with immunoglobulin G control, a CD40 agonistic antibody, anti-PD-1, or a combination of both anti-CD40 and the PD-1 checkpoint inhibitor. Not only did the research team find that CD40 is highly expressed in intrahepatic cholangiocarcinoma, but that this high expression was linked to improved survival—so treatment with a CD40 agonist could represent a way to drive activation of antigen presenting cells, T-cells, and natural killer cells.

“We treated mice with cytotoxic chemotherapy, and added CD40 and PD-1 and there was significant benefit both—in a delay of tumor growth, as well as its survival for these 4 mice treated with both cytotoxic chemotherapy and the combination of CD40 and anti-PD-1,” Diggs said. Now, this concept will need to be evaluated in patients with intrahepatic CCA, he said. Results for this research previously appeared in the Journal of Hepatology.

Using liquid biopsy to find actionable alterations. Pashtoon M. Kasi, MBBS, MS, an oncologist with the University of Iowa, presented a study that he said showed both the value of genomic testing in cholangiocarcinoma, but also the value of longitudinal monitoring of actionable somatic alterations in through circulating tumor DNA (ctDNA) profiling. Testing is important both at baseline to help complete genomic testing in what he called a “target rich disease” but it is also important in picking up acquired mechanisms of resistance.

“When I say actionable, these are actual drugs for which there is an FDA approval,” Kasi said, noting the recent approval of pemigatinib for FGFR fusions, and the appearance in National Comprehensive Cancer Network guidelines of other recommendations for therapeutic targets. He showed in one slide show at least a third of the patients studied had actionable aberrations, and the ctDNA profiling done with liquid biopsy was able to identify FGFR fusions. This is important, he said, because in a real-world setting, “Cholangiocarcinoma is one disease where tissue is often not sufficient.”

This could be important as the sequencing of drugs for FGFR fusions becomes a bigger treatment story, Kasi said. Following patients with liquid biopsy over time can allow for tracking whether some aberrations may be resistant to one therapy but not others, and whether other mechanisms of resistance emerge.

Exploring FGFR resistance with sequential biopsies. Another poster, presented by Ahmed Shalaby of The University of Texas MD Anderson Cancer Center and co-authors from Foundation Medicine, also explored the idea of the development of resistance in cholangiocarcinoma with FGFR rearrangements. Resistance to FGFR inhibitors have been reported in case studies, he said, and the study sought to identify the potential to identify actionable concurrent mutations alongside FGFR2. Using the Foundation Medicine database, the researchers identified 932 patients with cholangiocarcinoma harboring FGFR rearrangements; of those 932, they found 19 who also had potential resistant mutations. Using liquid biopsies, the team found that 15 of the 19 were from a hepatobiliary source. Mapping showed the diversity of FGFR resistant mutation across the 19 patients; including 7 who had FGFR rearrangements who had at least 1 comprehensive genomic profiling test. Shalaby highlighted the difference in results for the 17 of the 19 patients, who had some type of treatment and were tested in 2017 or later—which apparently reflects the use of FGFR2 inhibitors. Shalaby said the results show that in patients with cholangiocarcinoma, if FGFR2 point mutations can be detected in sequential biopsies, this may account for resistance. “Both tissue and liquid biopsies are able to identify potential resistance mutations,” he said, and liquid biopsies have value for exploring the FGFR inhibitor resistance.