Targeted Therapies, Triplet Regimens Becoming Focus in Biliary Tract Cancers

Rachna T. Shroff, MD, MS

In an effort to move away from standard combination chemotherapy, researchers are looking at additional regimens for patients with biliary tract cancers, as well as turning their focus to molecular profiling, explained Rachna T. Shroff, MD, MS.

“The biggest challenge is that, to date, we have one standard of care treatment, and that is gemcitabine and platinum[-based therapy]. And, that has been the standard of care for years,” said Shroff, an associate professor of medicine, chief, Section of GI Medical Oncology, leader of the GI Disease-Oriented Team, chair of the Data Safety Monitoring Board, University of Arizona Cancer Center.

The ongoing phase III SWOG 1815 trial (NCT03768414) trial is evaluating the regimen of gemcitabine hydrochloride and cisplatin with or without nab-paclitaxel (Abraxane) in 268 patients with newly diagnosed, advanced biliary tract cancers. The primary endpoint is overall survival (OS); secondary endpoints include progression-free survival (PFS), overall response rate, disease control rate (DCR), safety, and the correlation between CA19-9 levels from baseline to posttreatment.

Phase II data with this regimen previously demonstrated tolerability and efficacy in patients with advanced biliary tract cancers. At a median follow-up of 11.5 months, the median PFS was 11.5 months (95% CI, 6.1-not reached) and the median OS was not reached (estimated >20 months); the 1-year OS rate was 66.7% (95% CI, 65.9%-92.2%). With 34 patients evaluable for response, the DCR was 82.3% and the RECIST v1.1 response rate was 32.3%.

Molecular profiling, Shroff added, can determine whether patients harbor abnormalities in IDH1, FGFR, HER2, and BRAF. For patients with FGFR fusion—positive tumors, infigratinib, pemigatinib, and erdafitinib have all demonstrated encouraging activity in patients with cholangiocarcinoma.

OncLive^®: What is the state of cholangiocarcinoma treatment?

In an interview during the 2019 Gastrointestinal Cancers Symposium, Shroff highlighted the ongoing research efforts in biliary tract cancers, specifically with cholangiocarcinoma treatment.Shroff: In the treatment of [patients with] cholangiocarcinoma, there is a whole new horizon in terms of targeted therapies for these patients, which is an exciting development that has really come into fruition in the last few years. It is absolutely changing the landscape and how we approach these patients. The majority of patients with cholangiocarcinoma present with advanced disease, and so clinical trials and options for them beyond standard-of-care combination chemotherapy is really important.

What we have found is that in our patients who get molecular profiling for cholangiocarcinoma, about one-third to 40% of our patients actually have targetable mutations that we find. By that, I mean that there are drugs that we can use either in the setting of clinical trials or are approved in other indications. Therefore, it is really imperative in all of our patients that we send their initial tumor biopsy or liquid biopsy for full molecular profiling at the time of their diagnosis so we can line up their options for them as we line up their treatments.

In the setting of starting patients on standard-of-care chemotherapy, there are also other frontline chemotherapy trials. SWOG 1815 just opened in December 2018, of which I’m the national principal investigator, which is the first randomized phase III study in this country for biliary tract cancers. It is comparing the standard-of-care cisplatin/gemcitabine to a triplet chemotherapy combination with cisplatin, gemcitabine, and nab-paclitaxel.

Therefore, it is really exciting option for patients; we have seen some really impressive efficacy in the phase II study that we conducted at The University of Texas MD Anderson Cancer Center and Mayo Clinic. That is what the basis was for the phase III study. When and if patients progress on standard therapy, that is really where the targeted therapies come into play, because the majority of those trials have been in the refractory setting. These are the patients for whom once we get a sense of what their profile is, we actively look for the right trial for them. Some of the more common mutations that we see are IDH1 mutations, for which we have IDH inhibitors. There is a phase III study that is completing accrual any day now, so we should hopefully get a readout soon.

Regarding FGFR fusions—which is a rarer subset of our patients, but 15% of patients have them—there are a number of FGFR inhibitors that are in trial form currently—both in the refractory setting currently as well as in the frontline setting with chemotherapy. Then, there are less frequently seen alterations but ones that are still very relevant in being actionable, such as BRAF mutations, HER2/neu amplification, and these are all alterations that we can identify on next-generation sequencing and hopefully find trials for patients. It is part of the treatment paradigm to really sequence these patients upfront.

Shroff RT, Borad MJ, Xiao L, et al. A phase II trial of gemcitabine (G), cisplatin (C), and nab-paclitaxel (N) in advanced biliary tract cancers (aBTCs). J Clin Oncol. 2017;35(suppl 15; asbtr 4018).