Milind Javle, MD: I’m going to move on now to overall treatment strategies and sequencing in biliary tract cancer. As you know, there have been many exciting developments, 3 drugs approved in 2 years. We have infigratinib, pemigatinib, and lucitanib. We have several others that are NCCN [National Comprehensive Cancer Network] designated. That is trametinib and dabrafenib for BRAF V600E, and trastuzumab/pertuzumab. For NTRK fusions, you have larotrectinib, entrectinib. And certainly, for MSI [microsatellite instability]-high we now have pembrolizumab/dostarlimab. So, this is a very rapid trajectory. I’m going to get your opinion here, Ruth and Mark, especially, for how you decide to sequence therapy if the patient has an actionable mutation in the first-line setting, has no actionable mutation in the first-line setting, and then if the patient has an actionable mutation in the second- or subsequent-line setting. Can you give us a high-level view of those different categories? Ruth, let me start with you with first line, and perhaps Mark, you can talk about subsequent lines. So Ruth, first-line therapy, if there is an actionable mutation, say FGFR or IDH1, or if there’s not an actionable mutation seen.

Aiwu Ruth He, MD: It depends on what mutations, and also depends on the data from the prior trial, the response rate. I profile all the patients, and even before I have the results, I usually start patients on chemotherapy. If a patient is elderly, very sick, and unlikely to tolerate chemotherapy, then for sure if they have a mutation, I’ll try to get them coverage to treat them targeting those mutations. Also, if there’s a trial that tests those targeted therapies in the front-line setting, I always try to enroll those patients in the clinical trials. I think it’s a constant practice of weighing the risk and the benefit and also the adverse effect profile. A lot of those patients may not tolerate chemotherapy. Therefore, that’s sort of the general practice. If they have an MSI-high tumor, of course I will always give them immunotherapy up front. Then if they have an FGFR2 fusion, the response rate is so promising with the FGFR inhibitors. I have the temptation to give it to those patients, especially if they cannot tolerate chemotherapy. So it really is case by case.

Milind Javle, MD: Wonderful. Mark, in the second-line setting, you mentioned there are data with FOLFOX [folinic acid, fluorouracil, oxaliplatin]. Ruth mentioned data with 5-FU [fluorouracil] and nanoliposomal irinotecan, and then a host of targeted therapies. So how do you make that decision in your practice?

Mark Yarchoan, MD: I think the overall survival benefit of FOLFOX or 5-FU and nanoliposomal irinotecan in the second line is pretty small versus placebo. In most cases, if there’s a truly actionable mutation that’s identified, I will choose a targeted therapy over chemotherapy in the second line. Particularly, if the patients have an FGFR2 fusion or rearrangement where there really is an impressive response rate with many of these agents, or HER2 or Rett [syndrome] or some of the others, particularly NTRK or BRAF V600E. The response rates are impressive. They’re clearly higher than chemotherapy in an unselected population and often are better tolerated as well.

Transcript edited for clarity.