Treating Unresectable, Advanced Cholangiocarcinoma

John L. Marshall, MD: To wrap up this section, Milind, we’ve got a patient diagnosed with metastatic disease, or unresectable by today’s standards. You’ve got tissue, and you send it off for profiling. How do you start treatment with an average patient?

Milind Javle, MD: On average, patients with advanced or unresectable disease would start with systemic chemotherapy. As you mentioned, we would do next-generation sequencing, which would typically inform choices in the second-line setting. Whatever chemotherapy we choose would be a bridge to the next step, hopefully, in some cases of liver-directed therapy. Gemcitabine/cisplatin is still standard of care, and the median survival with that is about 11 months.

Trials, such as the gemcitabine/cisplatin/Abraxane vs GEM [gemcitabine]/CIS [cisplatin] or a variety of immunotherapy plus chemotherapy trials, might change the paradigm. At the time of progression, we will use the molecular sequencing in terms of intrahepatic cholangiocarcinoma. Forty percent of patients have valuable targets that you can investigate, either in the standard or in the clinical trial realm. In terms of cases that do not have actionable mutations, FOLFOX [fluorouracil, leucovorin, oxaliplatin], based on the ABC-06 trial, is a standard with a modest improvement in progression-free survival and overall survival over supportive care. That is the general paradigm. Within these, we seek outliers, patients who have liver-limited disease or similar to what we’ve seen in colorectal cancer with very oligometastatic disease. Can they be candidates for liver-directed therapy? We ask ourselves that question at every restaging.

John L. Marshall, MD: Sameek, I often get these patients for second- or third-line opinions, and I look at them and see what I call liver-dominant disease. Maybe they don’t have good targets, and it’s more chemotherapy vs another treatment. I present them in tumor board and to our IR [interventional radiology] gang. Are we underutilizing or overutilizing liver-directed therapies?

Sameek Roychowdhury, MD, PhD: For patients with metastatic disease, that can mean multiple liver lesions or multiple lobes involved. It could also be nodal involvement. It could be involvement in the lung, peritoneum, omentum. Metastatic disease is a wider array of patients. I focus on patients with liver-only disease for liver-directed therapy. Those with extrahepatic disease favor systemic therapy, clinical trials, early phase 1 and phase 2 studies. In select cases, we might consider somebody with extrahepatic disease. That’s been our practice for liver-directed therapy in the metastatic setting.

John L. Marshall, MD: Katie, I teach the fellows the list of drugs that we think are reasonable to try in a patient who walks in—good performance status, engagement, currently approved, not necessarily guideline. Let’s talk about what you would consider trying. I’m going to give us GEM and CIS. Give me a few more from your list.

R. Kate Kelley, MD: First line?

John L. Marshall, MD: Any line if they haven’t had it yet.

R. Kate Kelley, MD: Definitely 5-FU [fluorouracil].CAPE [capecitabine] by extension, oxaliplatin, irinotecan, and nab-paclitaxel.

John L. Marshall, MD: OX [oxaliplatin] if you’ve had CIS, or just a platin?

R. Kate Kelley, MD: The ABC-06 trial looked at FOLFOX as second-line therapy after GEM/CIS specifically and showed a benefit overactive supportive care.

John L. Marshall, MD: So both, OK.

R. Kate Kelley, MD: Yes, either. Irinotecan, depending on the bilirubin, and nab-paclitaxel.

John L. Marshall, MD: Not just Taxol, nab-paclitaxel.

R. Kate Kelley, MD: We might infer that they could have similar benefit. The phase 2 data we have from Milind and Dr Rachna Shroff’s trial is with nab-paclitaxel. There are also data referenced in the NCCN [National Comprehensive Cancer Network] Guidelines of GEM plus nab-paclitaxel from Vaibhav Sahai and team. The exciting part is what we’ll talk about momentarily about the molecular therapies that we get to add to the list now.

John L. Marshall, MD: Assuming there are no other molecular targets, is there anything else on the list that would make you say, “Let’s try that?”

R. Kate Kelley, MD: That list is my armamentarium. There are some old data with mitomycin that I haven’t used myself. I’m nervous to.

John L. Marshall, MD: You never will, is my guess.

R. Kate Kelley, MD: I don’t know. Maybe I’m missing something.

John L. Marshall, MD: Anybody got another rabbit they’d pull out of a hat?

Sameek Roychowdhury, MD, PhD: I will use PD-1 inhibitors.

John L. Marshall, MD: PD-1. Let’s assume no molecular anything.

Sameek Roychowdhury, MD, PhD: Even in the absence of TMB [tumor mutational burden], I will use PD-1 inhibitors.

John L. Marshall, MD: You’ll give them a try even in the absence of a target?

Sameek Roychowdhury, MD, PhD: Absence of PD-1, absence of TMB.

John L. Marshall, MD: There are some decent data in an unenriched population. What’s the response rate, around 10% or 15%, right?

R. Kate Kelley, MD: Five percent to 10%.

Sameek Roychowdhury, MD, PhD: Approximate in most solid tumors, as well.

John L. Marshall, MD: Milind, any other things on your list?

Milind Javle, MD: In our population we wouldn’t be approved for a PD-1 inhibitor, Sameek, so we can’t do it off-trial. There has been a study of regorafenib, the REACHIN study. It was a phase 2 randomized study. I have personally never used it, but it’s been used. John, capecitabine.

John L. Marshall, MD: We included that. I put that with Katie’s 5-FU.

Milind Javle, MD: These patients often have a good PS [performance status], even after third line. As Sameek said, they are great candidates for phase 1 and 2 trials.

John L. Marshall, MD: Not really anthracyclines. They had some early data, but we don’t go there. Good. It’s interesting, no real VEGF [vascular endothelial growth factor] inhibition here, right?

Milind Javle, MD: There has been a trial of ramucirumab in the first-line setting. It was negative with GEM/CIS compared with GEM/CIS. We had a trial when Dr Shroff was here of about 60 patients. I don’t think there are randomized data. There is something there, but there’s nothing approved, and we don’t use it off clinical trial.

John L. Marshall, MD: Thanks, everybody. This was a great discussion on today’s standard for the management of initial treatment, as well as initial treatment for metastatic disease. Thanks for joining us.

Transcript Edited for Clarity