Dr. Laura Goff:
Welcome to The ASCO Post Roundtable Series on the First-Line Systemic Treatment of Advanced Hepatobiliary Cancers. I'm Dr. Laura Goff, a medical oncologist and professor of medicine at Vanderbilt University Medical Center in Nashville, Tennessee. Joining me today are two of my colleagues. Dr. Spencer?
Dr. Kristen Spencer:
Hi, I'm Dr. Kristen Spencer. I'm a medical oncologist specializing in hepatobiliary cancers and Director of the Phase I Program here at NYU in New York City.
Dr. Laura Goff:
And Dr. Yarchoan.
Dr. Mark Yarchoan:
Mark Yarchoan. I'm a medical oncologist at Johns Hopkins in Baltimore, Maryland, focused on hepatobiliary tumors.
Dr. Laura Goff:
Today we'll be discussing the treatment and management of advanced hepatobiliary cancer with three patient case studies. Our first installment will focus on the first-line treatment of metastatic cholangiocarcinoma.
So case one, CB is a 45-year-old man who presented with right upper quadrant abdominal pain. He's otherwise healthy and currently active duty in the military. His mother has a history of ovarian cancer and his sister has a history of breast cancer. Cross-sectional imaging revealed moderate common bile duct dilatation with abrupt tapering at the ampulla due to a mass in the lower third of the bile duct. This mass encased the portal vein, common hepatic, and right hepatic arteries. Biopsy was done and demonstrated moderately differentiated adenocarcinoma. The CA19-9 was 598 and bilirubin was 2.4. A CT scan of the chest revealed bilateral pulmonary nodules consistent with metastases. So what additional studies should be performed at this time? What would you do?
Dr. Kristen Spencer:
I think as we commonly say in this world, tissue is the issue, right? So I think we certainly need a biopsy for a number of reasons. It's the diagnostic gold standard and we would love to send that off for molecular profiling if that can be done.
Dr. Laura Goff:
Great. And yes Dr. Yarchoan, tell me a little bit about your thoughts on the timing of molecular testing here in this first-line patient.
Dr. Mark Yarchoan:
Yeah. When I lecture the oncology fellows here, I often joke that the cholangiocarcinoma is the lung cancer of the GI oncologists because around 40% of patients with intrahepatic cholangiocarcinomas have something actionable on molecular testing. And so really this should be routine standard of care for all patients with cholangiocarcinoma. And I like to do this upfront because even if it doesn't necessarily impact the first-line treatment, I think the sooner you have the information, the better. And we know that even with contemporary front-line therapy, a number of patients don't respond and often don't respond relatively quickly. So the sooner you get the testing done, the more prepared you are for second line therapy where this information is particularly useful.
Dr. Laura Goff:
And Dr. Spencer, are you doing primarily blood, tumor? How are you getting your NGS testing done? Are you sending both at the same time? Tell me your thoughts about that.
Dr. Kristen Spencer:
Yeah, I think this is an interesting sort of area of development in bile duct cancers. I'm not routinely using blood at this point unless tissue failed. I think one of the things that I was sort of thinking when this case first was mentioned was we have an adenocarcinoma likely from a brushing or a bile duct biopsy and that tissue is often not sufficient for molecular profiling. So I'm actually interested in what you two would do in terms of would you biopsy the pulmonary nodules? Would you just try and send sequencing off tissue or would you just send blood right away? I think I would probably, depending on where the pulmonary nodules were, do a biopsy off of one of those if I could not get sequencing information off of the original biopsy.
Dr. Laura Goff:
Yeah. And I'll let Mark answer in a minute. We've been sending a lot of both. Having been a hepatobiliary oncologist for a long time, I think I've been burned a long time waiting to get back quantity insufficient on the biopsies that we do have, especially in these extrahepatic cholangiocarcinomas where we may, as you alluded to just have a little bit of tissue. But I'm seeing some nods from Mark as well, that maybe that we're kind of attacking on all fronts to try to get this really critical information.
Dr. Mark Yarchoan:
No, I totally agree. And in particular with cholangiocarcinoma, you often do find these sort of unusual chromosomal rearrangements or RNA splicing events. And so getting DNA and RNA can be very helpful for the highest sensitivity. So I tend to send both liquid and tumor when possible. In a case like this, the liquid will come back quickly and if you send a liquid and you get a KRAS mutation, you probably don't need to look harder because you have something there. But if you send the liquid and you don't find anything, then you have to look harder.
Dr. Laura Goff:
That's great. All right, well I will move on to what we did get out of the next-generation sequencing for him. The sequencing revealed a pathogenic BRCA1 missense variant and a variant allele fraction of 48.8% and then a pathogenic TP53 splice region variant. The VAF for that was 2.1%. So what are the options for treatment at this point and maybe involving the molecular findings or perhaps not? So Dr. Yarchoan I'll start with you. How would you treat this patient with first-line extrahepatic cholangiocarcinoma and these molecular findings?
Dr. Mark Yarchoan:
Yeah, I think this patient is a great candidate from everything we see here for sort of standard front-line therapy that's gemcitabine, cisplatin with a checkpoint agent, either pembrolizumab or durvalumab. I don't have a preference for one vs the other. I think they're both very reasonable front-line options. I think it's worth just talking a little bit about the molecular testing here. So this patient has a family history of BRCA-related cancers it sounds like. And here you see a BRCA1 missense variant that looks pathogenic. The VAF is 48.8%. That really sounds like this is a germline BRCA1. So this is likely BRCA-related cholangiocarcinoma. I think there is increasing data that BRCA is a risk factor for cholangiocarcinoma so this is likely related. Why do I say likely related? Well, it is possible to have a germline BRCA and then have a cancer that's not BRCA, right? It's the first hit, not the second hit.
And we don't know for sure with this patient whether this is a truly BRCA-related cancer, but I think it's likely. None of this affects the front-line treatment. Although having a BRCA mutation I think makes us excited that they might respond to the cisplatin component of the front-line regimen. One of the things that I would probably do at this stage is, many of the contemporary molecular testing algorithms will give you an HRD score, and that can be kind of a sanity check for a case like this. We expect this to be a BRCA-related cancer. So I really would look to see that the HRD score is consistent with a true pathogenic BRCA. And if so, again, doesn't affect front-line, but might be useful down the road.
Dr. Laura Goff:
And Dr. Spencer, I have a couple questions on the standard, the gemcitabine plus cisplatin and a checkpoint inhibitor. So do you have a frame of reference? And I know there's probably not a real clear answer, but do we have a frame reference of how long you're continuing the chemotherapy? Which agents and how do you approach that with a patient? Again, not necessarily right out of the gate, but when you're counseling the patient around what front-line therapy is going to look like, what do you tell them?
Dr. Kristen Spencer:
Yeah, this is a great question. So as you know, the TOPAZ trial after eight cycles stopped the chemotherapy and continued durvalumab in the experimental arm, whereas the KEYNOTE-966 trial allowed you to continue the gemcitabine. When you look at the sort of breakdown and exposure of agents on that trial, however, in fact, most patients are stopping the chemotherapy and continuing on the single-agent pembrolizumab. And that was actually true of the TOPAZ trial as well. It was really only a minority of patients that actually continued the gemcitabine and the cisplatin throughout the entire prescribed duration of therapy. So I think in reality we perseverate on this a lot as medical oncologists, particularly as we're designing upcoming trials in novel settings and with novel compounds. Do we allow you to continue the gemcitabine, do we not? I think it's probably a moot point. The way I counsel patients is that this therapy in the setting of a disease that cannot be potentially cured by a surgical resection or transplant is indefinite.
I try and talk to them about it like a chronic condition, like high blood pressure, high cholesterol that can only be controlled as long as we're treating it with something. I do say to them that there is the potential for stopping the two chemotherapy agents after 6 months if their disease is responding and continuing with just the single-agent immunotherapy. And I actually, in my practice, most of my patients are actually hoping to come off the chemotherapy. I think maybe it's just a consequence of Manhattan and people not liking to come into the city, but they want to stop with the days 1 and 8 chemotherapy and coming in and the labs and blah, blah, blah. So most of my patients actually end up changing over to the single-agent durvalumab after eight cycles, if not sooner than that.
Dr. Laura Goff:
And how is it in Baltimore, Dr. Yarchoan? Do people come off the chemotherapy as well? And even so, you alluded to the cisplatin and the potential BRCA. Does that change your thoughts about that? So sort of two questions in one.
Dr. Mark Yarchoan:
Yeah, I think my answer's pretty similar. Sometimes we push on a little bit beyond 6 months, but not indefinitely.
Dr. Laura Goff:
Great. Well, I really appreciate the insights from both of you. So I'm going to wrap us up with our key clinical takeaways for this case is that the treatment of metastatic cholangiocarcinoma with chemoimmunotherapy results in improved overall survival. The ideal duration of treatment with gemcitabine, with or without cisplatin remains undefined and I believe should involve a close attention to individual response and toxicity. And then actionable molecular alterations are frequently found and guide therapy, but are not yet utilized in first-line therapy selection. So this brings us to the end of this case. Please see the other segments for further discussion about the latest research in advance to hepatobiliary cancers or visit ascopost.com.
