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 and Dr. Yarchoan. Dr. Spencer?
Dr. Kristen Spencer:
Thanks, Dr. Goff. I'm Dr. Kristen Spencer. I'm a medical oncologist specializing in hepatobiliary cancers and directing the Phase I unit at NYU here in New York City.
Dr. Laura Goff:
Dr. Yarchoan.
Dr, Mark Yarchoan:
Mark Yarchoan. I'm a medical oncologist at Johns Hopkins in Baltimore, Maryland focused on hepatobiliary cancers.
Dr. Laura Goff:
Today we'll be discussing the treatment and management of advanced hepatobiliary cancer with three patient case studies. And our third and final installment, we'll focus on the first-line treatment of fibrolamellar hepatocellular carcinoma.
K.H. is a previously healthy 24-year-old woman who presented with a 6-month history of nausea, vomiting, jaundice, and right upper quadrant abdominal pain. MRI demonstrated a 10.8-cm mass in the right hepatic lobe with an associated satellite lesion and intraductal biliary component involving the anterior division of the right hepatic duct. Portal adenopathy measured 4.4 by 3.3 cm and retrocrural adenopathy measured 1.9 by 1.6 cm. Biopsy of the periportal lymph node showed hepatocellular neoplasm positive for DNAJB1-PRKACA gene fusion. So are there additional studies that you would pursue at this time or do we have a clear diagnosis and what are we dealing with? We'll start with you, Dr. Spencer.
Dr. Kristen Spencer:
Yeah, so I know we were talking about this just before this started, that this is a very rare distinct variant of HCC. So it's about 1% of HCC cases in the United States, and this is really the classic presenting patient, very young, typically adolescents and young adults and equal incidence in men and women, unlike the conventional HCC that we were just speaking about. And, I had just mentioned with the traditional HCC that we really like to know what the underlying status is of the liver; however, these cancers typically present in non-cirrhotic livers. So I think things like the Child-Pugh and perhaps the MELD score are less important and really nearly all of the cases have that gene fusion that you mentioned. That's a deletion on chromosome 19 actually. So I think in terms of imaging and that pathogenic fusion, I think I have all the information that I need in this case.
Dr. Laura Goff:
Great. All right. So Dr. Yarchoan, what are we going to offer this young, otherwise healthy patient that has this incredibly rare variant liver tumor?
Dr. Mark Yarchoan:
Yeah, I mean, just a couple of comments. I agree that we have the diagnosis here. Finding the gene fusion DNAJB1-PRKACA is really essential for making the diagnosis. These patients either have this fusion or in very rare cases can have protein kinase A over-expression through other means like with the Carney complex. It's a genomic syndrome, but you really do need a genomic evidence of activation of protein kinase A, and mostly through this shared fusion that these patients generally all have. This is a rare cancer. It's not that rare. It's about 600 people in the United States a year, mostly young. This is really right in the middle of the sort of age range where you see this tumor type.
Unfortunately, it's rare enough that we don't really have a standard of care for this tumor type. There's unfortunately very little data to truly guide therapy. I think many of us who see this tumor type, and we have a particular interest in this tumor type here at Hopkins with myself and Dr. Baretti, my colleague. But in general, we offer these patients a platinum-based chemotherapy. Gemcitabine/oxaliplatin plus lenvatinib is a very commonly used front-line regimen, but as with other rare cancers where there is not a clear established standard of care, I think it's always great to consider clinical trials whenever possible.
Fortunately, we and others do have trials for this tumor type. So we do tend to encourage clinical trial participation when possible. Just one other quick comment is these patients should really come through when possible a multidisciplinary clinic. In general in oncology, when patients have a primary liver mass with a non-regional adenopathy, as in this case, we declare that they are stage IV and incurable. This is a very weird tumor type where sometimes surgery can be considered even in metastatic cases and sometimes with very long-term survival. So a patient like this, I'm not sure I would start with surgery, but surgery would be part of the discussion even from the onset.
Dr. Laura Goff:
Great. And I know as you said, you guys have a particular interest. Anything that's on the horizon that we're looking at in clinical trials that we think may get the underlying mechanism of this tumor?
Dr. Mark Yarchoan:
Yeah, no, thanks for that question. There's this shared fusion, this DNAJB1-PRKACA. A lot of fusions in oncology, we have targeted therapy for, ROS1, ALK, et cetera, FGFR2. This fusion, at least right now, is considered undruggable and it's not for lack of trying. Targeted therapy has been developed that blocks protein kinase A, but it leads to unacceptable toxicity in the host. So our group has generally focused on immunological targeting of the fusion. There are many other fantastic groups working on targeted therapy and we certainly hope that that will pan out in the long run. But our approach has been trying to target this immunologically. We do have a study of a therapeutic cancer vaccine that targets the fusion event. Because the fusion's intronic, we can use a single vaccine to treat all the patients with this particular fusion event and we give the vaccine with ipilimumab and nivolumab, two checkpoints.
That's one of the trials that we have ongoing. And we do have other trials that are open or in development, including TCR therapy for this fusion event and also a trial targeting the abnormal metabolism, which is another cornerstone observation with this tumor type. So more to come. Around the country, there is a COG trial that should be opening very soon at the time that this is broadcast of a Bcl-XL PROTAC that has actually come from work from Dr. Sandy Simon at Rockefeller and others that we're also very excited about. So a lot of options and hopefully some of these will pan out.
Dr. Laura Goff:
Thank you so much. So the key clinical takeaways, fibrolamellar carcinoma or FLC is a distinct malignant process with a different epidemiology from hepatocellular carcinoma. These FLC patients are younger, typically do not express AFP, and contain the fusion protein, DNAJB1-PRKACA. There's no clear consensus regarding the optimal first-line treatment strategy, so clinical trial enrollment is highly encouraged. Case reports have demonstrated responses to multiple chemotherapy agents, immunotherapy, and some targeted therapies without a clear winner at this point.
So this brings us to the end of this case. Please see the other segments for further discussion about the latest research in advanced hepatobiliary cancer or visit ascopost.com.
