Marshall Highlights the Importance of Distinct Approaches to GI Cancers

John L. Marshall, MD

Distinctions in histology, molecular profiles, and tumor location have set diverging course of care for the treatment of patients with gastrointestinal (GI) cancers, according to John L. Marshall, MD. To address these varying pathways to care, cross-functional approaches to education and care have become paramount for clinicians.

Marshall was the coleader of the 7th Annual School of Gastrointestinal Oncology^® (SOGO^®), hosted by Physicians’ Education Resource^®, LLC (PER^®), a 1-day multidisciplinary educational conference on the emerging therapies and evolving standards of care in the management of patients with GI cancers. The hybrid symposium featured presentations on locoregional treatment of GI cancers, as well as case-based discussions on multidisciplinary, real-world management of GI cancers. 

“The main takeaway from this meeting is that there is a lot to learn,” Marshall, chief of the Division of Hematology/Oncology at Medstar Georgetown University Hospital and director of The Ruesch Center for the Cure of Gastrointestinal Cancers in Washington, DC, said in an interview with OncLive^®. “We learned a lot, we have moved the bar, but we have a long way to go. We know there are common malignancies, we know there are highly fatal malignancies as a group, and we know a lot of [clinicians] are familiar with them. It used to be an easy disease or group of diseases to take care of, [but] there is a lot going on in GI cancers.”

Marshall provided an overview of the main highlights from the meeting, including progress made, anticipated trends in research, and optimal treatment benefits for GI cancer.

OncLive^®: How has bile duct cancer set itself apart histology-wise from other GI cancers?

Marshall: When I first started in GI cancers, there was not much called ‘bile duct cancer.’ We used to call that ‘unknown primaries in the liver’ because you were not supposed to get adenocarcinomas in the liver. It has only been in the past 10 plus years that we have recognized that these adenocarcinomas in the liver cleanse [the body] of carcinomas and bile duct cancers.

We have to divide them into 3 categories [and] here I like to use a tree [analogy]: there is the trunk of the tree, and that is the common bile duct; there are the branches, the wood parts up in the tree, and those are intrahepatic bile ducts; and then there is that kind of knot off the side of the tree that is the gallbladder. And as we think about those 3 parts of the tree—the 3 parts of the bile system—we are increasingly recognizing that they are different. Yes, they are all adenocarcinomas [and] they are mostly included in all the clinical trials. But when we look at molecular profiling or precision medicine, we are seeing that they have different characteristics.

So, just like we did in upper GI cancers, where we separated esophageal GI junction and stomach, we are now increasingly separating common bile duct intrahepatic and gallbladder from each other.

How has bile duct cancer moved from obscurity to star of the show?

I was charged with the job of reviewing what has been going on in bile duct cancers and the answer is: a lot. My title was from obscurity to the star of the show.

That is increasingly true because with precision medicine, we are learning that there are important molecular subtypes—FGFR fusions or alterations, IDH1 alterations or mutations, and immunotherapy biomarkers—all of which are present in a high-enough percentage that they are worth looking for. And there are therapies that have significant improvements in outcome when they are applied. So just as you would measure molecular tests for almost all your cancers, the same now is true for cholangiocarcinoma and bile duct cancers.

Now, one of the other places it has become the star of the show and it is one more of our GI cancers where immunotherapy has worked, is in the TOPAZ-1 clinical trial [NCT03875235], a randomized study of gemcitabine plus cisplatin vs gemcitabine plus cisplatin plus immunotherapy. What we saw was an improvement in overall survival in that patient population and we are expecting an FDA approval in that space. So immunotherapy [is making] its way to bile duct cancers as well.

[Bile duct cancer] is absolutely not that rare of a cancer if you know what you are looking for. Precision medicine is key, and immunotherapy is an important part of that.

What are the anticipated trends for research in this area that will have the greatest effect on the landscape?

When we look at next steps with cholangiocarcinoma and bowel cancers, first we are applying the precision medicine and so now we have subcategories of this based on not only anatomy, but now also molecular profile. With each of those areas, we are seeing further activity of combinations and different lines of therapy.

We are also increasingly seeing liver-directed therapy approaches [and we are doing] this with our interventional surgical and radiation [colleagues] who are helping us to manage this. We have a lot of patients with liver-dominant problems. That sort of multidimensional approach is required in optimal management.

And then, how do we make the toehold we have with immunotherapy get bigger through combinations and other molecular characterizations to better understand who should get in therapy and who should not? So, [there is] a lot of ongoing work in the biotech cancer space.

What were some of the key takeaways from the Medical Crossfire^® debate on the incorporation of immunotherapy in GI cancers?

Each year we hold a crossfire session, and these are not intended to be slide-heavy, but [to rather to address] some critical questions that we all have about a key topic in GI cancers. This year, we picked immunotherapy; there is so much going on. It is really the Wild West. We were looking at immunotherapy being applied to GI cancers and so we walked through the GI tract [and asked] ‘does PD-L1 expression matter in upper GI cancers?’ And we decided yes, it does. Immunotherapy has a place through lines of therapy even in the adjuvant setting in certain cancers. PD-L1 expression probably is a good marker for who benefits and who does not.

We [also] looked at hepatocellular carcinoma [HCC], [a space that is] dominated by immunotherapy approaches, in the frontline and also other lines of therapy. Durvalumab [Imfinzi] showed positive results even as a single agent in HCC. The data with durvalumab in cholangiocarcinoma and bile duct cancers was there.

In pancreas cancer, [immunotherapy] is still dormant, we have not figured out how to crack that nut. But then if you go on further south to colorectal cancer, particularly rectal cancer, we talked about MSI-H [microsatellite instability–high] in the neoadjuvant setting [and asked] ‘do we use immuno-oncology [IO] therapy in the neoadjuvant setting and in rectal cancer?’

There are some highly provocative small phase 2 experience data showing 11 out of 11 [patients] having a complete clinical and radiographic response with just IO therapy and MSI-H rectal cancer. That would be transformative.

What can/should be done to ensure patients receive the optimal benefit from these approaches?

One of the main themes of the meeting was that molecular profiling is critical and in order to identify those patients who are candidates for immunotherapy and candidates for precision medicine target therapy. You need adequate tissue, you need to understand what the tests measure, and then you need to apply those in a multidisciplinary fashion to optimize treatment for our patients.

We are increasingly emphasizing organ preservation. And so, we are trying to not only care for our patients but allow them to maintain their quality of life. What we are seeing is what we were hoping, that these precision medicine tools are giving us those opportunities to both improve outcomes and maintain quality of life.