Melanie Cole, MS (Host): Welcome to the podcast series from the specialists at Penn Medicine. I’m Melanie Cole. Today, we’re highlighting biomarker testing in non-small cell lung cancer (NSCLC). Joining me is Dr. Melina Marmarelis. She’s the Medical Director of the Penn Medicine Mesothelioma Program. Dr. Marmarelis, thank you so much for joining us today. You recently participated in a relatively large retrospective study that found that approximately 30% of patients with biomarker-positive disease who underwent next-generation sequencing did not receive biomarker-driven targeted therapies as their first-line treatment. Can you tell us just a little bit about that and where biomarkers come into play in this picture?

Melina Marmarelis, MD: Yeah, no problem. So, we’re talking about metastatic non-small cell lung cancer, one of the most common forms of lung cancer. In the last decade, we’ve really had an explosion in both the detection of targets and the development of targeted therapies. So it’s become critical prior to starting any sort of therapy that we actually know a lot of characteristics about the tumor. So, this specifically is doing next-generation sequencing on the patient’s tumor prior to receiving any sort of systemic therapy. And what we’ve seen over the
years is that initially when this came to light, we were seeing really poor rates of biomarker testing, especially prior to initiation of therapy. Initially, over half of patients weren’t getting this recommended testing, and now we’re seeing closer to 20 to 30 percent that don’t get it depending on parts of the country and different demographics of patients. But it’s really important both to choose the correct treatment, but also to avoid treatments that might not be effective in patients. So it’s really precision medicine at its best.

Host: In your field now, how important is biomarker testing in NSCLC, and why is there an unmet need for this advantage in some patients with biomarker, positive, advanced, or metastatic NSCLC?

Melina Marmarelis, MD: So we know that if a target is detected, so for instance, if a patient has a mutation in EGFR or a fusion in the ALK gene, it’s really important that they receive targeted therapy, and that they not receive standard chemotherapy or immunotherapy. So, for instance, immunotherapy by itself really isn’t effective for patients that have EGFR or ALK alterations. So it’s become critical to really understand the characteristics of the tumor before we start treatment.

Host: What role has Penn Medicine played in the discovery or advancement of biomarker testing for NSCLC?

Melina Marmarelis, MD: Yeah, so the gold standard is still tissue testing. So a patient gets a biopsy, and the biopsy undergoes next generation sequencing. But that sometimes is not successful. So either there’s not enough tissue, or there are issues with the amount that’s available, because there are other competing tests that we do.

So, I think, the role that Penn has been able to play is really pushing liquid biopsy to the forefront. So, liquid biopsy is actually just a plasma-based test, meaning a blood test, and it looks for pieces of cell-free DNA in the blood. So for the patient, the experience is quite different from a biopsy, right? It’s just a blood test. They’re able to get some of the same information that you would get from next-generation sequencing on tissue. Penn has been able to play a role in a few ways. One, is that we showed that concurrent testing, so, both liquid and tissue testing can improve your rates of detection of a target.

So, that makes sense, right? Two shots on goal. You have two ways of trying to detect a target. You can increase your chances by, you know, more than 30%, in detecting one of these. And since we know that detecting and delivering a targeted therapy has a survival advantage, that’s really important. The second piece is, that is more operational.

So, we have run a clinical trial across the health system, trying to implement concurrent testing with both the liquid biopsy and the tissue. So, this is actually something that some of the providers may have seen in their electronic medical record. It popped up at the time of new patient visits and prompted people to order the liquid biopsy testing to ensure that patients got timely testing. And the most information that we could get prior to initiating treatment.

Host: Can you discuss briefly the current place of immunotherapy in lung cancer therapy, and what the future holds in that regard?

Melina Marmarelis, MD: I mean, immunotherapy is one of the most exciting things to have come to lung cancer. It’s one of the things that gives really durable benefit to patients, if they have a nice response. It’s a key tool that we have. The key to using immunotherapy is using it in the right patients. Patients for instance, with things like EGFR and ALK alterations don’t benefit as much from immunotherapy, but others that don’t have these alterations may benefit quite a bit. So we’re using immunotherapy in a lot of different settings. We’re using it as a first-line treatment for metastatic disease. Using it perioperatively before and after surgery, potentially. So, it really has a lot of different roles. And the question we’re asking ourselves when we see a patient is usually, is there a reason I shouldn’t give this patient immunotherapy? Because the default is that we’re going to start with some immunotherapy-based regimen.

Host: Well then along those lines, how is it changing the need for biomarker testing in early stage NSCLC? Tell us how they’re working together.

Melina Marmarelis, MD: Yeah, I think this is the next frontier for biomarker testing and it’s a much more difficult problem to solve. So in the metastatic setting, we had cell-free DNA, which you can pick up little pieces of the DNA in the blood, and that makes getting testing back to the provider much faster. In early-stage lung cancer, you often don’t have shedding into the blood. So those tests that we were using in the metastatic setting aren’t able to detect anything in the blood, so you’re really reliant on tissue testing. Thankfully, there have been a number of advances, and we are able to use higher-sensitivity, cell-free DNA assays to detect some of these things in the blood. There are a variety of types of tests that do this. The ones that are being used right now that have the widest range are tumor-informed, which means that they use a piece of the patient’s tumor and then they go looking for similar things in the blood. And because it’s so specific to the patient, they can actually detect things with a much higher sensitivity.

So we’re starting to look at that in early stage. I don’t think it’s yet replacing tissue testing. One of the challenges for tissue testing in early stages that the tissue tests often take several weeks. They take two to three weeks if you’re sending out often or if you’re doing a bigger panel. And patients don’t want to wait that long to make a decision about whether they’re going to start some sort of chemo immunotherapy or go straight to surgery.

So one of the things we’ve been able to do at Penn is we have implemented a faster, more limited assay that has a turnaround time of about five days, that can get us the information that we need actually to make that initial decision about perioperative therapy.

Host: So along those lines then, how can patients advocate for themselves to get complete biomarker testing so they can move on to the therapies that work best for their specific cancer?

Melina Marmarelis, MD: Yeah, I think that’s a great point. And it’s such an overwhelming time for patients that it’s hard to put more on them while they’re navigating this new diagnosis. But I think one thing, that I would hope for patients is that as they’re doing their research about their new diagnosis, that they, hopefully they come across something about biomarker testing, and I think ideally they would talk to their providers about it.

So, that might be a surgeon or a pulmonologist, the person doing the biopsy, because often by the time they get to a medical-oncologist, it’s been several weeks. And so if we order the testing at that point, then we’re a little bit behind the ball. Of course we’re looking at additional ways to prompt the system to actually get that testing done. But I think, of all the questions that patients ask, I think this is a great one to be asking their providers, as well as, has my tissue been tested for biomarkers? Has it gone through sequencing?

Host: I understand that a lung cancer translational center of excellence is being developed within the thoracic oncology precision program. What’s the mission of the lung cancer TCE? Tell us just a little bit about that.

Melina Marmarelis, MD: Translational Centers for Excellence have existed now for some time, and the thoracic TCE has also existed for some time. Its initial focus was on immunotherapy. So, this was at the start about 10 years ago when immunotherapy was really new in the lung cancer field, and it produced some really amazing projects in that realm. Recently, it’s been reimagined, to focus a little bit on some of the biomarker discovery that is so exciting in lung cancer right now. We have a lot of projects that center around liquid biopsy, mostly in the early stage setting, but some in the metastatic setting as well, and trying to figure out how do we use these new tools that we have in order to give patients better outcomes and make better
treatment decisions for them.

Host: Thank you so much, Dr. Marmarelis for joining us today and sharing all of this exciting information. To refer your patient to Dr. Marmarelis at Penn Medicine, please call our twenty-four-seven provider-only line at 877-937-PENN, or you can submit your referral via our secure online referral form by visiting our website@pennmedicine.org slash refer your patient. That concludes this episode from the specialists at Penn Medicine. I’m Melanie Cole.