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NTRK Fusion–Positive Non–Small Cell Lung Cancer

This is Part 2 of Updates in Lung Cancer, a four-part video roundtable series. Scroll down to watch the other videos from this Roundtable.

In this video, Drs. Justin F. Gainor, Ibiayi Dagogo-Jack, and Jyoti D. Patel discuss the management of NTRK fusion–positive non–small cell lung cancer (NSCLC). Dr. Gainor presents the case of a 44-year-old man with a 5 pack-year history of tobacco exposure who was diagnosed with metastatic NSCLC; molecular testing was initially negative, but subsequent targeted next-generation sequencing revealed an NTRK1 fusion, a key oncogenic driver. The faculty discuss when and where to order additional molecular testing or next-generation sequencing in patients such as this. They review recent clinical data surrounding two agents approved by the FDA for NTRK fusion–driven lung cancer, larotrectinib and entrectinib.


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Transcript

Dr. Justin Gainor: Welcome to The ASCO Post Roundtable Series on Updates in Lung Cancer. I'm Dr. Justin Gainor from the Massachusetts General Hospital. Joining me today are two of my colleagues, Dr. Ibiayi Dagogo-Jack and Dr. Jyoti Patel. I'd like to ask them to each introduce themselves. Dr. Dagogo-Jack? Dr. Ibiayi Dagogo-Jack: Hi, everyone, my name is Ibiayi Dagogo-Jack and I'm a thoracic oncologist at Mass General Hospital, and it's my pleasure to be here today, this morning, this evening, regardless of what time zone you're joining us from. Dr. Jyoti Patel: Hi there, I'm Jyoti Patel. I'm the Director of Thoracic Oncology at Northwestern University. So pleased to be here. Thank you so much. Dr. Gainor: Great. I'd like to thank you both again for being here. Today, we'll be discussing recent updates in lung cancer, including data from recent clinical trials in integrating these new developments into four patient case studies. Our second installment will focus on therapy for NTRK fusion–positive non–small cell lung cancer. We'll begin with this case of a 44-year-old gentlemen with a five pack-year history of tobacco exposure and past medical history notable for hypertension, who presented to his PCP with persistent cough. As is typical for thoracic oncologists when we see some patients, particularly younger patients, this patient had had trials of a proton pump inhibitor, albuterol inhaler, and empiric antibiotics, but yet his cough persisted. Ultimately, had a chest x-ray that showed a large right hilar mass, and subsequent imaging, including a chest CT and PET, showed a hypermetabolic right hilar mass with ipsilateral hilar mediastinal adenopathy and a right-sided pleural effusion. A brain MRI showed a 5 mm left cerebellar lesion. The patient underwent a thoracentesis, which confirmed a poorly differentiated adenocarcinoma, consistent with lung origin. In terms of molecular studies, this patient had PD-L1 testing, which showed a tumor proportion score of 0%, and other molecular studies included EGFR PCR, which was wild-type, and ALK/ROS1 FISH. Both of those were negative. This patient's provider sent off a commercial ctDNA assay, and that showed a TP53 mutation. We'll begin by, and I'll ask this for both of you, would you recommend any additional testing in this case? We have a young person, and so far molecular testing looks like it's negative. Dr. Patel: Oh, absolutely. We now know that there are multiple targetable mutations and this is just a minority of the population that we can see. So, clearly there are fusions, there are other point mutations, activating mutations, that haven't been tested, and so I would do a full multiplex testing with NGS on the tissue. Dr. Dagogo-Jack: I completely agree with that. I think one other thing to point out too, is that the mutation that was detected by ctDNA. So ctDNA or liquid biopsy, it has an imperfect sensitivity, and so sometimes you can miss things. And there's also the phenomenon of kind of clonal hematopoiesis, and P53 mutations can actually originate not in the tumor but from elsewhere. So I think, particularly in this context, when you don't find something relevant, I completely agree with Dr. Patel, that it's best to do a tissue analysis and a broader analysis. Dr. Gainor: Dr. Dagogo-Jack, the sensitivity for ctDNA assays, does it differ depending on the type of molecular alteration? Dr. Dagogo-Jack: Yeah, and I think I would start by the assumption that, you mentioned that this patient had a commercial assay, and so I'm assuming it's a next-generation sequencing-based assay. And so, in general, these tend to be DNA, so ctDNA, so it's easier to pick up simpler alterations, such as point mutations. It can be a bit challenging to detect, but the tests have gotten better, more complex things, such as amplification events, and that really goes to the fact that the majority of DNA in the circulation is not from tumor cells. And so when you're trying to find a minority of cells, you can get wash out from the normal copy number from regular cells. And also, then you get to the most advanced alterations like chromosomal rearrangements. Those can be challenging, particularly if there's a variety of fusion partners, a variety of break points to detect, and so the sensitivity drops off a little bit when you start going from point mutations to these more complex alterations. Dr. Gainor: In your patients where you have a high index of suspicion, but say you order the tissue-based NGS and it's insufficient. There's already been several single-gene assays ordered on this sample, including the immunohistochemistry for initial diagnosis, and then you go back and you try to request NGS here and your pathologist says, there's not enough tissue. What's your threshold in someone who's then also had a ctDNA assay that's nondiagnostic to recommend a repeat biopsy? Dr. Patel: It's really tough for patients. This is a young person whose life has been completely interrupted by a new diagnosis, and for so many of us, we want to do something, and so it is absolutely having really good discussions and shared decision-making about holding tight and doing the appropriate steps. So a repeat biopsy, just scheduling the biopsy can take several days, then the tissue confirmation to getting the NGS, you're really looking at a delay of about 3 weeks. And so a lot of factors go into that. How symptomatic is the patient? This patient might have a small effusion, but is it recurring significantly? Can you use that time to manage that effusion with a PleurX, for example? Or does the patient have critical disease, airway compromise, or multiple brain metastasis? So that understanding of how burdensome the disease will be with also understanding your intuition about, "Oh, I can probably wait these 3 weeks," and explaining to a patient, which it can be tough, that a medical emergency, emotional emergency is really hard, but that is the period of limbo for a lot of patients. And that's really where our team comes together and there are a lot of touch-ins by our nurses and our APPs and making sure that a patient that we're pushing off for, really, an action plan for 3 to 4 weeks remains asymptomatic. Dr. Gainor: I think that's a great point you make about the touch-in, times to touch base with a patient, because it's such an anxiety-filled period and knowing that you haven't forgotten about them, that you are pursuing these additional tasks and you're checking in on their symptoms, I think that is so crucial. That's part of my own practice as well, where it's, at least once a week, checking in on those patients. So in this particular case, there wasn't enough tissue, as alluded to. We did pursue a repeat biopsy, so the patient was referred to our interventional pulmonary colleagues and had an EBUS, and low and behold, the targeted NGS results revealed an NTRK1 fusion. I'll start with Dr. Dagogo-Jack, maybe just on the nomenclature question, because this can be a little tricky. We hear about TRK and NTRK; can you just tell us a little bit about the nomenclature for these alterations? Dr. Dagogo-Jack: Yeah. So I think it's less straightforward than what we're used to with other fusions. An ALK fusion is a genetic change that translates to an abnormal ALK protein. When we say NTRK-rearranged lung cancer, we're referring to alterations in three separate genes, so NTRK1, 2, and 3, that then lead to changes or aberrant signaling or basically increased activation of three separate proteins, TrkA, B, and, C. And so 1 goes with A, 2 goes with B, 3 goes with C. And so again, semantics, but it's a bit more complicated than what we're traditionally used to with other fusion subsets. Dr. Gainor: Thanks. That was a very good explanation of it. What do we know about patients with NTRK? Dr. Dagogo-Jack: It's a unicorn. Whoever found this is very – you'll find it, is what I will say, but it's quite rare. Dr. Patel: It's funny because some cancers are absolutely defined by it, some very uncommon cancers such as infantile fibrosarcoma, for example, where the frequency is over 90%, common cancers or just lung cancer, it's less than 1%. So certainly there is a wide range, and histology of the primary tumor may increase testing, but in lung cancer, where we test everyone with NGS, we're more likely to pick it up. Again, there are other cancers in which NGS has not been completely embraced, which makes it a little bit more difficult, and you worry that there are people that we're not finding with other tumor types that can benefit from these drugs. Dr. Gainor: We now have two FDA-approved drugs in this space. And so, maybe Dr. Dagogo-Jack, can you start? Take your pick. Just give us a summary of one of the two approved agents. Dr. Dagogo-Jack: Yeah. And I think it's important to note that unlike our other approvals that were histology-specific, tumor type–specific, these approvals were actually blanket approvals, in a histology-agnostic fashion, which was something new at the time and really set a precedent for other kinds of subsequent approvals. The drug I'm going to be discussing is larotrectinib. It was the first one approved for NTRK fusion–driven lung cancer and other cancers. This is based on data we've seen, a recent update now of over 200 patients. It's a bit hard, as Dr. Patel highlighted, to figure out the exact activity within distinct subsets, because there's such small populations of patients within these subsets, but across all the tumors, the objective response rate is around 75%. And then we see very durable activity. I think the most recent readout is on the order of 2 to 3 years from median progression-free survival. We've also seen signals of central nervous system activity, so intercranial efficacy of these drugs. In a lung cancer–specific population of about 20 patients, we saw similar to what we saw in all-comers, so about 70% response rate and about median PFS of 3 years in the most recent update. So very good, very potent drugs. Dr. Gainor: And what you're alluding to is a little different than some other approvals in lung cancer, where it's really tissue agnostic and explored in a basket. Dr. Patel, could you tell us a bit about the other FDA approved agent, entrectinib? Dr. Patel: Sure. This was certainly an interesting approval. Larotrectinib was approved for pediatrics in all tumor types—something really unprecedented. Entrectinib is a little bit different, in that it's active for NTRK, but also it's a TKI that is active in ROS1 and ALK1. And so the approval is in ROS1 and NTRK tumors based on phase 1 and expansion phase 2 trials. The number of patients that had NTRK fusions or alterations in the trial that had lung cancer was pretty low, but the response rate remained over 70%, median progression-free survival almost a year and a half, and similarly to larotrectinib, the duration of response is quite long, it’s several years and hasn't been reached. One piece that really stood out, I think, in the approval of early data that entrectinib tried to establish was the CNS efficacy. And so in a small number of patients, again, 5 patients, many patients had a pretty good response. The approval came for both ROS and NTRK simultaneously, which I think also made the decision on which drug to choose a little bit more difficult. Dr. Gainor: Yeah. And say, in this case, you both mentioned CNS activity, this patient had a 5 mm brain met, does that steer you towards one or the other? And what does that mean for side effect profile? Dr. Patel: So I think as we've had more data, I would feel comfortable treating this patient with either drug. Certainly, I think, early on, perhaps we had a little bit more data with entrectinib, but now there've been multiple presentations about the CNS efficacy of larotrectinib. So, unfortunately, it probably wouldn't steer me. Larotrectinib is pretty well tolerated. Certainly there's some cytopenias, some hepatic abnormalities, but that's in a minority of patients. Entrectinib is a potent CNS agent, and so perhaps they're a little bit more, in terms of CNS effects for patients, and maybe some fluid retention. Dr. Dagogo-Jack: One thing that we're not used to, one toxicity that's been elucidated with this class of drugs, is really the idea that when we think of patients as their cancer grows on a therapy, we stop it suddenly, and these drugs have this kind of withdrawal effect, and so it's something to note and to prepare our patients for that when we stop TRK inhibitors. Dr. Gainor: That's a great point. I think we could go on and on with this discussion, but in the interest of time, I'll just touch on the key clinical takeaways. NTRK rearrangements are seen in a very small subset of patients with non–small cell lung cancer, but these patients have characteristic clinical and pathologic characteristics, and these are key oncogenic drivers in non–small cell lung cancer. Over the last several years, we've seen FDA approvals of two agents, larotrectinib and entrectinib, both in tissue-agnostic indication. And based upon the impressive activity with both agents, both entrectinib and larotrectinib are really first-line agents for patients with NTRK-rearranged lung cancer. This brings us to the end of this case. Please see the other segments for further discussion about the latest data in lung cancer or visit ASCOpost.com. Thank you very much.
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