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RET Fusion–Positive Non–Small Cell Lung Cancer

This is Part 1 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 RET fusion–positive non–small cell lung cancer (NSCLC). The case presented is a 65-year-old never-smoker patient with metastatic NSCLC who was found to have an EGFR A118V mutation and a KIF5B-RET fusion. The faculty provide background on RET fusions in lung cancer and discuss the different testing modalities used to identify RET alterations. In addition, they discuss how the treatment landscape for these patients has changed in recent years, reviewing data on pralsetinib and selpercatinib from the recent ARROW and LIBRETTO-001 trials.


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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. Right now, I'd like to ask them to each introduce themselves. Dr. Dagogo-Jack. Dr. Ibiayi Dagogo-Jack: Hi everyone. I'm Ibiayi Dagogo-Jack. I'm also a thoracic oncologist at Mass General Hospital, and it's a pleasure to be here tonight. Dr. Gainor: And Dr. Patel. Dr. Jyoti Patel: Hi everyone. I'm Jyoti Patel. I'm a medical oncologist at Northwestern University in Chicago and pleased to be here and with great friends. So thanks so much. Dr. Gainor: Great. And thank you both for joining us this evening. Today, we'll be discussing recent updates in lung cancer, including data from recent clinical trials and integrating these new developments into four patient case studies. Our first installment will focus on therapy for RET fusion–positive non–small cell lung cancer. So we'll begin with a case, and I think this is an interesting case because it really shows how the management of RET fusion–positive lung cancer has evolved in a very short period of time. And this is a patient whose course starts in 2015, and I think that has some bearing as we talk about the management early on in their case. So this is a 65 year old, never smoker, really no past medical history who initially presented to the emergency department with chest discomfort. They underwent a cardiac evaluation, which was negative, but a CT angiogram performed showed a 5-cm left upper lobe lung mass. There was also mediastinal adenopathy, liver lesions, and several lytic lesions in the left ribs. The patient had a brain MRI, which was negative for intracranial metastases, and then subsequently was referred to oncology where a liver biopsy was performed and showed adenocarcinoma consistent with lung origin. Specifically, it was CK7-positive, TTF-1 and napsin A–positive. The patient underwent molecular genotyping using next-generation sequencing, and this showed an EGFR A118V mutation as well as a KIF5B-RET fusion. So I'll begin maybe with a Dr. Dagogo-Jack. Maybe you can tell us a little bit about just background on RET fusions in lung cancer. Dr. Dagogo-Jack: Yeah, happy to. So RET fusions are found in 1% to 2% of non–small cell lung cancer cases. The demographic population tends to be similar to what we think about with ALK and EGFR and ROS1, tends to be enriched in patients who have a minimal or limited smoking history. We do sometimes see a younger patient population too in this subset of non–small cell lung cancer. And I think one thing that we're always still sorting out kind of similar to work that has been done in ALK and other spaces is whether or not there's a particular predisposition for brain metastasis in this subset. But the jury is still out and work is still being done in that particular area. Dr. Gainor: And I know that there are probably general oncologists who are also joining us for this session and obviously we're going to be focusing on lung cancer, but do we see RET alterations in other cancer types? Dr. Dagogo-Jack: Yeah, we do. They actually were first described in other malignancies. So RET, the most common malignancies where we might see RET alterations. And I think it's important to use the word alteration here because in lung cancer, we think of it as rearrangements or fusions, but RET can also be activated through mutations and that's most commonly not in lung cancer, but in thyroid cancer where they're actually familial syndromes associated with RET mutations. And in thyroid cancer – if it wasn't confusing enough, you can also have rearrangements in a thyroid cancer. And so it's important to have tests that can capture the diversity of alterations that can impact RET. Dr. Gainor: I think that's a terrific point, really highlighting that RET can be altered via point mutation or a rearrangement, and there can be both somatic forms and germline syndromes. Tonight focusing on lung cancer, we're going to be focusing on RET fusions, and these are somatic alterations in non–small cell lung cancer. Dr. Patel, maybe you could tell us about preferred testing modalities to identify RET fusions? Dr. Patel: Certainly. A lot has evolved since you first met this patient in 2015. And I think by and large now with the multitude of driver mutations that we have, I think most of us would prefer NGS or full multiplex sequencing along with RNA. Primarily because we want a holistic take with minimal tissue, and we know that sometimes with just PCR assays, we will miss RNA alterations. Historically, a lot of these patients were picked up with FISH, and I think that's really changed in the past couple of years in which fewer institutions are doing FISH for ROS1 and RET, and now we're really seeing NGS. The other piece that has changed significantly is that although tissue remains the standard, the ability to find these in the blood with blood-based biomarkers has improved significantly. Before it was felt that many fusions were missed with blood-based testing, just technically it was quite difficult. Whereas now I think with our better assays, we're able to find these fusions and to follow them over time or to look for resistance. So in my practice, I tend to do both tissue and blood simultaneously. Certainly I think many people will do one at a time, but I feel like that initial period after diagnosis of a lung cancer, I want to keep things moving as fast as I can and get an answer for our patients and really a treatment pathway. So I tend to do NGS and blood for all of our patients at diagnosis. Dr. Gainor: And can you tell us are there differences in turnaround times between the two if you're sending them off simultaneously? Dr. Patel: So being at a larger center, we're able to do both of these in-house, and the turnaround time for our tissue is now about seven days. Blood, we are doing some in-house and sending out, but that ends up being closer to about 10 days. I think if some commercial entities can end up being two or three weeks, and that often has a bunch of delays from diagnosis to getting the slides, to sending the slides and then sending them out. And so sometimes you can get a sneak peek with blood, and the caveat here is that blood is great when it's helpful, when it's positive. A non-answer on blood doesn't mean that there's no targetable mutation. The concordance is about 70% broadly for patients with metastatic disease. But sometimes if you don't get an answer, it's absolutely incumbent to make sure there's adequate tissue. Dr. Gainor: Yeah. I think that's a really, really important point. Before we go on into the management of this particular patient, I think it is important just to call out if we look at the results here, I see both an EGFR mutation and a RET fusion. Are these mutually exclusive? What can we say about RET fusions with other oncogenic drivers? Dr. Patel: So RET fusions at diagnosis tend to be singular genetic events. And so often we'll see other drivers. Certainly this is unusual. RET can also be a mechanism of acquired resistance for EGFR. So it is a little bit of the chicken and the egg, but certainly a KIF5B-RET fusion, I think, would be felt to be the dominant one. One of the hard things was a lot of the commercial testing that I think both of you have alluded to is really understanding what is a somatic mutation and activating mutation, not one that is of unknown significance. And we'll often see that particularly in RET. I feel like I've seen patients who have had this picked up on mutation testing and then started on a drug without a great response. And you look back and you're like, oh, this person really doesn't have a fusion, nor do they have a classical activating mutation that you might see in a thyroid cancer as was mentioned. Dr. Gainor: Yeah. Good point. And I'll just say this is a real case, and that EGFR mutation, how I had looked at it was, this actually isn't in the kinase domain. It was extracellular, not thought to be activating. And it's just a reminder when you are getting those molecular points, just because you see a gene that's often associated with alterations, you actually have to look at the specific mutation. And so we felt that this patient, as was mentioned, that the RET fusion was really the dominant driver. So Dr. Dagogo-Jack, can you just give us a sense of how has the landscape changed for RET fusion–positive lung cancer in the last few years? Dr. Dagogo-Jack: Yeah, I think that there used to be some initial question that I'm happy has been put to rest about whether or not RET was truly an actionable driver in the sense that people borrow therapies that had previously been made to target other growth signals—so-called kind of multikinase inhibitors. An example would be like vandetanib or cabozantinib, and applied it to patients with RET-rearranged non–small cell lung cancer, and found that we didn't find the wonderful numbers that we see with other drugs that we consider efficacious in this space. So they had modest activity with response rates kind of in the 20% to 40% rate. They had not as durable progression-free survival or duration of response when these therapies were applied. So something under 6 months or so, which is really in stark contrast to what we expect from a very effective therapy and, importantly, because they hit not only RET but also hit the VEGF receptor, sometimes BRAF, sometimes other kinases, they were quite toxic. And so there are still some questions about whether or not the absence of activity had to do with the dose reductions that were necessary to make these therapies tolerable. And so it's been kind of heartwarming and great to see that this iteration or this wave of therapies for RET is really more selective and is really focused on finding drugs that are potent against RET but also selective and spare other receptors. Dr. Gainor: Yes, I recall actually around the time this patient was treated and diagnosed that there was that debate in the field. Is RET a bonified driver, or is it that we were using repurposed poor RET inhibitors at the time? And I think we now have an answer that absolutely yes, RET fusions are oncogenic drivers in lung cancer. And I think that really stems from the activity that we've now seen with the selective RET inhibitors that we'll get into in a few minutes. But just to round out this patient's case. So this patient, again, this was 2015, was treated with carboplatin and pemetrexed initially—even before checkpoint inhibitors were our standard bearer in the first-line setting. After 2 years developed progressive disease. So now we're at 2017. This is really when the selective RET inhibitors were entering the clinic, but still in phase 1 trials. This patient was therefore treated off-label with cabozantinib, with a best response of stable disease, really reminiscent of the modest activity that Dr. Dagogo-Jack was alluding to. And so now you now have this patient who's been treated with platinum doublet chemotherapy and treated with cabozantinib. How would either of you approach this case now? Dr. Patel: So certainly I think this shows the remarkable evolution in just a few short years. So in the frontline setting, certainly we know that response rates are modest with chemotherapy-based doublets, but a lot of these patients with fusions tend to have a longer progression-free survival than we'll see with some other patients. And so certainly I think frontline carboplatin and pemetrexed is reasonable and remains reasonable. However, these newer RET inhibitors have response rates that are 2- and 2.5-fold higher than what we'd see with chemotherapy with minimal toxicity. And so although these drugs were approved in the setting of many patients who've been multiplely pretreated, given the really high response rates, certainly I think the RET inhibitors pralsetinib and selpercatinib are very reasonable as frontline therapies. And so my personal threshold for frontline therapy with a TKI is probably upwards of 60%. And certainly we've seen that with the most recent clinical trials. Dr. Gainor: Great. Yeah. Maybe we can take a deeper dive on these. So maybe we'll start with pralsetinib and then we can talk a bit about selpercatinib as well. So Dr. Dagogo-Jack, can you walk us through the data for pralsetinib? Dr. Dagogo-Jack: Yeah. So the data that supported the FDA approval of pralsetinib were really based on work led by Dr. Gainor and others. So this is the ARROW study that looked at – it's a phase 1/phase 2 study that was designed initially to test the efficacy of this novel RET-targeted therapy across malignancies, and this study enrolled patients for the most part who had been previously treated with other therapies, including a subset of patients who had been treated with multikinase inhibitors. And so when we look at the data that applied to this forum, so non–small cell lung cancer patients, the study had about 120 patients, one-fourth of whom had never received any chemotherapy or any pretreatment and about three-fourths of whom, so about 90 patients, who had previously been treated with chemotherapy. As a reminder, of those 90 patients who'd received chemotherapy, about a quarter had also received a multikinase inhibitor, and it was encouraging and very refreshing to see that the activity was exactly as Dr. Patel has highlighted. So in patients who had previously received chemotherapy, the objective response rate was around 60% to 70%. Among patients who had not received any therapy, it was a tick higher, so about 70% or so. And the median progression-free survival, we've seen that data in patients who had previously received chemotherapy was about somewhere between a year and a half, and of benefit from the therapy. I think there was some debate initially. So there was an initial language in the protocol that patients who had not previously been treated had to be excluded or not eligible for chemotherapy. We saw recent data from ASCO this year, that when you really looked at patients after amendment, where it really wasn't specified that they had to not be chemo candidates, that the response rate was a bit higher, in the 80s, and we are still awaiting kind of the median PFS data. So very durable responses, very deep responses and, importantly, brisk responses across multiple patient indications in terms of the fusion partners, prior treatment, as well as prior MKI, or multikinase inhibitors. Dr. Gainor: I think that that's a great summary. And I think you hit a key point, which is looking at the patients who are treatment naive. I think in lung cancer we've been spoiled almost in that how many of our clinical trials, phase 1 studies leading to FDA approvals. And just as a reminder when this was a phase 1/2 study, the initial eligibility patients weren't eligible unless they weren't candidates for standard of care therapy. And so most of the patients were previously treated with the platinum doublet chemotherapy, and then the protocol was subsequently amended to allow treatment-naive patients. And post that amendment, we see higher response rates within the arrow study. Dr. Patel, maybe you can tell us a little bit about the LIBRETTO-001 study with selpercatinib. Dr. Patel: Sure. In many ways it was very similar. So it was a phase 1 study going to a phase 2 dose expansion. Interestingly, there are patients with multiple malignancies enrolled. So thyroid cancer was about a half of all patients and as well as some others. And of patients that I treated on study, I saw some thyroid and pancreas as well. And so dabbled a little bit, but the main analysis to sort of focus on for this is certainly for RET fusion lung cancer. And so most patients, again, in this cohort of over 250 patients who received prior platinum, patients who had not received or were treatment naive were added on later. So about 40 of those patients in a primary analysis set of over 100 patients. So again, very similarly, the patients who had received prior platinum had a response rate between 60% and 70%. Treatment-naive patients between 85% and 90% with a progression-free survival of over 16 months. So clearly deep responses, importantly, CNS responses were observed on both of these trials. Patients were able to stay on therapy for a long time, not only because their cancer was controlled, but because these therapies were very well tolerated. And so the toxicity profile was such a different approach than what we'd seen with older drugs like cabozantinib in which we were all constantly doing dose reductions and holding for patients. Many of our patients were able to return to function after having received multiple therapies. So certainly exciting. Dr. Gainor: Great. So we now have two FDA-approved drugs for RET fusion–positive lung cancer. And I think a question that many clinicians have then is how do we choose? Is there anything that distinguishes these two agents? Dr. Dagogo-Jack: I would say that they both are great drugs. I think that when we look at the safety profile or toxicity profile, there are a few, maybe one or two characteristic things that associate with one drug versus the other. And so selpercatinib is associated with a low rate, but notable rate of hypersensitivity reactions. Then so that's something that we have to keep an eye on. Dose reduction, interrupting the dose, and slowly re-escalating as well as starting our typical medications for managing hypersensitivity is usually effective in that setting. And then pralsetinib can be associated with more narrow type of side effects. So neutropenia is something to watch out for. Both of these although they spare VEGF relative to MKIs, they do cause a little bit of hypertension. So you have to keep an eye out for that. And then a common side effect I was hearing from many of my patients was dry mouth. So it's also something to keep an eye out. And of course we always have to monitor liver function tests and other laboratory tests while someone is on therapy. Dr. Gainor: Dr. Patel, anything to add on top of that? Dr. Patel: Not really. It's tough to have such a great option for two fantastic drugs. I think most of us would find, hopefully it'd be able to detect the RET fusion early in a patient's disease course. I think one piece that we'll learn in the next couple of years is if we don't, do these really have different toxicities after prior therapy? So in particular, I think patients who might've been treated with immune checkpoint inhibitors as part of the frontline therapy, they may have a few more toxicities. And so understanding that I think in the next few years will be of interest. Dr. Gainor: Yeah. And I also think it's going to be critical uncovering how patients develop resistance to these drugs, and then what do we do as the next line of therapy? I think that's also going to be – the next several years will help us and answer those questions. So we're reaching the close of this case. So I just wanted to summarize some of the key clinical takeaways. So we now have seen that RET fusions are a new oncogenic drivers in non-small cell lung cancer present about 1% to 2% of patients. We now have two FDA-approved, selective RET inhibitors, pralsetinib and selpercatinib. Both agents have shown very high response rates in patients who are treatment naive, as well as patients previously treated with platinum doublet chemotherapy. And I think you've heard from all of us that based upon the impressive activity in the treatment-naive setting, we would use these agents in the first-line setting. And future areas of investigation are going to be focused on the toxicity piece as well as on exploring mechanisms of resistance. So this brings us to the end of this case. Please see other segments for further discussion about the latest data in lung cancer or visit ASCOpost.com.
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