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Medicine Matters oncology

Hi. This is Stephen Liu, medical oncologist from Georgetown University. I am pleased to have with me today two guests with expertise in targeted therapy. First, we have Dr. Melina Marmarelis, a thoracic medical oncologist and assistant professor of Medicine at the University of Pennsylvania, really an expert in targeted therapy and in the treatment of non-small-cell cell lung cancer. Melina, thank you for joining us today.

Thank you for having me.

I'm also joined by Dr. Vivek Subbiah, associate professor in the Investigational Cancer Therapeutics department and the medical director of the Clinical Center for Targeted Therapy at the University of Texas MD Anderson Cancer Center. Vivek, it's always good to have you with us.

Thank you so much. Thank you. Thank you for having me.

Of course. I want to talk a little bit about some of these results. Melina, you're familiar with the data and with the drug. What are your impressions of pralsetinib and the ARROW trial overall? And if I could also ask, do your results, does your own experience with the drug match what you see in the trial?

Yes. I mean, I think the first thing to say is that the result of the ARROW trial are really exciting. You know, pralsetinib, a selective RET inhibitor, which is both more effective and less toxic compared to the multi-kinase inhibitors that were used previously to treat patients with RET, rearranged non-small-cell lung cancer.

And in the ARROW trial, pralsetinib was effective in both pretreated and treatment-naive patients, the overall response rate ranging from 60% to 70%, the median progression-free survival around 17 months in the pretreated group, which is really pretty impressive. The toxicity is manageable, which I think is the big difference from the targeted therapies we were using previously. And in comparing the toxicity and the efficacy to some of the other targeted therapies we use for, say, EGFR and ALK, the efficacy is probably not quite as good, and neither is the toxicity profile. But there's definitely room for improvement there.

My own experience with the drug is limited, but I did have more issues than I thought with toxicity at the full dose, certainly than I would have expected. But in going back through the data, about 38% of patients in the ARROW trial did require dose reductions due to side effects. So in the future, I'll consider starting patients perhaps at a lower dose and uptitrating or just keeping a close eye on that.

I think you definitely have to know what toxicity to watch for, and I'm very comfortable with dose reductions. I think that for some of my patients that have been on the longest are on a slightly lower dose. So it does require some adjustment but certainly, good to see these high response rates, very durable responses, as well.

Vivek, you are the senior author on the Lancet Oncology publication. So certainly, you have some experience with the drug. And with the RET space overall, we've seen these data. Can you describe maybe the typical treatment course for your patients?

Yes, thank you, Steve, for this question. And as we all know, patients with RET fusion-positive non-small-cell lung cancer are younger, more likely to have nonsquamous disease and be nonsmokers. And, in fact, they do present with a better performance status than other oncogene-driven cancers. With the increasing clinical availability of next-gen sequencing, we are finding more and more RET fusion-positive patients. Although they are 1% to 2%, I think the more we test, the more we find.

As we all know, historically, as Dr. Melina mentioned, patients with RET fusion-positive non-small-cell lung cancer had very few options beyond chemotherapy. And the multi-kinase inhibitor that were used, like cabozantinib, vandetanib, and other multi-kinase inhibitors repurposed for RET had these off-target toxicities. Again, ARROW, the pralsetinib trial, is the first prospective study to investigate pralsetinib for the treatment of RET-altered solid tumors, including RET fusion-positive non-small-cell lung cancer and, in fact, the second study to report on the outcomes of selective RET inhibitor, following the other selective RET-inhibitor selpercatinib.

The data, as seen in the publication, show that the response rate of 61% in previously platinum-treated patients and 70% in treatment-naive patients who were not candidates for available standard of care. And as Melina mentioned, again, the safety profile was manageable, and it was patient-dependent. Some patients could definitely tolerate the highest dose at 400 milligrams, and some patients we had to dose-reduce after a couple of months. And once they dose reduced, what we saw was the responses were similar across doses. I think there was no change in terms of response rate across any dose level. Overall, I would say pralsetinib has a very manageable safety profile and definitely shows on-target clinical activity in patients with RET fusion-positive non-small-cell lung cancer, irrespective of the prior treatment history or irrespective of the fusion partner.

Yeah, when we think of these nonselective RET inhibitors, the drugs we were left with before we had these selective inhibitors, RET was sort of borderline actionable because those drugs were really toxic, and the response rates were modest, probably limited by the amount of drug you could deliver. Here, we have very high response rates.

And in my experience it has been very well tolerated. It really has the feel for targeted therapy, where you expect that response, where you get that wide therapeutic window. But again, all of this starts with patient identification and testing, and we don't have these as options unless we know what fusions are present.

Melina, let's look at non-small-cell lung cancer specifically. Who should be tested? Or maybe perhaps more to the point, who should be tested and who is being tested for RET?

Yeah, I mean, that's a really great point, Stephen. And, you know, this day and age, all patients with non-small-cell, advanced non-small-cell lung cancer should be tested. I should probably just put a period there and stop, but I will add some qualifications.

You know, we focused mostly on nonsquamous non-small-cell lung cancer in the past since that's where these driver mutations were most prevalent. But now that KRAS G12C is targetable and that's prevalent in the squamous population, I think, really, we're at the stage that all non-small-cell lung cancer should have molecular testing.

There are several studies looking recently at how well we're doing at this. Unfortunately, we're not doing well at all. The MYLUNG Consortium presented their data at ASCO 2021. They looked at 3500 patients with non-small-cell lung cancer, and they looked at five of the NCCN recommended markers, so that being eGFR, ALK, BRAF, ROS1, and PD-L1. And they found that we were only testing all five of those about 46% of the time, and PD-L1 testing was the most common test ordered.

So if you take out squamous cell histology from that, it only improves to 49%. So it wasn't a bias based on histology, really. I thought it was interesting that PD-L1 was the most common thing tested because that can be high in patients with driver mutations. And those patients should get targeted therapy and not immunotherapy, so this can be a very misleading result in isolation.

In addition, the study didn't even include RET or MET or KRAS, which are also NCCN-recommended biomarkers. And the more you add, probably the worse we're doing at testing all of them. So it's a really big problem to be able to identify these patients that can benefit from targeted therapy.

Yeah, well said. Definitely everyone needs to be tested now. You can't properly make treatment decisions without that information. So, hopefully, we will do better in the coming years. Let's put it into practice though. Vivek, let's say you have someone with metastatic non-small-cell lung cancer, and you do the test and you find a RET fusion up front. Should you use a selective RET inhibitor as first-line therapy for everyone?

Thank you, Steve. As you know, we have the selective RET inhibitor pralsetinib approved for all RET fusion-positive non-small-cell lung cancers in the USA, regardless of the line of therapy. I think that the approval was line-agnostic.

And as we have seen in our clinical trial with the ARROW study, the patients who are treatment-naive had better responses and across all parameters did far better than patients who were platinum treated. The NCCN guidelines also reflect this. So again, if we identify a RET fusion up front, I'm sure oncologists would definitely want to start a targeted therapy so that we can spare them all chemotherapy. And this will also improve upon the quality of life, as well, for patients.

And taking a step back, on the ARROW trial, all treatment-naive patients with RET fusion-positive non-small-cell lung cancer initially were required for protocol not to be candidates for standard platinum therapy generally due to age, comorbidities, or other prognostic factors. In fact, during the course of the clinical trial in July 2019, because of the fantastic responses that we were seeing with this drug, the eligibility criteria were expanded by protocol amendment, allowing enrollment of treatment-naive patients who were candidates for standard platinum-based therapy to provide a steady population that would be more representative of a real-world population.

So, interestingly, the ARROW study, we presented the data in, I think, ASCO 2020 on the study before and after the eligibility division. With a longer follow-up, it showed an overall response rate of close to 88% in the post-eligibility revision subset, which included treatment-naive patients who were otherwise eligible for platinum-based therapy providing support for RET inhibitors as first-line standard-of-care therapy.

In fact, recently, in Europe, pralsetinib was approved. And it's the first and only precision medicine approved in the EU for first-line treatment of patients with RET fusion-positive advanced non-small-cell lung cancer. And this was a conditional approval based, again, on the results of the phase I/II ARROW trial in which pralsetinib led to durable responses in patients with RET fusion-positive advanced non-small-cell lung cancer.

So a short answer is first line, yes, we need to start these patients, RET fusion-positive patients, on a selective RET inhibitor. Yeah, I agree. I mean, you don't see a response rate close to 90% very often. Melina, let me throw in a little twist though. Let's say you have someone with metastatic lung cancer, a RET fusion, and your staging brain MRI showed a couple asymptomatic brain metastases. How would that change your management?

So there were a few patients on the ARROW trial that had baseline intracranial metastases, about nine patients. All of them had shrinkage of their intracranial metastases while on pralsetinib. That translated to about a 56% intracranial response rate by RECIST with three complete responses.

So I think that really shows that for patients with brain metastases and a RET fusion, targeted therapy is really important for good CNS control. And I would definitely favor targeted therapy in such a patient. Chemotherapy or immunotherapy is really not going to provide that same type of CNS-- potential for CNS control. Of course, if a patient has a symptomatic brain metastasis, you're going to have to consider surgery and radiation, but I think this is really good data supporting that it's active in the brain.

Yeah. It's very important for a lot of these drivers, RET included. But let's make it even harder now. So Vivek, let's say metastatic lung cancer, RET fusion. But you send your next-gen panel, and you start chemotherapy, and then the RET fusion comes back. So we detect the RET fusion after we've already started treatment. Do you transition here to target therapy, or do you wait?

That's a great question. And I would say I would qualify it to say that it depends. If the patients are doing well on chemo and have no side effects, I would probably continue chemo unless the patient has just stable disease or is not responding to chemo. If not, we would definitely switch to a selective RET sooner rather than later just to spare the side effect of chemo. And the chemo may be also a back-up option if, at some point, they stop responding to a selective RET inhibitor.

So again, my thought process is I think once we find the mutation, the fusion in a RET-positive non-small-cell lung-cancer patient, I think we need to have an honest, open discussion with the patient on the benefits, the side effects of both and see how we can personalize a customized therapy for the particular patient.

That is a tough situation. I think it's one that does happen sometimes. And it's difficult sometimes because you don't want to forfeit the opportunity to get benefit. And if you're waiting until progression, and you have to have progression, and progression can sometimes be an unforgiving act. And sometimes, the point is to avoid that from happening.


But, hopefully, we'll identify these in a timely manner. Melina, when we look at the ARROW data, can you speak a little to the durability of response with pralsetinib and maybe in contrast to what we see with standard chemotherapy?

Yeah, I think the durability of response and the median progression-free survival, the latter being around 17 months, is very impressive and in line with some of the other targeted therapies that we use. Of course, there have been some real-world studies that have shown that in the real world, it might be a little bit shorter. But it's still very effective. And compared to chemotherapy in these patients, I think it certainly provides more benefit for them.

I think that trainees and other colleagues are always so surprised when I tell them the response rate and PFS with chemotherapy. People think chemotherapy works for everyone. And when quote response rates of 20%, 30% with most regimens, people are quite shocked at that. But a lot of room for improvement. I think these inhibitors are right. When we find the fusions, they can work very well.

Unfortunately, as with most treatments, we don't expect them to work forever. And we do encounter acquired resistance. Vivek, do we know anything about acquired resistance to these new selective RET inhibitors?

Yes. So, unfortunately, as the rule with any targeted therapy or any oncogene-matched therapy, we do see acquired resistance from RET inhibitors. Again, de novo resistance and acquired resistance to RET tyrosine kinase inhibitors have been definitely observed in the clinic.

Taking a step back, the low response rates to the multi-kinase RET inhibitors, like cabozantinib and alectinib, are likely in part to the incomplete suppression of the oncogene RET kinase. Because of the off-target AEs, dose reduction was necessary with the multi-kinase inhibitors leading to resistance in those patients.

In addition, specific resistance mechanisms to multi-kinase inhibitors, like vandetanib, cabozantinib, lenvatinib, and other MKAs were noted, to, specifically, in the gatekeeper mutation. It's called the RET V804M and N, and it has been seen in both thyroid and lung cancer patients.

The good news is that the specific RET inhibitors, the selective RET inhibitors, pralsetinib, circumvent this resistance mechanism of gatekeeper mutation. However, the selective RET inhibitors face new challenges in terms of resistance caused by new mutations in the non-gatekeeper sites.

So there are two mechanisms of resistance, two major mechanisms of resistance to selective RET inhibitors. One is on target that is being increasingly described. And the other mechanisms are off-target. Again, this remains a very hot topic, as it's been less than a year since these drugs have been approved, and patients are still on therapy. But every month, there is another mechanism of resistance being reported to these drugs.

The on-target mechanism of resistance is through the G-10-- the solvent-front mutation mechanism. It's essentially substitution of the glycine 810 solvent-front residue with lysine, serine or cysteine. And we call them solvent-front mutations.

Again, this mutation is because of the way the mutation is formed and prevents the selective RET inhibitors from binding to the RET gene. And it was initially reported preclinically, and now it has been reported in clinical samples, as well, in both the selective RET inhibitors. And that remains an on-target mechanism as a solvent-front mutation.

Several off-target mechanisms are being reported, like KRAS amplification. An important mechanism of resistance with MET amplification has also been reported. In fact, there have been cases where they've combined a selective RET inhibitor with a MET inhibitor, like crizotinib, or even cabozantinib, to overcome the MET-dependent resistance.

Interestingly, we and others have reported novel mechanism of resistance through an acquired NTRK fusion as well. Again, this remains a hot topic, and there are several second- and third-generation selective RET inhibitors in clinical development, one to circumvent these solvent-front alterations. And, hopefully, we will see that data in the near future. Thank you.

Vivek, have we seen histologic change yet?

So, again, I don't think that it's been reported in terms of histological changes. There was one case report that showed adenocarcinoma turning into squamous cell cancer and another case showing adenocarcinoma turning to a more small cell or neuroendocrine type. And we see that with other TKIs, like osimertinib increasingly, but we haven't seen that much with RET inhibitors. I think the more patients are going to be on these drugs, we may see such mechanisms in the future.

Yeah, and you made a good point earlier, that what we've seen and reported in publications by yourself, by Dr. Jess Lin, and others is really more reporting on early resistance because a lot of those patients are still on the drug, and so they haven't progressed yet, so we don't know their mechanism of resistance. So we'll have to watch this space and see how it develops. But with that in mind, let me go to Melina. Would it be standard in your practice at Penn to rebiopsy at the time of progression on targeted therapy?

I think both of you point out that we're still learning about the resistance mechanisms of RET. And so with that in mind, and given the selective pressure of targeted therapies in general, my practice is to rebiopsy at the time of disease progression at a minimum with a liquid biopsy and, ideally, with tissue, as well. And both evaluate for resistance mechanisms, and, also, look for histologic transformation-- that's our practice-- and other driver mutations. And I think even though there haven't been that many reported, I think it's still a possibility and something that I worry about. In the case of RET and patients treated with RET inhibitors, I'm mostly looking for off-target resistance mechanisms that I might be able to target with another TKI, for example, as Vivek mentioned, MET amplification or MET changes.

All right, let me challenge both of your expertise, take advantage of you being here. You know, we're comfortable, and we've been talking primarily about using targeted therapy in the metastatic setting. This is where it was born. This is where it's made a huge impact.

But in December, 2020, we had our first FDA approval of a targeted therapy in the adjuvant setting. That was when osimertinib was granted FDA approval after the ADAURA trial showed that 3 years of adjuvant osimertinib after resection for EGFR-mutant lung cancer significantly improved disease-free survival. Would you extrapolate these results to a RET fusion-positive lung cancer? So Melina, we've got lined up for you to see a patient with a resected stage IIIA non-small-cell lung cancer, and you know that they have a RET fusion. Do you ever offer an adjuvant selective RET inhibitor?

And you leave the tough questions for the end. So I am certainly a believer in adjuvant osimertinib for stage II or greater and especially in patients with EGFR L858R and exon 19 deletions, which are most sensitive to osimertinib. That's where we have the data.

For everything else, including RET, the data does not support the use of adjuvant in the adjuvant setting yet. There are ongoing trials that are going to help us answer this question in many driver mutation populations. But I think it also raises a lot of questions about targeted therapies that are not as well tolerated as osimertinib, for instance. So 3 years of treatment is significant, both for physical toxicity and financial toxicity. So I think that's something we're really going to have to examine when we look into these other targeted therapies in the adjuvant setting.

I should mention that it is not on-label use. There is no data to that point yet. But Vivek, in the confines of your clinic, just between me and you, adjuvant pralsetinib, is there any role for that?

Great question. Thank you. I think this is not just a question just for RET fusion within non-small-cell lung cancer but all fusion, all oncogene non-small-cell lung cancers. Again, we have compelling data from osimertinib in EGFR-driven cancers. Of course, EGFR is quite common, and RET is still 1% to 2% of non-small-cell lung cancer. As Melina said, we don't have any clinical data yet.

So the question we ask is, should we extrapolate the data? It's not an on-label use. And it may also be hard to get data or do such trials, as we need to do a comprehensive genomic panel at diagnosis, especially in the earlier lines. Not many centers do a comprehensive fusion panel, maybe hotspot testing with EGFR or just to fish for ALK. That's all that's been happening.

Again, if we start doing NDS testing, a comprehensive exon sequencing panel that includes all fusions at diagnosis, then such trials are possible. And even if a trial is not possible, in such cases, I think there has to be a registry side of a thing so that we can track the outcomes of these patients.

Again, of course, none of these TKIs are without any side effects. Even osimertinib has warnings for pneumonitis, QTc interval prolongation, Stevens-Johnson syndrome, and others. So I think we need to take a step back and think about case-by-case. I think we should probably do, even if it's not a clinical trial, we should do a national registry to follow these patients and track the patients' outcomes so that we can learn from these patients so that future patients can benefit in the future.

Good plan here. What about neoadjuvant, Vivek? So if you saw someone that was borderline resectable, you saw a RET fusion, do you think you could ever use targeted therapy to convert an inoperable lung cancer to an operable lung cancer? I mean, this is something that you've done with NTRK, right?

Absolutely. I think this is a brilliant question. So we've done that for thyroid cancer in the neoadjuvant setting. In some cases, in young patients, especially with germline RET-aberrant thyroid-cancer patients.

We've converted inoperable patients with widely metastatic disease to operable patients. Again, although we as medical oncologists, we claim that these drugs are targeted therapies, ultimately, surgery is the ultimate targeted therapy. So that is an exciting option in select patients if you can convert a patient from being inoperable to operable. I think it'll be good to have, again, a national registry through a cooperative group of such patients.

One last scenario. I'll go to you, Melina. Our standard for unresectable stage III non-small-cell lung cancer remains chemoradiation and consolidation durvalumab based on the PACIFIC trial. Melina, in a patient who has completed definitive concurrent chemoradiation for stage IIIA non-small-cell lung cancer with a RET fusion, are you going offer durvalumab, do you think a selective RET inhibitor, or nothing? What are you going to recommend there?

So I think in this scenario, there are two competing pieces of information. The first is that the PACIFIC trial showed both a PFS and an OS benefit for durvalumab in an unselected population. The second is that we know that immunotherapy alone does not work well in patients with RET-rearranged lung cancer.

So for me, this is a conversation with the patient about these two competing pieces of data that are difficult to reconcile. For EGFR and ALK, I do not advise durvalumab after chemoradiation. For less-common driver mutations, like RET, I think gets a little bit more of a conversation, but I certainly am steering patients a little bit away from durvalumab in these scenarios.

I think I agree. The challenge is we're probably not going to ever have that data just because these are so rare. So at some point, you have to use your own judgment. These are tough ones.

We could keep going. This is easy for me because I get to ask the questions. But I want to thank my colleagues for their expertise and for being good sports for answering the tough questions. Dr. Vivek, Subbiah, Vivek, thanks for joining us.

Thank you.

And Dr. Melina Marmarelis, Melina, thank you for your time.

Thanks so much.

And thanks to everybody else for tuning in.