Activity Transcript

Segment 1: Identifying RET-Altered NSCLC: Why and When?

Solange Peters, MD, PhD: Dear colleagues, it's my great pleasure to discuss with you today the topic of identifying RET-altered non-small-cell lung cancer, trying to understand why and when it should be done. Very important in the recent 50 years, but more than ever in the last 10 years, we could see the emergence of very effective treatment strategies including chemotherapy, immunotherapy, but also to a broader extent, what we call precision oncology, using targeted therapy.

You can always showcase these targets and targeted therapy strategies looking at the non-squamous, non-small-cell lung cancer pie chart describing all the rare alterations that can be actioned on and that can be targeted by new strategies like tyrosine kinase inhibitors. This also defines a range of alterations, molecular alterations that have to be diagnosed, which encompass a list of around 6 or 7 targets today. And the ones which are still more or less under discussion, I would say less and less, are HER2 mutations and MET amplifications. I'd like to say that today probably the HER2 mutations have gone to the compulsory state. But it's a moving phase.

Importantly, you can see in this table, there is a long list of new compounds, not only one. It's a competitive landscape for each of the target, actionable, I would say, drivers. You have several drugs which can be used in order to avoid, to delay, to postpone, or even to have a long-term benefit without any chemotherapy, by just using targeted therapies. Importantly, when you think about the schedule of using this precision oncology personalized strategy in terms of patient journey across cancer treatments, many of these targeted therapies are used frontline. As you can see, for EGFR, ALK, RET, NTRK, MET exon 40, BRAF V600E, these are frontline, but some of these targeted therapies, because of the magnitude of activity, are still considered being second-line, EGFR exon 20, the HER2 mutation, the KRAS G12C. The evidence is also a moving field, but at the time being, you can see based on the approvals, most of them are frontline before chemotherapy. Some of them are after chemotherapy or chemotherapy immunotherapy (IO).

This defines, also, a priority in testing, and as you can see on these slides it's about the likelihood of being included in our molecular testing algorithm. So, the obvious come first, the EGFR, ALK, ROS, PD-L1, BRAF, and NTRK, and as you can see, RET is kind of having a strange journey between the frontline strategy but also with a quite low probability today to be tested for and only being part of the expanded panel, according to the most recent guidelines.

If you look also at the emerging biomarkers for potential oncogenic inhibition, RET was still in that scheme with a, I would say, weaker target, meaning, really, that the advances in RET are now major, but the rarity of these disease still make it likely that it will be missed or not looked for very often. Also, be aware that RET fusion or RET-fused, RET-rearranged non-small-cell lung cancers are so rare that we still don't really know the prognosis impact of such an alteration, probably being equivalent to the old common non-small-cell lung cancer, but we are very limited by the small number.

We understand that RET is a new target, which must be established. So how do we establish a biomarker? So, in precision oncology, in the oncogene addicted field, we are used to having several methodologies to look for the target. It can be immunochemistry for a new protein to be expressed like ALK, PD-L1, ROS1, and, to a lesser extent, NTRK and RET, you can use FISH to look at the chromosomal rearrangement. And of course, we like to use NGS, ideally, DNA RNA, but sometimes only DNA in order to have a massive parallel assessment of the targets. We are moving to liquid biopsy, but remember we have a bottleneck in sensitivity for liquid biopsies, which can be also analyzed by NGS.

Thinking about RET again, so in non-small-cell lung cancer, rearrangements of RET happen in 1 to 2% of non-small-cell lung cancer. This type of rearrangement I also find particularly and specifically in papillary cancers. Mutations in RET can also be found in medullary thyroid cancers, and rearrangements of RET very rarely, as you can see, in cholangiocarcinoma carcinoma, colorectal carcinoma, Spitz tumor, ovarian, salivary glands, but very, very rare. So non-small-cell lung cancer is already a difficult target to identify.

Somatic rearrangements of RET are frequently found in, for example, thyroid cancer, allowing to understand that many partners can be involved. So, the most frequent one is KIF5B, but as you can see, there is a long list of potential fusion partners, which results in a high expression of a protein, which usually is not expressed as a promoter of the expression of the RET genes, and also more important is the ability of RET to dimerize and have a downstream signaling which is constitutively activated.

On the testing algorithm for RET, again, we will probably miss some. There is a little piece of controversy. Should you, like with ALK, ROS, and NTRK, screen for this rare alteration using immunochemistry and then confirm with an orthogonal FISH or NGN, an orthogonal methodology, sets a question mark. In the ESMO guidelines, we prefer to propose first an NGS, ideally RNA based, but DNA can also be a solution. If you don't have NGS, we would prefer to do a FISH or an RT-PCR. And of course, the use of liquid biopsy is always limited by the fact that, if an alteration is not found, sensitivity is an issue. You have to go for a tissue biopsy. But we have a preference for NGS. But of course, NGS is expensive when you look for rare alterations. That's why, by using NGS, you try to cover many alterations and maybe being more economical.

The last table here is showing you how these tests compare. So, as I said before, immunohistochemistry has bottlenecks, bottlenecks of not only a moderate specificity false positive, like for ROS, but also a moderate sensitivity, meaning it is more difficult because you miss some, and for screening, it might not be considered as being adequate. As a strategy that can be used, and again, the favorite strategy is RNA sequencing by NGS. So, the most accurate, but also the one allowing the detection of expression and detection of the partner. Identifying how the RET rearrangement happened and whether it is actionable.

So, this is how we would advise to detect for RET, and I think you know everything about RET alterations, so please continue on to listen to the next section on the evidence for RET inhibitor therapy, RET targeted strategies in non-small-cell lung cancer. I thank you for your kind attention.

Segment 2: RET Inhibitors: Review of the Evidence

Benjamin Besse, MD, PhD: Welcome to this new chapter on RET inhibitors. I'm Benjamin Besse, I'm a medical oncologist in Gustave Roussey in Villejuif, Paris. Today, we will review the key clinical data supporting the use of RET inhibitors. We will use published data, but also present the updated data from the ESMO meeting in this year, 2022.

Let's start with pralsetinib. Pralsetinib is 1 of the 2 first-generation selective RET inhibitors, that has been developed in the study ARROW, which is a phase 1/2 study. Phase 1 for all-comers with RET-altered cancer, including RET fusion non-small cell lung cancer, but also medullary thyroid cancer. In this presentation, we will focus only in the RET-altered NSCLC. On the first set of the database, the response rate for 216 patients was 69%, the median PFS was 16.4 months, and the duration of response was 22.3 months. Much higher than what was seen with what we call the multikinase inhibitor, the previous inhibitor that was sometimes used in this population. In this study, the global patients were divided into strata. The treatment naïve patients that never received any treatment and the patients with prior treatment, where 100% of the patients received a platinum-based chemotherapy. The response rate and the magnitude of the benefit in these 2 populations was a bit similar, but for the PFS, it was longer in patients with prior treatment, probably because the follow up was not enough in the treatment naive population. On the waterfall plot, we can see that there is a shrinkage for most of the patients, even if it doesn't reach the positivity for partial response, but more importantly, in my opinion, very, very few patients have a primary resistance to the drug, which is, for me, the footprint of the addiction.

Regarding adverse events, few patients presented with grade 3 adverse events. The drug is, overall, well tolerated. The main adverse events are hypertension, decrease of neutrophils, and anemia. All grades included, the most common adverse events seen in more than 25% of the patients are constipation, hypertension, fatigue, musculoskeletal pain, and diarrhea. All these side effects are dose-dependent and easy to manage. Hypertension can be also managed by prescribing anti-hypertensive treatment while keeping the same dose of pralsetinib. Regarding the lab abnormalities: decreased lymphocytes, but most of all, decreased neutrophils, can be seen, leading exceptionally to infectious complications. This side effect is also dose dependent, as is decreased hemoglobin. There are some warnings in precautions for ILD like any TKIs, hypertension, toxicity of the liver, hemorrhagic event, in particular in the case of hypertension, TLS, impaired wound healing because each drug that targets via EGFR can impair healing, and embryo-fetal toxicity.

At ESMO this year, the data was updated, and we now have a cohort of 260 patients. The cohort was divided into the measurable population, and the efficacy population is 281 patients. I will focus on the latter cohort. Important to see that there were brain metastasis in 34.5% of the overall population, but in the patients that were naive of any treatment, 116 patients, 29.3% of the patients presented with brain metastasis, which is maybe a bit higher than what you can expect in the all-comers population with non-small cell lung cancer. So, there might be, for ALK-positive NSCLC, an increase of brain metastasis in this population. Important to screen with brain MRI for all the newcomers.

In terms of the efficacy, the response rate is consistent with what we have seen, overall, 65.8%, and quite similar in the treatment naive population or the pretreated population. The median PFS is very similar between the treatment naive population and the pretreated population, between 12.6 months and 16.4 months. Although the overall survival is not reached in the overall population, it's probably around 45 months. On the recent update, 15 patients have been assessed for efficacy on brain metastasis, and the response rate was 53%. So not very far from the overall response rate that you can see in all disease. Importantly, it has been reported that the fusion partner with RET, in particular CCDC6, could be prognostic in the ARROW study. As in a real-world dataset of patients not treated with inhibitor, there was a better prognosis for a patient with a fusion where the partner is CCDC6.

This positive preliminary data led to the launching of phase 3 trial first-line, where patients with untreated RET-positive non-small cell lung cancer are randomized 1:1 between pralsetinib or investigator's choice platinum-based chemotherapy, optionally with immunotherapy on the top of platinum-based chemotherapy. Primary endpoint is PFS and the crossover to pralsetinib in the control arm is optional.

The second RET inhibitor is selpercatinib. It has been investigated in the phase 1/2 study called LIBRETTO-001, exactly the same type of design that for pralsetinib with a phase 1 on allcomer RET-altered solid tumors, and then a more specific group for RET-positive non-small cell lung cancer. Again, the population was stratified between patients that previously received chemotherapy, or that was naive of any treatment. The best response in the patients pretreated with chemotherapy was 64% and in the previously untreated, 85%. PFS was 16.5 months in the pretreated population and not reached for the previously untreated population. We see the waterfall plot that with, again, this footprint of the addiction, where the patients had, very rarely, primary resistance to selpercatinib. Most of the patients had a benefit with disease shrinkage.

In terms of side effects, you can see that diarrhea, hypertension, fatigue, and liver toxicity are the main toxicities seen with this drug, not very far from what we can see with pralsetinib. The most common adverse event that you can see in more than 25% of the patients are increased transaminases, increased glucose, decreased leukocytes, decreased albumin, calcium, dry mouth, diarrhea, increased creatinine, increased alkaline phosphatase, hypertension, fatigue, edema, decreased platelet, increased total cholesterol, rash, decreased sodium, and constipation. The same warning and precaution apply to selpercatinib compared to pralsetinib, with a focus on the QT interval prolongation.

A very interesting study was presented at ESMO, where patients that progress on selpercatinib were offered to continue selpercatinib beyond progression. Among the 355 patients treated with selpercatinib, 120 patients continued selpercatinib beyond progression. Important to see that this population that continued beyond progression had a much higher rate of brain metastasis, 42.5%, compared to 29.9% in the initial population. There is clearly a benefit continuing selpercatinib in these patients. Some of these patients received radiotherapy. What we don't really know here is the proportion of patients with diffuse progression vs those with oligometastatic progression that might benefit from a local treatment and continuation of selpercatinib. On a swimmer plot, we can see that some of these patients that continue the drug beyond progression had very long control of the disease.

Similarly, this dataset drove the phase 3 trial in untreated RET-positive non-small cell cancer patients, where selpercatinib is compared to pemetrexed and carboplatin, and the addition of pembrolizumab is optional based on investigator's choice. PFS is the primary endpoint and there is optional crossover in the control arm to selpercatinib as in the pralsetinib trial.

Very good to see that this selective inhibitor has a very strong activity in patients with RET-altered NSCLC. But for all the TKIs, we know that at one point, the disease will find a way to escape the treatment and patients will recur. It's good to see that we now have next-generation inhibitors that are currently under development, some are in phase 1. It's not very clear what the mechanism of resistance are to the first-generation RET inhibitors. Very good to see that we potentially have new options in the future for these patients. With that, thank you for your attention, and please continue to list on a next section on a case-based discussion for managing patients with RET-altered NSCLC.

Segment 3: RET Inhibitors: Practical Considerations

Benjamin Besse, MD, PhD: Hello, I'm Benjamin Besse from Gustave Roussy Cancer Center in Paris. Welcome to this chapter entitled, “RET Inhibitors: Practical Considerations”. Joining me today is Dr Vivek Subbiah from MD Anderson Cancer Center. Welcome. During this segment, we will discuss clinical scenarios to showcase best practices in the management of RET-altered advanced non-small cell lung cancer patients. Vivek, could you give us a couple of examples of the potential side effect of RET inhibitors and how you manage them?

Vivek Subbiah, MD: Hi, let's talk about a couple of cases. The first case is a patient, a 57-year-old woman, never smoker here, presents with cough and fatigue, and she was found to have non-small cell lung cancer and pathology biopsy showed metastatic lung adenocarcinoma. When we tested her mutations, EGFR, ALK, ROS1, and BRAF V600E were all negative, and the PD-L1 stain was less than 1%. A comprehensive next-generation sequencing panel showed a KIF5B-RET fusion. Because the patient harbored a RET fusion, we started the patient on selective RET inhibitor selpercatinib. After starting selpercatinib, although the patient felt well and started doing well, the cough disappeared, the patient developed increased ALT and AST, and developed grade 3 hepatotoxicity.

Let's discuss here how we should manage hepatotoxicity with selpercatinib. We're going to discuss how to monitor, first, hepatotoxicity and how to dose modify for this unique side effect. We need to know, first, the baseline of the AST and ALT prior to starting selpercatinib. We should also be monitoring every 2 weeks in the first 3 months, and then monthly thereafter, or as clinically indicated. You may ask how to do dose modifications. For grade 3 or 4 hepatotoxicities, we need to withhold until resolution to grade 1 or to baseline and continuously monitor with weekly liver function studies. Once the liver function studies are grade 1 or at baseline, we can resume at a reduced dose. If the hepatotoxicity recurs at greater than grade 3 or equal to grade 3, unfortunately we have to discontinue the selective RET inhibitor in this case.

So, the next case, let's discuss a second case of lung cancer. This is a 65-year-old male, this patient was a former light smoker, he presents with cough, fatigue, and nausea. A CT scan showed a mass in the left upper lobe, and a biopsy was found to show non-small cell lung cancer and metastatic lung adenocarcinoma. The patient had a history of diabetes mellitus type 1, hypertension. Of note, the patient also recently had a COVID-19 infection 3 months ago, requiring 3 days of hospitalization for oxygen and had fully record recovered. When we did the comprehensive molecular analysis on this patient, the EGFR, ALK, ROS1, and BRAF V600E were all negative, and the PD-L1 staining was less than 1%. A comprehensive next-generation sequencing panel showed that the tumor harbored the CCDC6-RET fusion. Based on the CCDC6-RET fusion, the patient in this case was started on pralsetinib. The patient did well for a week on pralsetinib. His cough got better, his fatigue got better, his nausea got better. But unfortunately, after a week he got new onset shortness of breath with worsening cough. A CT scan was done that showed new onset ground glass opacities with a diagnosis of pneumonitis clinically.

Let's discuss how we manage pneumonitis with this selective RET inhibitor pralsetinib. First let's discuss, how do we monitor this? We need to withhold the drug and promptly investigate for interstitial lung disease in any patient who presents with acute worsening of respiratory symptoms, which may be indicative of interstitial lung disease, examples include dyspnea, cough, and fever. Again, this is challenging, especially in a patient with new onset shortness of breath with lung cancer. They could have a pleural effusion in the background of COVID-19 infection, so we want to make sure that these patients are thoroughly investigated.

Once we identify the cause of shortness of breath, we need to know how to manage, or dose modify with pralsetinib. So how do we dose modify? For grade 1 or 2, we withhold pralsetinib until resolution, and we can, in fact, resume by reducing the dose. Unfortunately, if this event recurs after even reducing the dose, we have to permanently discontinue pralsetinib for recurrent interstitial lung disease or pneumonitis. To begin with, if it's a grade 3 or grade 4 pneumonitis, we have to permanently discontinue for confirmed pneumonitis or confirmed interstitial lung disease.

Let's discuss the side effects of the selective RET inhibitors. Again, these drugs generally are reasonably well tolerated, and they have shown promising safety and promising efficacy, as you can see from the primary studies, but as with any tyrosine kinases, we've got to closely monitor for these side effects. In the case of selpercatinib from this original dataset, what they saw was hypertension and elevation of LFTs, and there's also a side effect of QTc prolongation and a grade 3 rash of 1%. In the case of pralsetinib, we do see some AST and ALT elevation, we do see hypertension as well. A unique side effect of pralsetinib is interstitial lung disease, and we see anemia as well. Again, the important aspect of knowing these side effects is we need to know the side effects so that we can know how to monitor them, and we can expectantly manage them proactively and not reactively. So, let's turn to another clinical case scenario regarding best practices regarding late discovery of a RET fusion.

Dr Besse: Thank you, Vivek. So, the case is a very young man, never smoker, 37-year-old, and he presented with bone pain. He has no medical history, and because of this bone pain, he had MRI of the bone and then a CT scan, and then a PET scan. It was, at the end, a presentation of lung cancer, very small T1N0, but with diffused bone metastasis. The easiest part to biopsy was bone, and you know that it can be tricky to derive some molecular analysis from bone specimens, but the histology was adenocarcinoma TTF-1, it was negative for ALK, and it was negative for the usuals, EGFR, ROS, KRAS, BRAF, and MET.

He was about to start pemetrexed-carboplatin and pembrolizumab, and then we saw the patient for a second opinion. He was really mildly symptomatic. He had level 1 pain killers, so it was easy to manage. I told the patient, "Well, maybe you are a never smoker, we have to chase if you have a molecular abnormality." He had a liquid biopsy, and within 15 days, we discovered RET fusions.

There was no approval for a first line RET inhibitor, so we had to offer the patient a clinical trial, and he was randomized to the chemotherapy arm. The patient was a bit disappointed, maybe the medical team was a bit disappointed. But 15 days after the first injection of chemotherapy, it was pemetrexed and carboplatin, he had a complete resolution of the symptoms and a very good partial response. So, we went on full cycle of platinum-based chemotherapy, maintenance pemetrexed, and it's been now 1.5 years and still in partial response, with very good tolerance. So, the message is that, chase the abnormality the earlier you can, but if you have started chemotherapy and it works, continue chemotherapy, and start the inhibitor when it will be at the good time.

I think we have seen that the side effects of the selective RET inhibitors are easily manageable, some like pneumonitis, ILD might be a bit tricky, but we have two inhibitors, so it means that we have more options for these patients. Again, in never smokers or light smokers, in particular, please always chase all the molecular abnormalities. With that, I thank you for your attention, and thank you, Vivek, for the great discussion.

Segment 4: Summary and Key Takeaways

Solange Peters, MD, PhD: Dear colleagues, it's my pleasure to summarize and try to leave you with some key takeaway messages from these wonderful talks given by my colleagues. First of all, it's quite important to keep in mind that testing for RET in non-squamous non-small cell lung culture has become a must. So, it is part of the molecular assessments that we need to do in order to best define the patient's treatment journey and cancer journey in the field of precision oncology. It can be tested ideally by NGS, ideally by NGS looking at the RNA parts, but it can also be tested by other methodologies; genome NGS, FISH, RT-PCR or immunohistochemistry. Of course, there are limitations in sensitivity and specificity, particularly for immunohistochemistry. So please go and discuss approaches with your molecular pathologist to make sure that in your center, this is being tested for systematically and without any exception. Of course, if you try to identify a biomarker, it's because you have a treatment strategy.

And in the second part of this module, we were able to see that we have evidence-based strategies to address the RET rearrangement in non-small cell lung cancer. We still compound selpercatinib and pralsetinib, which have shown to give a huge clinical benefit to patients. These 2 compounds have similar efficacy and side effects, which are highly manageable, slightly different from one to the other one, but still manageable with a response rate between 85% and 90% frontline, between 65% and 70% second line, with a CNS response in measurable disease varying between 70% and 80%. So, one of the best ranges of activity for a tyrosine kinase inhibitor in non-small cell lung cancer. Of course, today, phase 3 trials are ongoing against the frontline chemo I-O strategy, but already the data speaks for a frontline strategy.

So, the third part is of course, to try to understand how we can practically move forward with biomarker assessment. So, I think we need to install and discuss together how to systematically test in non-squamous non-small cell lung cancer for EGFR, for ALK. But for all EGFR and ALK-negative, one should be able to go for the rarer alterations, including NTRK, including BRAF, including ROS, including RET. And this has to be done systematically. Is it about reflex testing? Can we do reflex testing everywhere? Is it about looking together at the panel with your pathologist? Either way, you need to put in place a strategy, ideally in solid tumor's biopsies, if you cannot in liquid biopsy, to make sure that all these alterations are tested for. And the debate about reflex testing will still be very important in the future to make sure that we offer the best options to our patients. With this, I thank you for participating in this activity. Please continue on to answer the questions that follow and complete the evaluation. Thanks for your attention.

This transcript has not been copyedited.