Treatment of Metastatic Non-Small Cell Lung Cancer With Targeted Mutations

Intro Hello and welcome back to the Oncology Brothers Podcast. I'm Rahul Ghosain here with my brother and Co host Rohit Ghosain. We're both practicing community oncologist and our goal here is to keep our fellow community oncologist up to date with all that is happening in the world of cancer. Today. We're thrilled to be joined by Doctor Susan Scott, a thoracic medical oncologist from the Johns Hopkins Hospital to walk us through the rapidly evolving treatment landscape for metastatic non small cell lung cancer with actionable mutations in frontline. Susan, thank you so much for joining us. Speaker 2 Thanks for having me, I'm excited to be here. Speaker 3 Susan, welcome. We have a lot to cover in a very short time and we'll be flying through some of the approvals and treatment options we have here. So let's start off with a common ETFR mutations, exon 19 deletion and L858R point mutation in exon 21. Treatment for ETFR mutations For a long time we had the choice of OC martinibolone and then we had Flora two data which showed improvement in PFS, which was chemo plus OC in frontline. Then we recently saw Mariposa which is emivantamab plus lasertanib, oral survival was not reached where projected is to be one year better than OC Martinibollone. We also saw recently Flatiron data about 1/3 of our patients with ETFR mutation did not even get to the second line treatment. So the idea of using upfront best treatment is certainly very important, but this is all coming at a cost of side effects. Can you start us off here? How are you picking the right treatment in these settings? Speaker 2 Definitely. And I have this conversation multiple times a week now and it's always a long one. I consider all three of those options for newly diagnosed patients with these more classical AGFR mutations. I do think there is a patient that's still appropriate for Osmert NIB monotherapy, but I think that's a smaller proportion of patients than we might expect. I consider intensification of frontline treatment either with chemotherapy like floor 2 or with amivantamab like the Mariposa regimen for patients with higher risk features. But that ends up being most patients that we see. You know, in the studies it was 80% of patients that either had brain Mets or positive CCDNA or ATP 53 commutation or heavy burden of disease. The patients that I think of for Osimerton of monotherapy are usually thoracic only disease, no CTDNA detectable. Those often go hand in hand. A patient with bilateral lung lesions or some plural involvement, but low burden of disease can be on Osmerton and monotherapy for years and it's very well tolerated. As we look at this long list of drugs that may be one of the best tolerated on this list. It does have potential side effects. Rash and diarrhea being the most common, but usually quite manageable and resolving after the first few months. And then of course all of this is going to come down to patient choice and and preferences, comorbidities, etcetera. But those are the disease characteristics that I think of for a patient that could be fit enough for all three regimens. That would be my OC monotherapy patient. Then the choice between intensification regimens, I'm using both right now and a lot of it comes more to patient preference. Flora two data, the OC chemo. We don't have the overall survival data, but I'm really waiting for that. The OS data for very Posta looks really promising. That's a really encouraging improvement in frontline therapy if we can manage the toxicity for the duration, and it's a great option. It avoids chemo, and a lot of patients are very interested in that regimen. Hopefully we'll see in the next year. The overall survival data from Florida, too, might make our decisions very hard, but I think it's great to have options for our patients. The side effect profile is very different. The chemo to oncologist feels a little more comfortable. It feels easier to manage because we're comfortable with carbo PEM. We use it all the time. I don't see a huge increase in the cytopenias. A little bit, but it's not drastic myelosuppression. Amy Laz is totally different. The cutaneous toxicity of Amylaz with the dual EGFR inhibition is very real. The paronychia rash, the scalp rash, it's common. It's higher grade than we're used to managing. It's more like the old days with a lot in it. It's more like cetuximab. And then we have the cocoon data that just came out at ELCC, which I think is really going to help. It gave a tangible regimen, which is 12 weeks of doxycycline, daily corhexidine and of ceramide containing lotion every day. It really helped that kind of proactive approach and sun avoidance. So that's really great. Speaker 1 Susan, thanks for touching on that. Because what we're left with are these cross trial comparisons, right? We don't have any head to head trial comparison here. Again, just to reiterate, proactive in managing these cutaneous side effects that come along with Amylaz. Another thing to keep in mind with Amylaz is prophylactic use of anticoagulation, increased risk of VTE. With this and infusion reactions, we have to skip IRR data that was presented by Doctor Lopez. Again, being proactive. Hopefully the subcu formulation will also help with that. That's not available yet, but we are eagerly looking forward to this. So managing supportive side effect and balancing that with improved OS is something that we have to keep in mind with every single patient in front of us. And when it comes to EGFR mutated disease, if a patient is on single agent Osmertineb, then adding chemotherapy or switching to amivantamab with chemotherapy is a viable option at the time of progressive disease. If they're on Amylaz, then switching to chemotherapy is a potential option. Of course, we're eagerly waiting on few Adcs here. Her three date of DXD. But one thing to keep in mind, repeat NGS testing to look for that resistant mutation and tissues have been playing for a small cell clone. Susan, anything to add here in terms of sequencing outside clinical trials? Speaker 2 I agree with everything you said that I usually repeat a biopsy and do a liquid biopsy to rule out transformation of disease because I do see that about 10 to 20% of the time I agree with the sequencing. I I tend to consider the Mary Posta regimen, Mary Posta 2 Amy chemo for patients that are post monotherapy or who've had a longer platinum free interval or even pimotrexin free interval. So I don't count out patients that had gotten chemo previously, but not if it's been recent. Speaker 1 And again, when we're talking about sequencing looking for that resistant mutation also to data outside for Ultimertaneab and Amylaz, the resistant mechanisms look different for each one of them. OK, from common EGFR mutations on to EGFR exon 20 insertion mutation where again we have amivantamab with chemotherapy in frontline settings based off Papillon study which showed progression free survival improvement rather than waiting to use amivantamab in second line. EGFR Exon 20 Insufficiency Mutation Yeah. So this one's much more straightforward. The Papillon regimen AMI chemo is significantly better than chemo alone. We, we clearly amivantamab is an active agent here and improves progression free survival. We don't have the final overall survival. It wasn't, it was there's a lot of crossover. And so I think I'm not really waiting on the next output of the overall survival data. Just took up Pepe on it and went with it. It's much better tolerated. We do see some cutaneous side effects. We do see some edema, which is from the MET component of the Amivan amivantamab. You can see that in any AMI combination. It's not usually responsive to diuretics, but it's usually low grade and it's not typically a reason I change treatment. Similarly, kind of proactive management of the cutaneous toxicities and then the normal chemo management. Speaker 3 Rahul, when talking about EGFR Exxon 20 insertion, we should not confuse this with her two Exxon 20 mutation where we use trastuzumab Duroxycan. Her two Exxon 20 is rather the most common her two mutation that we see. Speaker 1 Yeah, no, absolutely. That is an important distinction. OK, sticking with this theme of uncommon EGFR mutations, Susan, we have a few options here as well. Uncommon EGFR Mutations Your preferred go to option keeping side effects and CNS activity in mind. Speaker 2 Or the S768IL861Q and G719X, these we lovingly call them in the EGFR world, the afatinib mutations because that's what is on the FDA label, though the NCC and guidelines which you know are reflected here do include both OC and afatinib AS preferred agents. We've seen a lot of retrospective data and kind of group data, a little bit of prospective single arm data coming out that OSA martinib does have some activity in these, though it tends to be less than the classical mutations. I still 80% of the time go with OSA martinib always for the L861 queues. They really behave more like a classical mutation. The 768 eyes usually come as a compound mutation and so I sometimes try Osmertin for them. The xx on eighteens which includes the G719X those those can be tougher and sometimes I will consider a fat nib. This is all considered assuming you can get Osmertinib, which is not technically FDA approved for that indication, but it does have some activity. Sometimes I also look for clinical trials for these patients because they're very rare. Speaker 1 And also Martini also has better CNS activity here as well. Speaker 3 And also clinical trials in these dire scenarios are always preferable. Now moving along from afatinib mutations to ALK positive disease, we have elective approved here for adjuvant setting as well as in metastatic setting. ALK mutations And then we also have great data on the loralatinib from what we saw last year from CROWN trial. But again, more side effects. We also have brigatnib Susan, for ALK rearrangements. What's your frontline approach and how are you thinking about sequencing here? Speaker 2 Yeah, Alka is an active area where I've changed my practice in the last year 18 months. The five year crown data did sway me in favor of more patients starting with Lorlatinib. I think it's hard to deny how much better the progression free survival and now the overall survival is with lorlatinib. It's cross trial comparison, but they have very similar disease characteristics. To have more than 60% of patients not even progressed yet at five years is really unheard of. And it biologically makes sense. Well, Latin, it is a newer generation of drug. It's more selective, it's more CNS penetrant. We expect it to have higher affinity and that longer better activity that it's not a no brainer because it is a real trade off with symptoms. Alectinib, you know the highlights for that are that it can cause some Constipation, a little bit of myalgia, sometimes very mild edema, LFT abnormality is uncommonly rarely anemia which I've had, but it's very uncommon. Generally pretty well tolerated patients can get through it. Similarly, brigatinib has that early pneumonitis risk, then a little more diarrhea than Constipation, but other once they get through GI and rash patients do well for many years on it. Lorlatinib, the two main toxicities that I talked to my patients about it with the two groups of toxicities, 1 is neurologic, which we expect with that great CNS penetration, but it could be central neurologic issues like cognition, mood, which can be really devastating to patients on a daily basis and then peripheral neuropathy as well. And then the metabolic complications so they can get diabetes, high cholesterol, weight gain, all of her medicines that patients stay on for years and years. These are real things that we have to manage and consider. So it's definitely an individualized decision. I am still using alectinib first for patients with low volume disease with the hopes that if they have an on target ALK mutation, which you know a lot of patients do, probably up to 50% though some of them don't respond to lorlatin, many of them do and so they can sequence them. We don't see the kind of duration with second line lorlatinib, but this is data and very small numbers of patients thus far. I think we're still learning more about how to sequence these for patients with a lot of brain metastases who just hear this and want the strongest, longest drug. I start with olatinib and dose reduce if needed. Take it from there. Speaker 1 You know, we're seeing the similar trend here, be it with Amylaz or Lorlatinib, you're using your best treatment options upfront. But again, this is coming with the cost of side effects. So out in the community, we really need to get better and better and get comfortable with these side effects, right? We have to focus on toxic, be it for Alka de bitters or EGFR inhibitors, again, just so that we can get very comfortable in managing these side effects. OK, let's pivot to some less common but equally important actionable mutations. Actionable mutations in rAS1 and EGFR Ras ONE rearrangement are available treatment options here. And importantly, when it comes to alchemy EGFR mutations, we are not exposing our patients to immunotherapy. What about Ras one? What about these other mutations that we'll touch on? Speaker 2 Great. No, I still don't use immunotherapy for Ras one fusions or rat fusions for that matter. They have a kind of similar immune cold phenotype. Outside of a clinical trial, it's just not part of my treatment algorithm. And I haven't seen any good data to show that in any clinical trial right now that they're responding. And then for so long, all we had was crizotinib and it actually was decent. I think this was the only type of lung cancer that I was really using crizotinib for the last five years and it was fine. But now we have repotrectinib and intrectinib both approved with excellent results and most importantly much better CNS penetration. That's always been a weakness of crizotinib and the newer Tkis kind of outperformed it for ALC and and Ross 1 is very similar to ALC actually genetically. And so a lot of the same drugs have been studied for the two. But in trectonib and repotrectonib are current options. There are some more in the pipeline. They because of the increase CNS toxicity do have increased kind of CNS like side effects that we see with some of the track activity that's the dizziness, unsteadiness, fatigue. Those are a bit more common with these track inhibitors which we used to treat Ross One. Speaker 3 Certainly keeping the side effects as Rahul and Susan, you both stressed, the quality of life has to be paramount in these patients, especially when the treatment is palliative approach. Now moving along to our B RAF mutation, at least in community setting, we have a bit more experience because of Melanoma and colon cancer and utilizing B RAF and mechan inhibitors. BRAF mutations in community-based cancers Your treatment choice here and importantly, choice of immunotherapy, though we know that in this space, immunotherapy and chemotherapy can be active. Speaker 2 Yes, so I do start with chemo IO or IO alone for patients with B ref mutations. This is based on a lot of evidence showing that there can be durable, long lasting responses to immunotherapy with or without chemo in these patients. Think about the Melanoma data. You know, I usually go for immunotherapy first, but I have a low threshold to stop if it's not working. I don't want to miss the opportunity for a targeted therapy. Speaker 1 Susan, when you're using immunotherapy, dual checkpoint inhibition or are you just sticking with single agent? Speaker 2 Great question. Usually single agent, I don't have much data with dual checkpoint inhibitors for B ref patients and lung in a large way that I'm aware of. But that's a great point. And then my choice for targeted therapy for B ref V600 AI do use right now Inka rafinibinimetinib more because it's more tolerable. The Brafinib trimetinib does have longer data with overall survival that looks really good. But the Ankobini data looks very promising, very similar, and I find that patients are tolerating a little bit better. Speaker 3 Community setting, we have a bit more experience utilizing BRAF and mechanic inhibitors. Now moving along to Entrac. Entropion A needle in a haystack. 0.5% to 1% chances of finding this in a non small cell lung cancer thoughts here Susan. Speaker 2 Yeah. So these are really rare for Entrek. It is a needle in a haystack. I think the most important thing is that we need to be looking for it. RNA fusion or RNA panels can look for these rarer fusions, which is important, but how? Because we use a fusion panel, but a lot of the commercial sequencing platforms do RNA seek that includes a lot of these fusions. So this is really important to look for and it can also be found on DNA. It's just sometimes harder to pick up. I have three of these patients. They're very, very rare. But all three of mine are have been on lyrotrectinib and it's been OK to manage. The CNS toxicity is something that we've had to manage a little bit differently than some of the other TKIS, and then like the LFT elevations that we're more comfortable with. There's also this pain syndrome that patients get where right before their next dose they get sore. It's not really a muscle soreness. It's kind of a total body pain. It's the peripheral neurologic effect of the drug. Speaker 1 I've seen two patients, one with breast cancer and one with lung cancer. And similar to what you brought up, dizziness, both patients actually brought up feeling as if they were drunk when walking. So we have to be cognizant about those reduction supportive care here as well. Yep. OK. Now on to met Exxon 14 skipping mutation. Metexon 14 skipping mutation This is different than C met IC expression. We can see this and resistant pathway to EGFR disease as well. Susan, your go to option here. Speaker 2 Yeah. It's also different from gene amplification, which we also look for in lung cancer and we're studying and has been studied with ketmatinib. But the approval right now is like you said for the Met Exxon 14 skipping mutation. Also often better seen on RNA than DNA. Cabatinib and tapatinib are pretty interchangeable in my mind. Tapatinib is once a day, cabatinib is twice a day. I use both right now. I'm on a tapatinib streak, but they both work really well. The side effects that I worry about for patients or edema, when it happens, it can be really difficult to manage. Not usually high grade or life threatening, but it's a lot of swelling and it's hard to get down, especially once it's started. Usually I hold the dose until it's resolved and then try to resume again at a lower dose. That's been my most effective approach. LFT abnormalities. I'm always looking out closely for those with Kamat and imitopotinib. I do also consider immunotherapy for some of these patients upfront. I usually don't use immunotherapy alone. I usually use it with chemo just in case there's not a lot of activity. I don't want to leave the disease totally untreated. This is more of a toss up for me than the BRAF patient tumors. I'm more inclined to start with immunotherapy medics. I'm 14. Skipping can happen in patients who've smoked and patients who haven't. It can happen in adenocarcinoma as well as pulmonary sarcomatoid carcinomas. It's pretty common among that rarer subtype. For patients that have other features of the tumor that are likely to respond to immunotherapy, like a high PDL, 1A heavy smoking history, I do consider IO first for them and then second line. But for patients that don't have that profile, I start with the TKI and then consider the immunotherapy later on. Speaker 3 The last one is red mutation. Red Mutation Thoughts here for the drug of choice? Speaker 2 Yep. So selprocatinib and prostatinib both have excellent CNS penetration. They're again pretty interchangeable. Selprocatinib is twice daily, prostatinib is once daily. This kind of goes back to Rohit, what you were saying about familiarity. I've tended to use percatinib for these patients. I was using it in a study with that we had for EGFR patients on acquired mutations. So I I got a little more familiar with it, but there's not a lot of data to guide us between 1:00 or the other. Prostatinib is associated with more cytopenias and bone marrow toxicity and infections as a result of that, which wasn't seen with sulfricatinib. So I suppose if you had a patient that had specific risk factors for one or the other, both can see these strange toxicities like Kylus effusions and other things like that, and then normal stuff like LFT abnormalities, they both can cause hypertension, especially cellbricatinib. That's something that patients need to be monitored for. Those of you in the community that use other Tkis, it's one of our only Tkis and lung cancer that do that. More multi kinase inhibitors will have that hypertension effect that I'm sure you're all looking for. Speaker 3 And they we can see this class effect itself. Wow. Outro In the last few minutes, we've touched on 10 plus exitable mutation in non small cell lung cancer. Our hope is as a practicing physician, this brief discussion would guide you to the right direction and show the importance of comprehensive NGS testing. Susan, thank you so much for taking the time to go through this fast evolving space for our listeners. Let us go over a quick recap. Speaker 1 In today's discussion with Doctor Susan Scott from the Johns Hopkins Hospital, we had a chance to cover metastatic non small cell lung cancer with actionable mutations and frontline. I'll pick up where you left. The importance of comprehensive NGS testing is non negotiable and retesting a progression in certain circumstances to look for that resistant mutation or to look for that small cell clone can be important. We touched on the recent overall survival data from amivantamab and side effects to keep in mind with amylase combination when comparing this to osmertinib alone or osmertinib with chemotherapy in patients with EGFR mutated. Speaker 3 Disease. We also touched on treatment options including alectinib, tulolatinib, tubrigatinib in ALK positive space. Importantly, acknowledging no activity of immune checkpoint inhibitors in selected mutations, whereas certain mutation could still drive benefit from immunotherapy and chemotherapy is critical. Besides approved agents, we also touched on some key side effects to look out for. Thanks for joining us. We look forward to seeing you at ASCO 2025. We are the oncology brothers.