Dr. Benjamin Levy & NPC Rasheda Persinger, at ALKtALK
BENJAMIN PHILLIP LEVY, MD, Clinical Director of Medical Oncology
Johns Hopkins Sidney Kimmel Cancer Center at Sibley Memorial Hospital
Associate Professor of Oncology
RASHEDA PERSINGER, Nurse Practitioner
Johns Hopkins Sidney Kimmel Cancer Center at Sibley Memorial Hospital
Deborah Kimmel, a patient since January 2018, gave an introduction.
“Dr. Levy is one of the leading Thoracic oncologists practicing today. Ms. Persinger and Dr. Levy are a part of Johns Hopkins Kimmel Cancer Center. This facility is at the forefront of cancer treatment and a teaching hospital. Dr. Levy and Ms. Persinger focus specifically on lung cancer patients and they have treated many patients with genetic mutations including many ALK+ patients. On a more personal note, Dr. Levy provided me with fact-based, solid information, explained my diagnosis, explained what genetic mutations are, and put everything into a picture that I can understand. I am so very fortunate to have him on my cancer journey with me.
Any patient who sees Dr. Levy will know Ms. Rasheda Persinger. For all the years I have been with Dr. Levy, I have to say that Ms. Persinger keeps every train on the track. She has a team of seven nurse practitioners who report to her and she coordinates patient treatment across broad spectrum of disciplines.”
Dr. Levy: Thank you, Deborah, for those kind words.
I am a Thoracic Medical Oncologist from Johns Hopkins and I specialize in non-small cell lung cancer. As fate may have it, I do see many patients of rearranged lung cancer, such as EGFR and ALK lung cancer. I started in the field in 2008, after I finished my oncology training in New York City. At that time, nobody was going into lung cancer; not a lot was going on. I happened to be attached to a mentor who told me that we are starting to understand lung cancer better. Fast forward 12 years, just the pace of genomic discoveries has been incredible. The running joke was “I went into lung cancer because it was easy.” Yes, it was. There were only three drugs when I started in 2008. Now, there are over a hundred drugs and that is a testament to the science, to the field, and to advocacy. You guys have supported a lot of this advancement. I want to thank you from the bottom of my heart. My passion is in targeted therapies. I wanted to turn over to my nurse practitioner or “my boss” to highlight the fact that “it takes a village” when you are treated. I hope that when you are at a place getting treated, you feel that there is a team for you. Lung cancer is too complicated and too complex to be navigated by one person (Oncologist) alone. I wish I could bring everybody on this call. At Johns Hopkins, I have my nurse navigator, the social worker, the financial clearance office, and the integrative care team that we work with.
Ms. Persinger:
It is such an honor to be here. I want to talk a little bit more about the difference between a Nurse Practitioner and an Oncologist. We balance each other. Dr. Levy is very humble but he really knows his stuff - his thoracic specialty. I like to think Dr. Levy looks at the “woods in a field” but I would help navigate and help patients with all the weeds in the woods. I don’t think Dr. Levy can say enough that there’s no way there could be one person that can handle all the multitude of concerns and problems that arises as you go through this journey. There has to be a team approach. I agree with Dr. Levy that if we could show the whole team here, because we are just a part of a team that makes the wheel turn and make things look so simplistic, but it is very complex behind the scenes. Personally, when I was young in nursing school, I had a family member who was like a surrogate family member who was affected by cancer. This experience changed my trajectory in terms of what I wanted to learn. I have learned about various parts of Oncology since 2003. As I migrated through my journey as a nurse, a registered nurse, and now as a nurse practitioner, this role allows me to assess patients, follow up with patients and provide alternate care with Dr. Levy.
General Questions:
Question: If a patient walked in through your door tomorrow, what would you recommend as your first line treatment?
Dr. Levy: My first line for you would be generally Alectinib. I think that’s based on the ALEX trial. There are now three trials that have compared a next generation targeted therapy to Crizotinib. There’s the ALEX trial (Alectinib vs. Crizotinib). There’s the ALTA-one trial (Brigatinib vs. Crizotinib). The Crown trial compares Lorlatinib vs. Crizotinib. The reason why I chose Alectinib is because it has gotten the most mature data. As Rashida can tell you, we’re very comfortable with dose adjustments on Alectinib. Most patients tolerate this medicine quite well, four pills in the morning and four pills in the evening. We can make adjustments as needed based on toxicity, so Alectinib is my general first line therapy. That is not to say that I do not forget folks on Brigatinib on the front line. Brigatinib has good efficacy too. There are some international investigators who do use Brigatinib as a first line. I just happen to use Alectinib.
Question: We have a very knowledgeable patient group here. We know everyone has their own journey; everyone has their own side effects. Doctors see a bunch of patients. How do you go from one patient to the next with a blanket to cover everyone? I know you know it’s not one blanket because you are smiling.
Dr. Levy: I know I am looking at Rashida because she’s just so good at this and understanding. You know we get so busy at times. I am doing research and everything that I have going on. Sometimes Rashida has to pull me in to really elicit the nuances of a particular case and this is why again it takes a village. It takes different perspective from one team member. It takes listening and understanding to what each patient is saying. I think we do a good job. But every patient has exactly what you said: every patient has their own story. You just have to be careful with one patient’s story. It may be very different from the next patient that comes in. A patient comes in and he’s in his 70’s who says this is no problem on 600mg twice a day. Then, the next patient who is in their 40’s or 50’s who is saying “I’m really struggling.” It is your job to not say “how is that possible that someone 20 or 30 years older than you is doing fine and you are not”. I think it takes listening and sitting down to listen to the situation to come up with the best plan that we do for all our patients, even outside of ALK.
Ms. Persinger: I saw a question in the chat room. Someone asked and they were following up on our comment in regards to dose reduction. You know that patients may hide their symptoms in fear of having a dose reduction and in their mind thinking that’s progression. I just wanted to really speak to it. It is a true feeling patients do feel like. I think from our standpoint, that is why it is so important for us to make sure patients can understand what Dr. Levy mentioned earlier. We are individuals and a study is a study. You can be an individual and not be similar to people represented in the study. I think letting patients know, acknowledging what they are feeling because what you are feeling is true. It’s what you see, you live this day in and day out. We are on the outside. You have family, friends, or jobs that are important to you. Our goal is to prolong life and we want to kill cancer as much as we can, but we don’t want to do that at the risk of compromising your quality of life. It’s just important for us to reiterate, to reassure patients that it is okay if we have to dose reduce. We’ll have to take it by scans and your symptoms. We will see what happens together. Maybe we can try dose reduction, maybe we need to increase dose. We’ve had a patient off on a lower dose for about a few months. The scans did not really show there was any progression, but the symptoms dissolved. Patient wanted to go back up dose. For Dr. Levy, he really means shared decision. We discussed and we increased his dose back up.
Question: You mentioned you are seeing more EGFR and ALK patients. Can you expand on why you may be seeing more ALK or EGFR patients?
Dr. Levy: These are top level questions that I would expect from this group. The short answer is that we are not sure why we are seeing an uptick of never-smoking lung cancer. Why is this uptick, this increase in EGFR and ALK-based lung cancer in my region as well. So, I just lived in New York City and practiced thoracic oncology for 12 years. I ran the program at Mt. Sinai before I moved to Hopkins. I just did not have that experience in New York City. So it may be regional in the DC/Baltimore area/Northern Virginia/Maryland area? It is unclear to me why. I have a fellow that rotates with me and tells me that they had never seen something like this. These are all driver mutations. What could be going on? We will be doing some research in the lab looking at potential genetic footprints on the tumor that we can analyze. Maybe it can be linked to environmental exposures? I don’t have much to go over that, but we’re looking at ways that environment might be playing and how to capture this on the tissue.
Questions: Do you think it might be just simply that biomarker testing is becoming more prevalent than it used to be?
Dr. Levy: It is. But I still think we are woefully not doing as good as we should. If you have heard me talk before, we’re still kind of in the dark ages on how successful we are with this. Maybe that’s a little bit of hyperbole but yes, some of this has to do with the fact that more patients are getting accurate genotypes or having molecular testing done.
Question: Just talking about the patients that you had on the Alectinib trial who are still progression- free and doing fine. We have a member that just joined our group today that has been on Crizotinib with no progression for nine years. If you can have a patient on Crizotinib for 9 years, you can for sure find patients on Alectinib for longer than 9 years.
Dr. Levy: I mean it when I tell my patients when, or if you progress. I have a group of patients that I know have not progressed yet or have not developed disease progression. So, you know it is not an absolute.
Question: Would you ever go back to Crizotinib if you failed on other TKIs?
Dr. Levy: Yes, in rare circumstances. I’m sure you guys are aware that there are mutations that can occur post Lorlatinib that are sensitive to Crizotinib. It’s a game of whack-a-mole where you knock one mutation down and another comes up and you knock it down again. It’s rare but the whole idea of sequencing of TKIs is a really complicated one. This mutation, L1198F, is a mutation that can occur post Lorlatinib and can be sensitive to Crizotinib. We are still learning about these mutations. Questions like, what to do after Lorlatinib? What to do after Alectinib? We are still building knowledge and science on this. What to wed the right treatment to the mutation that we identify.
Question: To detect the sub-mutations that you might have requires biomarker testing, not just at the initial diagnosis but after progression. But that is still not routinely covered by insurance. What is it going to take for us to get to the point where insurance will recognize that should be the standard of care?
Dr. Levy: I think we are getting there. It is groups like yourselves that are so powerful. It is also the physicians that can really move the needles here. We haven’t had too many issues and we do both tissue and blood on most of our patients. There are scenarios where I wouldn’t consider blood but most of the time we try to do both. It comes up with patients all the time. Do you do both? Do you do one? If we are to move this needle and move this field forward, even if you know there’s a chance that nothing we find will inform a subsequent treatment decision, we need to have this data so we can move it forward.
Question: If you did well on Crizotinib for 35 months before progression, is there any relationship to how long you will have on Alectinib before progression?
Dr. Levy: I don’t know. Not a lot of data on this. For a patient who has been on Crizotinib for a long time, does it mean that they will be on Alectinib for a long time? It could be possible given the fact that there are some mutations that are just more sensitive to these TKIs. So, there’s a possibility. I will say, one thing about progression is that it is one of the most difficult decisions that I have to make. Whether it is a true progression or not in a patient who is on a targeted therapy? And perhaps one of the pearls from this talk is when your doctor is saying “oh the scan shows growth, it’s time to switch therapy.” Maybe this is where things get very nuanced and very detailed where you ask the physician to look at the scan and say “is there real growth here?” I mean does this 2 mm of growth really warrant a therapeutic switch? Going back to the question, I really do not know if being on Crizotinib for a long time does or does not mean you will be on Alectinib for a long time. I hope you do.
Question: For stage 3 lung cancer, the patient had Alectinib after surgery. Do we have a clinical trial to test whether that’s a good thing to do or not?
Dr. Levy: No, no we don’t. We don’t have a lot of data on this. There are some trials that are being looked at. The broader question is similar to EGFR. These drugs are great for advanced-stage patients. Can we leverage it for earlier stages? I think we should. There’s going to be some movement with a big global national trial called the LCMC4O, which is simply essentially looking at Alectinib and other targeted therapies for early stage lung cancer, resectable stage lung cancer. But at stage three, we are still wrestling with what to do for ALK-rearranged lung cancer. I can tell you, a patient with stage 3 ALK, I don’t have a lot of them. If they had chemotherapy and radiation, I would consider. However, it would be heresy among other investigators to say this. I would consider potentially putting them on Alectinib, although we don’t have a lot of great data for it.
Question: Do you see any patients who have both ALK and EGFR? Would you consider trying both types of TKIs?
Dr. Levy: Rare. They are very rare. I have one in my whole career. I think we wrote it up. They are there and they happen. What TKI to choose is a challenge. Do you go with an EGFR-directed target medication, or an ALK one, or both? I would look in the blood to see which variant allele fraction is higher. Was it EGFR or ALK? Which is also very tricky. I may consider doing both at dose-reduced levels. I may escalate up if need be.
Question: You mentioned mental health as a side effect of Lorlatinib. Have you find similar side effect in Alectinib? Do you think it is because Lorlatinib has higher penetration into the brain?
Dr. Levy: No. (Alectinib is) not like Lorlatinib. No, I think it is not just due to better penetration. What we’re seeing with Lorlatinib is different. My experience with Lorlatinib may be different than others. But we have had a couple of patients who had some true psychosis that I just don’t see with Alectinib.
Question: How often do you recommend a PET scan vs doing CT scans?
Dr Levy: Great question. I usually don’t get PET scans unless the CT scan is showing something. I do CT scans on everybody every three months. I will consider a PET scan once a year on a patient who just wants to take stock and see where we are with things or if the CT scan is showing something equivocal, then I do a PET scan. But, I don’t do a PET scan every three months. I do CT scans and also an MRI of the brain every 9 to 12 months in the absence of symptoms. Everyone’s got their own interval and there’s no data on this. But, I tend to do every 9 months.
General Comment on early stages lung cancer: “I was diagnosed stage 3A at Hopkins (a US hospital). I had a lobectomy and adjuvant chemo and radiation. I went almost three years after without taking anything before I had progression. That was when I was put on Alectinib.”
Dr. Levy: I wish we had some data on how to use Alectinib post surgery.
Question: I see my nurse practitioner a lot more than my doctor. The role you play is not just giving patients medications. Can you expand on your role?
Ms. Persinger: Ideally, we like to alternate follow-ups and it is ideal to see the oncologist on the scan visits. However, there are some times, especially when scans are completely stable or we have regression and it’s very straightforward, I will see the patient at scan follow-up. Our goal is that we usually try to get the patient seen by Dr. Levy on their scan visit and otherwise he just alternates.
Question: Can Dr. Levy tell us about your podcast? I have been kind of haunting you and looking at you through the internet. How can we listen to your podcasts? Because I think they are very insightful.
Dr. Levy: We have done a few of these podcasts. You know these are through Hopkins. I did some of these and I’ve been interviewed as well. I can tell you actually, the best podcast video that I’ve ever done is the one that talks about our team and how it takes a village and how to navigate the system. I was with Rashida Persinger and Candance Graham Atterton, she’s our nurse navigator. We did a video panel discussion “live” with an audience and no mask. It is at the Living Room with the Addario Foundation (editor’s note: this is now called the GO2 Foundation). Just look “Hopkins Levy Persinger podcast” to really get a sense. This Living Room really talked about the journey for the patient. It wasn’t focused on ALK but it focused on everyone’s role here and how patients can be their best advocate. How they need to be sometimes and that it takes a village to get everyone through this process.
Alectinib Questions:
Question: Can you please tell us about the ALEX trial that you were involved with?
Dr. Levy: Most of you are probably aware of the ALEX trial with my previous institution. We had a tremendous amount of excitement about Crizotinib. I believe ALK-associated lung cancer was discovered in 2007. Crizotinib was developed and implemented in 2011. It only took four years, which is pretty remarkable when you think about other mutations and other discovery of drugs against those mutations often takes 30 to 40 years. So, everyone was quite excited about the Crizotinib story. But, once we started to see the benefit of Alectinib over Crizotinib, it was clear that our patients that were on Alectinib had shown lack of toxicity and had shown improvements/outcomes. We’ve learned a lot from the ALEX trial in the past three or four years and it’s been a remarkable run. It’s not over. If you do not know, it was a head-to-head trial to ask which of these targeted therapies or tyrosine kinase inhibitor (Alectinib or Crizotinib) is better. We found in the study that Alectinib way outperformed Crizotinib. I just want to mention something about this study. One is that the response rates were higher and the chances of tumor shrinkage were higher with Alecintib. Two is that the tumor remaining in check before progression was much longer on Alectinib than on Crizotinib. Thirdly, we still have not hit the median overall survival yet on this trial and this trial is four or five years old. The trend is incredibly favoring Alectinib vs Crizotinib. Because of these, Alectinib became the standard of care. I want to mention two more things. One is the chances of tumor shrinkage in the brain were much higher using Alectinib than on Crizotinib. The quality of life is better on Alectinib. So for all these reasons, ALEX trial solidified Alectinib as standard of care. I say “standard of care” because there are other drugs that are making their way to be standard of care. Some of you may remember a trial compared Brigatinib to Crizotinib similarly. It had shown Brigatinib being superior to Crizotinib. It is pretty remarkable to see patients still remain on that study and are doing well on Alectinib when this trial started around 2013 or 2014.
Questions: There is a lot of discussion over the dosages in our groups. What would you recommend (for Alectinib)?
Ms. Persinger: As we prescribe the medications for patients and patients wants to know, what is the recommended dose? I would recommend the dosage should be what was given in the study. As providers, it is important for us to layer in what we found - a balance of a good quality of life, toxicity and dose. You can still derive a benefit even if you have a dose reduction. I think about a patient when we recommend a dose reduction because we thought it might be contributing to necrosis in her brain. Yes, as providers, we want to max out the medication dosage that was in the trial but there is still efficacy that we can see from patients who have had a dose reduction.
Dr. Levy: That is why we have Rasheda on the call. She can encapsulate better our experiences on our dose modifications. She’s absolutely right. I would say, one thing is that to be your own best advocate. It’s okay to tell your physician, “Look, I know the data is great, 600 twice a day, but there are some patients who just don’t tolerate well at the dose and that’s okay.” There is still meaningful benefit with dose reduction. We probably do dose reduction in 25% of our patients. I would say our older patients too; we have several patients in their 80’s. Even some younger patients would come in and say “I did not want to say anything but I just want you to know I have terrible nausea or I’m letting you know I’m just so fatigued.” I think it’s important for the nurse practitioner and the physicians together not to dismiss patients’ challenges. There are challenges with Alectinib such as edema or extreme swelling in the legs or the abdomen. So, we’re okay making some dose reductions knowing that there’s still a benefit with those reductions. We don’t want to get down to 150mg twice a day but we do have a couple of patients on 150mg or 300mg twice a day. But, be your own advocate, make sure you voice your concerns so that dose adjustment can be made. It’s all about quality of life.
Question: If you have someone who can’t tolerate Alectinib because of whatever reason, maybe then you can go to Brigatinib? Is it a lateral move? How would that work?
Dr. Levy: This is where I tell patients that this is where medicine is an art and not a science. We know so much scientifically but we have to practice the “art of medicine.” It is important to be with somebody in a team that knows the art of medicine. We don’t have a lot of great data on this and in fact we don’t have great data. We know from the Japanese data that 300mg is the Japanese dose, 300 twice a day is the Japanese dose. 600 mg twice a day is the US/European dose. I have a patient on 150mg or 300mg twice a day. He was like, “is it worth it?” I think it is. He thinks it would be better if I just come out and switch over to Brigatinib instead. Maybe he can be able to tolerate a full dose there and that wouldn’t sacrifice therapeutic efficacy. So, I think it’s a shared decision. I am open. I take a lot of my cues from the way patients feel and what they are interested in doing. We don’t have a lot of great data on this. If a patient could not even tolerate 150mg for twice a day, I would consider switching them to either Brigatinib or Lorlatinib. It really depends on the scenario and what true toxicity is for that patient.
Question: Why is the Japanese dose at 300mg twice a day and the US/European dose at 600mg twice a day instead?
Dr. Levy: That is based on the PK analysis, when you look at ways drugs are dosed in the blood, then the tolerability correlating with that. In the end you know the Japanese population tends to be a little bit smaller and with smaller BMI (body mass index) than patients in Europe. That’s how the dose was defined. I have two Japanese patients who know their data and said, “I want 300mg twice a day.” So, that’s what we did because that’s the Japanese dose. But, for most of my patients, it’s 600mg twice a day.
Questions: I have been stable on Alectinib for over 6 months. Should I plan for progression now? If not now, when?
Dr. Levy: What to do with a stable patient, when and if progression happens? I always tell patients, when and if you progress. I have plenty of patients who have remained on Alectinib since I’ve known them. So I can tell them back in my New York days and I still keep in touch with these patients. There are so many of these patients who have not progressed yet or have not developed disease progression. I always tell patients that the science is evolving so quickly, I don’t know what is going to be available in six to 12 months from now. Six months ago, I probably wouldn’t intelligently discuss TPX0131, which is in preclinical trial. I probably couldn’t talk about some of the peptide vaccines that are going on now. So, fast forward to April 2022, there’s going to be a different discussion. So, I try to hold up some patients; some patients really want to know. I understand, I am a planner too. I just tell patients that we’re going to leave the question mark there. It is a good question mark to leave right now. It is tough leaving a question mark. Maybe leaving with a question mark will end up with an exclamation mark in the end? So, that’s how I coach patients with it.
Question: If someone needs dose reduction on Alectinib, do you titrate down or do you stop and restart for maximum relief from side effects (fatigue and myalgia/muscle pain)?
Dr. Levy: I don’t remember ever stopping somebody cold turkey (editor’s note: US phrase = stop abruptly) on Alectinib. Rashida?
Ms. Persinger: We’ve always dose reduced and then just kind of reassessed. Not a patient that’s coming to my mind that we’ve just stopped.
Question: There’s an insightful question here. What are the progression rates for the Japanese on their Alectinib dose relative to the rest of the world (ie, international dose)?
Dr. Levy: I’ll have to pull up the Japanese data, but they were similar. It may have been a little bit less for the Japanese but I can look at their data. But, they are close. The Japanese patient population vs the 600mg twice a day in the US were relatively similar in their progression-free survival rates. I don’t have it off the top of my head.
Question: It is not uncommon to have progression only in the brain. You can increase as high as 1800mg dose. Do you know whether the Japanese are doing something similar? If so, are they doing it from 600mg to 900mg or are they going even higher than 900mg?
Dr. Levy: I don’t know the answers to the Japanese data. When there’s a lack of penetration or potential growth in the brain on a current dose of Alectinib, if it’s a small amount of growth, we often just radiate it. But, if there’s true growth, you’ve got two options. You can either bump up the dose of Alectinib post the therapeutic dose that you started with, or you can switch them to another TKI. This is one of the more challenging scenarios that we have. I don’t know in the Japanese literature if they did go up for disease progression only in the brain and what the results were for those.
Lorlatinib Questions:
Question: When will Lorlatinib become the drug of choice?
Dr. Levy: It’s a great question. We will have to see how the CROWN data matures. I want to back up and say that we all struggle within our committee meeting in that there’s not been a head-to-head comparison between any of these drugs (Brigatinib, Alectinib, and Lorlatinib). We are all kind of guessing here. We are using the transitive property. We are looking at the medicine compared to Crizotinib and see which one out performed Crizotinib the best. At the beginning, it looked as if the Lorlatinib data is a little stronger than Alectinib over Crizotinib. I am not sure. I am not sure how everyone is familiar with EGFR on this call. In that space, we saw an evolution of frontline care because we had a direct head-to-head comparison between the next generation therapy versus an earlier generation. Here, in ALK, we have three next generation drugs that are really good and all have been compared to Crizotinib in their own trial. So, we do not have a head-to-head comparison here. I like to use Lorlatinib when we talk about sequencing out of a clinical trial setting. I have struggled with giving Lorlatinib because in my mind, Loraltinib is not as well tolerated by my patients. In committee, we talked about paper toxicity and the real world toxicity that we see. In the CROWN data, it looked like it is pretty well tolerated. But, we do have challenges, or, I have had some challenges with it. I’m happy to share those. It’s going to take a lot for me to switch from using Alectinib to using Lorlatinib as front line. International and national leaders have different thoughts on this. There are people who feel like it should be used right away. We just don’t have any head-to-head data to say one way or another.
Mr. Persinger: I wanted to add that there are some side effects that we do not see in Alectinib that is from Lorlatinib. Hyperlipidemia and neurotoxicity are two symptoms. We have to understand that there are going to be different side effect profiles using Alectinib vs. Lorlatinib and these may compromise a patient’s quality of life.
Question: When you dose reduce Lorlatinib, what is the lowest dose that you typically see your patients?
Dr. Levy: I have gone down to 50mg. We’ve had some challenges with hyperlipidemia, peripheral edema or swelling of the legs, in the abdomen. We have some folks with some CNS issues, unfortunate episodes of psychosis and depression that are out of character. Again, this is where it takes a village. You’ve got to listen not only to the patient but the patient’s family which is not so easy to do during Covid because family is not allowed in. We want to engage not only the patient but the patient’s family. This is the reason that I went into this field. We have couple of folks that are on 100mg of Lorlatinib and are doing rosy (=good). But there are some who are really struggling with 100mg of Lorlatinib. Because of my experience with Alectnib, it’s going to take a lot for me to switch Lorlatinib to the frontline.
Question: There’s an internal poll for Alectinib vs Lorlatinib, “How do you feel on the drugs?” The only ones that can vote had to have had both medications. From the beginning, there were always people polling better on Lorlatinib. About 20 to 10. It’s been running for about 6 months now and it is still like that. It is about 50 to 25 (Lorlatinib vs Alectinib).
Dr. Levy: That’s very interesting. That’s a pretty good sample size. That’s a publishable sample group. It is very interesting because that has not been my experience thus far. You know it may be a testament to the drug working really well post Alectinib. You know people may feel lousy toward the end of their lifetime journey on Alectinib and then hop on to Lorlatinib. Maybe the drug works really well. I’d be curious to see if you re-polled maybe six or 12 months down the line and see what people would say.
Ms. Persinger: I would be interested to see if you can do a subset, like who may have cardiovascular comorbidities in addition to their cancer on Lorlatinib. How are their experiences with Lorlatinib as it relates to some of the side effects.
Dr. Levy: It’s all about quality of life, the most underrepresented part of this whole story. How patients are feeling. These type of data are very meaningful and even more meaningful for someone like me to look at. You will be polling more patients than I’ve seen in my practice, so that’s great.
Post-Lorlatinib Questions:
Question: We brought up some future of ALK medicine and you brought up Turning Point (TPX0131). Can you give us a little background about the company and what other things they are involved with?
Dr. Levy: Turning point is a relatively new biotech company that is really invested in the next generation targeted therapies, not just for ALK, but for other mutations as well. They have a drug that they just pushed at AACR (American Association for Cancer Research) for RET. They have a wonderful drug for ROS1. And they are developing a new drug called TPX0131 for ALK. This drug is still in preclinical development. It may be helpful to know a little about how mutations occur. There are two broad categories of mutations: solvent front mutations and gatekeeper mutations. Those are just a fancy way of saying protein from the gene is no longer allowing the drug to bind to its pocket. Alectinib does a nice job in binding to its pocket. However, if you develop these two type of mutations, the pocket does not allow you to bind. This new drug, TPX0131, is really niche. They are small and they can get into that pocket and that’s how they were specifically designed and developed. It looks like, post Alectinib, a patient who progressed, roughly 40-50% of the time will develop a solvent front mutation or a gatekeeper mutation. This is where this drug can really work against. In this case, Alectinib just cannot bind anymore. These new drugs can fit in that. Turning Point has a success story with ROS1. At least right now, we have a drug called Repotrectinib which is a drug that is developed specifically post Crizotinib for ROS1 lung cancer. The drug looks very good. It is designed the same way TPX0131 is designed for ALK’s solvent front mutation or gate keeper mutation. It’s not going to be in our hands for probably another 6 to 12 months but I look forward to it. I think that one way to tackle resistance is to develop these new novel niche drugs that can bind in the pocket. Another way to look at tackling resistance is with immunotherapy. You know that immunotherapy as a single agent is probably not the best drug for ALK-rearrangement lung cancer. I had a couple of people who had done well, but immunotherapy as a single agent is probably not the best way to treat an ALK-rearrangement lung cancer. But there are combination approaches that are being looked at and explored. There are different types of immunotherapy that aren’t yet approved, so we’ve got things like peptide vaccines that you may have already heard about from other folks that have talked that may also help tackle resistance. I look at resistance therapies as the newer next generation targeted therapies that go against solvent front or gatekeeper mutations. Then, immunotherapy and immunotherapy combinations that can occur. Some of the standard drugs that we have or some vaccines that are being looked at by MGH (Mass General Hospital). Lastly, I’ll say that, you know, I know that we feel chemotherapy is a bad word. But, there are many patients post targeted therapy who do extraordinarily well on chemotherapy. It’s not my first choice, but there are some patients who have very long tails, especially on a drug called Alimta, which we know works extremely well for ALK-rearranged lung cancer. It is very well tolerated, given over 15 minutes, every three weeks.
Ms. Persinger: Can you speak on the fact that, even when you start patients on chemo, depending on where their progression is, that you will continue them on the oral therapy as well?
Dr. Levy: Yes. It’s a great point, Rashida. Sometimes, when patients do have to go on chemo, either because they are waiting for trial or we think it’s the best drug for some, sometimes we will continue the targeted therapy and add in the chemo. This is where things get extremely nuanced and detailed. This is where Rashida has to remind me sometimes, “did you continue the TKI?” So, I mean, it does take a village and we really try to. It’s nuanced in medicine as an art and not a science. I think we are just beginning to scratch the surface with the science here, what to do after Alectinib/after Lorlatinib/after Brigatinib.
Question: What is your experience when someone has been failing on TKIs and goes on chemotherapy. Eventually, it actually kind of resets the cancer where they can go back onto a TKI and it’s effective? You had some experience in that?
Dr. Levy: Yes. I have limited experience with this. Borrowing from the EGFR literature, there is an experience where once patients have a TKI break and they get chemo, the cancer can be resensitized to the TKI that they received prior to chemo, depending on how long the chemo was on. The longer the chemo, the more likely, potentially if it was a year ago and the patient’s been on chemo for a year and they came off of Alectinib for some reason. And yes, there has been some data suggesting the tumor is resensitized to Alectinib. Not a lot of great data and the medicine is an art, but it is certainly worth exploring. I would say every patient is so nuanced and so individualized that, as Rashida was mentioning, as we talk about nuances of toxicity with patients, we are talking about nuances of their treatment pathways.
Question: Can you talk about some post Lorlatinib treatment strategies, especially if patients have progressed quickly on Alectinib and Lorlatinib?
Dr. Levy: This is an unfortunate a scenario that we see. We’re just learning about what to do. I can tell you off trial, not a sexy reply, but I have a couple of patients who progressed too quickly that I used chemotherapy to cool them off a little bit and wait for the next trial. This is also an important call to look at mutations. As I mentioned, there are mutations post Lorlatinib that are sensitive to Crizotinib. L1198F mutation is resistant to Lorlatinib but sensitive to Crizotinib. Also, this is where TPX0131 is going to make a difference. Potentially immunotherapy combination (I know it sounds vague) but we’re just scratching the surface of what to do post Alectinb and post Lorlatinib. I can tell you, for patients progressing quickly on both (Alectinib and Lorlatinib) I would really probably give them chemotherapy first and then think about clinical trials after chemotherapy. Hopefully chemotherapy would cool things off.
Question: Would you be doing chemotherapy with Lorlatinib in that situation?
Dr. Levy: If the progression is really quick, probably not. If they did not derive any meaningful benefit, probably not. But, I would consider if the patient was on it for six or seven months. Sure.
Question: If it was quick progression, would you consider just chemotherapy on its own or would you consider chemotherapy with immunotherapy?
Dr. Levy: One of the most controversial therapeutic strategies is which chemo. I generally do Carboplatin and Pemetrexed alone. I don’t add in immunotherapy only because, if you are going to add in immunotherapy, it may cause harm when you reinstitute another TKI in the future.
Future Research Questions:
Question: What do you think are the most promising avenues of new research for ALK lung cancer? How about the most promising clinical trials for people who have exhausted their TKI options?
Dr. Levy: I think I have alluded to this earlier. I think the next generation targeted therapies like TPX0131 are going to be a game changer for the right patients. It may not be for all patients. So, I think that’s one area where we’re really making a lot of movement and traction. I think the other one that’s coming is harnessing the patient’s own immune system to turn against the cancer. We are very new at this. The why we have not been able to do that successfully with ALK is a whole other story. But, potentially having vaccines that can turn the immune system against a particular type of mutation is one area where we’re going. Another not super exciting path but gaining traction is adding chemotherapy to a TKI upfront. I know historically chemotherapy is just thought of as just bad with lots of toxicity and it’s challenging. But there are many patients who do really well on chemotherapy and even add chemotherapy to an ALK targeted therapy. It is maybe the way to go. I have a lot of thoughts on this and I know we’ve got a lot of questions. I have a feeling that we might head this way, but we will see.
Question: Do you have thoughts on newer technology such as CRISPR and CAR-T therapy?
Dr. Levy: Yes. I think you know it’s an incredible movement with CRISPR and truly understanding gene editing and understanding the genomics of tumor. I did not even mention something like CAR-T. We’re beginning to take a patient’s immune cells out and genetically re-engineering them to go after the cancer and then reinfuse them. That has not gained a lot of traction yet clinically in lung cancer. But, I think in 10 years from now, we’ll be talking about this.
Question: What can you say about future lung cancer vaccines and your take on it?
Dr. Levy: Historically, we have failed at vaccines until the 90’s and early 2000s. I think the technology is getting better even outside of cancer. Look at how we’re succeeding with viral vaccines. I think there’s going to be a niche here. We’ll see some of these peptide vaccines that are loaded in and generate an immune response against a particular mutation that you know causes resistance for targeted therapy. It sounds great on paper, it works beautifully in mice, but what sounds great on paper may not translate into the clinical realm. We will see. I’m on the LUNGevity advisory board and certainly we’ve looked at some of these grant proposals for some peptide vaccines for ALK. I think it’s a way to harness the immune system against ALK-rearranged lung cancer. We are just not there yet, but we are getting there.
You can watch the entire video recording here: https://www.youtube.com/watch?v=u-ryx8i80hw
Questions have been compiled and organized and may not be in the exact order in which they appear in the video.
Compiled and transcribed by: Alice Chou