Dr. Alice Shaw at ALKtALK, Feb. 2022

Dr. Alice Shaw, MD, PhD, Boston, MA

Global Head of Translational Clinical Oncology at Novartis

Attending physician, Center for Thoracic Cancers at Massachussets General Hospital

Associate Professor of medicine at Harvard Medical School

Transcript of ALKtALK, February 6, 2022

Introduction

I am from Maryland originally. Then, after high school, I came up here to Boston, and I have been in Boston since. I have been in Boston since college and medical school, graduate school, and all my medical training. I did a lot of basic research here first, studying basic transcriptional regulation of blood cell development. That was when I was a graduate student and then as a postdoctoral fellow. I was at MIT with Tyler Jack studying the KRAS oncogene. Around 2007 I decided I really want to be closer to patient care, so, at that point I transitioned from a basic investigator at MGH and MIT to a translation and clinical investigator at Mass General. Somehow, fortuitously, ALK was actually discovered by a team in Japan when I first started at MGH as a clinical investigator. It was one of the Aha! moments, because we could tell even just from that very first study, that was published in Nature, that ALK was going to be a really big target. At that time, many of you don’t realize, but we really had very little in the lung cancer space. We were just learning about EGFR as a target, and that was really it. So, in 2007, ALK came along, and, I think, it really kick-started the whole field of precision oncology. Some of you may already know some of the history of ALK. There was also serendipity, because, when ALK was first discovered in 2007, we were already testing Crizotinib, which was the first ALK inhibitor in the clinic.

Again, some of you know this story, but for those of you who don’t, Crizotinib was actually being developed for a different target, called MET, but we did know that it inhibited ALK. So, when the first pivotal study of ALK was published in 2007, we started working very closely with John Iafrate, who, I think, you guys met last year, to begin diagnoses of patients with ALK. We also worked very closely with Jeff Clark and Eunice Kwak, who were running the phase one trial. We basically could pivot very quickly and start enrolling patients with ALK into the phase I trial of Crizotinib. I remember so clearly the very first ALK patient who we treated with Crizotinib. He had started as a patient of Tom Lynch’s, but I knew him well from the trial, and he had started on Crizotinib the day after Christmas in 200,7 so, I think that was about 14 years ago. Within days he was feeling better. Within a few weeks, I believe, he actually had even been able to return to skiing. It was just like this incredible transformation. So, at that point, seeing this very first ALK patient and his response in 2008, I think, many of us knew that ALK-like targeted therapies like Crizotinib were going to be really transformative for patients. So, soon after that first patient we started enrolling more outpatients. Linnea was one of the first ALK patients as well who we treated in the phase I Crizotinib study. I think many of you know her or know of her. 

I actually have a number of patients who we started on the phase I Crizotinib study back in 2008 or 2009 who I still follow today that are still on Crizotinib. That is pretty incredible. I think, all of that just really highlights to us that ALK cancer just has this incredible, remarkable sensitivity to targeted therapies. Again, to remind you that back then all we had were EGFR targeted therapies, and so, this was really a huge development at that time. But, unfortunately, even as amazing as these responses were, we actually started to see fairly early on that many of our patients on Crizotinib were developing resistance and actually relapsing even as early as within the first year. So, it became very clear that to continue to advance the field, we really needed to understand what was driving resistance. I set out working with a number of my colleagues at MGH, including Jeff Engelman and Justin Gainor, to study resistance by modeling it in the lab, and also, I think, more importantly, by studying biopsies or cancer specimens from patients. For about a decade, we studied resistance very intensely. In parallel, we teamed up with various biotech and pharma companies to develop better ALK inhibitors. Early on, we started to identify resistance mutations to Crizotinib for which second generation inhibitors like Ceritinib, Alectinib, and Brigatinib were very effective in pre-clinical studies. So, most of our work was able to really set the stage for testing these second-generation agents in patients who have become resistant to Crizotinib. Then, soon after, we moved these agents into the first-line setting where we knew that they had even greater impact. But, again, with second generation inhibitors, we saw this problem of resistance rearing up again. 

So, we launched many different studies to understand resistance to the second generation drugs and started working on third generation drugs (Lorlatinib with Pfizer) which had been developed specifically to overcome resistance and designed specifically to penetrate into the brain to address the problem of brain metastases. Soon we were able to bring Lorlatinib into the clinic and show its activity after first and second generation ALK inhibitors. What’s recently been important to show is that Lorlatinib is particularly effective when given as a first line therapy. This is because Lorlatinib can really block all of the known single ALK resistance mutations. Lorlatinib can treat brain metastases but also can protect the brain from metastases. Now, about two and a half years ago, we were continuing to push the boundaries. I think, for ALK, we were even planning ahead well beyond Lorlatinib at that point. We were planning combinations, doing lots of basic research into how ALK+ cancer evolves over time, why it is that some rare ALK+ cancer cells persist or survive despite being exposed to an ALK-targeted therapy. We knew that ALK+ cancers rewire and reactivate other pathways to cause resistance, so we were also studying why ALK+ cancers don’t respond to drugs like Keytruda or Opdivo, these so-called checkpoint inhibitors. We’re also laying the groundwork for this new 4th generation class of ALK targeted therapied which we will come back to. But it was clear to me at that time that, as an investigator and having treated so many hundreds of outpatients, we really needed to go beyond the current toolbox of targeted therapies and really think "outside of the box", because it really felt like we needed to continue to have a rich supply of treatment options for patients. 

Around this time, as I was coming to this realization, that my former colleague and friend Jeff Engelman had moved to Novartis to lead the oncology R&D (research and development) at Novartis, and he actually ended up recruiting me to Novartis to work with him and to lead early clinical development. Initially I was actually quite hesitant to go in large part because of all of you, my patients, but I also realized that it would be an incredible opportunity to apply what I had learned and lead in the ALK space, so that I could help other patients in need with different types of cancer. I realized it was an opportunity to learn about all of the innovations going on outside of ALK space in order to bring some of those learnings back to ALK, hopefully in the form of new and different therapeutic approaches. So, about two years ago, I transitioned myself to Novartis Institute of Biomedical Research (NIBR). It is just right across the river from MGH and about a quick 15-minute ride. I currently lead a group of about 200 clinicians and researchers. We develop, design, and execute phase I, first in human trials of all different types of therapies, targeted therapies as well as immunotherapies, CAR T therapies, and even the new so-called radio-ligan therapies. We also treat all different types of cancers. Some of you know that I’ve been able to maintain my clinic at MGH. It’s very small, but I do come back every Thursday afternoon and I have a small panel of patients, some ALK, and some ROS1, and a few others. I have been really-really happy to be able to maintain my work with my former colleagues like Justin, Jess, and Ibi. I know, they have been doing amazing work continually to push all the ALK research forward. 

Q: We usually talk about brain progression but how does ALK affect bone progression? How do you treat patients who have bone progression?

Yes, you are right. We often speak more about progression in the brain, because we had shown previously, for some reason, ALK+ lung cancers have a propensity to spread to the brain. Fortunately, it is less of an issue now that we have such a brain-penetrant drug like Alectinib, Brigatinib, and Lorlatinib, although we still face this problem. But the truth about ALK is that it does tend to disseminate or metastasize early and often. Sometimes it is not just to the brain but to other organs as well. Bone is one of those organs that ALK cancer can spread to. I have had patients over the years, for whatever reason, we don’t understand, their progression tended to be primarily only in the bone. This happens for other patients with different types of lung cancer as well. How we manage that is typically through continuing to target ALK itself, because, of course, the cancer that’s growing in the bone is still the same ALK+ lung cancer. It may have acquired a resistance mechanism. So, if you have a patient on Alectinib and now they have primarily progression in the bone, we do a liquid biopsy. We sample and sequence the circulating tumor DNA, and, if we find a mutation like G1202R, we’re going to move on to a drug like Lorlatinib which should work everywhere including in the bone. But, there are other bone-specific things we do think about. So, for example, sometimes we will need to use local therapy, like radiation, because a patient may be experiencing pain at the site of progression in a bone. Radiation can be very effective at treating the pain.  Sometimes, especially if there has been a fracture or it looks like there is going to be an impending fracture, we may even have to involve an orthopedic surgeon, so, we actually go to surgery and stabilize that bone. The other thing I would say about bone metastases is that when a patient has progressive bone metastases, we do want to make sure their bones are as strong as possible. Using drugs, what we call bisphosphonate drugs like zoledronic acid (Zometa), is very important. It has been shown that those type of drugs decrease the risk of skeletal events like fractures. So, these are important treatments to be aware of besides the therapy for systemic disease such as another targeted therapy, or maybe chemotherapy, or a trial. Also, radiation could be indicated. Surgery could be needed. Of course, keeping the bones strong is very important to keep in mind. 

Q: There have been some questions about therapy and how you handle availability issues. One of our friends in Germany said there are not always the same options available internationally as there are in the United States. In the States, sometimes maybe doctors even take a little bit of risk and try things that maybe they wouldn’t do because there’s not actually published data on these yet. One of these things is dose escalation. Would you ever say that someone could start on a low dose of TKI and work their way up according to progression? If they reach the maximum dose, would they be okay to go beyond that to see if it would work?

So, you are really getting at how we personalize even the dose of a targeted therapy based on an individual and their own sort of medical condition. We do that to an extent. I would say that all the medicines that we use for ALK are approved at a standard dose. That means that the standard dose was established in the clinical trials based on looking at the safety and looking at the exposures of the drug that were reached in patients. Oftentimes the standard dose is based on the pharmacodynamic effects, meaning that we were able to show how effective the drug was, and that ALK was fully inhibited. Usually it’s our hope that the standard dose really represents the best balance of safety and efficacy, but what we’ve seen over the years is that it’s hard to find the right dose because everyone is different. So, just as an example, Ceritinib was one of the first second generation inhibitors approved that is not used very much anymore, but it was a good learning case, because of the dose that was selected. When you go back in time to when we were just developing Ceritinib, we had very few other options for patients failing on Crizotinib, so, there was a huge rush to make this drug available to patients. I think in the rush of developing Ceritinib, the sponsor or the drug maker, could have done additional studies which could have honed in on the right dose. But, there were really eager patients everywhere around the world clamoring to get access to this new drug, so, they chose a dose of 750 mg once daily fasting. I think, most of the investigators who worked in that trial knew it was too high of a dose, and so, even though it became the standard dose, I think, many of us were concerned, because very few patients could tolerate that standard dose. In the end, what happened was that most patients, if they even started on the standard dose, would definitely have to reduce dose. Those of us who worked with that drug knew that they would need to be dose-reduced, so we started treating at a lower dose. We already were making some modifications based on our own experience. I would say that played out for many of the other ALK inhibitors, especially for Lorlatinib. Many of you may be on the Lorlatinib standard dose of 100 mg once daily. Again, many of us who worked in the phase I trial felt that was going to be too high of a dose. In fact, it’s more likely that the needed dose was chosen because the sponsor was really hopeful that we could also inhibit one of the resistant mutations in ROS1, but for ALK Lorlatinib was incredibly potent, and even 75 mg was just as potent, yet 100 mg was the standard dose. Again, I think Lorlatinib is a good example where probably the standard dose is a little too high for most patients, so, I routinely start patients at 75 mg rather than 100 mg. What about starting even lower, Gina? Because you were saying start low and then bring it up according to what’s going on with progression? That we don’t do, because, if you start really low, like at most kind of sub-therapeutic levels, then the worry is that you could very gradually cultivate resistance because the cancer cells aren’t being exposed to really therapeutic or highly efficacious doses. So, when we dose-reduce, I would say, if I start at a slightly lower dose, it is still at a very active dose, one that has shown previously in clinical trials to be very active, and patients will have almost certainly the same outcome as if they started at that slightly higher dose. Now, I don’t start too low, but I start oftentimes one dose level down based on sort of experience in clinical trials or clinical trial overall experience. We do the alternative, which is to do dose escalation in some cases, particularly with drugs like Alectinib. Many of you may be on Alectinib, so you are familiar with Alectinib, and it is very well tolerated at the standard dose of 600 mg twice a day, but at 600 mg twice daily, it covers the body really-really well; it also covers the brain but not quite as well. So, many years ago, we had seen that we had a number of patients on standard dose of Alectinib who were starting to have a bit of breakthrough in the brain. So, a spot in the brain would start to grow back, and what we found was that, if we brought up the dose of Alectinib higher than the standard dose, for example 900 mg twice daily, which had been tested in clinical trials, we actually could induce regression again in brain metastases. So, we had a whole series of patients like this and we published on it. I would say, for Alectinib that’s quite routine for us now that, if we have a patient who has CNS brain only progression on Alectinib, if everything else in the body looks good, oftentimes our first approach may be to escalate Alectinib dose up to 900 mg. Of course, we have other options like SRS or radiation therapy, but I think if SRS is not an option, than Alectinib dose-escalating can be highly effective. I think we have flexibility. I do sometimes like to start at a slightly lower dose that is just as efficacious, but I don’t start too low, and I do sometimes escalate, especially if there are issues with brain penetration, brain progression only. 

Gina (moderator): This is about personalized medicine and personalizing toward patients, so everybody’s situation might be a little bit different.

Dr. Shaw:  I mean, it would be great if we had a blood test that could tell us the drug level is right and, in fact, some cancers, for example, GLEEVEC (a medicine used in chromic myeloid leukemia, CML), they do test drug levels. I wish they would do a test for drug levels. Over the years, I have had many patients ask me, “Can’t we just test my level of Lorlatinib to see if I am actually at a therapeutic level?”. We don’t have a way to do that, but I wish that we did.

Question: A lot of ALK+ patients continue on living and you know a lot of us are younger so some are having families and things like that. I wanted to see if you could address fertility in men and women on TKIs in general. 

It’s a very complicated question. I think that ALK does play an important role in an early neurodevelopment of a fetus, so, we do feel that, certainly, we would never treat, for example, a pregnant woman with an ALK inhibitor, because we would worry about the impact of the ALK inhibitor on the developing fetus. Now, in terms of male and female fertility, you know, we don’t know the real impact, because you guys probably know, on clinical trials part of the informed consent form is that you can’t actually get pregnant or father a child while you are on a clinical trial. That was because we worry about the potential impact of any new drug on an embryo and a developing fetus. So, we don’t know exactly the impact on fertility, but we generally do advise that you don’t have children while you are on an ALK inhibitor, I would say, especially for the mom, because, of course, the baby is inside the mom for nine months and that’s when they are going to be susceptible. For dads, the guidance is that men should also not father children while they are on a ALK inhibitor, but I have over the years had an occasional male patient who did father a child when he was on a commercial ALK inhibitor and not on a trial, obviously, so, I know that’s possible. But, again, I never had any sort of data on their fertility or anything like that. It’s a very complicated question. Usually, what we do at the time of diagnosis is, if we have a young woman or man and we know that they are interested in a family down the road, we do have a meeting with a fertility specialist right away, so that is something you should definitely keep in mind.

Q: We also have heard of decreasing testosterone levels?  Are there decreasing estrogen levels too?

Not that we have seen. We’ve seen decreasing testosterone levels with Crizotinib, and, in fact, it was primarily the total testosterone levels but not the biologically relevant free testosterone. So, keep that in mind, it was with Crizotinib and not with other ALK inhibitors. 

Q: Can you bring us a little bit of hope and tell us about the things that you think are the most promising pipeline drugs after chemotherapy when Lorlatinib fails us? What’s next?

There’s a lot coming in the pipeline for ALK. Starting with ALK itself, I mentioned earlier about a new class of 4th generation targeted therapies that have been designed specifically to overcome double or triple - what are called compound - ALK resistance mutations. Just a little bit of history on this. When we were developing Lorlatinib, I had been starting to see patients developing resistance to Lorlatinib. We were doing biopsies on patients, and we found that a number of patients who had received - almost all of them actually had received - sequential ALK inhibitors like Crizotinib -> Alectinib -> Lorlatinib, or Alectinib -> Brigatinib -> Lorlatinib, and what we were finding was about 20 to 25 percent of patients were acquiring two or sometimes three ALK resistance mutations. We went on to show that these ALK mutations were accumulating after each ALK inhibitor, one after another in sequential fashion. At that time (this is a number of years ago), I probably shared this early data with Jean Cui, who some of you know has been an advisor and designed, developed, and made Crizotinib. Jean at this time started Turning Point Therapeutics. She is a brilliant medicinal chemist, so she actually started to design molecules that could specifically overcome these compound mutations that we saw in the clinic. So, many of you know that TPX-0131 has entered phase I clinical trial last year. That drug again is a specific ALK inhibitor designed to overcome particularly compound mutations that include G1202R as one of the mutations. There’s also another 4th generation drug called Nuvalent. I had also started working with Nuvalent when we were seeing these compound mutations emerge. So, Nuvalent also has a 4th generation drug that should enter the clinic second half of this year. But, one thing to just take note of is that these new ALK inhibitors are very specifically designed for these compound ALK mutations. We know that they may have potentially less activity against certain single ALK mutations, and I actually think their role may be somewhat limited to at least a fraction of patients after Lorlatinib where we have a biopsy, either liquid or tumor, that shows the presence of these compound ALK mutations. I just want everyone to know that it’s not like it’s going to be a new ALK inhibitor that can work on all patients. It will probably work on a subset of ALK patients after Lorlatinib. 

Now, there are many ways to think about targeting ALK. I know, when I spoke at the ALK Summit in Aug 2021, we talked about PROTACS which are proteolytic targeting chimeras and just basically a new type of approach to targeting ALK by degradation within the cell. There are a number of PROTACS for ALK that have been described pre-clinically, so, that could be an approach to think about if you could just degrade all of the ALK. That could be another way, an alternative approach to the Tyrosine Kinase Inhibitors (TKI) like Alectinib or Lorlatinib. I would say, the challenge with these PROTACS is that they still require some binding of ALK, and oftentimes the binder is a molecule like Ceritinib or Lorlatinib. So, again, mutations can arise that now prevent binding. So, I think, the degraders are also going to run up against the problem of resistance. Then, the last thing I will just mention around ALK itself. You know John Iafrate who has spoken to you in the past about his project. He is going after not ALK but after the partner protein EML4, and he is working with another investigator at MGH (Mass General Hospital) to target very unique cysteines within EML4 that are required to dimerize together, to come together. And if you can target these cysteines and prevent dimerization, than ALK can no longer be an active oncogene. So, this is a very distinctive mechanism of targeting EML4/ALK that is quite interesting. Again, though, at some point, if this work progress continues on, it may still run up against a problem where the cancer can mutate the cysteines that are targeted, and now, again, it have basically averted this drug. So, I think, these are interesting approaches to keep in mind. I think resistance is always there. So, what that automatically makes me think about is that combinations are going to be really critical, so as to further decrease the chance of a cancer becoming resistant. Combinations can be much more able to do that than a single drug can do alone. 

Then, beyond just thinking about how you target ALK, I think, we really have to go beyond ALK and think about ALK inhibitors. For example, our TKIs are really an anchor, and with that anchor we need to add other drugs, maybe other targeted therapies, maybe other types of modalities like chemotherapy or radiation therapy, because resistance is just so complicated. So, we know we’re not going to be able to prevent resistance just with these ALK TKIs. We have to be a little more creative, a little more ambitious, a little more risk-taking, and think about these types of combinations. I think, many of you know that we already have a number of combinations in the clinic. We’ve been targeting for example, ALK and MET because MET is known to be amplified in roughly 15- 20% of patients after Alectinib or Lorlatinib, and MET can drive the resistance. So, we already have a study combining ALK and Met inhibitors. We also have a number of trials combining ALK and MEK inhibitors, so we are trying to target downstream of ALK as well. Some of you may know that two trials are in the clinic targeting ALK and a protein called SHP2, an important downstream regulator that is involved in the MAPK pathway as well, so, again, a kinase pathway downstream of ALK. I think, these types of combinations are really important, because this MAPK pathway has been shown quite critical in terms of reactivation and drive resistance. Then, there are some other combinations, just to keep in mind. We and others have developed targeted therapies for a molecule called YAP. YAP is a downstream transcription regulator in the Hippo signaling pathway. There’s a lot of data, preclinical data out there now, saying that activation of YAP can enable cancer cells to survive even though they are being exposed to targeted therapies like Alectinib, for example. There is even some data showing that YAP can drive resistance. So, something to keep an eye on are these YAP inhibitors that have just entered the clinic of Novartis.  I should be clear that they are being tested currently as monotherapy, by themselves, but the hope is that there is encouraging early data that those YAP inhibitors could be great combination partners for targeted therapies like ALK inhibitors. Last thing that I will just return to is that I mentioned that, besides these sort of other novel combination partners, I don’t want people to forget about traditional therapies like chemotherapy and radiation therapy. We already have data that chemotherapy can combine with EGFR targeted therapies in the first line setting and improve progression-free survival and likely overall survival as well. Many of my patients also have incorporated radiation into their regimen where we try to use radiation to eradicate any residual disease and also to treat solitary sites of recurrence. So, just to keep in mind, what I said earlier about the use of orthogonal therapy, targeted therapies, and other types of therapies to further reduce the bulk of the cancer and eliminate residual disease or persisting disease. 

Q: Can you address cellular therapies like TILs, and how do those fit in with ALK?

I guess, you are getting at immunotherapies right now. How do we see immunotherapies for ALK? As I mentioned right off, unfortunately, drugs like Opdivo and Keytruda do not work well in ALK patients. There have been many retrospective studies now and even some clinical trial data showing that ALK patients really do not respond to immunotherapies, highlighting that we need different approaches to activate the immune system in ALK patients. You mentioned one approach which is around TIL (Tumor Infiltrating Lymphocytes). There are a number of companies, Iovance is one of them, that have been advancing this TIL technology. Many of you know that what they have seen so far, particularly in melanoma, is quite exciting. Basically, there’s a surgical specimen of cancer that’s removed and the TIL are extracted and expanded and then reinfused into patients. So, these tumor infiltrating lymphocytes contain these killer T-cells that, hopefully, once they are expanded and now reinfused, can exert their anti-tumor activity. As I said, the activity they have seen in melanoma especially in the first line has been quite impressive. There has been data as well in non-small cell lung cancer, and I had seen some data that included EGFR patients as well, where some did have a response, but I would say overall there is still a lot of work on TIL technology. My worry about ALK in particular is that ALK+ cancers tend to be “immune deserts”, so, there are not really very many infiltrating T-cells in our ALK+ cancers. This TIL technology relies on the presence of these lymphocytes in the tumor. They have to be expanded and re-infused, so, if you really have none of these lymphocytes in the first place, the whole manufacturing process is going to be at risk. So, it's definitely something to keep an eye on, but I do think that is going to be potentially quite challenging for ALK, just given the baseline. Now, some of you know that ALK+ cancers are simpler than other lung cancers. Right? They are not smoking-induced, and they don’t have the genomic complexity of the typical non-small cell lung cancers. Because they are kind of quiet and don’t have a lot of differently looking proteins on them to trigger an immune response, I think, we need to understand more about the immunophenotype and the immune landscape of ALK + tumors. I think many of you know that Justin Gainor and Jess Lin are working on the ENIGMA project, and part of that is to profile as many ALK+ cancers as we can to understand what are the neoantigen landscapes. What are the altered proteins that are in ALK+ cancers? I think that type of work is going to be really crucial to develop immune-based strategies for ALK patients. 

Q: When you look at all these things together, what is the thing that will let us get past TKI resistance, and do you think it is even possible for us ever to make ALK+ cancer into a chronic disease?

I do, and I think I mentioned early on that I have had patients now who - of course they are not the norm, but I have had patients - have been able to continue in full remission basically on a single ALK inhibitor. It could be Crizotinib for over 10 years. It could be Alectinib they are on now for over 8 or 9 years. Also, if they are on Lorlatinib for over 5 years. The fact that even some ALK patients can achieve these incredible durable remissions gives me hope that, if we could understand the biology of everyone’s ALK+ lung cancer, we would have a much better shot at basically making the disease more of a chronic condition, like what you are saying. But, unfortunately, monotherapy with a TKI itself for most patients is not the answer. I think, to make it this sort of a long-term chronic condition I really think what I am envisioning is that we really will have a shot at making ALK+ cancer chronic once we incorporate more treatment modalities beyond just the targeted therapy. And that is why I do think I envision for the future that we start with the best therapy upfront and, hopefully, at some point, one day that will be actually a combination of something that will hit ALK but also hit the pathways that we think are most important to drive resistance or drive residual disease which then leads to resistance. Then, after we start with the most aggressive therapy upfront, we still have to come in again with some type of different therapy and orthogonal therapy to eliminate any residual disease, some of which we can see on scans and some of which we cannot. So, we may use radiation, we may need alternative medication to go after these drug-resistant cells. I also think we really need to have better monitoring when patients are on ALK inhibitor therapies and even on these combinations.  We should adapt treatment at the very first sign that resistance is starting to emerge rather than let it becomes a full-blown clinical relapse, but at the first sign of molecular detection of the relapse. We add a therapy or we switch therapies because it’s always so much easier to treat early on rather than when it becomes clinically overt. So, I am really hopeful that we will get there, but it’s going to be not as simple as just one therapy or one therapy after the other. It is going to be multi-modality approach that we need to take. 

Question: The molecular changes that happen through circulating tumor DNA or liquid biopsy are really becoming more common. People will do liquid biopsies on progression. Can you just address liquid biopsy and its potential to really detect cancer at an early stage?

We do use liquid biopsy quite a lot these days. Typical example is that we have patients in the clinic who have been doing fine on their targeted therapy, but their latest scans show that there is likely some progression going on in the lung or the liver. There’s some change. Oftentimes in the old days, before we even had circulating tumor DNA, we would be thinking about a biopsy and working with interventional radiology to perform an ultrasound-guided biopsy, but these days we do have access to a number of different platforms to analyze circulating tumor DNA, and that oftentimes can be revealing if the cancer is actually shedding some of the DNA into circulation. We can capture it and sequence it, and then sometimes that can tell us what is driving the resistance, the progression that we are seeing on scans. So, I think, in that setting you have now visualized the disease on a scan, what we call macroscopic recurrence, and circulating tumor DNA (ctDNA) can be helpful. But, what you are getting at is that how could it be detected even earlier?  As I was just saying, I think that’s really the key, because we want to detect recurrence as early as possible. I do think it is more actionable when we have much much less disease, and so there are more and more sensitive technologies that are being developed to try and detect even the tiniest quantities that are there of these mutations. I think there will be more and more testing of these new technologies, and they will need to be tailored to each patient’s cancer to actually be able to detect it at such low levels. I think this will give us an earliest view into what is evolving at the levels of cancer cells instead of waiting just for the scans to tell us. So, I would keep an eye out for these new technologies.

Question: Some of us are staying on targeted therapies for years. Do you foresee any problems with that? Do you see long term side effects of targeted therapies?

I am not sure how many folks are even on Crizotinib at this point but with Crizotinib we definitely do have a lot of long-term cumulative side effects. Edema, for example, is very common with Crizotinib, and you can scan a waiting room and tell who’s probably on long term Crizotinib, because you look at their ankles and they have gotten huge, swollen ankles. So, Crizotinib is very well known for that as a long-term side effect. I have had patients on Alectinib for many years now, and the main side effect I see is that they are not progressing, they are not getting worse, but they kind of persist with fatigue, low grade anemia, for example, not requiring intervention, but a little bit lower than baseline, and maybe some edema and constipation with Alectinib, but, I have to say, overall for the patients I have had on long-term Alectinib, I have been pretty pleasantly surprised that there aren’t really any accumulative or worsening side effects during the years that patients may stay on it. For Lorlatinib, it is similar in that there are some edema problems in some patients on long-term Lorlatinib, but not all of them will struggle with edema. But, I feel like once patients are on any of these drugs past a couple of years, many patients, of course, you guys, are so amazing that you kind of know, and you figure out how to manage these side effects well. So, I would have to see if I have many long term patients on these targeted therapies, and pretty much what you have in a couple of years is pretty much what’s going to stay with you, with the exception of Crizotinib where the edema tends to build.

Question: I want to ask you a little about your participation with the University of Michigan project. I am so excited, because I’m flying to Michigan, and we are going to actually get some cells harvested and generate some genomic mice. I’m super excited about that. So, looking at the personalization of medicine, this really brings me a lot of hope, because I’m kind of at a point where we don’t have any other therapeutic options that seem to be working for me. So, I just wanted to see if you could address your role in that and what you expect to happen from that project and how the project can help ALK+ patients.

This is an incredible gift from a patient, Judith Tam, to support ALK-focused research at University of Michigan’s cancer center. This is a whole team of physicians, scientists, engineers, pathologists, and surgeons, all working together, really focusing on ALK. Sophia Merajver is the lead investigator. Another one of the investigators is Peggy Sue, one of my former Mentees, who knows everything about ALK. Actually, the overall goal, I'd like to say, is to study ALK+ cancer to develop ways to predict the tumor sensitivity of ALK+ cancer cells to drugs, ideally in a rapid timeframe. And, of course, most importantly, as we are studying how these cancers develop, the goal is for those investigators to develop new therapies that will work for resistance. The program will have an advisory board, a scientific advisory board to provide high-level guidance. I feel so very honored to be on with Shirish Gadgeel, another ALK investigator whom some of you may know. This team has already been starting to work with each other in Michigan to spread the word and actually establish a network in connection with other ALK investigators, including my former team at Mass General. I just spoke to Peggy this past weekend, and I know she is going to come and speak to you guys here in March with other team members from Michigan. So, she will be able to get into more details about specific lines of investigations they are planning. It is really an exciting time and I think we are going to see a lot of progress very quickly.  We are so excited about that. Thank you so much Judith. 

Question: What about vaccines? Can you kind of address how you think vaccines fit into our treatment and if you think that is something that could potentially be an actual cure?

I have been kind of racing through here. But, as I was saying about combination approaches, multi-modality approaches, as I mentioned, targeted therapies, chemotherapy, radiation therapy. But actual immune-based therapies, which would include vaccines, I would also put into that category. I am envisioning the future is that, of course, we start with an ALK inhibitor, like I said, that’s our anchor, always the ALK inhibitor, but we build on that with, for example, another targeted therapy that shuts down the whole MAPK pathway. Then, we can use radiation to eliminate any residual disease that we see on scans, or maybe we combine that with chemotherapy. We are following closely for any signs of recurrence using really highly sensitive circulating tumor DNA technologies, and we also potentially incorporate immune-based strategy. Again, I think, when we have really low levels of disease, that could be the best opportunity to try and trigger an anti-tumor immune response that could very well be done using a vaccine. There are other ways to activate the immune system as well, but, since you asked about vaccine, I think many of you know that Mark Awad, again, one of my former Mentees, has been working on an ALK peptide vaccine for a number of years. He’s teamed up with Roberto Chiarle at Children’s Hospital as well as a biotech company, Elicio, the company that’s focused on vaccines for cancer patients. There is a lot of pre-clinical work supporting the potential efficacy of these peptide vaccines, and these are ALK+ models, mouse models, but the hope is that all will translate well into human patients. They have been working very hard, and Mark told me that they have even better potential peptide vaccines right at this moment that they are going to progress forward. Likely, by the end of the year, the hope is that they will be able to submit to the FDA plans to start the phase I trial soon, so, we are looking at maybe another year or so. I think, one of the challenges here is how we will best test an ALK vaccine. We test in a fully resistant setting, but probably not because it will be very hard to rely on a vaccine by itself to overcome all resistance. Perhaps we test it in combination with an ALK inhibitor? Or we test it in combination with a checkpoint inhibitor like Keytruda or Opdivo to further enhance the chance that you activate the immune system? So, I think there are a lot of design questions as well, and I am very hopeful. Again, if we can understand the immune landscape for ALK+ cancers, if we have a number of different “shots on goal”, a vaccine approach, for example. There are other approaches that we could take to perhaps engage the immune system by a bi-specific type of antibody approach where you are basically bringing activated T-cells close to the cancer, if you can find an ALK specific protein that you can target with this strategy. There are a number of different strategies, I think, that we can take to try and activate the immune system. I do think that it will turn out to be an important component of the multi-modality approach that we take for ALK in the long run.

Question: One of the things that I asked you if it was okay to ask was about Linnea, because she was a hero to many of us, and I know as her physician, it must have been incredibly hard to lose a patient. How do you handle that? We are so thankful that you are here, and you are in this space, and you are doing this but this situation must be incredibly difficult, because she was so amazing. So, I just wanted you to talk a little about Linnea.

Some of you probably knew her, but some of you probably did not. I do think, Gina, like you said, she was really amazing. I cared for her for over 12 years, and I think many of you, who knew her or read her blog, knew that she was not just a lung cancer patient. She was a survivor and a passionate lung cancer activist. She liked to use the word activism. She had incredible insights, and she could share them so articulately both verbally and also in her writing. She was a really talented artist who painted some beautiful paintings. She was a devoted mom of three children. She cared so much about people; that was really something that always struck me. Despite the fact that, obviously, Linnea had her own health issues, she was always trying to help other people. Just such a kind, genuine person. I often have described her, I think, even when we did the tribute at her celebration, I have described her as my hero, and, I think, she probably is a hero to those of you who knew her as well. Just an incredible beacon of hope and inspiration. Her passing was really really hard and very painful, I think, for many of us. The other thing I wanted to share about Linnea is, if you followed her blog, you know all this, but if you don’t, just to say that Linnea was also so brave and courageous. Back in 2008, she had no idea, she didn’t know much about phase I trials. Obviously, no one knew anything about Crizotinib. She was the 4th patient ever to go on Crizotinib, but, you know, she jumped at the chance to go on this clinical trial. She volunteered basically to go on a drug that had very little information behind it at the time, and she did so well on Crizotinib, and this gave her courage to do many additional trials. She ended up participating in a total of 6 phase I trials. So, think about that. She was basically pivotal in developing not just Crizotinib but also Ceritinib and Lorlatinib. She was one of the first patient on each of those drugs. I think, she just shared her experiences so freely. I think she really showed people that phase I trials are really important to us. They are scientifically driven studies. They are your only access to potentially new medicines that can be transformative. So, in addition to being my hero, I also think of her as a trailblazer, really redefining what phase I trials should be and highlighting how a phase I trial can be transformative for patients. It has been hard to lose Linnea and other patients as well. I mean this past year has been pretty hard actually. We have lost a number of amazing patients. I would admit that it’s very easy to sometimes kind of get lost in the grief of it, but it is important to remember all the positives. I know Linnea would want us to remember the positives. She lived with her cancer. She was diagnosed I think 16 years before. I think, 2005 was when she was first diagnosed and during that time Linnea lived really well. She was able to create incredible memories with her loved ones, and they have, and all of us now have, a lasting legacy of Linnea. So, I have worked hard over the years to always think about the positives and try to channel the sadness and grief into something that’s productive and meaningful, be it a new avenue of research or an opportunity to teach others, an opportunity to collaborate with others. So, I think in some ways the loss that we all experience can be motivating to many of the researchers. It reminds us of the urgency that patients are all waiting. So, I hope that answers your question. It’s very sad but I want to make it into a positive thing for the memory of these patients.

Gina (moderator):  I think, one of the things that makes you two so much alike is that you, like Linnea, care so much about patients and about people. If that heart wasn’t there, then I think you two wouldn’t have been such an amazing duo.

Compiled and transcribed by: Alice Chou

The original ALKtALK session: https://www.youtube.com/watch?v=JWxCq3T6S4s