Dr. Jessica Lin and Dr. Ibiayi Dagogo-Jack at ALKtALK

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Dr. Jessica Lin

Attending physician, Hematology/Oncology, Massachusetts General Hospital

Instructor, Medicine, Harvard Medical School

Dr. Lin: I first began interested in oncology in my undergraduate years. I started out as a biochemist, but I met a mentor who was a pediatric oncologist who also worked in basic research. He really inspired me and made me interested in medicine and taking care of patients.  So, I went to medical school. I actually tried my best to explorer other specialties but could not find an area where I felt as passionate than oncology. The patients that I met, the mentors that I met on the way were the two most critical factors that influence my decision to be in oncology.

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Dr. Ibiayi Dagogo-Jack, MD

Associate Professor, Harvard Medical School

Attending Hematopathologist, Department of Pathology

Children’s Hospital Boston

Attending physician, Hematology/Medical Oncology, Massachusetts General Hospital

Instructor, Medicine, Harvard Medical School

Dr. Dogogo-Jack: I never realized that we (Dr. Lin) have such a similar path. My family lives in Tennessee and there’s a St. Jude Children’s Hospital. One of my neighbors actually works at the hospital. So while I was in high school and undergraduate, I was in the hospital doing lab work and volunteering in the pediatric hospital. It is a very inspiring place, with a wall of success stories. When I went to medical school and saw that is not the case for adult oncology, I wanted to make the difference. Meeting patients and mentors along the way lead me to be on this path.

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Dr. Jessica Lin and Dr. Ibiayi Dogogo-Jack explain their new clinical trial combining Lorlatinib with a SHP2 inhibitor, TNO155.

Dr. Dagogo-Jack: It is very fitting that we are discussing this topic with ALK Positive group because it is your fundraising efforts and support that brought this trial into fruition. We are constantly seeking feedback.

This is a complex combination, and I would like to go back and explain why this combination was chosen.

Our experience here at Mass General is shown here on the slides. (Slides were shown on the screen during the ALKtALK beginning at the 5:22 mark of the recording, which is posted on our YouTube channel here: https://www.youtube.com/watch?v=ugX1otfvRO4&t=19s.

If we looked for mutations after the failure of a 2nd Generation TKI (Alectinib, Brigatinib, and Ceretinib), we find that about 54% had ALK Kinase Domain mutation, MET amplification at 16%, and 30% of other/unknown resistance mechanism. Most of these changes are still ALK dependent changes.  About 40% of patients develop an ALK-independent change.

However, this shifts as you look at the reason why one fails after Lorlatinib. We find that 33% had ALK Kinase Domain mutations, MET amplification is at 22% and 45% of other/unknown resistance mechanism was found.  After Lorlatinib, only about 1/3 of the patients still has ALK dependent tumor. 2/3 of the patients now have ALK-independent changes in their tumor. The best way to attack ALK-independent tumor is to not use another ALK TKI but to find a combination that allows more blockage to those extra growth signals.

A slide was shown with most basic yet numerous proteins involved in ALK signaling.

There are 3 important downstream signals that an aberrant ALK protein activates: the PI3K/AKT pathway, the JAK/STAT pathway, and most importantly the RAS/MEK pathway.  All these pathways lead to cells to proliferate and survive.  When your tumor is sensitive to an ALK TKI, it is enough for the TKI to block the ALK protein effectively enough to block all three downstream pathways.  With the ALK-independent change, other signals are recruited by cancer to continue growth.  We are continually studying what these signals can be. There are many that have been described in literature:  EGFR, FGFR, HER2, and MET.  I have only listed a few here. These are some other growth proteins in addition to ALK that was found to drive cancer. A given tumor may have a multiple of these proteins.  Not all patients have the same types of bypass signals. So, if you have a bypass pathway or an ALK-independent mechanism, it is not enough to just shut down ALK with an ALK TKI because all these other pathways can activate these downstream pathways even after shutting down ALK.  Most interesting, in the laboratory, we have found that RAS/MEK pathway is one of the most important one to be shut down. The entry point to that pathway is a pivotal protein called RAS. For RAS to be turned on and signal, RAS need a whole bunch of other proteins and one of these proteins is SHP2. So, for this particular clinical trial, we are looking to block SHP2, hoping to block RAS from being turned on.  Even with extra signal from the bypass tracks, RAS is not turned on enough to help the tumor cells to grow. So, that’s the basis of what we would like to accomplish in this clinical trial.

Stepping back, using an ALK inhibitor, we block the ALK from activating all the downstream pathways. If you have a bypass pathway, we can give an EGFR or HER2 specific inhibitor but you do not know exactly which pathway is the bypass pathway. The test that we use in the clinic, next generation sequencing (ngs), tumor genotyping, and molecular profiling doesn’t usually give us an answer. So the rational is to pick a protein that is important for all these pathways and to shut it down with the hopes that we can benefit more patients.

Some of you may be familiar with our Lorlatinib combinations studies. This Lorlatinib and SHP2 inhibitor is one part of this protocol.  This protocol is currently open. We have already started the study using Lorlatinib with combination with Crizotinib (an ALK inhibitor but also a MET target pill). Another arm is Lorlatinib with Binimetinib, which is a target to a different pathway that we did not discuss here.

We are adding this new arm with TNO155 in a few weeks (phase 1) dosage right now.  We are trying to figure out if it is safe to do the combination and what is the best dose to use in combination. We are using blood and tissue samples to select the correct group of people in the future. After we figured out the correct doses, we will go into phase2: Dose expansion. I am highlighting this because this combination is mainly for people already had Lorlatinib and is progressing on Lorlatinib alone.

In general, most Lorlatinib single dose is at 100mg, in this study, we are using Lorlatinib at ½ dose (50mg) because we really do not know how these drugs will interact with each other. So, for our phase 1, we will start a low dose then escalate up. Another thing I want to highlight is these two medicines are oral treatments, pills. We are hoping to start enrolling patients in the next two to three weeks.

Questions specific about the combination trials.

Q: What are some of the qualifications to be able to enroll in this trial? Do you need measurable lesion? Can you go onto the trial after you had chemo?

Dr. Dagogo-Jack: This trial was developed irrespective of your chemo history. All are welcome regardless of your chemo history. We initially want to have patient who does have measurable disease. So, in our phase 1 trial, we want to know how safe it is but also how well it works. To achieve that, we need some types of measurable disease to access the response. Technically, we do not need multiple sites, just one area where we can evaluate for response. However, it will be different for phase 2 where we really looked for how effective the treatment is.

Q: Is there any preliminary mouse data?

Dr. Dagogo-Jack:  Yes, we do have mouse studies and cell line studies.  I did not show that slide because it would be delving down too deeply for this talk. The mouse studies and the cell line studies are why we are so excited about this trial. In short, there was an experiment where a post-doctoral fellow took a cell line that originated from biopsies with resistance to an ALK inhibitors, if you give them more ALK inhibitors, the cell lines continue to grow. However, when you selectively block certain proteins such as EGFR or FGFR, you can get the cell lines become sensitive to treatment again. If you look at samples across 10 patients, the protein that needs to be blocked are so different between patients. Sometimes, you will even need to knock out three proteins.  One important observation is that if you knock out SHP2 then the majority of the cancers were affected.

Q: Can you compare a MEK inhibitor vs a SHP2 inhibitor?  Do you think one is more promising than another? Does it depend on the patient?

Dr. Dagogo-Jack:  These two inhibitors are both targeting the RAS/MEK pathway.  But when you look at the data from other tumor types (a KRAS lung cancer for example) it seems blocking SHP2 is more effective. The reason we hypothesized is that SHP2 may cut off better this pathway better than MEK inhibitor. We do think the side effects between the two are going to be similar because you are targeting essentially the same pathway. Some side effects that we tend to see are gastrointestinal, nausea, diarrhea, and some heart effects. There is a little more nausea and diarrhea on the SHP2 inhibitor when compared to the MEK inhibitor.  So we monitor patients very closely for all these side effects on either of these drugs. Most of the effects are reversible but it can change the way your heart functions. This MEK protein is expressed in the eye so it may lead to changes in the eyes so we will monitor your eyes more closely. That eye change is more commonly seen in MEK inhibitor than SHP2 inhibitor. So, there are some similarities and some differences between the two medication. We are still figuring it out.

Q: What about brain penetrance?

Dr. Dagogo-Jack: We are still learning. By the time a medicine gets to a clinic setting, the medicine has gone through several alliterations.  We found out in the preliminary experiments, if we target MEK with high brain penetrance, the drug can cause a lot of side effects.  So, on purpose we did not make MEK inhibitor that can penetrate into the brain. We are still learning for the case of SHP2 inhibitor.  Since we don’t know, for this study, for anyone with brain progression, the patient must be treated first, especially if they progressed on a powerful brain penetrance drug like Lorlatinib.

Q: How many people accepted into trial?

Dr. Dagogo-Jack: When you are in a dose escalation study, you are limited by how quickly you can put people in the study.  We will enroll people in a group of 3. We want to make sure the three people can tolerate the medication before we enroll more people. For the dose escalation phase of the trial, we expect to enroll about 12-15 people staggered in 2-3 months. In expansion part of the study, we hope to enroll about 25 people. But we want to do the safe thing and right thing to do, we will pause after the first set of 10 people wait and then enroll the next set of people.

Q: If a patient has lots of Lorlatinib side effects when they were only using one drug alone, would you suggest this combination study?

Dr. Dagogo-Jack: I think it will be tough. One of the eligibilities is to be able to tolerate Lorlatinib at 50mg. The combination of two drug may introduce more toxicity than one drug alone. For example, this trial may see some enhancement of some Lorlatinib side effects such as edema may be worse in combination. Both Lorlatinib and SHP2 inhibitors has some edema issues by itself for some patients. The patient must have good conversation with their oncologist about which side effect you are having.  We are not expecting the neuro-cognitive side effects, slower speech, and slower processing to be worse in the TNO155 trial, but some other side effects may be magnified in the combination.   

Dr. Lin: If a patient is struggling with the lowest dose of Lorlatinib, I would not expect the combination to be easier to tolerate, right? That should be a good inkling for you to see if the combination trial is best for you. If you found Lorlatinib monotherapy to be that challenging and you had to reduce to the lowest dose (50mg) and the side effects were still debilitating, then you will still expect Lorlatinib in combination should have at least similar or more side effects.

Q: How do you decide which arm of the clinical trial would a patient be placed? Especially if no sub-mutation was found because difficulty of biopsy location or nothing was found by the biopsy?

Dr. Dagogo-Jack: It is a very good question for a clinical trial with multiple arms. Are we going to randomize? Or are we going to pick who gets what arm? For the MET amplification arm, it is a biomarker selected arm.  You should have a MET amplification before you go to that arm.  For the others, we are basically putting patients in based on slot availability. Recognize some patients might be more responsive to a MEK inhibitor vs a SHP2 inhibitor, we have actually not limited the ability for a patient to cross over from one arm to another.  So, if the SHP2 inhibitor did not work for you, maybe you can go onto the MEK inhibitor arm and vice versa. Ultimately it will come down to slot availability.

Q: If a patient crossed over from one arm to another, would they count as “one” in the trial?

Dr. Dagogo-Jack: Yes. But we also created leeway for the trial called “backfilling.”  We recognize that for some people there are not a lot of other viable therapy left for them and this is something we really believe in or a patient is really excited about this trial. If we know which dose is safe, in rare instances, we do have the option to give a dose of the drug to the patient using the dose that we have already explored to be safe.  

Q: Is this study only be offered at Mass General?

Dr. Dagogo-Jack: Yes, it is only at Mass General for time being and some at Dana Farber as well.

Q: Is there any ability for you to do remote participation?

Dr. Dagogo-Jack: The trial is only in Boston.  We are trying to do as much as possible remotely.  Because this is a new combination, we have to keep a close eye on it, be more vigilant to capture all the side effects, and address them more quickly.  For this trial, it does require patients to come to this site physically.  Hopefully as the patient have been on the trial for a longer period of time, there will be more flexibility to space out each visit and perhaps some virtual visits.

Q: Has SHP2 inhibitor been used in other drug combinations for other cancers? Are there any results for those yet?

Dr. Dagogo-Jack: It is a very good question. That’s why initially I said the combination study is open already but we are just introducing this arm of the study right now. We had always wanted to put this arm into the study but this SHP2 inhibitor is a brand-new drug whereas the other drugs are known drugs that was used for other indications.  For the brand-new drugs, it must go through a test trial by itself. That has happened up to this point.  The reason why we are cleared now for this combination trial is because company is doing a trial using SHP2 inhibitor and EGFR TKI combination right now in parallel to our study.  So the company already observed that it was safe to be combining at this dose with another inhibitor. At least in lab, SHP2 combined with EGFR is more effective than alone.

Q: Which company makes TNO155?

Dr. Dagogo-Jack: Novartis.

Q: Has the combination trial with EGFR TKI started yet?

Dr. Dagogo-Jack: Yes, it has started. In the future, there will be combination with KRAs inhibitors too.

Q: You mentioned that it is probably not brain penetrant. Based on its molecular structure would you suspect that this inhibitor is brain penetrant or not?

Dr. Dagogo-Jack: I suspect that this inhibitor is probably not penetrate the brain significantly.

Dr. Lin: Can you repeat about the importance about patience with brain metastasis eligibility for the trial?

Dr. Dagogo-Jack: If you had prior treatment with Lorlatinib or another brain penetrance inhibitor and the cancer has grown in the brain in that setting, then you must have to had the brain metastasis treated before joining this trial.  Two reasons: we do not know if this medicine will penetrate the brain. Also, we do not want to risk the brain metastasis growing and progressing while you are on trial and causing you more symptoms.

Q: If someone is on chemotherapy now and is doing okay. Is it possible to pause chemotherapy and go into this trial instead? Maybe it will be less toxic?

Dr. Dagogo-Jack: It is possible.  As long as you are tolerating your chemotherapy well, we always value every single therapy we have. So, I would not necessarily recommend someone to interrupt chemotherapy for this study because we do not know how well you will tolerate this medicine in this study.  We do not know how well it will work. Hopefully, the study is still here after you are completed with the chemo.

Q: Assume you get the best result ever, how long do you go before a phase 2 trial? How long for phase 3? Do you foresee something like this as a 1st line with combination with an TKI?

Dr. Dagogo-Jack: These are all very important questions. That is why we are interested in investigator-initiated studies. Pfizer and Novartis (pharmaceutical companies) are interested in this as well. Hopefully, we can see some promising signal to have a great response for a long time. Then the correct strategy is to do a multi-center study where you can enroll more patients and get a greater sense of how effective this treatment is. Eventually, to move this treatment toward the 1st line setting in the future.

Q: How frequent with a visit to Boston be required in trial?

Dr. Dagogo-Jack: For these trials, we always start with closer monitoring and then space out later. In the initial period, we will start with a visit every 2 week for the first 6 weeks. Right now because of how TNO155 is dosed, it is 3 week cycle. You take TNO155 everyday for 2 weeks and then you take one week off. The cycle is shorten than a typical chemotherapy cycle, it is only a 3 weeks cycle. You need to have at least one visit for every cycle for monitoring.  However, the goal is eventually gain confidence in our doses so we can make it to be 6-9 months per visit. As we finalized the doses, we showed that the drugs are working and you are tolerating it pretty well, we can space it out less frequently. We can actually put amendments into the trial to make it such that you do not have to visit as frequently. 

Q: Can the scans be done at local hospital or must be in Boston?

Dr. Dagogo-Jack: It can be done locally. Please coordinate the Mass General team and we would like to have the disc (information) at Mass Gen.

Q: If you see the combination are tolerated well, would you consider 3 drug combination? Laboratory has done some triple combinations.

 Dr. Dagogo-Jack: I would say “never say never”. But let’s prove it (the two-drug combination) is tolerable first.

Q: Can an international person participate in the trial if they can travel to Boston for all the required visits?

Yes.  Dr. Lin is also nodding her head.

Dr. Lin: Anytime greater distance is involved, it will make logistically more challenging. It takes more discussion in terms of travel, cover the cost especially if you do not have insurance.  If those obstacles can be overcome, then absolutely. If we think the trial is a good option for you and the benefit outweigh the challenges, for sure. Absolutely.

Q: If you find that the toxicity in the combination is too harsh, would you consider alternate dosing?  For example, giving drug separately from each other for a period of time and then switch to a different drug?

Dr. Dagogo-Jack: Yes. There is already an alternative dosing written in the protocol.  The advantage of this drug being a new drug is that Novartis is exploring alternative dosing schedules as well.  Two weeks on and two weeks off. So that would be something we would pivot to if we encounter that our 2 weeks on and one week off is not working, giving the patient one extra week of recovery. We hope we can use the experience from Novartis.

Q: Do you know if there is a SHP2 inhibitor that is more likely to be brain penetrant?

Dr. Dagogo-Jack: I don’t know but I will look into it.  For example, BRAF inhibitors and MEK inhibitors were not suppose to get into brain. Now, researchers are developing a version that can get into the brain 5 years later.  I do think it is possible to make a version that can penetrated the brain.  It is not that researchers cannot develop the medication but when drug did penetrate the brain it caused more toxicity. So what they need to do is to increase penetrance without enhancing toxicity. It seems simple for me to say but there are greater minds out there that can come up with a good solution for this problem.

Q: Can a patient participate if they stopped a TKI because of intolerance to that TKI? For example, if one developed a liver toxicity and they have not started on a new TKI yet. Would they be a candidate for the trial?

Dr. Lin: Yes, assuming that the TKI you talked about is not Lorlatinib. Some TKI has toxicity that does not recur. Of course, the patient will need to be monitored much more closely. It would not preclude this trial as an option for you.

General Questions

Q: Can the drugs that you talked about be prescribed on an off-label basis, not in trial?

Dr. Dagogo-Jack: For Lorlatinib and Crizotinib, I think you can because both drugs are FDA approved drugs for ALK. A lot of the time, the limit for the “off label use” or compassionate use or single person protocols are the insurance, whether the drugs will be covered or not. For a new drug like TNO155, it might be very difficult.  For a drug like Binimetinib, in theory, it may be possible.  However, as the prescriber, I would want some preliminary evidence to guide me before prescribing to a new protocol. I want to make sure whatever I am prescribing will be helpful to a patient. I do have patients who have Lorlatinib and Crizotinib prescribed outside of the trial. 

Q: if you have co-occurring cancer at diagnosis, does that impact the eligibility for the trial? I have been treated for CLL, I am now MRD (negative), and off treatment.

Dr. Dagogo-Jack: It really depends what kind of co-occurring diagnosis. Most of the time, we say for solid tumors to not have aggressive tumors too close or within a few years that requires treatment. We usually exclude things like pre-invasive superficial bladder cancer, skin cancers (like squamous cells or melanoma cells that have been removed). We are also increase flexibility around some hematologic cancers such as CLL (chronic lymphocytic leukemia).  The reason people make these eligibility exclusions is because investigator need to tell what if something is growing.  So for this case, it would be easier to tease out CLL in a MRD (negative) state.

Q: If your chemotherapy stops working, have you ever seen a case where chemotherapy had re-set so that the cancer is now responding to a TKI treatment again?

Dr. Lin: We certainly do see cases where the tumor that not seen an ALK inhibitor (TKI) for quite some time, going back on an ALK inhibitor to put pressure back on ALK positive cells can reinduce responses.  We call it a “retreatment effect.” What we don’t know is how long the duration of that TKI will last.  For example, if you were previously on the same TKI and your cancer had gotten worse, and you went off of the TKI and went onto chemotherapy. Now, going back on the same TKI, our worry is that the duration of your response may be shorter than compared to you if you are on the TKI for the first time. So, yes, we have seen some “retreatment effect.”  Particularly, we have seen it with brain metastasis.  Let’s say, you had a brain met that was responding to a TKI.  But for some reason, you went off of the TKI and went to chemo.  Then, if you go back on a brain penetrant TKI, we certainly see an induction of CNS responses.

Q: What is your thought on going to chemo between TKIs such as between Alectinib and Lorlatinib?

Dr. Lin: I cannot say right or wrong. At Mass General, we are a proponent for re-biopsy.  So, we would like to know why is it that you are progressing on Alectinib. If there is an ALK resistance mutation that explains tumor’s resistance to Alectinib, then we would favor another TKI such as Lorlatinib as another option. Because we know Lorlatinib can be highly effective if your tumor is known to have an ALK mutation and is still ALK dependent. In the absence of ALK mutation, we know the efficacy of Lorlatinib is inferior than chemotherapy. So that is when a discussion comes into play to decide going to Lorlatinib or doing a short interval follow-up instead of going straight to chemotherapy.  That discussion tends to be very complicated discussion taking into consideration of the disease burden, the pace of change, and how the patient had tolerated the TKI

Q: Do you have an opinion on the new drug called TPX0131? We have been closely following that on the ALK Positive Facebook group. Do you expect it to begin a phase 1 trial soon this year in the US?

Dr. Lin: I do. I anticipate a trial to start the end of this year in US. It will be earlier for other countries like Australia. We will open this trial at Mass General. So, you know that I am enthusiastic about this novel compound. Partly because right now we lack any ALK inhibitor after one progressed on Lorlatinib.  Lorlatinib becomes the common end point. If your tumor is known to have compound mutations (two or more ALK mutations), generally we don’t a have good option to attack that. This TPX0131 has some pretty good pre-clinical data that suggests this drug should be potent against at least a subset of the compound mutations.  So, we will open up a trial at Mass General probably close to the end of the year. And we are excited about it.

Q: Is there a way to access how patients will tolerate combinations or medications before? For example, identification of cytochrome b450 genotypes? Such studies might predict drug tolerance?

Dr. Dagogo-Jack: That is a very insightful question. It is speaking about the whole field of Pharmacogenomics and whether we can predict.  The science is still in its infancy as far as our novel combination goes.  Hopefully, there will be ways to do it. The way we get around it now is that we are putting out “blanket statements” to avoid certain drugs that can interfere with that pathway. Other things that we know can be predisposed to toxicity; so, we keep a close watch on it.  We may expect some toxicity in the eye so we will monitor more closely and check ocular baseline conditions (ophthalmological).  All of the trials have language on heart function that we would look at. We will always review medication to make sure that you are not already on a medication that may perturb the heart while you are on the study mediation that may also affect the heart. It would a good direction we should go in.

Q: For a patient found earlier than stage 4 (stages 1-3), is there any potential harm for staying on a TKI for long term even after achieving NED (no evidence of disease) apart from the side effects?

Dr. Lin: It is a difficult question and a data free zone. Early than stage 4, we have not been using TKI as the standard of therapy after surgical resection or chemo/radiation. This area is evolving rapidly because of the EGFR data where they are looking at adjuantal trials right now. If you have been prescribed an ALK inhibitor in the earlier stage setting and is tolerating it very well, what therapy duration is really optimal is unknown. In all these trials, there was a set duration for all these participants whether it is 1 year, 2 years or 3 years. We do think that once the TKI is removed, then there is a higher likelihood that the tumor cells can proliferate and the tumor can recur. At that point, it ends up becoming a very one on one, personalized discussion taking into account what side effects had been and how its influencing your day to day life.  For one patient, it might be I have been on it for two years, have not experiencing any side effects, my blood counts have been fine, I am not having any fatigue, and I really want to continue because it makes me really nervous to go off of the TKI.  Then, that is a different conversation than for a different kind of patient. Where a patient has slowly worsening anemia, getting more easily fatigued. That changes the conversation.

Q: As you know, Lorlatinib has recently been approved as a 1st line treatment in the US. Would you routinely prescribe Lorlatinib or another TKI?

Dr Lin: For me, it’s absolutely a discussion. We are fortunate in ALK Positive Lung cancer that we have a support/advocacy group like this where everyone has the opportunity to get familiar with the options and even review some of the data. In clinic, I actually find that you already know a lot. You have done lots of background info and is prepared. It would be best for us to discuss together.  This is the data for Alectinib; and the is the data for Lorlatinib. This is the reasons why we should think about this instead of another. The efficacy for Lorlatinib is certainly the best we have seen from all the next generation ALK inhibitors. The curve for preventing brain metastasis is just impressive. As you all know, there’s a lot of conversation about side effects with Lorlatinib; some are quite unique to Lorlatinib.  I do like Lorlatinib as a first line option but for those patients who are very concerned about potential mood or cognitive side effects because they had a high anxiety at baseline or depression.  Or they have a very high functioning job that they cannot even imagine any impairment in that arena, then perhaps Alectinib is a better option.

Q: We had an internal poll of members who had both Alectinib and Lorlatinib at different times.  Which TKI do they feel better on? Members chose Lorlatinib 2:1 to Alectinib.  I thought the result would be the other way around.  The results totally blew me (Colin) away. 60 people answered.

Dr. Dagogo-Jack: This is so complex. We always talk about side effect like it is something it can stand on its own. But, in reality, how you feel is a combination of your side effects and other cancer symptoms combined together. Perhaps, Lorlatinib was more successful at treating the cancer so the patient can feel better overall than when they were on Alectinib.

Q: If you were diagnosed with ALK+ Lung cancer (of course we hope not), would you start yourself on Lorlatinib?

Dr. Dagogo-Jack: If it is me with brain met, yes on Lorlatinib. That would be my short answer.

Q: If you don’t have brain met?  

Dr. Dagogo-Jack: If I don’t have any brain met, then it is a conversation. It’s a tough choice. But it is a kind of a tough choice because Alectinib works so well.  The question is now: Sequencing. Is it better to take one and then another one. Or do you start with the best one? What we know is that not everyone has Lorlatinib as the next option. How do we measure that and make the right decisions?  But, I have given Lorlatinib as 1st line already. We had a very informed conversation about this choice that lasted about 30 minutes and that was what the patient wanted.  I think that has to be on an individual level.

Q: Can you speak about Alectinib dose lowering? Some members had to reduce Alectinib doses due to side effects. Do you think it is still effective at a lower dose? Is it something you do with your patients?

Dr. Lin: For any of these TKIs, if the side effects are not reasonable to continue, I would certainly take a hold, pause and then reduce the dose. Yes, Alectinib can be effective at lower doses.

Q: Would recommend if a patient is on Alectinib now but pre-emptively switch to Lorlatinib?

Dr. Lin: Again, I think that’s a discussion. There is really no one right answer for every patient. If after a lot of discussion of efficacy and side effect, oncologist and the patient feel that it is the right way to go.  There’s no one right or wrong answer.

You can watch the entire video here: https://www.youtube.com/watch?v=ugX1otfvRO4&t=19s

Compiled and transcribed by: Alice Chou