ALKtALK with Dr. Alice Shaw

Editor’s Note: A special thanks to Marc Rosenzweig for creating and scheduling the ALKtALK programs. Alice Chou graciously committed her time to transcribe the January ALKtALK with Dr. Shaw so that it would be available here for other ALK patients.. Thank you so much Alice Chou for your hard work and generosity!! . . and a big thank you to Dr. Shaw for spending her Sunday evening with our group answering these questions.

Dr. Alice Shaw, MD PHD, Boston, MA

Global Head of Translational Clinical Oncology at Novartis

Attending physician in Center of Thoracic Cancers at Mass General Hospital

Associate Professor of medicine at Harvard Medical School

Introduction:

I have been in Boston for many years, residency and fellowship training in oncology in 2000 and I have always been interested in lung cancer. It was a very different field 20 years ago. It was clear that so little was known about the underlying biological reasons for lung cancer and therefore for the few therapy options at the time. It was mostly chemotherapy! It motivated me to begin to get into research.  I began in the study of KRAS, a driver oncogene in lung cancer. KRAS we have known for many decades. EGFR was discovered in 2004.  It was incredible to see that mutant oncogene get targeted therapy.  Lab-research-lab interaction (bench to bedside to bench) was very exciting at the time. ALK in lung cancer had just been published in Japan when I joined Mass General.  Back then, it was just another potential for other oncogenes.  We worked hard to develop a diagnostic test FISH assay for ALK and we had Crizotinib just at a phase 1 trial. We were quickly able to identify patients and use them in the trial. Amazing responses was found around 2007. Within 2 years, we knew resistance was developing. The resistance is not unique to Crizotinib but plagues all therapies, even immunotherapy. A large effort to develop 2nd generation inhibitors was made in collaboration with the pharmaceutical companies, and trials were done. Many patients are getting benefits from all these TKIs.  We worked with companies to push Lorlatinib through on clinical trials and has shown to have high brain penetrance. It’s an amazing ride so far.  In the span of 13 years, we have had 5 medicines approved and several combination therapies in trial and an increase in understanding of what ALK lung cancer is. 

GENERAL QUESTIONS:

Q: We did an internal poll, both Alectinib & Lorlatinib, if they both worked similar, which one do you feel better on? I(Colin) was expecting Alectinib. But the result was: 45 Lorlatinib vs 25 Alectinib.

Lorlatinib can be challenging for some patients. It is important to understand dose reduction.  Lorlatinib 100mg as standard dose is known to be on the high side. There was a lot of debate at the time. 75mg is what I (Dr. Shaw) wanted. Several reasons: they want to cover all the mutations and ROS1. It was hard to treat the ROS1 mutation even at 100mg.  So, the team decided to err on the side of the higher dose.  I typically start patients at 75mg. 50mg is still responding well for some patients. You cannot be shy about dose reduction. It can help minimize side effects, even with brain protection.

Q: What does it mean to have an ALK wild type progression? Is ALK lost so you cannot use TKIs?

Oncologists talk about resistance in ALK wild type. You always have the ALK rearrangement. The oncologist meant the absence of an ALK resistance mutation. Something else, an ALK-independent mechanism is responsible for the relapse. If you have progression on Lorlatinib but your oncologist said you have “ALK wild type” resistance, then that means you have a much lower chance of another TKI working for you.  You can still do the ALK vaccine (ALK-fusion is still there) and it may work for you.

Q: If a patient is allergic to CT contrast, it is harder to monitor them? Are there another technical strategies to monitor?

It is common to have allergy to contrast. Years of chronic exposure may cause the development of allergies. This situation does come up a lot in the clinic.  If you have a problem, I would consider a PET scan in the interval.  We use contrast because it is better at visualizing certain things. For example, with no contrast you cannot see well in the liver. I will monitor with regular CT scan, every other or every third time at scan, add a PET/CT instead.  That will just give us some reassurance that we are not missing anything.

Q: After the initial diagnosis of a PET scan, when do you do another PET scan?

Like I just mentioned, if you cannot have contrast with your CT, we will add PET scan every once awhile. We don’t monitor routinely with PET scan. Unless the CT shows concern, I will prescribe a PET scan to see that area better. Or if you have progressed by a very obvious CT scan, I will do a PET to get a “restage” to get a sense of where active sites are.

Q: Do patients with brain mets on 2nd, 3rd generation TKIs always get MRI for monitoring every 3 months? Even if mets are found to be stable?

2nd generation TKIs have good response in the brain and for longer. But if there is a brain met history, I will continue to monitor every 3-4 months. Similarly, even if you are on Lorlatinib, it does have strong coverage, but tumor resistance may still arise. So, I will still monitor the patient usually every 3-4 months. You can still have brain mets without any symptoms. If they are tiny, you can very easily target these CNS lesion with radiation. You want to have active surveillance, especially on 2nd generation drugs.

Q: If a patient has no brain met history, how often do you do a brain MRI?

I will survey a patient on Alectinib every 6-9 months.  Similarly, if you are on Lorlatinib, I will scan every 6-12 months, not every scan. There are some oncologists that monitor every year and there have been cases where patients did develop some brain mets between that one year monitoring.  So, that’s why I dropped it down to 6-12 months.

Q: What do you think about Consolidative therapy? Do you believe it will become standard of care?

We do consider consolidative therapy for every patient.  This is not limited to patients on Alectinib but on all therapies.  If they have a great response, we are also looking for the opportunity to get rid of residual disease. Our protocol at Mass General is to do consolidative treatment within 6 months of therapy, that is when it is at its maximal response. However, the maximum response could be at 8 weeks, 16 weeks.. typically within 6 months.

Q: For our newer members, they read online and get recommendations from friends. What do you recommend in terms of food, diet and sugar?

Bottom line is, we are unsure. Why not try and be as healthy as possible? Eating well and exercise sometimes can help you tolerate the drugs better, so why not do it? How do you feel? Quality of life is also important. For patients on Alectinib or Lorlatinib, I do talk to them about weight gain because it is a big issue.  It may not feel very great with the extra weight.  We talk about strategies with diet such as limiting carbohydrates and exercise.  There have been exercise studies that show that exercise does help and has a positive impact on cancer. But again, the most important part is that patients report that they feel better. Another side effect is edema and that can often be improved with regular exercise. Doing all these may be good to treat cancer but more importantly it can improve your quality of life.

Q: What about the Covid-19 vaccine?  Do our TKIs interfere with the vaccine?

Patients with cancer should have the vaccine. These are called mRNA vaccines, not inactivated virus vaccines. These mRNA vaccines contain the coding of the spike protein mRNA of Covid-19.  From all the data so far, the vaccine looks quite safe. ASCO, ESMO and many are all recommending it, though cancer patients were not included in the trials. There is no reason not to take it. Actually, the net benefit is that you will get protected at 94-95% which will minimize the risk of getting Covid-19.  So, once the vaccine is available, ALK patients should take it, with rare exceptions.

Q: What are your thoughts on using chemotherapy such as Alimta to treat oligo-progression or in conjunction with a TKI to treat oligo-progression?

For oligo-progression, our preferred method is radiation treatment, if a lesion can be easily irradiated.  If it is not easily reached, we can consider adding Alimta. Typically, if you are on a 2nd generation TKI such as Alectinib, Brigatinib, or Ceritinib and you have oligo-progression and it is hard to radiate, we generally will just go on to Lorlatinib. If you are on Lorlatinib and if it is hard to radiate, then we will add some chemotherapy such as Pemetrexed or Caboplatin-Pemetrexed.

Q: Since you have been in academia and now in a pharmaceutical company, what are some insights you can provide about how to accelerate the journey for ALK to become a chronic disease?

After so many years at Mass General, I recently moved to Novartis to head up early clinical drug development in Oncology. It has been a huge positive learning experience.  While at Mass General, I did work with pharma to develop all these TKIs.  But to be honest, as a scientist, I don’t know how drugs are developed. It was eye opening and fun to think about.  You can think very broadly. For example, you can apply lessons from other disciplines to an ALK setting and see if it will help.  I have learned much from how a drug is developed, basic science, challenges in growth and development; this information can help with clinical drug developments. It is hard to make a good drug. To find a good combination of good basic science, good drug development is even harder. You want the best research to inform us as to the combinations to use and not just guess.  If you have combinations, there are many toxicities and you must pick the best ones for the patients. You need to develop clinical models that are predictive. These similar clinical models can help predict safety too. What I have seen this past year is that there is incredible knowledge and potential.  My goal for going to pharma is to learn about drug development and to apply this to the clinic.

Q: Dr. Camidge talked about tumor markers.  What are your thoughts on it?

Some oncologists follow them. We know sometimes these markers can be falsely elevated and can lead to anxiety. For some patients they can be tracked very well and give an earlier sense of when relapse is happening. We actually had a phase 1 study to track patients on Ceritinib with tumor markers. A minority of patients (about a 20-25%), tumor markers tracked pretty well. When they relapsed, it went up and when it was regressing, the tumor markers went down. However, the majority may not be informative or they may not be tracking at all.  That gave me some pause. If patients are tracking with tumor markers and they are tracking pretty reliably, of course we will continue to follow.  But I do not routinely do tumor markers on my patients.

Q: How do we encourage pharma to fund more ALK combination trials with ALK inhibitors?

Novartis made Ceritinib and it is not one of the major inhibitors due to its toxicity. I don’t know yet. I am still learning right now.  We are doing some combination studies at Mass General. Imagine if a sponsored trial was open even at just 5 sites, data collection would be much faster and more patients would have more access. Advocacy groups will be important in helping to explain the need. People think ALK is doing great. There are some combinations in trial. Pharmaceutical companies might be shying off more. Education is necessary! ALK patients are still in need.

Q: What about any results from the Alchemist trial?

It is a trial sponsored by NCI, looking at using TKI as adjuvant therapies after resection. So patients like EGFR went on a TKI after resection or some ALK patients went on a TKI or a placebo after being resected. I have heard it is hard to find ALK patients to use Crizotinib after resection. If I had a patient after resection, I would choose to use Alectinib instead of Crizotinib.

Q: If Lorlatinib becomes first line and the patient has a heart condition, would you start with Alectinib instead?

I would say yes, possibly.  If the patient has a significant mood disorder at base line, I would also start with Alectinib first.  So, there are a few cases where I would consider another TKI instead of Lorlatinib as a first line.

Q: What is the current prognosis and life expectancy?

Colin answers: If you were diagnosed in 2006, maybe you had one year left. If you were diagnosed in 2016, maybe 2-3 years? Now in 2020, you are looking at 7+ years. Come back in another 4 years and the number will be higher, like 10 years or much longer.

Dr. Shaw: I do get this question a lot.  When we first identified ALK patients back in 2008, it was before Crizotinib was available.  When we looked back, ALK patients who did not receive ALK TKI therapies did not do well at all.   The survival was very similar to average lung cancer patients and they don’t really do well because of the absence of good therapies, especially back then. Every year, it seems survival is getting better.  If a patient asks me now, I would not even say a number because it changes every year.  Colin, you said 7 years, however I have seen 8 years or longer.  We will eventually have no number because patients are doing well and that number gets bigger and bigger.  That is what we want.

Q: I have heard ALK is a more aggressive form of lung cancer. The average was even less than the average for lung cancer patients if there’s no therapy for it. Would you agree with that?

I would agree. Additionally, I would support that it is harder to identify ALK non-metastatic lung disease because it tends to be metastatic early.  All these increases in numbers are showing incredible promise and it is showing where we are going.

ALECTINIB QUESTIONS:

Q: Is it advisable to take Alectinib and combine it with radiotherapy or immunotherapy in order to get a better response?

No, I would not combine any ALK TKI with any immunotherapies.  I am sure there are some exceptions, however targeted therapies just do not mix well with immunotherapy. When you have Alectinib and immunotherapy by itself, the side effects are very well tolerated.  However, when you start to mix the two, we see a lot more toxicity. In a clinical trial, on paper, it may not seem like a lot more, however when I go back to the data, there were much more issues with the skin (rash), pneumonitis, liver irritation as well. I have seen patients struggling with a lot of toxicity.  So, no, I would not advise you to do that. Also, there is no pre-clinical or clinical evidence that adding immunotherapy would help Alectinib at all.  It might actually hurt Alectinib because the toxicity may force the patient to go on a lower dose.

About Alectinib in combination with radiation, we have used them at the same time, but not necessarily in combination.  We use them in a multi-modality approach; where there was one small residual disease site and we will use radiation therapy to irradiate some dormant cells at one spot. So, I tend to use them in conjunction to each other to eliminate any residual disease to treat any precursors that can later on develop some more resistance.

Q: Do you know a patient who had a full response on Alectinib and then progressed later in the body? Do you believe a dose reduction can impact the individual PFS (progression free survival)?

Even if you are doing well on Alectinib, relapses can happen. I can see that is very discerning. We just discussed about residual disease. If you cannot see it, then you cannot irradiate it.

600mg twice per day is at the cusp of efficacy, I would not drop too much. If you drop too low, it may be easier to relapse at lower doses. Especially if you drop it down to 300mg twice per day, that is too low. I do see more CNS relapses at lower doses.  The best dose is 600mg twice per day. In some early research, we have shown 900mg was helpful in reducing CNS relapse.

Often, there are patients on a reduced dose of 450mg or 300mg, twice a way.  The question is should I bring it back up?  This question is asked a lot.  The question was how was the toxicity? A common problem is liver function test elevation - that is why some dose reductions happen. There is really no published data on this so you must do it cautiously with your oncologist. Some go on low dose for 3-6 months, then if stable, sometimes they re-consider increasing the dose again.  The rationale is to try to prevent any brain metastasis.

Q: If you are doing well on Alectinib, would you switch to Lorlatinib?

This scenario came up when the ALEX study came out.  Everyone wanted to go from Crizotinib to Alectinib.  However, I think we should consider it on a case by case basis. For those on Crizotinib, some of them they are still doing well 5, 10 years later. If they were doing long term Crizotinib well, I did not switch them. If a patient just started Alectinib, would I switch them to Lorlatinib? I think this is where I would do case by case. One subclass of patients where I might consider is those patients with brain metastasis or who have leptomeningeal disease at baseline because control of CNS is critical. 

Q: Have you seen cardiac issues such as CHF (congestive heart failure) on Alectinib?

CHF or cardiomyopathy as it is sometimes called - we do not see any drop in injection fraction that tells you about potential CHF with Alectinib.  That is based on clinical trials and my own clinical findings. However, you might get a case here or there, possibly. But in general, we do not think about ALK inhibitors causing cardiomyopathy because there is really no expression of ALK in cardiac myocytes.  It is a little more complicated for Lorlatinib.  Lorlatinib causes a lot more water retention. That extra fluid in the body can cause some strain on the heart.  So, if someone has some underlying issues with heart disease, I have seen it worsen that underlying heart disease.  But in general, I do not believe that ALK inhibitors should cause CHF.

Q: If you are doing well on Alectinib right now, would you go up to 900mg?

If you are doing well at 600mg, I do not feel the need to increase up to 900mg. With more Alectinib you will have more toxicity such as more fatigue, muscle aching, or more headaches. I really would bump up Alectinib if there’s any evidence of new brain mets or worsening of existing brain mets.

LORLATINIB QUESTIONS:

Q: Do you believe Lorlatinib will become a 1st line drug? Or just in specific situations? Some doctors may not use it as first line, what is your thought on that?

Crown data is impressive. However, in these studies, it is done in comparison with Crizotinib. This is a cross trial comparison against Alectinib vs Lorlatinib [Alectinib compared with Crizotinib and Lorlatinib compared with Crizotinib]. It is not ideal because the best case is to have Alectinib compared head to head with Lorlatinib.  But, at the time, Crizotinib is the standard of care.  Given that limitation, the Lorlatinib benefit over Crizotinib is significantly greater than that of Alectinib over Crizotinib. The risk of progression/death on Lorlatinib was reduced by the higher percentages (72-78%). Whereas the reduction on Alectinib or Brigatinib showed a reduction of about 50%.

ALK lung cancer has a high propensity to spread to the brain. Why is it easier to spread to brain?  We saw this really early on but we do not know the reason. But to prevent and to treat it is incredibly important. Here, Lorlatinib has a clear advantage because it is the most potent and brain penetrating TKI that we have.  We saw a very significant and clear reduction in brain mets. In patients who had brain mets at the start of the trial, about 70% with brain mets to start, had a great response to Lorlatinib and it has eradicated the lesions in the brain. With the other TKIs such as Alectinib, Brigatinib and Ensartinib, the complete response rate is in the rage of 25-30%. We know Lorlatinib blocks many single mutations plus has better brain potency, so I suspect it to be better than Alectinib.

We are looking into specific subsets of ALK patients that may benefit better.  For example, we are looking into molecular subsets of patients.  We have not seen any obvious subsets but are still looking.  Could there be a greater benefit from one ALK rearrangement? We will find out.

The basic teaching of oncology is that we want to use the best therapy upfront. Patients tend to derive the best benefit if we do the best treatments first.  I can see Lorlatinib shifting into 1st line treatment.

Q: How do people ask for 75mg to start?

If you are newly diagnosed, you should start around 75mg of Lorlatinib. Patients just have to ask and have an oncologist feeling comfortable enough to do it.  In the case of an EGFR mutation lung cancer, the drug is Tarceva.  The recommended dose is at 150mg, but we prescribe 100mg all the time for the most sensitive exon 19 deletion mutation.

Q: If you are on 100mg now, how can you tell your oncologist that you want to reduce dose?

Oncologists may not use the standard dose all the time. Just as long as the oncologist understands the drug, a lower dose at 75mg will become routine. 

Q: If Lorlatinib is 1st line, what are some options if the tumor becomes resistant to Lorlatinib? How do you decide at that time what option to choose?

This is a good question and is applicable to everyone; if you have Lorlatinib as a first line or Lorlatinib as a 3rd line.  The mechanism or resistance is important to understand. When we did a study now, usually patients had prior exposure to a TKI.  Patients might have even gone on several TKIs, one after another right now.  This sequential use of TKIs will shape the mechanism of resistance.  If we use Lorlatinib as 1st line, we do not have the data as of now. A patient can be placed on Lorlatinib as a first line and not yet be progressing. So, we do not understand it yet. In a laboratory setting, with sequential TKIs, several mutations arise. However, in the laboratory, with Lorlatinib as a 1st line TKI, we may not see any ALK resistance mutations. Lorlatinib is so potent against almost all single mutations. We know eventually, resistance does arise.  What could it be?  We do not know from the clinic yet.  However, our data suggests that an ALK-independent mechanism gets turned on, such as other kinases or other growth stimulating pathways to evade Lorlatinib.  These new signals replace the ALK signal because all aberrant ALK has been shut off.  One candidate is MET. We have already seen its importance in sequential TKI settings. That is the rational basis for the combination studies where you combine ALK and MET inhibitors.

If you develop resistance, in any setting, I would put an effort to do a re-biopsy, whether it is a simple blood biopsy, Guardant NGS (next generation sequencing) biopsy, or a tumor biopsy. This way, we can learn about potential driver information and we can decide what to choose next.

ALTERNATIVE RESISTANCE QUESTIONS:

Q: For the combinational trials of Lorlatinib with MEK and/or SHP2, it might be too toxic in its combination use. What is the rationale of its use and of its intermittent use?

You are talking about the combination use of the two clinical trials of Lorlatinib with a MEK inhibitor (Binimetinib) and Lorlatinib with a SHP2 inhibitor (TNL155) at Mass General. The developing the combination is already a little challenging because of toxicity. I am very interested in the dosing part, especially the Lorlatinib and MEK inhibitor may require some intermittent scheduling.  The three-drug combination is very interesting with Lorlatinib, MEK inhibitor, and SHP2 inhibitor. But potentially, there’s a lot of toxicity because you are hitting the pathway really hard.  Let’s try the two-drug combination first before going onto a three drug combination.

FURTHER RESEARCH QUESTIONS:

Q: There is a talk about a 4th generation TKI in trial? What is the current progress with that?

There is some data of TPX-0131 in the public domain. We have shared the compound mutations from our clinic with the researchers to focus on. The data looks promising. For me, it’s not just one compound mutation that develops in patients; there is a large array of multiple mutations. Many of these mutations are not similar or non-overlapping with other patients. As more patient data comes out, we are finding so many combinations. With so many single mutations and the combinations of multiple possible single mutations, it feels harder for one drug to take care of all those mutations/combinations.  So perhaps, it is likely to have more than one 4th generation drugs that can treat most of these mutations.  So, the solution may not be so simple.  We might need a mix of them (4th generation drugs) to combat it.

Q: What is the most promising potential treatment for ALK? Post- TKI? Or other fields?

ALK TKIs are most important for an ALK patient. When resistance develops, we know something else needs to be done. We don’t know what that is yet. It is probably a combination and possibly cross platform. For that I mean is, not just a simple TKI or just add a MET inhibitor.  It is more like you knock down the cancer with an ALK TKI, then come in with another approach like immunotherapy or ALK vaccine or chemotherapy, trying to eradicate all drug tolerant cells. I think we have to think beyond just targeted therapies.

If you want to watch the entire video, this is the YouTube link. The questions have been organized and are not in the same order as on the video. https://www.youtube.com/watch?v=q2p8K-qkVtg

Compiled and transcribed by: Alice Chou

Photo credit: Jim Harrison