Targeted Therapy TALK: Translating the Latest Advances into Precision Care for ALK-positive Advanced NSCLC

First, let us go through some basics of lung cancer. Currently, there are going to be an estimated 226,000, 227,000 cases diagnosed this year. Unfortunately, 125,000 of those will result in a death or 125,000 deaths from lung cancer. Globally, in 2022, those numbers were 2.5 million and 1.8 million deaths. So clearly a high volume of patients.

Overall survival rate in the United States still remains a dismal 27% for all patients with lung cancer, and metastatic cancer patients, only 8.9%. We know that non-small-cell lung cancer does account for 80% to 85% of these patients, and we really need to think about these patients not just as non-small-cell lung cancer, but really as what is their alteration.

[00:17:42]

~50% of Patients With Advanced Nonsquamous NSCLC Have a Driver Mutation Targetable by an FDA-Approved Agent

Dr Bestvina is frustratingly younger than me, so she would not remember a time when EGFR was all you had to think about. Now look at this. So KRAS, EGFR, ALK, NRG1, EGFR, MET, HER2, ROS1, BRAF, RET. I am in Tennessee, I have run out fingers, so I cannot keep track of all of these in my mind.

[00:18:11]

Biomarker Testing in Advanced NSCLC

What we really need to do is look at these NCCN guidelines, recognize that they exist to remind us to test for all of these 10 or 11 different items. Because they play a huge role in our patients and over half of our patients will have alterations, they can help guide their first-line therapy.

[00:18:28]

The Importance of Biomarker Testing in NSCLC

Now, why does this matter? This is old data from 2019. We all know the answer to this. If patients have driver alterations and we treat them with a targeted therapy, their median overall survival is over a year and a half. If they do not receive targeted therapy, it is less than a year. This is vitally important for our patients and why we do have to work so hard to keep up with these multiple different biomarkers.

[00:18:54]

Targeted RNA Sequencing Can Complement DNA-Based NGS by Increasing Oncogenic Fusion Detection

I think we are in an era where we have to go 1 step further though. It is not just the easy button of testing for DNA alterations, but we also have to think about RNA sequencing as well.

If we look at some of the Memorial-IMPACT portfolio in their database, we see that in patients who were fusion negative on DNA, those that were tested with RNA 14% or 33 patients were found to have fusions positive by RNA. If you break that down into ALK, ROS, MET, RET, NRG1 and others, we see that 10 of those patients had ROS1 fusions that would have been missed by DNA sequencing alone. Of those 10 patients, 8 of them received clinical benefit. It is really important that we not just stop at what we could have stopped at a couple of years ago, a broad-based NGS sequencing on DNA, but that we also consider testing for RNA as well.

[00:19:52]

Posttest 1

Now, based on the wisdom of the last 3.5 minutes, do you guys have any changes to when you would think about testing RNA sequencing, if we can bring that poll up?

1. Never;
2. Rarely;
3. Sometimes;
4. Frequently; or
5. Always.

We will look at those results. Good. We are seeing a shift towards more testing always and frequently. I would be interested to hear the thoughts as we get towards the end today about why some people would not want to do that testing.

[00:20:38]

Posttest 1: Rationale

Why do I think this as we just talked about? It is because we find patients who are missed with DNA testing alone.

[00:20:47]

Optimal Treatment of Advanced ALK-Positive NSCLC

I am going to pause now. I will pass it over to Dr Bestvina and listen to her thoughts on optimal treatment.

Dr Christine Bestvina (University of Chicago Medicine): Thank you so much, Dr Bauer. With that, we will move on to optimal treatment of advanced ALK-positive non-small-cell lung cancer.

[00:21:05]

Case 1: Patient With Metastatic NSCLC

We will start with a patient case. This is a real patient of mine who has given me permission to share her story. It is a 27-year-old female PhD student who presented to urgent care with 3 months of increased fatigue, dry cough and self-palpated supraclavicular fullness. She got a chest x-ray in urgent care which showed fullness of the right suprahilar area. CT of the neck and chest revealed a 1.2 centimeter cavitary lesion in the right upper lobe, but innumerable bilateral pulmonary nodules as well as diffuse lymphadenopathy.

Ultrasound-guided supraclavicular biopsy was performed, which showed metastatic non-small-cell lung cancer. PD-L1 was 70%. Tissue molecular testing is sent. An MRI of the brain shows no intracranial disease.

[00:22:04]

Poll 3

We will move to the next polling question. In your current practice, would you start treatment with this information at hand?

1. Yes;
2. No; or
3. Uncertain.

Okay. Interesting breakdown. Almost exactly a third said yes, a third said no and a third said uncertain. Let us talk a bit more about what I did for this patient.

[00:22:48]

Case Continued: Patient With Metastatic NSCLC

I did not start treatment with that information at hand. She was generally clinically stable and I felt like we had time to await the molecular testing. She was also a 27-year-old never smoker. So I felt that there was a very high chance she could have a targetable alteration.

I sent a ctDNA assay at that first clinic visit. One week later, the ctDNA came back with an EML4-ALK fusion. I do have to say that ctDNA testing has become a huge part of my practice for patients who are newly diagnosed when the molecular testing is still pending because the turnaround time is just so fast and you can get these answers back faster and give answers back to the patients and help start your treatment planning.

Tissue RNA fusion did confirm that EML4-ALK fusion, which returned about 2 weeks after the ctDNA results had already come back.

[00:23:53]

Pretest 2

We will move now to our next pretest question. In your current practice, what would you consider to be optimal first-line treatment for this patient? We have PD-L1 high at 70% EML4-ALK fusion. Would you choose:

1. PD-1/PD-L1 monotherapy;
2. PD-1 inhibitor plus pemetrexed plus platinum chemo; or
3. ALK inhibitor with alectinib;
4. Crizotinib; or
5. Lorlatinib.

Okay, let us take a look at the results. A pretty wide breakdown here, including PD-1, PD-L1 monotherapy, chemoimmunotherapy, alectinib, crizotinib, and lorlatinib.

Let us take a deep dive into this data.

[00:24:56]

Advantages of Many Targeted Therapies

In general, when patients are found to have 1 of the 9 actionable alterations that we look for on molecular testing, we typically want to start with that targeted therapy first. There is several reasons for this.

We can see quite rapid responses, particularly with oral tyrosine kinase inhibitors on the order of weeks. Typically, we will see higher response rates with these targeted therapies over chemotherapy. We have become accustomed to response rates as high as 70% to 80% with many of these TKIs.

Additionally, the altered toxicity profile, which varies from chemotherapy, it is not always better, not always worse, but just different and something that we have become accustomed to monitoring and managing for patients.

Oral administration is often preferred by patients. They are able to spend time away from the office, from the infusion center, more time with their family. Many of these targeted therapies lead to an improvement in overall quality of life for the patient over traditional chemotherapy.

[00:26:13]

Next-Generation ALK Inhibitors

When we look across different ALK inhibitors, there are 3 generations of ALK inhibitors that are currently available in the clinic. We have:

• First-generation crizotinib;
• Second-generation ALK inhibitors, which includes ceritinib, alectinib, brigatinib and ensartinib; and then,
• The third-generation ALK inhibitor, lorlatinib.

As we move up in generation of TKIs, we see increased potency in selectivity, increased CNS penetration and activity, as well as better coverage of on-target resistance mutations.

[00:26:52]

Guideline Recommendations for First-line Therapy for Advanced/Metastatic ALK-Positive NSCLC

Currently, 4 of these TKIs carry a preferred recommendation by NCCN, and that includes alectinib, brigatinib, ensartinib and lorlatinib. I know it can be confusing to pull up NCCN and see 4 different choices. How do we choose between these 4 different ALK inhibitors and what would be best for the different patient for each individual patient?

With that, we will take a look at the data of these 4. I will also say though that the guidelines do recommend starting an ALK inhibitor monotherapy first before systemic therapy. Even if that ALK rearrangement is discovered after starting first-line therapy with, let us say, chemotherapy, that current treatment should be interrupted and the ALK inhibitors should be initiated. That is because of several improved outcomes with these ALK inhibitors that we will look at now.

[00:27:51]

ALEX: Alectinib vs Crizotinib for Patients With Previously Untreated Advanced ALK+ NSCLC

Here we have the ALEX trial, which compared alectinib to crizotinib for patients who had previously untreated advanced ALK-positive non-small-cell lung cancer. Here we see the progression-free survival of 34.8 months vs 10 months with crizotinib. Really impressive hazard ratio at 0.43. This did have a confirmed overall survival with a hazard ratio 0.67.

Alectinib has been a great choice for our patients. This is also a drug that is quite well tolerated.

[00:28:34]

ALTA-1L: Brigatinib vs Crizotinib for Treatment-Naive Advanced ALK+ NSCLC

With brigatinib, we had the ALTA-1 trial. This also compared brigatinib to crizotinib. Here we saw a median progression-free survival of 24 months vs 11 months with the crizotinib.

Overall survival, here you will see on the right, did not meet statistical significance here with a hazard ratio of 0.8.

[00:29:01]

eXALT3: Ensartinib vs Crizotinib for Previously Untreated Advanced ALK+ NSCLC

We have the newer kid on the block with ensartinib. This is the eXALT3 study, which compared ensartinib to crizotinib. Median progression-free survival here was 25.8 months vs 12 months with crizotinib. Again, the overall survival in this trial did not meet statistical significance for an improvement with ensartinib.

[00:29:30]

CROWN: Lorlatinib vs Crizotinib for Previously Untreated Advanced ALK+ NSCLC

Then lastly, we have the CROWN trial. This was presented at ASCO just shy of a year ago now. This is the updated 5-year data looking at progression-free survival for patients who were previously untreated ALK-positive who were randomized to either lorlatinib or crizotinib.

The median progression-free survival in the lorlatinib arm was still not reached at 5 years or 60 months. 60% of patients remain progression-free at 5 years, which is really quite remarkable. To me, this trial was a landmark achievement in metastatic non-small-cell lung cancer. This is compared to 8% progression-free survival in the crizotinib arm.

The PFS favored lorlatinib among all subgroups, and we will look at a few of those now, but that included patients who had poor prognostic biomarkers. In fact, we do not have the overall survival for this drug, but it is because we have not hit the number of events needed in order to do that analysis. Patients are fortunately living so long that we cannot perform the overall survival analysis, which is again quite remarkable.

[00:30:56]

ALK+ Lung Cancer Often Goes to the Brain

CNS efficacy is something that is quite important to discuss as we look at these different treatments of ALK-positive non-small-cell lung cancer. This is a retrospective study that looked at patients who are ALK-positive and ROS1 positive. You will see that the majority of patients who are ALK-positive will experience CNS metastasis at some point in their treatment trajectory.

So preventing these as well as treating the brain metastasis if they are present at diagnosis is a really important factor when deciding the right treatment.

[00:31:36]

Selecting ALK TKIs: Second- and Third-Generation Associated With Superior Intracranial Availability

What is this intracranial availability? Essentially how well do these drugs cross over that blood-brain barrier and does that bioavailability allow for improved treatment of brain metastasis?

Here you will see with alectinib and lorlatinib that the CSF to plasma ratio is quite high, meaning this drug really is getting into the brain. And that for patients who had brain metastasis, you will see that progression-free survival here was not yet reached with lorlatinib, but was improved with alectinib and brigatinib 2 drugs known to have CNS efficacy over the other drugs here. So really important factor when deciding the right TKI for different patients.

[00:32:28]

CROWN: PFS in Patients With or Without Brain Metastases

Here is the progression-free survival in patients with or without brain metastasis. On the left, you will see patients with baseline brain metastasis. On the right, you will see without. I think the important take-home message from this slide is that regardless of presence of baseline brain metastasis, patients did better with lorlatinib and remarkably better. These are really impressive hazard ratios with baseline brain mets hazard ratio of 0.08; without baseline brain mets hazard ratio 0.24.

The reason why I think this slide is so important is because as we were learning to use lorlatinib in the clinic, 1 of the discussions that was had was that maybe this is the good drug for patients with baseline brain metastasis, which I would agree with based off of the graph that you see on the left. But I think the alternative is also true if patients do not have baseline brain metastasis, you are seeing an incredible spread of those curves I think showing that this is still the right treatment option for these patients.

[00:33:37]

CROWN: IC Progression by Investigator in ITT Population

Here is the intracranial progression-free survival by investigator. This includes patients with and without brain metastasis looking at intracranial progression. Patients did have serial MRIs. This is asking the question of how long did it take before either new brain metastasis developed or baseline brain metastasis grew.

Again, really impressive data here. 92% of patients who were on lorlatinib had no evidence of CNS progression at 5 years, given the slide we looked at a few ago where the majority of patients who have ALK-positive disease do develop brain metastasis at some point in their course. This is again really remarkable that 92% of patients remain intracranial PFS of 5 years. This is important for patients. The remaining without SRS without, whole brain, the cognitive function can be preserved. They can keep doing what they need to do, working, taking care of their families and other things.

[00:34:45]

CROWN: IC Progression in Patients With or Without Brain Metastases

Again, here is another way of looking at that data based off of presence of baseline brain metastasis or not. On the left, you have those patients who did have baseline brain metastasis, very impressive intracranial PFS at 5 years of 83% in a group who all had baseline brain mets. No progression after 5 years for 83% of those patients.

On the right, for patients who did not have baseline brain metastasis, 96% remained intracranial PFS at 5 years.

[00:35:22]

Sequencing ALK Inhibitors

What about sequencing? This is also something that always comes up with TKIs. I think as clinicians, we often want to keep as many tools in our tool bag as we can so that if patients experience progression, we will have something to switch to. But I think this is a really telling graphic that here that argument does not hold up because if patients receive either frontline alectinib or brigatinib, and here you will see the median PFS numbers for those drugs.

When lorlatinib is given in later lines, the median progression-free survival is much lower than what we have just looked at frontline. The sum of that first-line, second-generation TKI plus lorlatinib second-line does not reach what we are seeing with front-line lorlatinib. So huge argument here for best drug first.

[00:36:20]

CROWN: New Resistance Mutations in ctDNA After Lorlatinib Treatment

Then what about the resistance that develops? When patients experience progression on trial, a ctDNA sample was collected. It is important to know that this is not a tissue analysis. So it may not be the whole story. But even with this ctDNA analysis, we are seeing that for patients who were on lorlatinib, not a single developed an on-target, ALK-based resistance mechanism showing how good that penetration is across the different ALK mutations. This is different than what we see with the crizotinib patients where we do see on-target ALK resistance develop.

In the lorlatinib arm, we instead see bypass mechanisms develop or in 42% of patients unknown why that resistance developed.

[00:37:13]

Key Factors to Discuss With Patients When Choosing an ALK Inhibitor

When I am choosing a drug with a patient or a next-line of therapy, I will often talk through these 3 large points. We will talk through efficacy of the next line of therapy. We will talk through what is the toxicity profile, what adverse events they may expect to experience, how will that affect their quality of life, patient preferences on tolerability vs aggressiveness of drug. How frequently do we need to monitor the patients, monitor their labs and their symptoms?

Lastly, what is the CNS efficacy of this drug? How likely is it to treat brain metastasis if they have them? And how likely is it to prevent brain metastasis if they do not have any when we are starting this new line of therapy?

[00:38:05]

Challenges for ALK-Positive Patients Still Exist

There are still many challenges that exist for ALK-positive patients, including how quickly we can turn around this testing. Unfortunately, testing still often takes between 2 and 4 weeks to come back for patients, which is a very long time to wait. When somebody has just told you, you have metastatic lung cancer, how can we improve those turnaround testing times, as well as increase the rate of patients who are receiving appropriate testing such as RNA testing?

How do we appropriately treat and prevent CNS metastasis? And then how do we choose the right line for most of these patients?

[00:38:49]

Case 1 Revisited: Patient With Metastatic NSCLC

With that, we will return to this case. Just again as a brief reminder, 27-year-old female who presented with metastatic lung cancer, no CNS involvement, PD-L1 70% and tissue molecular testing revealed EML4-ALK fusion.

[00:39:14]

Posttest 2

I will ask again after we reviewed all of the data. What would you use as first-line therapy for this patient? Would it be:

1. Immunotherapy/monotherapy;
2. Chemoimmunotherapy;
3. Alectinib;
4. Crizotinib; or
5. Lorlatinib.

Let us look at your answers. Okay, great. 68% would now prefer lorlatinib. For me, that would certainly be the right choice here. That is what we started the patient on. Lorlatinib as frontline therapy for this young patient with an ALK fusion.

With that, I will turn it back to Dr Bauer.

[00:40:10]

Coordination of Care and Management of AEs With ALK Inhibitor Therapy

Dr Bauer: Thanks, Christine. That was great talk. I appreciate it. I hope everybody enjoyed that whirlwind of data. It was great. I think that my guess is those holdouts, Christine, who are still looking at maybe doing chemo-IO or IO alone, might have some hesitancies about the side effects that come along with some of these treatments specifically lorlatinib.

We are going to talk about those and hopefully put those worries to ease because I agree that this patient, the right first choice is going to be an ALK inhibitor and specifically lorlatinib based on the CROWN data.

[00:40:50]

Pretest 3

We are going to give you another quick pretest. Which of the following adverse events that occur in most patients treated with lorlatinib should be monitored prior to and after initiation of treatment?

1. Anemia;
2. Elevated CPK;
3. Hyperlipidemia; or
4. Hypertension.

The answer to this question when we go through this is almost universal with lorlatinib. We are going to talk about how you counsel patients and manage that going forward. I think we can probably put up the results of that.

We had a smattering across the board and I think this is great because this gives us some good opportunity to learn. Hyperlipidemia is the most common side effect we see with lorlatinib affecting truly 80% to 90% of patients. But we are going to talk about that a little bit going forward and how to manage it.

[00:41:49]

ALK TKIs: Distinct Toxicity Profiles

Looking at these toxicity profiles, and this is a lot of words, so please do not try and read it. I want to walk you through how we think about these drugs because alectinib, everybody is comfortable with it. You give it to the patient, you start it and everybody does well. Maybe a few percentage of patients have grade 3 or greater anemia, LFT abnormalities. We can manage those.

Brigatinib is a little bit different, right? When we started with that drug, there was this big concern about pneumonitis. We have almost completely fixed that with some step up dosing, but we will talk about that in a minute.

What we really see in practice now are elevated CK, elevated lipase, some hypertension and some elevated amylase.

Ensartinib, as Dr Bestvina said, the newest kid on the block because it just got FDA approval, is rash, elevated ALT and pruritus. Those are pretty standard TKI side effects like we are used to all of those.

Then we go down to lorlatinib. What do we see with that? Hypertriglyceridemia and hypercholesterolemia really seen in almost all patients, 20% and 16%, respectively, grade 3 or greater, weight gain and hypertension. We are going to talk about all those, but I think actually the most important point on this slide is the fifth column on the right, all the words. We see AEs leading to dose modification, including reductions, interruptions, and discontinuation.

If we start with alectinib, this drug we are all very comfortable with, we see that 20% or 19% of patients needed interruptions, 16% needed reduction and 11% had to stop the drug due to treatment-related adverse events.

We go to brigatinib, reduction is 29%, so maybe a little bit more hands-on and discontinuation stable or equivalent at 12%. Ensartinib, we saw the reduction at 24% and discontinuation at 9%. And then lorlatinib, dose interruption is 49%. It is more hands-on. Dose reduction, 21%, again, more hands-on, but only 7% of patients had to come off of treatment because the side effects could not be managed.

Now a little bit of a background from my experience with this, I had the chance to work with lorlatinib in the first-in-human dosing, the first cohorts. This was going on in early 2014 rather when alectinib was in phase III trials. A lot of the patients we were seeing on this were heavily pretreated with multiple prior therapies, and so they had a lot going on. So there is a lot of discussion about the CNS adverse events, which we are going to touch on.

And a lot about, well, this is a hard drug to take. What I would submit to you guys actually is if you look at those numbers, reframe this a bit. It is not a hard drug to take if only 7% of patients have to come off of it. It is a more hands-on drug in management intensive drug to give as providers. But I think with what Dr Bestvina showed us in the data, it is probably worth it to our patients to figure out how to manage it and move forward with this drug for our patients. That is what we are going to talk about tonight is the management of that.

[00:45:03]

Management of Anemia With Alectinib

A few of the other side effects that are maybe a little bit more unique to each of these ALK TKIs. Alectinib can cause a hemolytic anemia. As soon as we see our patients with anemia, we want to rule out the common things, the menstrual blood losses, iron deficiency, B12, and folic acid deficiency. If we think there is a hemolytic anemia, obviously go through the process of that and hold the drug until you know that the labs are stable or better.

If it is confirmed that this was a hemolytic anemia, you can reduce the dose of alectinib and resume at that point.

[00:45:42]

Management of Diarrhea With Brigatinib and Other ALK TKIs

Brigatinib, in addition to the lung toxicity which we will talk about in a second, does cause some diarrhea as can all TKIs. So please do not try and read all these words. Just remember that we manage diarrhea with brigatinib like we do with everything. We fluid replete. We use over the counter Imodium. We throw in some loperamide, if needed. You go up to codeine, if necessary.

But grade 1 or 2 diarrhea, continue the drug and manage it symptomatically. We get to grade 3 or 4, probably pause a drug and consider resuming at a dose reduction.

[00:46:17]

Management of Pulmonary Toxicity With Brigatinib

The pulmonary toxicity with brigatinib the pneumonitis that we were seeing. Remember, we have almost eliminated this with a step elevation of dosing to start. So a 7-day lead in at 90 mg before going up to full dose. You still need to pay attention for pneumonitis in your patients.

Home O2 monitoring is appropriate for these patients. Obviously, if they start to get hypoxic, you need to support them fully in the hospital in the ICU with ventilation and aggressive high dose steroids, if necessary.

[00:46:51]

Management of CPK Elevation With Alectinib, Brigatinib, and Other ALK TKIs

Now, alectinib, brigatinib and lots of them can cause elevated CPK. This is most often just a lab abnormality, but of course you want to watch out for any signs of true myositis. You want to watch for muscle pain and weakness. You withhold the dose and dose reduce if they do have true myositis. If it is just a CPK elevation, you can monitor that and continue dosing through it.

[00:47:20]

Safety Summary: CROWN vs ALTA vs ALEX vs eXALT3

Now the safety summary for these. Again, I am going to draw your attention to the bottom line of this, truly the bottom row, AEs leading to treatment discontinuation in the CROWN, ALTA-1L, ALEX and eXALT studies. What we saw are pretty consistent levels of treatment discontinuation across the different TKIs.

These are cross trial comparisons and you cannot use them to say that 1 is better than other. I would certainly not sit here and say, well, the lorlatinib AE discontinuation were only 11%, but alectinib was 14.5%. No. But what we can say is all this discussion about lorlatinib being a hard drug to take does not pan out in the data with appropriate management. It can be well tolerated and can be used for a long, long time as the CROWN trial 5-year data puts out.

[00:48:12]

CROWN: Time to Onset and Duration of AEs

I want to dive in a little bit more into these lorlatinib adverse events because they are unique. When I sit down and counsel a patient when I am getting ready to start among lorlatinib, what do I talk to them about?

Well, first and foremost, I say, look, you may run 10 miles a week, you may eat a super healthy diet, you are going to have hypercholesterolemia due to this drug, and I am right 9 out of 10 times. We see the start of hyperlipidemia within 2 weeks and it can get up to a grade 3 or greater within about 5 or 6 months.

Why does it get to grade 3 or greater? Because a lot of patients do not want to start another medicine. Why does any grade continue out almost out to 108 weeks or out to 36 months?

Well, it is because you do not have to manage this like a cardiologist. We see hyperlipidemia, we manage it to get it down close to 200 and patients do okay with that. We are going to go into detail on all these in a second guys.

Hyperlipidemia, hypertriglyceridemia, the same. What about that edema? We do see a peripheral edema, typically lower extremity, but it can be upper extremity that starts at about week 3 or month 3 or 4. We saw it in 85 patients, it got to grade 3 and 6 patients on Month 5.

This is a little bit separate and apart from the weight gain, which starts a little bit later and actually persists to a greater degree longer. These can be together, they can be separate side effects and we are going to talk about them.

What I really want to focus on, on this slide is the onset of peripheral neuropathy and CNS side effects. CNS side effects are much talked about in relation to lorlatinib, fortunately much talked about but not that frequently seen. They do start typically at about Month 4, both the neuropathy and the CNS side effects and most are appropriately managed with dose reduction.

We are going to talk about that, but just a reminder that most of the grade 3 adverse events lasted less than 3 months except for the weight gain.

[00:50:19]

CROWN: Management of Hyperlipidemia Events

How do we manage hyperlipidemia? Again, we start statins. Who would not about lorlatinib? If somebody has had an allergic reaction or a myositis related to statins in the past, maybe not the right drug for them because most patients are going to need a statin. We saw hyperlipidemia with lorlatinib in 149 patients, and most of these were grade 1, some grade 2, some grade 3.

I think about hypercholesterolemia in my lorlatinib patients. I think about hypothyroidism in my checkpoint inhibitor patients. I do not worry when the TSH goes from 4 to 0.1 up to 20, no problem. I just started them on Synthroid, right? You do the same.

For these patients I say, “Look, you are probably going to be started on, in this case, I use Crestor because the choice of the statin matters. Pitavastatin, pravastatin or rosuvastatin are preferred statin agents in these patients due to interactions with CYP3A4 enzymes.

With most of these, we are able to completely resolve it or partially resolve it down to a level that is tolerated. It is important for you all to know that on the CROWN trial, even in patients who developed hyperlipidemia, there were no increased cardiac events in the lorlatinib arm vs the crizotinib arm. Though this is a lab abnormality, it does not cause increased cardiac events in patients and can typically be easily managed with appropriate statins.

[00:51:52]

CROWN: Most CNS AEs Were of Grade 1/2 Severity

What about these CNS adverse events, which there is again much discussion. What do these adverse events look like? Well, we saw 63 events in 149 patients. Any CNS adverse event. Most of them were grade 1 or grade 2 cognitive effects, which we talk about like it is scary. If we were all in a room and I could ask you to raise your hands and ask how many people saw patients on chemotherapy that complained of brain fog, I expect that most practitioners would raise their hands.

When we talk about cognitive effects with lorlatinib, that is what it is. It is simply a brain fog, sort of a sluggish thinking. There were 31 patients who had some mood effects, which could be best be described probably as depression. You do want to watch for that.

We saw some speech effects, which is really, it is not a word finding difficulty, it is not a stuttering. It is just a slowed speech pattern. Again, in Nashville, you take an old 45 and just turn the speed of the turntable down and they just talk quite slowly.

There were some reports, 8 patients of some psychotic events. These can be acute, they can be quick and they can be obviously very traumatizing for the patient. These go away with appropriate management. All of this guys, it is super important to know that if you withhold the drug or you lower the dose, the CNS side effects do resolve back to baseline.

[00:53:22]

CROWN: CNS AE Over Time

Over time, so over 5 years of follow-up for the CROWN trial, we were able to look and see was there a trend towards almost a cumulative effect? Did we see increase in cognitive effects or depression or psychotic events or speech effects over time? I am able to reassure you we did not see those things. We saw continued incidents here and there, but not a trend toward increased incidents or prevalence over the 5 years.

[00:53:51]

CROWN: Most CNS AEs Did Not Require Medical Intervention

Most of the CNS adverse events did not require medical intervention including no new con meds added. A lot of patients will tolerate a grade 1 brain fog if they know what the drug can do for them. A lot of patients actually will lie, cheat and steal to stay on that drug with grade 1 brain fog if they think it can help them.

What we saw in all those CNS adverse events, 118 of them, is 68 patients did not have any intervention and we still had 33% of them fully resolved. They got back to normal, they accepted it as baseline or went back to baseline. 24% did not resolve. But those are the patients who are like, I can tolerate this kind of mild brain fog. It is okay.

We did add some antidepressants in patients who had depression. There is some dose interruption and dose reduction. Again, with dose interruption or dose reduction, those CNS side effects do resolve to baseline typically in about 10 to 12 days.

[00:54:54]

CROWN: Weight Gain

Weight gain was something that we really did not expect with this. It probably actually has to do with fact that ALK and TRK are very close on the kinome map[?]. They are very, very similar. NTRK2 plays a role in metabolism and weight balance. I can remember early in the phase I, a patient, they were coming over from South Carolina to visit and the husband was very concerned about the patient, his wife's weight gain.

Of course I am in a phase I clinic. I am like, “Hey, we are not losing weight. Life is awesome. Let us not worry about this.” He is like, “No, no, no, she is gaining.” I am like, that is cool, unless you tell me she is eating 5 Snickers bars a day, I am not concerned about this.

This is at 10:30 in the morning. They stopped, looked at each other, looked back at me and she said, I just had my second Snickers more of the day.

There is something to a legitimate weight gain that we see in these patients. What is grade 3 weight gain? That is 20% of your body weight, what we all gained during COVID, but that matters to patients and so we want to pay attention to that.

How do we fix it? It is really just lifestyle modification, exercise and diet control involving our multidisciplinary team to get some nutritionists involved. I do think this is an important point to make that weight gain is not a 100% correlated with edema. Certainly some overlap, but you can have a peripheral edema that does not lead to weight gain and you can have a weight gain that does not have any kind of peripheral edema that you can identify. So we need to pay attention to these things as 2 different side effects.

[00:56:33]

CROWN: Management of Weight Gain Events

How did we manage the weight gain? Diet and exercise and lifestyle modifications. Some resolve, some did not. 50% did not resolve. Again, this is an issue that we have to talk to patients about and it can be a big deal from an emotional standpoint like hair loss can be with chemotherapy. So we want to counsel patients carefully on this.

[00:56:56]

CROWN: Dose Modifications for the Management of CNS AEs

I want to jump back to the CNS adverse events because this is an important thing to talk about. Again, please, too many numbers, do not read the slide. When we looked at CNS adverse events on the CROWN trial, how many patients had CNS adverse events? 86.

How did we manage those? We either did not intervene, we added a con med, we reduced the drug, we interrupted the drug or some combination thereof.

What did we see with appropriate management of these patients? Well, 33% or 28 patients had resolution their CNS adverse events with no intervention. It just got better. 24% or 28% of patients did not have resolution without intervention. But with intervention, all those different switches, we can flip bottom line, top or bottom right corner. How many patients had to stop the drug on the CROWN trial due to CNS adverse events? It was 2 patients for 2% total.

Again, with appropriate management, we can keep these patients on trial.

[00:58:03]

CROWN: Affect of Dose Reductions in the First 16 Wk on Efficacy

Now, we as medical oncologists, are always worried about dose reduction because dose reduction affects efficacy except for not here. When we look at the CROWN trial, patients who had their drug reduced in the first 4 months of treatment showed no difference in progression-free survival or time to intracranial progression.

If we want to go through why that is, and I can nerd out on all the PK/PD data from the phase I trial, we can do that in the Q&A session. But rest assured that this recommended starting dose of 100 mg is likely equivalent to 75 mg for almost every de novo first-line patient that we see.

[00:58:51]

Summary

We know that ALK inhibitors are different. We know that their toxicity profile differ. Lorlatinib does have some unique side effects, but the management is really no different than what you do on a daily basis with TKIs, with chemo, with IOs. We talk to the patient and caregiver, especially with regard to the CNS toxicity and the depressive stuff because as good as I think I am at talking to a patient in the course of 15 minutes, their loved one is going to have a better fix on how depressed they may or may not be.

When grandma sparkles does not want to go to the kid's baseball game anymore, something is wrong. She is not going to tell me that, but grandpa is going to tell me that. That is important because if we can give a better quality of life and keep them on an effective drug longer, if we can manage that.

We talk to the patient, we talk to the loved ones, we manage these side effects. If it is really affecting quality of life, then we lower it and we do so with a pretty low threshold to do that and know they are going to get benefit. We reevaluate, we make sure they are doing better and we keep them on treatment going forward.

[01:00:02]

Posttest 3

Thousands of words. Can anybody identify for me the most common side effect we see with lorlatinib? Is it:

1. Anemia;
2. Elevated CPK;
3. Hyperlipidemia; or
4. Hypertension.

Go ahead and cast your votes now and we will flip over to the results here in 5 or 6 seconds.

Let us go to those results. Most of us heard that message that hyperlipidemia is most common in lorlatinib.

[01:00:45]

Poll 4

Now based on the discussion we have had over the past 45 minutes or so, does anyone here have a plan to make changes in your clinical practice based on what you learned in today's program? You heard Dr Bestvina say that lorlatinib looks to be the best-in-class drug in patients with ALK fusions, that giving patients without fusions checkpoint inhibitors is probably not the right answer. You have learned about the side effects and the management thereof. Does anybody feel differently about how they would manage Dr Bestvina’s patient going forward? We will pull up the results of that now. Maybe we will pull up with the results of that now.

It is a 100%. Christine, you and I get an A+. Everybody feels like they have learned something. Marcus, do we have those results or no? If not, no huge deal. Well, okay, no results for this. We got an A+, Christine. We are doing great.

Dr Bestvina: Awesome.

[01:01:51]

Poll 5

Dr Bauer: Take a moment to enter one change that you may or may not make based on the poll today? You can enter an answer in the text box that just popped up.

[01:02:13]

Q&A

Dr Bauer: Guys, thank you so much for your time. Dr Bestvina, great discussion. I appreciate your time as well. Are there questions that we want to go through and think through as a team?

Dr Bestvina: We actually have 3 excellent questions in the Q&A. I will put the first question to you, Todd. Which the question is, essentially once the ctDNA results come back, so you send a ctDNA, it shows an ALK fusion. Would you go ahead and would you start an ALK inhibitor based off of those results or would you wait for the tissue testing?

Dr Bauer: That is a really good question because I think we are probably on the same page about this. Tissue remains the gold standard. In my mind, a positive liquid biopsy or circulating tumor DNA test positive is positive. It is real. It is there. Negative means I probably want to wait on the tissue to confirm, and I want to wait on the RNA to doubly confirm as well.

Yes, a positive ALK circulating tumor DNA is a discussion with my patient about starting actually lorlatinib if I am being full disclosure over alectinib.

Dr Bestvina: Yeah, absolutely agree. To have a false positive is extremely, extremely rare with ctDNA. If it comes back as positive for this patient, I actually went ahead and wrote for the lorlatinib based off of the ctDNA results. Then it is, of course, always nice to see the tissue come back positive again later. But I think Todd, just to really reemphasize the point that Todd made a “negative ctDNA”, meaning a test in which you did not find an actionable alteration, that is something that I am still waiting on the tissue to come back for because that is where the sensitivity can be a bit limited.

Dr Bauer: Well, and in that vein, if somebody needs treatment today and you do not have these results back, my default, and I think Christine, you and I have talked about this before, is I am good to give carboplatin pemetrexed together alone for cycle 1. Why do I do that and not give the triplet? Well, we go back to the EGFR data that says if somebody has been exposed to a checkpoint inhibitor and then they get an EGFR, TKI, they are increased risk for pneumonitis.

If they need treatment now, cool, give them chemo-chemo. If they do not have a target, add the Keytruda in at that point. Two things about that one. I think that immunotherapy is not vital in the first-line of therapy. It is not going to fix anybody today, whereas chemo can.

Number 2, checkpoint inhibitors very specifically in an ALK-positive population do not work well. I do not care what their PD-L1 measurement is. I do not care what their anything is. I would strongly encourage you to not use a checkpoint inhibitor in a patient with an ALK fusion because it just will not be effective.

Dr Bestvina: Absolutely. Sometimes when that PD-L1 comes back as high, it is so tempting not to do it.

Dr Bauer: Well, the commercials are exciting. I mean, people like bounding through fields hugging, everybody is happy.

Dr Bestvina: The patients like it. I would say very frequently. I have patients who end up having a targetable alteration come in initially asking for chemotherapy. And so it certainly can be a long discussion with the patient about why we are holding off on treatment or why we are just giving chemotherapy for a cycle as we weight these results.

We have got quite a number of good questions, so I am going to move on to the next one. Now that we are using alectinib in the adjuvant setting, if a patient progresses, what would be the choice in the metastatic setting? It is an excellent question. I have given adjuvant alectinib. I have not yet had a patient progress during that time, but if they did, my plan would be to get a biopsy of whatever the progression was so that we can look at the resistance profile and make decisions based off of that.

But it is important to know that lorlatinib is approved in the post alectinib setting and that most likely would be the default next line of therapy. Any other thoughts, Todd?

Dr Bauer: Yeah, no, I am just excited, because this gives me a chance to totally nerd out on the dosing of lorlatinib. A little bit of background for those of you who are sticking around for the victory lap here. Lorlatinib was originally designed as a rescue medicine.

Why do people fail alectinib and brigatinib? Often, it is due to in-frame resistance mutations. You have your fusion protein and you get a mutation in the middle of it. The most difficult to overcome is the G1202R resistance mutation. Lorlatinib works very well on that. That is what lorlatinib was designed to do.

I was the biggest fan in the world of saying we should save this for a rainy day until we started to see the frontline data. My comment earlier about the dose level of 100 mg vs the first dose reduction of 75. 100 mg was selected for lorlatinib as a recommended phase II dose because of increased on-target time against G1202R.

In that resistant population, 100 mg is a better dose. In a front-line population, there is probably not a significant difference. However, and please listen to this, I still start everybody at 100 mg. There are people who do it differently. They start at 75 and say, if that is going to be good enough, decrease toxicity. I do not care.

What I worry about with the drug where I now have 2 patients, and Christine, I just got an email last week about this. My second patient who has been on lorlatinib for 10 years with metastatic lung cancer. I do not know if the lower dose works for 10 years. So I am going to try the higher dose. If I have to reduce it, I have a low threshold for that. I am cool with it, right? Like, you come in, you say, “Hey, I am feeling pretty down and my thinking is not clear and I do not want to go watch the baseball games.” I am going to lower the dose. But why not try it at the higher dose, recognizing that all of these side effects do get better at dose reduction, nothing is permanent.

That is why I think I started at the 100 mg. That is why the 100 mg dosing is there. That is why I agree with you, lorlatinib is the default second-line agent if they have been on alectinib in the past.

Dr Bestvina: Excellent. I think that leads very nicely into 1 of the other questions. What is your opinion about starting lorlatinib in patients suffering from minor cognitive troubles? For me, this might be a patient population where I would consider starting at the 75 mg dose in the previously untreated setting. Same thing for patients who have a history of psychiatric disorders or other things that I am worried about. I may consider starting at 75 for those patients and just seeing how they tolerate it. Great question though.

Dr Bauer: Yeah, I will totally agree and say also, what is their social support look like? I live and practice in Nashville and I can drive 20 minutes away and be out in the middle of nowhere. If I have got an 80-year-old that lives in the middle of nowhere and their closest family member is 30 minutes away, I do not have the comfort necessarily that somebody is going to raise their hand and say, actually his thinking is not quite right, because that is going to be a little bit more isolated. So you do have to pay attention to that for sure.

Dr Bestvina: Excellent point. Then the next question, do you prescribe the statin or do you send the patient to their primary care or cardiologist for the statin?

I, in my practice, will go ahead and write for the statin. As Todd pointed out, there are certain statins that you want to avoid with lorlatinib. So I hesitate to send them outside of my practice and have them end up on 1 of the statins that we do not want them on. We tend to start it ourselves.

Dr Bauer: I will say, I look at this as I broke it, I got a buy it situation. It is like antihypertensives and bevacizumab. That is my issue. I caused it. I can manage a statin pretty well. I am not trying to get their total cholesterol down to 175. Ballpark is good enough. This is always going to make me chuckle a little bit, like we are really worried about the 10-year cardiovascular risk of a cholesterol of 250 in somebody with metastatic lung cancer. We have won the game, guys. That is a great problem to have to worry about for this patient population. I will start the statin. If I cannot control it, then I will get cardiology on board.

I will say if the triglycerides do not come down appropriately, fibrates are the right thing to add on for that. You do not want to do anything but those particular statins and fibrates.