: In terms of best approaches for molecular testing for patients with metastatic non–small cell lung cancer, there are different methodologies that could be used with either plasma or tissue. My general approach is to look at broad molecular profiling because we have 7 approved targeted therapies for 

 mutated lung cancer matching the TKI (tyrosine kinase inhibitor) to a great targeted therapy. We have osimertinib for 

, among others; alectinib and brigatinib for 

 fusions; larotrectinib and entrectinib for really rare 

 mutations; and dabrafenib and trametinib for 

To capture all of those, I look at broad-based genomic profiling, next-generation sequencing (NGS). You could look at tissue. You could look at plasma. There are pros and cons for each one. If I need something quickly, I will often send plasma since you don't need to set up a biopsy if you need additional tissue, and you get the results in a week. If there's a big surgical specimen sitting in the bank, I'll often use tissue. Where I don't have tissue, I'll first try with plasma as I'm setting up the biopsy.

There are methodologies, such as IHC (immunohistochemistry) and FISH (fluorescence 

 For IHC, there is an FDA-approved test, and those can come back quickly. There are certain situations where, if I really suspect there's an 

 fusion and I need to start treatment quickly, I will occasionally send that as part of a targeted panel to get the results quicker. Generally, I send next-generation sequencing for broad genomic profiling.

: My personal approach is to use both liquid and tissue next-generation sequencing at the time of the diagnosis. I believe that those tests are complementary. An alternative approach would be to do next-generation sequencing on tissue and save a plasma NGS, or so-called liquid biopsy, for patients in whom tissue was insufficient. I wait until I have all molecular testing before I initiate therapy. In general, most of your patients with metastatic non–small cell lung cancer will also have PD-L1 testing done.

I expect that PD-L1 testing will come first before I have the results of the molecular testing. I always wait for the molecular testing results before I start chemotherapy or any kind of treatment. Occasionally, I have to start therapy before NGS results are back because the patient is highly symptomatic and rapidly declining. In this case, I would recommend not giving immunotherapy with the first cycle. The reason to hold immunotherapy is to avoid emerging adverse effects, such as pneumonitis, if immunotherapy was given before tyrosine kinase inhibitors.

If you think about testing for our patients with metastatic non–small cell lung cancer, you need to remember to test. There are several ways of testing for molecular alterations. In some instances, immunohistochemistry or FISH are appropriate. I use next-generation sequencing, which has both a DNA and RNA capacity. I know that some institutions will have a rapid immunohistochemical screen for 

, and others. It doesn't really matter what system you use as long as you use the one that assures that your patients with metastatic non–small cell lung cancer get tested for all the abnormalities that have FDA-approved drugs.

 could be a part of NGS. Alternatively, you can order those genes separately. The most important thing when deciding to test and what company to use is to check your platform, if you're using an NGS platform, and make sure that the company you're using is testing for 

 is a new addition; we weren't testing for 

 fusions 3, 4 years ago. In my practice, I prefer NGS over single-gene testing for 2 reasons: (1) I believe NGS testing saves tissue, and (2) it's likely to save costs because now we have to test for 7 molecular abnormalities. I think the cost will probably add up if you use single-gene testing.

If you identified a molecular abnormality that has an associated targeted therapy, you should go ahead and treat. For example, if you use the single-gene testing and find that you have an 

 mutation, that's enough for me to start treatment. Our patients with oncogenic drivers are unlikely to have 2 separate oncogenic drivers in the same patient. Those cases have been described, and at this point, we do not know if they should go for 

 first, for example, for patients who have both of the alterations.

It is not necessary to complete the NGS testing if you already know that your patient has an 

 mutation. NGS testing does give you some additional information. We know that patients who have, for example, a 

 mutation have a worse prognosis than patients who don't have either. They're also more likely to transform into small cell lung cancer. Even though I'm not making any treatment decision based on that knowledge, I do find that it does give me some prognostic information. I might also look at that patient a bit more closely.

Another tip that I have for next-generation sequencing is if you have a patient who is never a smoker, or is a former light smoker, who has a higher incidence of molecular abnormalities… If you did not find it on your DNA-based next-generation sequencing, you could consider RNA-based testing, which would be more sensitive to fusion.

 It is great to discuss the proper molecular testing paradigms nowadays for our patients with non–small cell lung cancer, especially when we face situations where the tissue is either somewhat limited or very limited. Fortunately, we have a lot of different ways to facilitate that effort, to enhance the completion of molecular testing, which is critical to put our patients on the best treatment path and achieve the best long-term outcome. We want to make sure that we understand the patient’s tumor the best upfront. I complete biomarker testing.

Now, how do we deal with this situation of having potentially limited tissue? Issue number 1 is to make sure that we have good communication between members of the treatment team. This is where a multidisciplinary tumor board is so important to educate each of our colleagues. For example, with our pulmonary colleagues, we know that every time they do a biopsy, their biopsy might be needed for molecular testing. They do their absolute best to do a number of different passes, build a specimen that’s…enough to allow molecular testing, even from a cytology specimen. It’s the same way for interventional radiologists. We know that they need to take a couple different cores, as long as they’re safe from a particular patient, again, to allow the need for molecular and biomarker testing through the patient’s treatment continuum.

Still we’ll face situations when what’s obtained is limited due to safety concerns. Lymph nodes or nodules might not allow much of a specimen to be obtained. The next issue is having the pathology department ensure there’s appropriate tissue stewardship, that the tissue is prioritized for testing that’s necessary, as opposed to potentially wasting tissue for immunohistochemical stains that might not be absolutely necessary. Both coordination and stewardship are very important.

Lastly, we’ve been greatly assisted through the development of ctDNA (circulating tumor DNA) technology, liquid biopsy technology, where you have a patient with very limited tissue where we cannot perform all the molecular tests. We can utilize this platform, ctDNA testing, to complement the tissue testing we’ve been able to do. It is dependent upon the tumor burden of the patient, the stage of the patient, the yield of ctDNA testing, but in the metastatic lung cancer case, 70% to 80% yield is expected. A large majority of the patients will have informative ctDNA results, and they are strongly reliable enough to guide treatment. For example, if you detect an 

, we have strong data to say that the patient should benefit from the targeted treatment just as much as if we had detected the same mutation abnormality from tissue-based testing approaches.

Videos

Molecular Testing for NSCLC

 Lung cancer has enjoyed tremendous progress in understanding oncogenic-driven subsets. We used to pay attention only to histology in treatment selection. Now we have 7 oncogenic drivers, all associated with FDA-approved targeted therapies. Those are the EGFR, 

In addition, we have 3 other abnormalities such as 

 [human epidermal growth factor receptor 2] exon 20 insertions, which have compounds in clinical trials with preliminary evidence of efficacy. With novel targeted therapies, we see unprecedented survival with some of the drivers. Take, for example, recent update of the ALEX trial for 

-rearranged lung cancer. The alectinib arm in this trial showed a 5-year survival of 67%, and this data set is only 37% mature.

The median survival has not been reached, and the median follow-up is already 48 months. We also have learned in the past 10 years that the CNS [central nervous system] is currently a battleground for many of oncogenic-driven patients. In response to that, all novel targeted therapies are being developed with CNS coverage in mind.

-rearranged non–small cell lung cancer has evolved recently, there have been a lot of exciting developments. For the past several years, crizotinib, which is both an ALK and ROS1 inhibitor in addition to be initially developed as a MET inhibitor, has had potent activity in ALK and ROS1.

That was the first-generation ALK inhibitor, and it was compared with next-generation ALK inhibitors, alectinib and brigatinib, in the ALEX and J-ALEX trials for alectinib and in the ALTA-1L trial with brigatinib as first-line therapy. There was a substantial improvement in progression-free survival with bringing these next-generation ALK inhibitors, such as alectinib and brigatinib, up front. Alectinib had a median progression-free survival of about 3 years, and brigatinib median progression-free survival was about 2 years.

This really changed the landscape of how we treat ALK-positive non–small cell lung cancer. When we talk about 

 non–small cell lung cancer, crizotinib is a really good ROS1 inhibitor. Its approval was based on a study of about 50 patients. It was published in the 

 in 2014. The median progression-free survival was a bit over 19 months, so really effective response rates at around 70%. Lately, there’s a new approved ROS1 inhibitor, entrectinib, which also appears quite active and has CNS penetration as well. It’s a bit better than crizotinib, which is also an advantage.

It’s been great that we’ve had these new ALK and ROS1 inhibitors to bring to the clinic. Also in development is lorlatinib, which is approved for ALK non–small cell lung cancer after progression on a prior ALK TKI [tyrosine kinase inhibitor] and also has activity in 

 non–small cell lung cancer, although it’s not approved for that indication.

 fusions are oncogenic and lead to downstream activation of signaling pathways. In lung cancer, 

 fusions are found in approximately 1% of patients. The incidence is slightly higher in a subset of lung cancer called lung neuroendocrine carcinomas. We have 2 FDA-approved histology-agnostic 

-fusion agents, such as larotrectinib and entrectinib. Those drugs have remarkable activity with a response rate of approximately 60% to 70%. Responses appear to be durable, and CNS activity has been reported with both larotrectinib and entrectinib. We definitely need to be testing for 

Overview of Rare Driver Alterations in NSCLC

We have all these wonderful drugs. It’s exciting, but it’s confusing. Probably just as confusing is testing. There are certainly a lot of competing testing strategies—tissue, NGS [next-generation sequencing], DNA based, RNA based, liquid. Where does that fit in? Josh, I’ll start with you. Give us your best practices for testing at Penn Medicine, how you see the field moving, and what you’re doing for your patients.

Thanks. Every patient who comes in, at least with nonsquamous, non–small cell lung cancer at Penn Medicine, has a DNA-based mutation assay and an RNA-based fusion assay. It’s done in house. The advantage of the RNA-based fusion assay is that it is much better at detecting fusions. We know that DNA-based assays can miss them. We also know that things like 

exon 14 skipping alterations are difficult to identify because they happen in the intron. Most of the time, when I detect a 

 alteration at my site, it’s not detected on our mutation analysis. It’s detected on the fusion as a 13-to-15 fusion. That’s 

In terms of my incorporation of liquid biopsies, I do use them rather frequently. There was a series done by my colleague Charu Aggarwal showing increased sensitivity and identification of alterations when it’s done concurrently with tissue in the first line. I will say, I’m more likely to do it when I’m questioning the quantity of the biopsy. If a patient comes as a second opinion and I don’t know the adequacy of the sample, I will send a liquid biopsy in that first visit. In addition, if a patient is very sick, I will send a liquid biopsy at that visit because it comes back faster. I do a lot of concurrent liquid and tissue testing.

The critical element is that now, with 7 FDA-approved targets for lung cancer, doing single-gene testing is definitely not tissue efficient. There was a wonderful ASCO [American Society of Clinical Oncology Annual Meeting] presentation by Nate Pennell showing that it’s also not cost efficient. From my perspective, there is no role at this time for single-gene testing. We should be doing panel testing broadly.

Those are all good points. Lyuda, what is your approach on testing at UCSD [University of California San Diego]?

At the time of the first consultation, we do both liquid and tissue biopsies. If the liquid biopsy comes back positive with oncogenic drivers, treat based on that. Don’t wait for tissue. The tissue is NGS [next-generation sequencing], of course. I haven’t done single-gene testing for quite some time. I do use RNA assays, but only if I don’t find an oncogenic driver on the DNA assay. Practicing in California, our incidence of 

 mutation, and everything else is pretty high, so I just can’t easily justify RNA assays on everyone just yet. But if my DNA assay didn’t find anything, especially if I have a nonsmoker, then I refer to the RNA-based NGS.

Becca, what is your experience at Massachusetts General?

Similar to what Josh was saying, we do NGS on both DNA and RNA to detect point mutations and fusions. We do think that the RNA-based testing is important to catch all the rearrangements for the reasons that Josh outlined. We test all advanced non–small cell lung cancer patients. With these multiple alterations, you can see them across all histologies and all smoking histories, so it’s important to test everyone. We use liquid as well. It’s complementary. For example, if you look at a series of autopsies and at different metastatic sites, there are differences among the sites. You can imagine that there are limitations to what a tumor biopsy would get you. Liquid biopsy obviously has the mutations as well. If it’s not a very DNA-shedding tumor or if disease is confined within the lungs or not widely metastatic, you might not pick up as much. These are complementary mechanisms. I do think the days of testing only a very small number of genes and then doing sequential testing are way behind us. We cannot be doing that with the number of alterations that we have good targeted therapies for.

Yes, those are all great points. The only thing I will add is, first, a consideration of liquid for all patients, given that tissue oftentimes is not sufficient. A negative liquid biopsy tells you nothing, but a positive essentially rules it in. Second, all of us are probably doing our in-house assays. If you’re not, and you’re sending it out to a commercial platform, make sure they’re doing RNA sequencing as well. There are too many fusions that are better picked up by these platforms that are now relevant and actionable, and they’re missed. We know it. There’s a big difference in the discussion that goes down. There are big differences in the outcomes for these patients when you’ve identified a target and can deliver targeted therapy vs if you can’t. I would just make a call for everyone to think about where they are sending it to if they aren’t doing it in house, and whether they are optimally interrogating the tissue to pick up on all relevant alterations.

Thank you all for this rich and informative discussion. Before we conclude, I’d like to get final thoughts from each of you. Lyuda, you get first crack.

That was wonderful. The moderating was great. My colleagues were fantastic. It’s very nice to feed off one another. The 1 thing I wanted to bring up that we didn’t discuss in the testing is managing your PD-L1 positivity before you know your NGS. Many of us have in-house PD-L1 testing, so it’s very likely that your PD-L1 results will come before your molecular testing results. I strongly advise not to start immunotherapy for PD-L1 greater than 50% if you do not know your molecular alterations. If it’s an 

 patient, (a) immunotherapy is not going to work, and (b) you can potentially increase the risk of pneumonitis if you then sequence with 

It’s been an honor to participate. I’d like to give you all a blue ribbon with a gold star on it for today’s presentation. The key point, now that we’re talking about these different targets, is that it is absolutely essential that every patient get tested. We have to make sure the testing is done—that it’s done correctly, and that it’s done comprehensively—so we can make sure we improve the outcomes for every patient.

Thank you, Josh. Blue ribbon and gold stars in the mail today, overnighted. Becca, what are your final thoughts?

Thanks, everyone. This has been fun. As has been said before, testing is so critical. There are so many alterations that matter, both with FDA-approved drugs and drugs that are not FDA approved but are in clinical trials and are very active. We need to be testing everyone. All of us on this panel have the incredible luxury of these molecular pathology departments within our institutions that supply us with state-of-the-art testing. For many people who don’t have that, who are sending tissue or liquids out, we need to develop better ways to be able to interpret the quality of the test that’s being used. Too often we see patients referred with such-and-such alteration. When you actually look, they weren’t testing for it correctly. That’s a big area that needs focus because we know that there are good drugs to use, but the testing needs to be done correctly.

Again, those are really good points. I want to thank the panelists. This was a fun exchange, and probably the easiest exchange I’ve done through Zoom in a while. You guys made my job pretty easy today with all the intelligent commentary and perspective from each of your institutions. Thank you again. To our viewing audience, we hope you found this 

® discussion to be useful and informative.

Optimizing Testing Strategies in Non–Small Cell Lung Cancer

I just want to briefly finish with 1 of the rarer genotypes among cancer: 

 fusions. I’ll briefly review the data with both larotrectinib and entrectinib. The larotrectinib data were the poster child for a basket trial. They were taking patients irrespective of tumor type or histology, and if they had an 

 fusion, they were all treated with larotrectinib. There were more than 17 different tumors treated. Incredibly, the age range of this trial was 4 months to 73 years. The large majority—more than half—were treated with either 2 or 3 lines of therapy prior to the drug being delivered. Not unlike the other targeted therapies we’re talking about, the response rates were anywhere from 70% to 80%. It is probably underrepresented in the lung cancer space. There were 3 or 4 young patients with other types of tumor sarcomas that were thought to be advanced stage, in whom they were able to give this drug, shrink it down, and do limb-sparing surgery for cure. This is an incredible advance. The responses were durable. There are some adverse effects with this drug, but it tends to be really well-tolerated overall. You do see some weight gain and hyperphagia that can be seen as part of the 

 physiology, but overall it is a reasonably well-tolerated drug.

The second drug, entrectinib, published in 

. There were roughly 50 patients with more than 12 tumor types in the study. It was another basket trial with response rates of 50% to 60%. We’ve already talked about some of the entrectinib adverse effects. I will be transparent, and say that I have not yet found an 

 fusion, and I have not used these drugs yet. I’m still looking. I’ll turn it over. Becca, have you seen 

 fusions? Have you used either of these drugs?

There have been 1 or 2 at my institution. I have not treated these patients. They’re exceedingly rare in lung cancer.

What’s frustrating is that I actually treat salivary gland tumors as well. You would expect that I would have seen a patient with 

 fusion, but I have not. I keep looking. I keep looking.

We have the most experience. I never found a lung cancer patient with 

 fusion. I’m still looking, but since I have an 

 trial open at my site, I’ve seen gastrointestinal 

 fusion. I’ve seen a wonderful response in an anaplastic thyroid cancer patient with 

 fusion, where the drug clearly prolonged the patient’s life because he had a very bulky disease in the neck with respiratory symptoms. My experience with entrectinib is exactly as published. There is some perioral numbness when they start. An interesting bit of information about those drugs is, when you stop the drug for toxicity or whatever, a patient can have hyperalgia. They have a pain syndrome, and they get scared. Just be aware, if you hold the drug for any reason, and explain to your patient that they might have an exacerbation of pain that is not cancer related. Then, once you put them back on the drug, the pain goes away.

Those are all good points. Thank you, Lyuda, for your perspective on 

NTRK Fusions in Non–Small Cell Lung Cancer

We have 2 more new genotypes to talk about. The first is 

 exon 14 skipping mutation, and the last is 

 fusion. Becca, do you want to talk to us about the relevance of 

exon 14 skipping mutations and some of the new drugs that are either being tested or approved? It’s incredible to try to keep up with all these drugs for the different genotypes. I don’t envy the challenges that exist for community oncologists in trying to keep up with this. But this is another approval that we’ve had in the past 2 or 3 months, with another probably coming soon.

 is interesting. People have been trying to target 

 for a long time, and there are many different ways to measure 

. This is an area where when we get to the testing discussion, it’s important to talk about. There’s 

 exon 14 skipping. With exon 14 skipping, there are a host of different changes at the genomic level. These are primarily mutations or insertions/deletions around the splice-site regions. What they do is cause the exon 14 to be spliced out, and the receptor that gets expressed is 1 that is more stable on the cell membrane. It’s not degraded as much. In the patients who have these 

 exon 14 mutations in their cancer, it does seem to behave as a driver.

 inhibitors that have been looked at. Crizotinib, as you all know, was initially developed as a 

 skipping. It’s been published, and the response rate was 32%. The waterfall plot looked more impressive than that response rate because the majority of patients had some degree of benefit.

 inhibitors that currently have some data out there include tepotinib, which was just recently published. The response rate was 46%. There are multiple response rates reported for a liquid biopsy vs tumor biopsy, or independently reviewed vs investigator reviewed. They all fall around the same 46% number. Then capmatinib is FDA approved. There, the data are broken down by first line and then subsequent lines. In the first-line setting, in patients who had never had prior treatment, the response rate was 68%. Then in the second and third lines, it was 41%. At ASCO [the American Society of Clinical Oncology Annual Meeting], the second-line capmatinib cohort was reported, and there the response rate was 48%.

Overall, there are several potential options in this setting with nice response rates. With the capmatinib data, I would be using it in the first-line setting and would expect to have nice responses there.

Lyuda or Josh, do you have any experience with either of those 2 drugs? Is there any experience with toxicities? I have not used either capmatinib or tepotinib yet. Josh, what is your take on the data or experience with the drugs?

I have just recently prescribed a couple of patients capmatinib. I haven’t seen any toxicity yet, but it’s too early. It feels like yesterday that it was approved, so that’s too fast for a toxicity take. But 1 of the things that is most interesting about the 

 population is this drop-off in the response rate from the first line to the later lines. It really emphasizes the importance of using the best drug first. Patients with 

 exon 14 skipping alterations tend to be older. They may have more comorbidities, so it’s really important to use targeted therapy first. I had been using crizotinib. This is a different setting from what I described before with entrectinib and crizotinib. In 

, crizotinib works well. It doesn’t have CNS [central nervous system] penetration. In this setting, crizotinib works OK—maybe a bit worse—and doesn’t have CNS penetration. I’m much more likely to replace capmatinib in this setting than I was in 

. But it’s a complicated space, for sure. When tepotinib becomes available, it will be a coin flip. Both drugs are very active, CNS penetrant, and well tolerated.

I don’t have personal experience with those drugs because I have trials that I put my patients on for the 

 exon 14. The data presented are certainly compelling enough that if I didn’t have a trial, the next patient with 

 exon 14 mutations I saw would be prescribed capmatinib.

In general, as a class effect, peripheral edema is seen with the 

inhibitors. It seems like the more selective and potent the 

 inhibitor, the more edema we see. There is definitely more edema than with crizotinib. That tends to be something that accumulates over time. I found that compression stockings help a lot. Lymph edema massage actually helps a lot. In general, these are pretty well-tolerated drugs, and the edema seems to be 1 of the major issues we see.

Just to highlight what Josh was saying, we see 

skipping across all histologies in non–small cell lung cancer. That includes adenocarcinoma, squamous cell carcinoma, and pulmonary sarcomatoid carcinoma. We see it in smokers, as well as never smokers, and there is this predominance in older adults. The importance of testing is really highlighted by this particular alteration.

MET Exon 14 Mutations in Non–Small Cell Lung Cancer

 fusion, which is yet another fusion that can be seen in non–small cell lung cancer. There are some very good drugs coming out that target 

 fusions and alter the way we approach these patients and treat them. We’ll talk about how to test for fusions at the end in our testing section. Josh, do you want to walk us through the data we have with LOXO-292 in 

 fusion lung cancer and the Blueprint Medicines drug pralsetinib?

Yes. I did a bit of foreshadowing a moment ago when I mentioned cabozantinib because previously, the only drugs that we had for treating 

fusions were from medullary thyroid cancer. We know that in 

-mutated cancers, cabozantinib and vandetanib have efficacy, but they bring substantial toxicity. When those drugs were used in 

 fusion-positive lung cancers, the efficacy wasn’t there, in terms of response rate or progression-free survival. More recently, there have been 2 drugs that have come out that are highly active in 

 fusion-positive cancers, both papillary thyroid cancer and non–small cell lung cancer. Those are selpercatinib, which has recently been granted FDA approval, and pralsetinib, for which I’m sure the approval is coming down the pike.

Selpercatinib and pralsetinib both had response rates, at least from the treatment-naïve standpoint—66% for pralsetinib, 85% for selpercatinib. Those are really impressive. Both have CNS [central nervous system] penetrance, and both pretty well tolerated. With the 

fusion inhibitors, the big adverse effect that we see across both of them is high blood pressure, but that’s controllable with antihypertensives. There are some LFT [liver function test] abnormalities, but nothing to write home about. These are a game changer. When these drugs were only available on trials, if I found a 

 fusion, I would tell a patient, “If you don’t have a trial available at your site, this is something to travel for. This is something to get on a plane for, pre-COVID-19 [coronavirus disease 2019].” This is a huge advance for our patients, and I’m very excited that now we have access to selpercatinib.

Yes. We’ve been involved with selpercatinib and the LIBRETTO-001 trial. This is a very clean drug, which hits its target nicely and selectively. We’ve had medullary thyroid patients and lung cancer patients who have come in. Specifically in our lung cancer patients, some of them who are symptomatic start to feel a difference in 5 to 7 days. These are some of the things we see with osimertinib. But it is well tolerated, aside from maybe some dry mouth. Becca, what are your thoughts on these drugs? Have you been part of some of these efforts, and where do you see this field heading?

Yes, we’ve had both drugs in studies at our institution. We have had patients on both, and I agree. A couple of years ago, there was this talk of 

. Is it really a driver? As it turns out, we just didn’t have the right drug. If you have a very potent and selective inhibitor, then yes, it’s a driver. We just didn’t get to the drug levels we needed with the other drugs that were being used before because of the ancillary toxicity. These are great drugs, as you’ve said, and are game changers for the 

Lyuda, what are your thoughts? Are there differences between these 2 drugs—pralsetinib and selpercatinib—based on the data?

There are not clinically meaningful differences. Josh was very elegant in discussing the slight difference in toxicities, but I don’t think they’re clinically important. I don’t have experience with pralsetinib. I have experience with LOXO-292, and my experience is exactly as it’s published in terms of toxicity.

RET Fusions in Non–Small Cell Lung Cancer

Let’s move on to another rearrangement that’s actionable with new therapies, and that’s 

 rearrangement in lung cancer. Becca, do you want to talk about how you treat these patients, some of the emerging data, and which drugs you use?

 rearrangements are described in lung cancer like many of the other driver rearrangements. They are more often in people who have a very light or no-smoking history and no carcinoma. 

, so many similar drugs can be used, but it is important to know that it’s not exactly the same. For example, we talked a lot about alectinib in 

, and it’s important to recognize that there are different drugs with different levels of activity against 

There have been data in the past using crizotinib in this setting with a nice response rate. The response rate was over 70% in a series done with crizotinib in 

 patients. One of the things we’ve noticed about 

 patients is that their duration of response to a drug like crizotinib was longer than, for example, 

 patients using crizotinib. For some reason, they seem to have more prolonged benefit. More recently, entrectinib is another drug that’s entered the 

, and it reported a response rate of 77% in a pooled analysis.

To answer the question of whether I would use entrectinib or crizotinib, which I’m sure is coming, I don’t have a lot of experience using entrectinib. The toxicity profile is a bit daunting. It does have great CNS [central nervous system] penetration in a patient with CNS metastases, whereas we know crizotinib doesn’t have great penetration into the brain, so I would consider it. But there have been adverse effects, such as dizziness and cognitive changes, so it wouldn’t be clear that everyone gets entrectinib in my mind. It would be a case-by-case decision, depending on where the disease is and the patient’s general functioning, whether I would with crizotinib or entrectinib.

That’s a good review. The entrectinib data do look as though there is some CNS penetrance. I don’t know if we saw the intracranial response with crizotinib in the 

 papers. But it seems as though there may be better CNS penetration. The other thing about entrectinib—correct me if I’m wrong—is that the drug doesn’t really work postcrizotinib. It’s probably not the best drug to give. If that’s the case, what do you do next if you start with either of these drugs?

There are data for lorlatinib after crizotinib. Lorlatinib has activity in both treatment-naïve and postcrizotinib settings for 

 patients. In the treatment-naïve setting, the response rate was 60% or so. Even postcrizotinib, the response rate to lorlatinib was about 35%. That definitely has activity.

There are also other drugs that are being investigated in clinical trials that look interesting. There’s TPX-0005 [repotrectinib], which is being looked at. That was designed to deal with some of the solvent front mutations that can come up in resistance. That’s an interesting trial to think about in someone who is progressing, especially if they have a solvent front mutation. There are a lot of drugs being developed in that space.

Josh, what are your thoughts on which of these drugs you usually reach for when treating 

-rearranged lung cancer, and what you do next?

I tend to use crizotinib in the first line. Crizotinib is highly active and is well tolerated in this space. Entrectinib introduces toxicity, as Becca very accurately said. In later lines, the only drug that’s approved and has efficacy against those solvent front mutations is cabozantinib, which I try to keep my patients as far away from as humanly possible, given its toxicity. But the repotrectinib, which is the TPX-0005 drug, is a really exciting agent in this space with substantial activity. That’s the analogous drug to something like osimertinib or alectinib in this space, and I’m really excited for that drug to become more widely available.

Yes, we’re part of that trial and the drug has real activity in the 

-rearranged lung cancer patients. We saw that at ASCO [American Society of Clinical Oncology Annual Meeting] last year. There was a nice response rate with repotrectinib in 

-rearranged lung cancer postcrizotinib. We’ll see more.

I’m sold on the CNS efficacy, having had experience with entrectinib as part of a clinical trial. In my experience, the dizziness is real, but it gets better with time. I’ve never had to dose reduce for dizziness with entrectinib, so I switched.

So you’re an entrectinib user in the front line for most patients?

ROS1-Rearranged Non–Small Cell Lung Cancer 

We all talked about this, and I’ll just throw it out there: to biopsy or not biopsy? If biopsying, do we use plasma or tissue? I’m probably the outlier here, but I’m a lorlatinib user, postalectinib. The data we have in the resistance setting indicate that patients who develop secondary mutations may respond better to lorlatinib than if they don’t. But even if they don’t, lorlatinib elicits response rates similar to chemotherapy. I have not been, off a trial, routinely biopsying patients. My experience is that the younger patients I have on alectinib have progression that’s a little different, and it’s a little more critical that we get going on a second-line therapy. We don’t have time to do the biopsy. What are people’s practices? I heard this peppered throughout this conversation, but does everyone on the panel routinely biopsy patients at progression? If so, is it tissue or plasma biopsy? Lyuda, I’ll start with you.

I do. I routinely biopsy them for 2 reasons. No. 1 is that small cell transformation has been described as an 

 resistance. I haven’t seen one, but there is a patient in our group who was found to have a small cell transformation. We did suspect it because the progression was very quick, so you do have some clinical factors. But 1 of the reasons to rebiopsy is to allow small cell transformation. If you have some acquired alternative pathways, that might sway me toward using a different drug. If I find a 

 amplification as a mechanism of resistance, could I go back and use crizotinib, for example, which has dual 

Also, in the lorlatinib data, the efficacy of lorlatinib depends on whether you have a secondary 

-resistant mutation. If you have an actual 

-resistant mutation, then your response is 70%. To your point, if you don’t have an 

 resistance, the response rate is still 30%. You can still make an argument that we shouldn’t do the biopsy. I’m also 1 of the NRG-LU003 sites for the NCI [National Cancer Institute]–NRG Oncology 

 master protocol. It’s covered by the trial, so I’m not putting my patients at any financial risk by doing it.

Briefly, Josh first and then Becca, what are your thoughts on routine biopsy in this setting?

I view doing repeat biopsy at the time of progression on TKI [tyrosine kinase inhibitors] as the standard of care, regardless of which TKI I’m administering. Our data on mechanisms of resistance have been derived from seminal papers and fantastic work by single centers, but they are small series. What we see in those small series is a bunch of outliers. Each patient is unique. You look at something like 

fusion, which we’re seeing after resistance to osimertinib. We’re seeing these very rare alterations, and it’s critical to understand what is happening in the biology of the patient’s tumor because it can guide our care. It is very unlikely that we are ever going to have a phase 3 clinical trial evaluating patients who have received alectinib and then have 

fusion, and then they have this. We’re going to need to make some conclusions based on the biology that we’re seeing in front of us.

I agree. I am always surprised by what I find at biopsy, and that speaks to the fact that we can’t make assumptions about what’s happening at resistance. We actually need to look. Tumor biopsies, in my mind, are still the gold standard. We use more liquid, and if there’s not a safe biopsy option, that’s very reasonable. But for transformation to small cell, for multiple reasons, tumor biopsies are what I try to do as much as possible.

Those are all good points, and this is a very good discussion.

Rebiopsy at Progression of ALK-Rearranged NSCLC

That was a very nice review. You prefer alectinib first line and brigatinib upon progression.

That’s interesting. I’ve seen brigatinib used post-alectinib, and it doesn’t look bad. It hasn’t been out there as much as lorlatinib. Becca, what are your thoughts on optimal frontline drugs? I agree with Lyuda. We have alectinib and brigatinib. There may be some differences in the CNS [central nervous system], in toxicity, and in terms of how many pills to take a day. What are your thoughts? What you do at the time of progression?

For my first-line patients, I am an alectinib person. It is such a well-tolerated drug in terms of toxicity, and with those updated survival data, it’s very compelling. Alectinib has great CNS penetration, and given how well tolerated it is, it’s hard for me to switch from that to anything else. One of my issues, and the reason why I didn’t switch to brigatinib, is very funny—rare, but I don’t want to have to deal with it—toxicity. Some people can get an ILD [interstitial lung disease] or dyspnea-type event early on. That can be managed with the new dosing guidelines. That was much better, but it’s 1 of those situations where you’re starting a patient and don’t want to have to deal with a toxicity of respiratory issues, because we’re starting a new lung cancer patient when I have an agent with which I don’t see that. Alectinib has remained my first-line choice.

In the second-line setting, lorlatinib definitely has activity after alectinib. That tends to be what I go to. I will rebiopsy patients as much as is feasible. There have been bypass mechanisms of resistance seen, and that’s important to know about. In those situations, you would want to target those bypass mechanisms as well, and use clinical trials as much as possible.

Josh, what are your thoughts on optimal frontline approaches and sequencing strategies for 

It’s interesting. My experience in using alectinib has not been completely rosy. I will say that the rate of LFT [liver function test] abnormalities—I’ve seen it pretty frequently. I’ll look at the patient individually. I would say that alectinib is the most common drug I give in this space. But if I had a patient who had some liver issues or concerns about pills, it’s 8 pills a day, as opposed to 1 pill a day. That’s a big difference. These are variables that might affect my decision-making, but at the end of the day, I end up giving alectinib most often. As Lyuda said very eloquently, I don’t have a reason to overcome that inertia and change for the vast majority of my patients.

In the second line, I tend to repeat testing to evaluate what molecular targets may be appropriate for targeted therapy. I end up using lorlatinib more often. My concern moving forward, having seen the data on brigatinib in the second line, is that lorlatinib is not well tolerated. Having brigatinib as an option there is very nice. For my next patient who is progressing on alectinib, I may be more likely to use brigatinib.

What are some of the issues you’re running into with lorlatinib toxicity that would change your practice? What is it specifically about lorlatinib that’s a challenge for you?

Lorlatinib causes hypercholesterolemia. That is not as big of an issue. The larger issue is the CNS effect and the mental slowing. There are case reports of people having real psychiatric problems on the medicine, so my patients are a bit resistant to receive the drug. In regard to the toxicity with brigatinib and those pulmonary events that Becca was commenting on, Lyuda wrote a fantastic paper on how to manage those and her experience in that space. I’d love to hear you talk about it. I think it’s 1 of the most important papers in this space.

Thank you, Josh. The pulmonary toxicity with brigatinib is real, but if you have experience with it, you start realizing that it seems scarier than it actually is. It is not pulmonary toxicity that makes me worry about brigatinib. It’s just, as Josh pointed out, inertia. I have a drug that I’m already using. Why do I want to change? The pulmonary toxicity or early onset pulmonary events usually happen on day 2 of brigatinib. They’re well managed, and that is the reason why brigatinib has 90 mg followed by a 180-mg dosing cohort. The incidence is dose related. The purpose of the paper was to show that you can actually treat through that without having to interrupt the drug if your toxicity is mild. The 1 point I also want to make, to feed off what Josh said, is that brigatinib is a welcome addition for our patients without fusions. Before, if I was giving alectinib and the patient had a liver toxicity or a horrible allergy, which sometimes happens, I tended to hold off, dose reduce, then start. Now I just move on and go to brigatinib if a patient has severe liver toxicity, without playing with the dose.

Treating ALK-Rearranged Non–Small Cell Lung Cancer

For the sake of time, we’re going to move on to gene fusions and 

 exon 14 skipping mutations. The first gene fusion that’s relevant in lung cancer, right after 

 rearrangement, and we’ve made so much movement. Lyuda, you’ve been a part of the science of that and intimately involved in some of the studies. Do you want to talk about 

 rearrangements in lung cancer in general, and what the options are currently? We have some new first-line options, and maybe we can throw it to the panelists to discuss what to do at time of disease progression.

Sure. If you look overall at all comers, 

 rearrangement in lung cancer impacts about 5% of patients. The incidence increases if you select for nonsmoking patients or nonsmoking patients who are 

 negative. We’ve had more drugs than patients, as the joke goes about 

 fusion. Currently, there are at least 5 drugs that have an FDA approval for different categories of patients without fusions, and a couple more in development. At ASCO [American Society of Clinical Oncology Annual Meeting], there is 1 abstract that gets my feel-good award, and this is a pat-on-the-back award. That is ALEX, whose investigators have presented their continuous update on survival data. Five-year overall survival [OS] with alectinib was 67%. When I started treating lung cancer 15 years ago, I could not have imagined in my wildest dreams that I would have a 5-year survival of 67%. The nice thing about ALEX is that this data is still immature. There is a 37% maturity, and the alectinib arm did OK—about 45%. 

 Still, the 5-year overall survival with alectinib is very impressive. We still have not reached median OS.

I was also asked to cover brigatinib. There was no efficacy update on brigatinib at ASCO. There was an efficacy update for brigatinib based on variance, as well as 

 mutation, by Ross Camidge. Basically, it works. It’s better than crizotinib, regardless of your variant and presence or absence of 

 mutation. The most recent first-line data that we have on brigatinib is based on the ALTA-1L trial that was presented at ESMO [European Society for Medical Oncology] Asia Congress in 2019. The ALTA-1L design is very similar but not identical to the design of the ALEX trial. Patients with 

 fusion lung cancer were randomized to brigatinib versus crizotinib. Prior chemotherapy was allowed on ALTA-1L, which is different from ALEX. Enrollment for ALTA-1L was also based on local testing, and ALEX was based on central testing. The primary end point in ALTA-1L was blinded independent review of PFS [progression-free survival]. In ALEX, it was investigator-determined PFS. The ALTA-1L trial was positive, showing improvement in PFS of brigatinib over crizotinib. It was a PFS of 24 versus 11 if you use blinded independent review, and 29 versus 9 if you use investigator-determined PFS. The activity seems to be present in patients with or without brain metastases. That is what we expect, knowing that brigatinib does have CNS [central nervous system] activity.

 space right now is, what is the right sequencing? I know you’re going to ask me that question, so I’m just going to say it out loud. For my next patient who has presented to me with 

 fusion, what is my drug of choice? Currently, if you look at FDA approvals, we have crizotinib, ceritinib, alectinib, and brigatinib. All 4 of them are approved in the first line. Currently, the true front-runners in that space are brigatinib and alectinib. I will put my name on the record. When ALTA-1L came out, I was using alectinib, and when the data came out and weren’t better than alectinib, I kept using alectinib. Now this is my drug of choice. Since I was involved with brigatinib for quite some time, that got my award for the most disappointing news of 2019, because I was definitely rooting for the drug. It is an approved agent, but right now I didn’t find a reason to switch. The question of sequencing still needs to be investigated. I strongly advise anyone to enroll in the NCI [National Cancer Institute]–NRG 

 Master Protocol, which answers the question of sequencing.

In my practice, I use brigatinib second line after alectinib, and I’ve seen responses. Those data regarding postalectinib response with brigatinib from both France and the United States showed a response rate of 30% to 50%. I’ve seen responses to brigatinib postalectinib.

Trials in ALK-Rearranged Non–Small Cell Lung Cancer

Let’s move on. I’ll make sure to get those to you, Josh. There is now testing for 

Lyudmila A. Bazhenova, MD, University of California San Diego

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