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Dr. Justin Gainor: Welcome to The ASCO Post Roundtable Series on Updates in Lung Cancer. I'm Dr. Justin Gainor, the director for the Center for Thoracic Cancers at the Massachusetts General Hospital. Joining me today are two of my colleagues, Dr. Ibiayi Dagogo-Jack and Dr. Jyoti Patel. I'm going to allow each of them to introduce themselves. Dr. Dagogo-Jack?
Dr. Ibiayi Dagogo-Jack: Hi, everyone. My name is Ibiayi Dagogo-Jack. I'm a thoracic oncologist at Mass General Hospital, and it's a pleasure to be here today.
Dr. Gainor: And Dr. Patel?
Dr. Jyoti Patel: Hi there. I'm Jyoti Patel. I'm a thoracic medical oncologist and direct the thoracic oncology program at Northwestern University. Thanks so much.
Dr. Gainor: Great. Thank you both for joining us. Today, we'll be discussing recent updates in lung cancer, including data from recent clinical trials, and integrating these new developments into four patient case studies. Our third installment will focus on therapy for ALK fusion–positive non–small cell lung cancer.
Case three is a 31-year-old patient with a history of prior gastric bypass surgery and minimal tobacco exposure, one pack-year, who presented to the emergency department with progressive cough, shortness of breath, anorexia, and unintentional weight loss of 20 pounds. As part of their workup in the emergency room, a chest X-ray was performed, revealing a large right pleural effusion. This was followed by a chest CT, which confirmed a large right-sided pleural effusion, a right hilar mass, mediastinal adenopathy, numerous liver lesions, and extensive osseous metastases. A brain MRI was negative for intracranial metastases. The patient underwent a thoracentesis, which revealed a poorly differentiated adenocarcinoma. PD-L1 immunohistochemistry was one of the first molecular studies to come back, showing a tumor proportion score of 90%. The sample was then sent for targeted next-generation sequencing with an anticipated return of 2 to 3 weeks.
So, with this, I'll start with Dr. Patel. How would you approach this patient? A young patient, minimal smoker, but very, very symptomatic, and we have incomplete genotyping data right now.
Dr. Patel: Sure. This is really tough. This is a young and really sick person, and so you want to do all you can. Despite having that PD-L1 of 90%, which is oh-so exciting, knowing that he's a never-smoker, given his young age, his likelihood of having a targetable mutation that would have a much higher response to the appropriate TKI than pembrolizumab is significant. So, certainly, I would wait for his NGS, if he were to decline. Right? So, if I met him in the hospital, if he had liver disease that I would worry would progress in the next couple of weeks, then this is a patient that I'd probably start chemotherapy on. Given that it's adenocarcinoma and he’s young, I'd probably do carboplatin and pemetrexed, really avoiding the immunotherapy primarily because of the concern for toxicity down the road.
So, we know that layering an EGFR TKI after immunotherapy, osimertinib in particular, increases risk of IRAEs, pneumonitis, hepatitis. So, you have to be mindful because, again, this is a young person whose likelihood of having an EGFR mutation is probably at least 20%. So, it is balancing those odds, could I wait those couple of weeks to make sure I have adequate information for a treatment plan?
Dr. Gainor: Yeah, I think those are all excellent points. Indeed, I selected this case in particular because of that high PD-L1 expression, really just to underscore the point that in patients with limited tobacco exposure, while so tempting and exciting to see that high PD-L1 expression, in someone where you think there's a high likelihood of having an oncogenic driver, we really should withhold the PD-1 inhibitor. I completely agree with you. I think if you really feel like you need to start systemic therapy, then in someone like this, I would start carboplatin and pemetrexed and leave out the PD-1 inhibitor, at least for cycle one, until you get that data back.
So, returning to this case, the patient, ultimately, targeted NGS panel returns with an EML4-ALK fusion. The patient, after drainage of the pleural effusion, actually felt, symptomatically, much better. The team was checking in frequently, it wasn't decompensating, it was clinically stable, so it could wait for the NGS panel results. Dr. Dagogo-Jack, in someone like this, NGS 2 to 3 weeks, are there other faster ways to get ALK testing back?
Dr. Dagogo-Jack: There are. I think two thoughts here. One is, what is your substrate for the testing? So, one would be using a liquid biopsy or plasma might've been a faster way. Then, another thing is that, for ALK testing, there've been a variety of tests that have historically been used to identify the activation of ALK: either immunohistochemistry, which is a rapid turnaround and leverages the fact that the ALK protein itself is not expressed in normal tissue or normal lung tissue. So, that's a fast test. Also, sometimes FISH can be a little bit faster than NGS, but again, the limitations of these types of tests is that you don't get the comprehensive analysis looking for EGFR in multiple other targets in the same fashion.
Dr. Gainor: Great. So, now we know, this patient—great news—has an ALK fusion. This is an area where drug development, over the last 10 years, has really exploded, and we have different generations of ALK inhibitors. Dr. Patel, can you just give us a broad overview of the different generations of ALK inhibitors and what distinguishes one from another?
Dr. Patel: Sure. So, certainly, evolution of three generations in a decade is pretty remarkable. So, crizotinib was actually developed as a MET inhibitor and then was found to have efficacy in the ALK population. So, this is the first drug that was approved, and patients had rapid responses. Soon after, ceritinib and alectinib were approved after crizotinib, ultimately found to be superior to crizotinib. Soon on their heels afterwards, brigatinib, so this has been a little bit tough for us, because they've all been compared to a drug we don't use anymore, primarily because crizotinib is less effective. It doesn't have CNS penetration.
So, we have a number of drugs that are highly effective and a number of drugs that are well tolerated, that have CNS activity, that we use based upon our preferences and patient preferences and availability of drug. We don't really have direct head-to-head comparisons, but ceritinib, alectinib, and brigatinib are these drugs that we call second-generation drugs. Most recently, lorlatinib, which again was approved after one of these drugs stopped working, so at resistance initially, has also been tested in the frontline setting and now is approved. So, it's certainly gotten much more difficult. Before, it was a very linear process of how you go through these drugs, but now there's much more shared decision-making and really thinking about a much longer path when we're looking at mechanisms of resistance and tolerance over time, because patients can be on these drugs, hopefully for years, without resistance.
Dr. Gainor: You touch on the heart of the debate right now, which is, do we start with a second-generation ALK inhibitor and follow that with the third-generation inhibitor lorlatinib, or do we jump straight to the third-generation inhibitor lorlatinib?
So, I'll turn to Dr. Dagogo-Jack. Maybe you could just give us an overview of the data for second-generation inhibitors compared to crizotinib, just for some background before we tackle the harder question of which path to choose.
Dr. Dagogo-Jack: Happy to answer this question. So, the second-generation ALK inhibitors, as you've heard from Dr. Patel, that category encompasses ceritinib, alectinib, and brigatinib. There's a fourth one, ensartinib, that's not approved yet, but we've seen encouraging data for. The first data we had were crizotinib compared to chemo. We knew, based on that study, that crizotinib was better than chemo. So, the iteration of studies have, for the most part, compared second-generation ALK inhibitors to crizotinib with the exception of the first approval of a second-generation ALK inhibitor for first-line treatment. That was ceritinib, and that actually compared ceritinib to chemotherapy. So, we didn't quite get an answer to the question that we needed, but it showed that ceritinib was better than chemotherapy, not surprisingly.
The two studies that have really had the most relevance, as Dr. Patel highlighted, don't compare them head-to-head, was the ALTA-1L study evaluating brigatinib compared to crizotinib. Then, then the ALEX study, which is a global study, and there's been iterations of this same study: J-ALEX in Japan and the ALESIA study in China, comparing alectinib in the first-line setting to crizotinib. All of these have shown, overwhelmingly, that it's better to start with a second-generation ALK inhibitor. We see with crizotinib maybe 9 to 12 months of progression-free survival. With these second-generation ALK inhibitors, depending on which way you assess PFS, so if you use independent review committee, it tends to be about two years uniformly across, and then by investigators somewhere between 2 to 3 years across. So, substantially better.
Dr. Gainor: For patients who do start on a second-generation inhibitor, what do we know about subsequent therapies in those patients?
Dr. Dagogo-Jack: I think that we are still figuring things out, but we do know that lorlatinib, the third-generation ALK inhibitor, was tested, and a part of the data that led to the approval of lorlatinib did have a subpopulation of patients who had previously received a second-generation ALK inhibitor without crizotinib. We see that lorlatinib has significant efficacy in that space, particularly for patients who have what we think of as ALK-dependent resistance, or the cancer has progressed as a result of acquisition of these kinase domain mutations, which we tend to think of as occurring in the majority of cases. So in 50% to 60% of tumors, we would identify these mutations.
Dr. Gainor: So, based upon the activity of lorlatinib, in that post–second-generation inhibitor-resistant setting, it's now been moved in the first-line setting, and Dr. Patel alluded to this. Maybe you could walk us through the CROWN study comparing lorlatinib and crizotinib.
Dr. Patel: The CROWN study was just presented at the end of last year. This was a trial in which patients who had asymptomatic CNS metastasis were allowed, or they'd been previously treated. The primary endpoint was progression-free survival. So, it was significantly improved with lorlatinib: not reached, versus about 9 months on crizotinib. Then, more importantly, was the survival without CNS progression, so sort of a straight line. These are not so dissimilar in these early results from what we see with second-generation drugs. So, the curves look a lot like alectinib and brigatinib. So, this is, certainly, a very reasonable drug to use in the first-line setting. I think the toxicity that was seen in the frontline setting was not very different from what we'd seen in later lines of therapy with lorlatinib, which has some distinct toxicity.
So, again, because it's got so much CNS efficacy and penetration, some of our patients will have CNS effects, whether that is anything from anxiety to weird dreams or hallucinations. Again, that's in a minority of patients. More predictably, patients have hyperlipidemia and often end up on a different medication or edema. So, thinking about, again, the duration that patients may be on these drugs may sway you one way or another.
Dr. Gainor: Dr. Dagogo-Jack, for people who aren't as familiar with using lorlatinib, how do you typically manage some of that neurocognitive toxicity that Dr. Patel alluded to?
Dr. Dagogo-Jack: So, the neurocognitive toxicity can have different manifestations. So, there are the trouble multitasking, memory impairment, and then you can also have mood toxicity. So, labile moods, anxiety, etc. You can also have speech effects, so slowing of speech. In general, these can be mitigated by dose interruption and dose reduction. So, in general, patients did not have to stop therapies as a result of these toxicities. So, I monitor for these very early and have a very low threshold to reduce the drug. It's reassuring to note that, even at 50 mg or 75 mg, so that is a 25% or 50% dose reduction, the drug still retains significant CNS activity.
Dr. Gainor: Dr. Dagogo-Jack, we heard from Dr. Patel how she looks at the efficacy data and thinks about first-line decision-making. What's your experience and how do you approach first line? Do you choose a second-generation drug or third-generation agent?
Dr. Dagogo-Jack: I'm going to cop out a little bit by saying I've heard several camps of thought, which I think are all very reasonable. There are people who say, "I have the most familiarity with alectinib and brigatinib, so I'm starting there." Others say, "I want the ability to sequence, potentially with lorlatinib after, so I'm starting there," and others who say, "I liked the lorlatinib data," and as Dr. Patel highlighted, the lorlatinib data are particularly compelling with respect to the CNS efficacy. There was something like, in the small population of patients with measurable brain mets, 71% CNS complete response rate. So, I think that's food for thought for someone who has a substantial burden of CNS disease. That is not to say that alectinib and brigatinib don't have excellent CNS activity, but in that particular patient population, in a patient who I'm not as worried about the cholesterol elevations and other neurocognitive toxicities, I might think about lorlatinib in that population, but it's good to have multiple great drugs.
Dr. Gainor: Yeah. I would point out, even outside of the CNS activity, the hazard ratio is around 0.28. So, it was quite impressive for lorlatinib and quite distinct from alectinib and brigatinib where it's more a 0.47 to 0.49 range. So, more to come.
So, just to summarize the key clinical takeaways here, ALK rearrangements are present in 3% to 5% of lung cancer. We now have five different FDA-approved first-line ALK inhibitors, but for all intents and purposes right now, most clinicians, in terms of preferred agents, are using either the second-generation agents alectinib or brigatinib or the third-generation inhibitor lorlatinib on the basis of the CROWN data. We really need additional follow-up to help sort out what is the best sequencing strategy. Ultimately, first-line decision-making will be based on patient preference, toxicity profile, understanding of resistance, and long-term follow-up.
So, with that, this brings us to the end of this case. Please see the other segments for further discussion about the latest data in lung cancer, or visit ascopost.com. Thank you.