Introduction: A Model for Targeted Treatment in Non-Small Cell Lung Cancer (NSCLC)

DR LOVE: Good afternoon, everyone. I’m Neil Love from Research To Practice and welcome to Implications of Recent Datasets in the Current and Future Management of Non-Small Cell Lung Cancer with Actionable Targets Beyond EGFR.

We have a great faculty today, Dr Ibiayi Dagogo-Jack from the Massachusetts General Hospital in Boston, Massachusetts, and Dr Corey Langer from the Perelman School of Medicine at the University of Pennsylvania in Philadelphia. And so we’re really looking forward to talking about this today coming right off of the World Lung meeting that just concluded today. Corey actually has taken 2 red-eyes in 3 days because he's heading out to the ESMO meeting. So he’s the first one I’ve heard who is doing that.

Here’s where we’re heading tonight. We’re going to be talking about targeted therapy beyond EGFR.

And as always, we’ll be talking about some nonapproved FDA — non-FDA-approved indications of agents and regimens. Check out the package insert for more information.

So here’s where we’re heading. We split up this topic level into 2 parts. And Dr Langer is going to present some slides and cases to start with and then Dr Dagogo-Jack.

But I want to just take a breath and get your thoughts a little bit about generic issues related to targeted treatment in general and how they tie in, particularly to some of the mutations that we’re going to be talking about today. Particularly, Ibiayi, you know, when we get beyond EGFR and ALK. There are a lot of uses — it seems like EGFR and ALK has always led the way and everybody else is kind of trying to come pick it up. We learned things with EGFR and ALK and we wondered can we apply them. So there are a lot of themes that I’m curious about. But the 2 that I’m really curious about is, first of all, adjuvant therapy. Of course, Ibiayi, we know about the ADAURA trial with osimertinib. We’re going to talk today about ALINA and alectinib. But we also have all these other mutations. And I’m kind of curious if you have an educated patient, maybe the patient is a medical oncologist, who is in the adjuvant situation with one of these other abnormalities. Maybe it’s RET, maybe it’s BRAF, HER2. You think about targeted therapy, they look at these adjuvant trials. Any situation where you’d be open to considering, if you could access it, adjuvant treatment beyond the big two, so to speak, Ibiayi?

DR DAGOGO-JACK: Neil, it’s definitely tempting. And I think that we all have to realize that a lot of these are so rare. So anticipating a study that just specifically enrolls such patients and reads out in a timeframe that we need it is going to be very hard. And so I think one of my colleagues put it nicely in a discussion in the Stage III setting, right? What is the efficacy and what is the tolerability of the drug, right? So I think for something like, maybe like a RET or a ROS lends itself more than a MET, a BRAF, a KRAS. And in HER2, we’re still in the ADC space with some ILD, as we’ll talk about. So I would be quite hesitant to incorporate it for that setting. But I think of the list that you have in front of me, perhaps ROS is the one that kind of sifts to the top, and maybe followed by RET. But again, it’d be a very nuanced conversation, acknowledging lack of data.

DR LOVE: So Corey, we’ve been having —

DR LANGER: I absolutely agree with Ibiayi.

DR LOVE: Yeah, we’ve been having these discussions for a long time, ever since gefitinib came out. And immediately, people were thinking about adjuvant therapy. Another sort of generic issue related to this is Stage III disease, Corey. Are there situations where rather than durvalumab, you’re going to use targeted therapy? Would you do that, for example, with a RET patient?

DR LANGER: Same issues as Ibiayi pointed out. I would have an even lower threshold, I think, in Stage III. When we look at the PFS curves in the recent LAURA trial, those who just got chemoradiation alone actually did quite poorly. And there’s a tendency, I think, now to view individuals with Stage III locally advanced unresectable who have a target mutation, a fusion, one of the more active ones, to treat that patient as if, in fact, they have sort of early Stage IV. So for, again, RET and ROS1, very low threshold. Not so much for BRAF, MET or KRAS. The data are not so stellar there, at least compared to the other agents. When we are achieving PFS 2 years and beyond, I think that really points toward a change in our therapeutic paradigm.

DR LOVE: So Ibiayi, speaking of Stage IV, there’s also the issue of when to use targeted therapy as first-line treatment. Again, with EGFR, they had randomized studies. You maybe remember the IPASS study. I think it was chemo versus gefitinib, I think, actually. And a similar study, I think, in ALK. But then now, you have all these other maybe even more rare mutations. Are you going to wait for trials? I think there’s a trial for RET trying to look at all this. Although I’d like to put some money on that one. But anyhow. What do we need? For example, KRAS G12C. You hear people talking about, well you need to see at least a 40%, 50%, 60% response rate to consider, you know, bring it up to first-line without a randomized study. Are we going to have randomized studies like that, Ibiayi?

DR DAGOGO-JACK: I think people are trying for the — they’re certainly trying, right, for the randomized studies, particularly if you have a high enough prevalence. But for me, I think the key questions are, how well does immunotherapy work in this population? If immunotherapy doesn’t work that well. And also, what is the response rate and the PFS with these treatments? I think once you start encroaching on that 50%, 60%, 70% response rate, I have kind of more confidence. And also, the toxicity, right? Because that’s what’s deterring something like trastuzumab deruxtecan from immediately being adopted in the first-line setting. That ILD makes people say, hey, maybe that study is not a bad idea to do in the first-line setting.

DR LOVE: Yeah, that’s a great point. Corey, another sort of principle that we learned from EGFR and ALK is the idea of treating asymptomatic patients with brain mets with systemic treatment, holding off on radiation, particularly whole brain. Again, that’s done all the time now with EGFR and ALK. In what situations are you comfortable doing it with other mutations, Corey?

DR LANGER: Pretty much across the board depending on the nature of the brain metastases. If they’re relatively small, if the patient is essentially asymptomatic or minimally symptomatic, there’s no vasogenic edema, I will definitely start with the TKIs. And I will extend that to BRAF, MET. Maybe not KRAS although I’d certainly consider it. We’ve seen data with HER2 as well. So there, a low threshold. If the tumor is big, the patient is highly symptomatic, if there’s a lot of vasogenic edema, you need to address that. In some cases, even preferentially resecting the tumor, getting more information from the standpoint of molecular targets and then proceeding accordingly. And we’ll often mix and match stereotactic radiation with the TKIs. I think the main issue is trying to avoid whole brain radiation in the long-term, cognitive effects that we’ll typically have over time.

DR LOVE: So the last thing on my list is role of immunotherapy in targeted disease. Last night, we were doing our program on EGFR with Dr Yu and Dr Sabari. I was asking about ivo, ivonescimab. I’ve got to learn how to pronounce that better. But anyhow. This bispecific, Ibiayi, that targets VEGF and PD1. We’ve been hearing about it for the last year. They presented a Phase III trial. We’re going to talk about it tomorrow. It actually beat pembro in high PD1 patients. But we’ll see what the faculty thinks about that tomorrow. But there was another study looking at EGFR relapsed disease that we talked about last night, again, with this ivo plus chemo, which seemed to show a benefit in EGFR patients. Now this ivo has a VEGF thing on it, and we know bev has some activity. But right now, Ibiayi, what do you think about checkpoint inhibitors with all these other mutations? You’re going to present your KRAS case, the patient got chemo/pembro first line. So some of these, obviously, you’re comfortable, and everybody is comfortable giving IO up front. Which ones?

DR DAGOGO-JACK: I think BRAF. So people have tried to look at this in a retrospective fashion. I think the ones that have kind of filtered to the top in terms of having a comparable benefit to all-comers would be something like a BRAF, a KRAS. BRAF is heterogeneous, so you also have to take into account smoking status. And I think I’m on the fence with HER2, though the way the clinical trial is being run includes immunotherapy in the first-line setting.

NSCLC with ALK, ROS1 and NTRK Rearrangements — Dr Langer

DR LOVE: Alright. Well, let’s move on. And we may pick up some of these things as we go along here. And we’re going to shift to Corey’s topic of ALK, ROS1 and NTRK. And speaking about giving off-label adjuvant therapy, this is a patient Corey actually gave adjuvant alectinib to before the ALINA data. So I guess it can be done if you believe in it. What happened? I guess this patient, you were kind of surprised, had more extensive disease than you thought. What happened with him, 57 years old?

DR LANGER: Absolutely. So this was a young gentleman, in my book, 57-year-old never smoker. Incidental finding, had renal colic. Ultrasound showed a nonobstructing left renal stone. But at the same time, they did a chest x-ray, and they saw a very small nodule. That precipitated a CAT scan and then ultimately, a PET. A 2.8 cm right lower lobe nodule, sort of low-ish SUV, maybe 3 or so. No other suspicious uptake. The mediastinum was negative, both on CT and PET. So clinically, Stage IA3. Underwent a robotic right upper lobectomy with a good lymph node dissection. I think that is key. Some thoracic surgeons seem to ignore the mediastinum. Showed moderately differentiated adenocarcinoma with 6 out of an 18-node sample having microscopic invasion. So the patient was up-staged from 1A3 to IIIA. MRI of the brain was negative. And fusion panel, we were doing this almost as a demonstration project at the time, did show EML4-ALK. So we knew this at the time even though there was no data yet from the ALINA trial.

So the next step, what were we going to do. With the involvement of the lymph nodes, we certainly felt strongly about giving adjuvant chemotherapy. We started with pem/cisplatin, 3 cycles. Toxicities forced us to change cis to carbo because of GI side effects and vertigo. And then we had a long discussion, what we call shared decision making, about the utility of alectinib. This predated the ALINA data, but we had already seen the ADAURA data. We knew that drugs like alectinib and lorlatinib would work quite well in this setting, or at least presumably quite well in this setting, that toxicity was manageable. And I did not do this alone. I certainly presented this patient to our multidisciplinary tumor board. I consulted with outside medical oncologists including a colleague of Ibiayi, and we jointly decided to go ahead. And the patient went on alectinib 600 BID, full dose, and remains on it to this day. So it’s 2 years. I’m not sure how, whether we’re going to stop at 3 years. Again, that’ll be shared decision-making. But given the fact that this patient had microscopic involvement in those nodes that we were unable to detect clinically, certainly upped the ante.

DR LOVE: So I really appreciate your thought. We don’t want to be glib at all about using off-label adjuvant therapy. It’s a very serious decision. It may not benefit the patient. They may be just as well or better off without it. So I’m glad you brought that up. I actually was even more curious about the chemo here, Ibiayi. I was just flashing. I think the first time I worked with Corey was when the adjuvant chemo data was coming out. And I was like, really? Hazard rate of 0.86 or something? You’re really going to do it? But in any event, it’s still an issue. And here, he’s giving it again. And even in the trial, they didn’t give it. So maybe you could just comment on what was done in the trial, how it compares to what they did with ADAURA, and what your philosophy is in general about adding in something that’s going to increase the cure rate.

DR DAGOGO-JACK: Yeah. I think it was a bold leap in this trial, right? As a reminder, the ADAURA trial actually gave the option to give chemotherapy. And most people who we tend to give chemotherapy to anyway, got it. So these were, like, the Stage II and Stage III, the majority of them got it, versus Stage IB at that time, so greater than 3 cm, the minority got it. Whereas in the ALK setting with the ALINA trial, it was actually chemo versus the alectinib, which was a bold leap. It was a positive study, but I don’t think it definitively answered the question of whether or not adding chemo to alectinib would be better than doing that. And because we know that chemo has a survival benefit by itself and ALK-positive lung cancers are quite aggressive with a kind of propensity to recur after resection, I agree fully with Corey, even if I saw this patient today, I would be quite tempted to incorporate chemotherapy.

DR LOVE: And I’m taking it that both of you think less about chemo in a lower-risk situation, Corey?

DR LANGER: Yes. So if this patient did not have nodal involvement, it was maybe a bigger tumor, a IB patient, I would have probably just gone ahead with alectinib alone. I think it’s the nodal invasion that is my bifurcation point in terms of therapeutic decision-making.

DR LOVE: Alright. So Corey put together some slides reviewing some of the data on these alterations. Corey?

DR LANGER: So I’m going to try to go through these quickly. First, for ALK, we know it’s relatively uncommon but certainly more common than RET and ROS1, about 5% to 7% of all non-squamous non-small cell patients. Testing for ALK rearrangements, as far as I’m concerned, is mandatory. Certainly, in all patients with non-squamous non-small cell regardless of smoking history, and in all never-smokers or remote former smokers regardless of histology. Without question, the TKIs that target ALK are extending survival. These are relatively old data, nearly 7-year median survival time with second-generation TKIs. And that’s about 6 years longer than we would have seen in the pre-TKI era. And as Ibiayi has already pointed out, immunotherapy does not work well in ALK or EGFR or ROS1. It works a little bit better, actually a lot better, in BRAF and KRAS. We would reserve checkpoint inhibitors for second, third or fourth line, more commonly, third or fourth line.

These are the major studies. This is about 80 slides worth of data consolidated into a single slide, 4 separate Phase III trials all comparing second and third-generation ALK TKIs versus our erstwhile standard, crizotinib. And all showing major superiority, doubling in PFS for alectinib and brigatinib. Median PFS not even reached for lorlatinib compared to criz. Improvements in patients with or without CNS metastases. Improvements in intracranial control and a delay in intracranial progression.

So these are the current NCCN guidelines. And I think our 3 preferred agents are clearly alectinib, brigatinib and lorlatinib. The big question is whether we should start with lorlatinib first and then follow with chemo or other clinical trials of TKIs, or start with a second-generation agent such as alectinib or brigatinib and then go on to a third-generation TKI like lorlatinib, and then subsequently to chemotherapy.

So this is the CROWN trial that is a 5-year update on lorlatinib versus crizotinib. Nearly 300 patients, 1:1 randomization, asymptomatic treated or untreated CNS metastases were permitted. You needed to have targeted lesions, and they were stratified by the presence or absence of brain mets and ethnicity with PFS as the major cut point.

And we see a sustained benefit. And if anything, a plateau. At 5 years, 60% receiving lorlatinib are free from progression. Whereas for crizotinib, it’s under 10%. And this benefit is seen across the board regardless of the presence or absence of brain metastasis, ethnic origin, sex, age or even smoking status. Forest plots are really quite resounding with hazard ratios consistently under 0.20.

And then, we also see a major improvement in intracranial control. In patients without baseline brain mets, the 5-year intracranial progression-free survival is 92% compared to about 21% for the crizotinib group. And this is clearly better than we’ve seen historically with alectinib and brigatinib, which in turn, were much better than crizotinib. The hazard ratio for this comparison is really in p-value territory. Hazard ratio of 0.06, showing major intracranial benefit.

So this is the across-the-board comparison at 2, 3, 4 and 5 years. At 4 years where we have data for the other 2 agents, 63% progression-free for lorlatinib compared to 43% for alectinib, 36% for brigatinib.

But we’ve got to be careful. These are cross trial comparisons. They’re not statistically valid. And toxicity is still a major concern.

So this rather busy slide really illustrates the toxicities that we see with lorlatinib. Hypercholesterinemia, hypertriglyceridemia, easily controlled with statins, occurs fairly early on. But then, other more disturbing toxicities, mood effects, peripheral neuropathy, cognitive changes in a good proportion of patients, up to 40% or more Grade 3 or 4. In about 2% to 5%, we also see edema and weight gain, fatigue, arthralgias. The patients that I have started on lorlatinib, we’re getting weekly phone calls frequently just in terms of toxicity management. It really calls into question whether we should start at full dose or perhaps a lower dose.

So Dr Lin, Ibiayi’s colleague, during the ASCO plenary session as the discussant basically said lorlatinib would be her preferred initial therapy for most patients. And I think the key word here is most.

My approach is a bit more pragmatic. I will definitely give lorlatinib for younger patients with limited or no comorbidities, aggressive tumor or CNS involvement. I’ll reserve alectinib or brigatinib for older patients with limited tumor burden, the absence of CNS invasion. And I would love to see a randomized trial comparing lorlatinib to a second-generation TKI, dealer’s choice, with OS as the primary endpoint along with quality-adjusted survival.

DR LOVE: Before you go on, could I just ask both of you to comment a little bit on your own experience in terms of toxicity and tolerability, particularly related to lorlatinib compared to alectinib? Ibiayi, can you comment on that and particularly how it plays out in the older patients that Corey was alluding to?

DR DAGOGO-JACK: Yeah. I think across the board, alectinib is a much better tolerated drug than lorlatinib, and a bit easier both on the patient and the provider in terms of monitoring. Lorlatinib has these neurocognitive adverse events that we see in somewhere around 30% to 40% of patients on clinical trials. And probably in the real world, a bit higher than that. I do tend to notice the cognitive effects more in my elderly patients. So I agree with Corey that that’s a population, particularly if they have other comorbidities, that might give me some pause.

DR LOVE: So Corey, again, I feel like every day, we’re talking about patient involvement or if they want to be involved in the decisions. There’s so many times in oncology where it’s really a very difficult decision that really should involve the patient. Again, maybe you can provide a, you know, most docs have very, very few patients with ALK, who are in general practice. So I’m just kind of curious, maybe you could talk a little bit more about kind of how you explain to patients what to expect in terms of neurocognitive effects from lorlatinib. And how much of an issue is it? Again, older versus younger.

DR LANGER: So older patients who already have some neurologic issues, I would generally favor alectinib a priori. In younger patients, particularly those with very aggressive tumor with neurologic — with CNS invasion with brain mets, I will favor lorlatinib. I’ll discuss the potential effects and tell them that our best treatment for that is a dose pause and then a dose reduction. Over time, we sometimes re-escalate. But it does become a big issue. And it’s varying. Some people just have minor cognitive changes. Others have major CNS toxicity. And there are also psychiatric issues, a fair amount of depression.

DR LOVE: Sounds like a tricky thing to explain to a patient. Alright. Well, let’s keep going.

DR LANGER: So this is a new ALK inhibitor, NVL-655, doesn’t have a name yet. But it’s being looked at specifically in the setting of lorlatinib progression. IC50s are superior to both the second-generation drugs and lorlatinib. And if we look at a patient-derived xenograft, MGH953-7, it seems to be superior to lorlatinib, and there seems to be a dose relationship with efficacy. So if we look at the 93 patients that were accrued here, virtually all, with 2 exceptions, had non-small cell, you can see 70% had received 3 or more prior lines of anticancer treatment and nearly half had received 3 or more prior ALK TKIs, particularly alectinib predominantly. And if we look at toxicity, it essentially spares the TRK-related neurotoxicity that we’ve seen with other drugs. Overall, only 2% had to discontinue due to treatment emergent AEs, 5% were dose reduced. The major toxicities were transaminitis, some nausea and dysgeusia, but we’re not seeing the neurologic side effects that we’ve seen with many of the other TRK inhibitors.

And here are the response rates. Overall, 44%. No surprise, those with prior exposure to lorlatinib, the response rates are a bit lower, again, in the same range, 43%, 44%. Those who’d had no lorlatinib previously, 67%. And those with ALK resistance mutations, response rates of about 60% to 80%.

ALINA, we’ve alluded to it. I’ll spend just a few seconds on it. This was the Phase III that compared alectinib to platinum-based chemo in Stage IB through IIIA. Again, 4 cm or larger, N1 or N2 disease. Disease-free survival based on the investigator’s assessment.

Again, a whopping advantage, 35% absolute improvement in disease-free survival at 3 years. Data cutoff, the overall survival data, really immature. So we don’t have true OS data, but the hazard ratio here is 0.24.

And across the board, regardless of subgroup, on these forest plots, we see a benefit. And that includes the IB group as well as Stage II and IIIA.

And we see a benefit intracranially. CNS disease-free survival at 3 years, 96% compared to just under 80% for chemo with a hazard ratio of 0.22. I am not sure I’m completely ready to abandon chemo, as Dr Dagogo-Jack has pointed out. But these data are quite compelling. And I think we actually need a study looking at alectinib plus or minus platinum-based chemo. And, frankly, I would do the same sort of study in the EGFR population.

So ROS1. Again, phenotypically, very similar to the ALK patients. Lower incidence, 1% to 2%. Mutually exclusive with EGFR, HER2, KRAS, BRAF, et cetera. Again, the same guidelines. ROS1 testing should be done in all adenocarcinoma patients regardless of smoking history. Break-apart FISH is the gold standard. IHC-positive, you can confirm it with FISH testing. We have 3 separate drugs approved, crizotinib, entrectinib and repotrectinib.

DR LOVE: Before you go on, just to go back to Ibiayi. Any issues with diagnosis of ROS1? Do you think there may be people with ROS1 who are getting missed?

DR DAGOGO-JACK: I think so. And I think misdiagnosed as a false positive if you rely on IHC alone. It’s not a very specific test. And missed, depending on who your operator is for FISH. And so I think moving towards kind of a DNA — RNA NGS ideally would be the best way to identify this.

DR LOVE: You were saying before we began that you do that routinely at MGH. Everybody gets RNA and DNA NGS?

DR DAGOGO-JACK: They do. And I think ROS1 is a stubborn one, right? So ALK always has the same, 80% has the same fusion partner. ROS1 has a variety of fusion partners which can complicate things a little bit too in terms of just relying on DNA depending on who is reading your assay.

DR LOVE: Alright, Corey, please continue.

DR LANGER: So here are the data. I would say, based on some of the more recent data, that repotrectinib has essentially displaced crizotinib and entrectinib. You see PFS of nearly 3 years, equivalent response rates. Both entrectinib and repotrectinib have shown CNS benefit.

These data were just updated. We have 2 separate cohorts, those who are TKI naïve and those who have had prior TKI, mostly crizotinib, with response rate as the major endpoint.

We’ll skip ahead to the actual responses. In the treatment-naïve first-line setting with ROS1, astounding response rate, 78%, with median duration of response not reached. This is a major waterfall plot with virtually everyone benefiting. PFS, again, not reached in this population nor is overall survival at 18 months, so 70% free from progression, nearly 90% still alive.

And in the second-line group, mostly crizotinib exposed. The response rate here is a bit more down to earth, 38%. But, again, the majority exhibiting a benefit. Median duration of response, over 14 months. PFS, median of 9 months. And median survival just north of 20 months. So really important data.

We see CNS activity in both groups, in those who are treatment naïve as well as pretreated. And intracranial progression-free survival at a year, 91% in the TKI naïve and 82% in those who were previously exposed.

And acceptable toxicity. Dose modifications, treatment emergent AEs, 45% of patients needed dose interruption, 34% dose reductions. But fewer than 10% had to have their TKI, repo, discontinued. Generally, for dizziness or some degree of ataxia. But, again, reduction, I think, in some of the typical NTRK side effects.

New data from this meeting, taletrectinib. This is not yet FDA approved. Again, similar cohorts, TKI naïve and prior ROS1 exposure, 2 separate groups. Not unsurprisingly, a much higher proportion of patients with brain mets in the TKI-pretreated group, 56% compared to 34%.

Response rate, the major endpoint. The TKI-naïve group were up to 85% response. In those who’ve had — with intracranial response rates of 67%. And in those with TKI prior exposure, the response rate is 62%, with intracranial response rates of 56%. Median follow-up here is still fairly short, under a year and a half, but very exciting data with acceptable toxicity.

Again, no treatment-related AEs leading to death. The rate of neurologic emergent AEs were low, primarily dysgeusia and dizziness. Fewer than 10% had to have their treatment discontinued for toxicity. And just over one third required dose reductions with transaminitis, diarrhea, nausea, other GI toxicities leading the list.

And finally, another new drug, we don’t have much data for it yet, zidesamtinib, which avoids the TRK-related neurotoxicities. So a potential advantage ahead of taletrectinib, repotrectinib, entrectinib, lorlatinib and crizotinib in this category.

And this is an ongoing study looking at multiple categories of patients with ROS1 as well as other solid tumors that express ROS1. So stay tuned, data forthcoming.

DR LOVE: So actually, I want to hear about repo in NTRK. This is interesting. Keep going.

DR LANGER: So NTRK is exceedingly rare. The community doctors who are in the audience probably haven’t seen this. I have to confess, I have seen exactly 1 case. I don’t know if Ibiayi has seen more.

DR LOVE: Two.

DR LANGER: And that actually preceded the approval of these drugs. So there are 2 approved — 3 approved drugs now, entrectinib and larotrectinib. We actually had an update literally yesterday at the meeting that Jessica Lin gave on larotrectinib with 33 patients. Those numbers have declined a bit. The overall response rate, 66%. PFS, about 22 months. Overall survival, just north of 3 years. So data that are very similar to EGFR. Again, this is a fusion, not a mutation.

But exciting data for repotrectinib. This was just approved 2 and a half months ago. Another example of a disease agnostic biomarker-specific approval for repotrectinib in patients with solid tumors that are expressing NTRK. And if we look at the TKI-naïve population, 62% response rate, 12-month PFS, 64%. And even those who’ve been previously exposed, so actually, second-line data in this category, 43% overall response rate with about one quarter of patients free from progression after prior exposure presumably to larotrectinib. So very exciting data.

DR LOVE: So I know you’ve got this crazy case where this patient got 4 TKIs and ended up responding to the last one with ROS1. A lot of disease there. We’re kind of running a little bit behind, but can you just talk about what happened there globally? And this patient actually had fourth-line TKI, and how long with metastatic disease with ROS1?

DR LANGER: She’s had 7 years of treatment. She initially went a naturopathic approach, and then her disease got a lot worse. She had multiorgan involvement. We can see the — so this is her baseline PET is over here, and you can see a massive tumor on the left side, big pleural effusion, liver mets, bone mets. She went on crizotinib and had a wonderful response and it lasted 4, 4 and a half years. She did require periodic SRS to the brain for CNS involvement. Then ultimately, did have disease progression. And we tried to salvage her first with lorlatinib, which she could not tolerate. Intractable dizziness and fatigue. We then went on to entrectinib, which as I learn more about this disease, was not expected to work and did not work. Again, she didn’t tolerate it. She was off treatment for nearly 6 months. We were debating whether to go with chemotherapy or hospice. And then, repo got approved. So she started repotrectinib in January. And you can see the major shrinkage. The films on the right in January, a big mass in the left upper lobe, loculated effusion. About 80%, 85% shrinkage in that primary mass, bone mets that are now recalcifying. You see new bone formation. The sites of some of these bone mets. So she’s literally gotten a new lease on life thanks to repotrectinib. And her quality of life is still not wonderful. She’s suffering side effects including edema, fatigue and constipation. But she is grateful to be alive.

DR LOVE: Any comments, Ibiayi? It kind of sounds a little bit like metastatic HER2-positive breast cancer. You keep changing the drugs and they keep working. A fourth-line TKI having this kind of effect. Any comments, Ibiayi?

DR DAGOGO-JACK: No, I think it’s amazing. I would wonder if this patient had a reason that her cancer doubled down in ROS1. Was there a 2032R? Were there particular mutations? But yeah, especially that kind of initial response to crizotinib is quite durable.

Current and Future Treatment of Metastatic NSCLC with RET, MET, HER2 and KRAS Alterations — Dr Dagogo-Jack

DR LOVE: Alright. Well, let’s move over to Ibiayi’s topics. And we’re going to begin with a case of a 69-year-old lady. What happened with her, Ibiayi?

DR DAGOGO-JACK: Yeah. So this is actually a gentleman. A 69-year-old who —

DR LOVE: Oh, sorry.

DR DAGOGO-JACK: It’s okay. So he had a 12 pack-year remote smoking history. Had some neck pain. Got an x-ray that showed a spot in the lungs, confirmed on a CT. Got imaging that really showed it was just in the lung. Had some staging studies that confirmed that. And ultimately, he went for a wedge resection, and had a Stage I lung cancer which, based on the size, no adjuvant therapy was recommended. About a year later, he had an unusual presentation of recurrence. He felt a nodule on his skin that ended up being a metastasis. Got more widespread imaging at that point that showed a brain metastasis and bone disease. Had testing. As mentioned, Neil, we do RNA NGS. And that showed a RET rearrangement. And so he started treatment with selpercatinib. He did okay. So it’s a fairly well-tolerated medicine. He did have hypertension and dry mouth, which is something we see. They were fairly well managed. And he was on treatment for 3 years. We’ll talk a little bit more about, like, expectations for first-line TKIs for RET. But he did develop brain-only progression, ended up having a solvent front mutation, or a particular kinase domain mutation. And ultimately, diminished such that he couldn’t access a subsequent line of treatment. But he did get quite durable benefit from a TKI.

DR LOVE: So when we were talking about adjuvant targeted therapy, I was actually going to ask you, what do you think about using it in lower-stage disease? And here, we have Stage IA who recurred with RET. But any thoughts, just getting back to that issue of offering therapy with a lower risk than actually was in the trials? I’d say the same thing for ADAURA.

DR DAGOGO-JACK: Yeah, I think it’s a tough proposition because when do you stop it. I think we have to have sharper tools, right? Our ctDNA needs to get better. Our MRD assays, et cetera. Because if someone is going to have a metastasis in the skin a year later, I bet you might have found something kind of along the way, right? Maybe we were blinded or misled by the staging imaging.

DR LOVE: Corey, anything you want to say about this interesting scenario where 3 years into treatment, there’s this frontal met and the patient has this G810S mutation and then gets leptomeningeal disease?

DR LANGER: We are seeing increasing incidence of leptomeningeal disease. Our patients are now living long enough to develop this. Initially, it seemed to be an ALK and EGFR phenomena, but we’re seeing it increasingly in other targets and other oncogenic drivers. And unfortunately, sadly, it’s the modus exodus for many of these patients. So I’m not surprised that this happened. Ordinarily, in such a scenario, if the brain were still under control, I probably would have gone on to systemic chemotherapy with a pem/carbo regimen. Pem and carbo work fairly well in these diseases. And I’ve been able to salvage some folks for years at a time.

DR LOVE: Alright, Ibiayi, let’s talk about some data.

DR DAGOGO-JACK: Excellent. And so I’ll launch right in. So we’re going to discuss 4 targets, RET, MET, HER2 and KRAS. And we’ll start with RET.

So as many of you know, RET rearrangements are seen in 1% to 2% of non-small cell lung cancers. We have 2 FDA-approved drugs for this. These are selpercatinib and pralsetinib, approved for the last few years. Initial approval was actually in a line agnostic fashion, but many of us actually rapidly adopted these in the first-line setting based on the differential efficacy. So 80% response rate if given first versus 60% if given later.

We also know that these drugs have great intracranial activity, as seen on the next slide, that actually rivals and is quite comparable to the systemic activity. And so with this patient, that was the reason why we didn’t start with brain radiation when he had that smaller metastasis.

So many might argue whether or not a study like this was truly needed, but I guess it’s good to validate the data. This is the study that really kind of validated the approach of prioritizing a RET TKI in the first-line setting. This is LIBRETTO-431. This is a global Phase III study that randomized patients who had untreated metastatic RET rearranged non-small cell lung cancer to selpercatinib versus chemoimmunotherapy in the first line. Appropriately, 75% of patients crossed over to receive a RET TKI if they were assigned to chemotherapy. This was, as expected, a positive study, doubling of median PFS from under 1 year to about 2 years. If you recall, my patient had 3 years. And so there can be some people who do better or people who do worse. And there’s a 20% improvement in the systemic efficacy, so going from a mid-60s to a mid-80s response rate, as well as intracranial efficacy. And so I think the position of this trial in history was just to validate current practice, right? So it was practice affirming, not necessarily practice changing.

And so now, we’ll pivot to MET. So there are multiple and, I would say, diverse MET alterations in non-small cell lung cancer. To date, the most relevant one has really been MET exon 14 skipping. That’s where we really have the targeted therapies. Here, we’re talking about drugs like capmatinib and tepotinib. But today, we’re actually going to focus on MET overexpression. There is a lack of consensus and lack of kind of particularly assay development that needs to catch up with respect — and the reason I mention this is that there’s a lack of consistent documentation as to the proportion of tumors that have MET overexpression. And for that reason, it ranges all the way from 20% to 50% across the literature. For the subset that we’re going to be discussing, that is nonsquamous EGFR wild-type non-small cell lung cancer, it’s thought that about 25% of such tumors have MET overexpression.

And so this is just to say that repurposing capmatinib usually has no place in this setting. And so this is data at this point looking at tumors with MET overexpression, defined as 3+, without a MET exon 14 skipping. And the response rate was only 25%. And so there’s renewed interest in thinking about targeting MET overexpression as we have new MET antibody-drug conjugates.

And so we’re going to focus on one of these. This is telisotuzumab vedotin or teliso-V. We saw data from this presented by Ross Camidge at ASCO, and it was subsequently published in JCO. This is a MET ADC that basically links a MET antibody to an MMAE payload via cleavable linker. And the study that we’re talking about here is the LUMINOSITY study. This is a Phase II study. There were several cohorts. The only cohort we’re focusing on today is the one that’s moving on for further development. That is that EGFR wild-type nonsquamous non-small cell lung cancer. And in this trial, we’re looking at the objective response rate.

So there are 2 patient populations that were enrolled in this particular cohort that we’re focusing on, both of which had overexpression of MET. Intermediate population had 3+ staining in 25% to 49% of cells. And high was greater than — 50% or greater tumor cells had a 3+ staining. The response rate in c-MET high was 35%. Intermediate was 23%. Median PFS and overall survival were comparable across these cohorts. This was not a comparative study, by the way. So the median PFS was around 6 months, median OS, around 14 months which, to me, is pretty respectable numbers. And for this reason, this drug is being explored in this patient population in a Phase III study called TELO-MET against docetaxel.

I do think that we probably shouldn’t squint and kind of brush past the toxicities with this particular drug in that 25 — 22% of patients discontinued treatment related to toxicity, namely, ILD/pneumonitis or peripheral neuropathy. So the toxicities are not unanticipated, right? So we see the MMAE payload causing neuropathy, vision changes. And then we see as far as peripheral edema and hypoalbuminemia, that’s what’s expected from the MET toxicities. ILD was seen in about 10% of patients, 5% of which were Grade 3 or higher. So we really need to work out the toxicities with this particular drug.

DR LOVE: It’s interesting that you see ILD with this agent. Corey, we’re going to talk about T-DXd where, I guess, we have more history in terms of pneumonitis from ADCs. Just anticipating that, I’m just kind of curious. I’m always curious how people approach screening for ILD once we get beyond breast cancer. The breast cancer people, they have their own approach. The GI/GU people. How do you screen for pneumonitis when you are using an agent like this one or T-DXd with the high probability? Do you do any kind of clinical screening? Do you do an enhanced CT of the chest on a routine basis?

DR LANGER: Our patients virtually always are getting CTs of the chest. So enhanced imaging, I think, would be quite useful. If they have baseline interstitial lung disease, and the problem is lung cancer patients in particular will often have that, I’m a bit reluctant to consider these agents. I’m very worried about the potential for symptomatic ILD.

Another complicating feature, individuals who’ve gotten chemoradiation will often have a fair amount of fibrosis. Whether that counts the same as ILD is unclear, but that gives me pause.

And then my final concern really has to do with ADCs in general. The numbers look okay, but they’re not phenomenal. Response rates of 25%. I guess median survival was about 14 months. We’re going to compare that to docetaxel or docetaxel/ramucirumab. I’m not sure I have tremendous optimism about positivity for that sort of trial, particularly in the setting of these toxicities. ILD, keratitis, the typical myelosuppression that we can see with ADCs. So I think outside of a true oncogenic driver, we’ve got to be really careful.

DR LOVE: Anything you want to add to that, Ibiayi? Of course, last night, we were talking about patritumab. And obviously, dato is of interest. And whether or not that’s going to be useful in patients with targetable mutations. But any thoughts? Corey often has a conservative approach to new things. Do you feel — are you similarly hesitant about ADCs or more — we talk about them every day, I feel like, regardless of tumor type.

DR DAGOGO-JACK: Yeah.

DR LOVE: Any thoughts, Ibiayi?

DR DAGOGO-JACK: Well, you’ve given me the pleasure of discussing the 2 biomarker-selected ADCs, right? And so we are really, really trying our best to enrich for responses here. I didn’t mention they weeded out 2 other populations before proceeding with this. We tend to think of MET overexpressing as being particularly aggressive cancers. And so maybe docetaxel will fare worse in that population and this will squeak by. We’ll see.

DR LOVE: Alright. Well, let’s talk about T-DXd. It’s interesting, one of the first things I thought about when I saw the pan-tumor approval for IHC 3+ was lung because you guys were — I was like, why isn’t this approved? And then the pan-tumor approval came and solved all the problems. But meanwhile, then we saw the data. So let’s talk about it.

DR DAGOGO-JACK: Exactly, yeah. So the exact type of sequence that we talked about with HER2 where you start with — with MET where you start with the mutations and then you broaden it to overexpression. So T-DXd, so first, taking a step back. HER2 alterations are present in lung cancer. HER2 mutations in 2% to 4% of lung cancers. We have an approved targeted therapy, but it’s an outlier. It’s an antibody-drug conjugate. This was approved at a 5.4 mg/kg dose based on this noncomparative study, DESTINY-Lung02. Based on the wariness around the ILD rate at the higher dose, at this lower dose, we have great efficacy. So a response rate around 50%, median PFS around 10 months, and half the rate of ILD and half the rate of dose reductions. We’ve also heard mentioned in our earlier slides that this actually penetrates the CNS as well.

But I think the more kind of exciting data is how can we expand this to HER2 overexpressing tumors. And as Neil mentioned, we had a pan-tumor approval. For the lung subset, that was actually based on a cohort in DESTINY-Lung01, 5.4 mg/kg dosing. They actually had 2+ and 3+ expressing tumors. It’s thought that this is somewhere between 10 to 23% of non-small cell lung cancers. In this small dataset, the response rate was around 53%. Median PFS, around 7 months. At World Lung, we saw DESTINY-Lung03 which included some EGFR-positive patients. Similar kind of smaller size dataset, but confirming kind of the response rate in this setting, around 40%. Median PFS around 8 months. So I read these data as I should be testing for HER2 overexpression irrespective of kind of what other target is there. In all-comers with non-small cell lung cancer, you might have a therapeutic opportunity here.

And this is the slide for the DESTINY-Lung03 that I was referencing.

And just showing that response rate, 44%, 8 months for median PFS.

And I think in World Lung, there was also some interesting data talking about tyrosine kinase inhibitors in this population. So a lot of toxicity with earlier attempts at tyrosine kinase inhibitors and less specificity. So we saw the SOHO-01 and BEAMION trials looking at BAY 88 and zongertinib. The response rate was encouraging here with both of these drugs, around the 70’s. Median PFS around 10 months. But still, diarrhea remains a concern, somewhere between 50% to 90% of patients. Particularly with BAY 88, one third of patients required a dose reduction. That number is around 11% with the zongertinib drug. I think what was encouraging about zongertinib was that there was a little bit of an early hint at CNS penetration with this particular drug. So maybe some room for oral targeted therapies in the space of HER2.

DR LOVE: Before you get into KRAS, just a couple other points. What do we know, Ibiayi, in terms of HER2-low? Of course, that’s used all the time in breast cancer. I don’t know how much data we have outside of breast cancer. In breast cancer, it’s defined as 1 or 2+ IHC with FISH-negative. I see trials, I think even you showed some data there, with 2+. I don’t think these people were FISH. But any evidence right now that you see benefit from T-DXd in HER2-low?

DR DAGOGO-JACK: Yeah, I think we still have to sort it out. We’re borrowing, I think, a lot of these studies are using kind of the GI way to query, GI and breast sometimes to query HER2 overexpression. I think we still have to sort through what proportion of tumors have 1+, 2+, et cetera before we can answer those questions. But yeah, it is something compelling to look at.

DR LOVE: I’m kind of curious. I’ve heard tons of cases of T-DXd, both from investigators as well as docs in practice. With breast cancer, I have a pretty good feel about how that plays out, including HER2-low where you see some pretty useful and durable responses. Corey, you guys now, you’ve got your feet wet with HER2-mutant disease. Now, overexpressing. Have you seen patients who had useful responses? I know you’re concerned about toxicity. But have you actually seen people benefit the way we’ve seen in breast cancer?

DR LANGER: Definitely. HER2, I think, is a different story. This is an oncogenic driver. The response rates are in the 50% range. Median PFS approaching a year, as Ibiayi has pointed out. So I think, at least in this setting, the ADC is performing quite a bit better than it may just in the IHC-positive setting. For 3+, I would certainly consider it. For 2+, I might be on the fence. For 0 and 1, it’s not approved, and I wouldn’t give it based on the results. So I think this brings up a broader point. How are we going to test for all of this? Right now, we are doing PD-L1 by IHC. And I foresee a panel of IHCs that will include HER2 and probably MET, assuming the teliso-V or some similar agent comes along, and probably other markers. So it really underscores the need to get very generous biopsy specimens because we’re not done with the IHC. We have to do fusions. We have to do next-generation sequencing. We have to probably have some additional tissue to spare for unknown tests in the future.

DR LOVE: So Ibiayi, we were talking earlier at the beginning about the criteria to go with first-line targeted therapy. What about T-DXd, both in HER2-mutant or HER2-overexpressing patients? If you could or have you used it first-line in metastatic disease?

DR DAGOGO-JACK: So overexpressing, I think a little early just based on that response rate, et cetera. But I think I have been tempted for HER2-mutant with that response rate in the 50% range. There’s a clinical trial exploring this, the DESTINY-Lung04. I’ve had a patient who really, really wanted it. And so we did give it off label. But again, that is an off-label use of the drug. You have to monitor closely for that ILD.

DR LOVE: So for the people who are out there raking the leaves and don’t have the video available, I saw Corey shaking his head yes as Ibiayi was speaking. Can you comment in terms of first-line for HER2-mutant?

DR LANGER: I agree with Ibiayi. I would put them on the trial. I’m a little bit uncomfortable doing it off trial. The comparator here is KEYNOTE-189. I’m not sure that would be my comparator, whether it’d be pem/carbo or maybe pem/carbo/bev. But the trial is ongoing. We’ll have our answer eventually. And I remember during one of your prior RTP sessions, we actually took a survey of both the audience as well as “onc experts,” would we give it first line or second line? And it broke down 50/50. Right down the middle.

DR LOVE: That’s the way we do our consensus conferences. If everybody does the same thing, we call it a consensus. Anyhow. Let’s finish out with KRAS G12C, Ibiayi.

DR DAGOGO-JACK: Awesome. So KRAS G12C, same story — similar story, 2 drugs approved here. So sotorasib and adagrasib both approved in 2021, 2022 based on Phase II data with response rates around 40%. Median PFS around 6 months.

But, of course, the obvious question is, how do these stack up against docetaxel since those definitely are not first-line numbers? And so the first trial looking in the second-line setting compared to docetaxel is CodeBreaK 200. This is sotorasib versus docetaxel. All of these trials actually wanted to improve progression-free survival. And they did, very modestly. So with CodeBreaK 200, it was a 1.1-month improvement from 4.5 to 5.6 months, though there was kind of a doubling of objective response rate. OS was not seen, though it was not necessarily powered for that.

And I think one of the things that we always think about with docetaxel is the toxicity, right? And so this drug across the board had less pronounced toxicity, though a little bit higher diarrhea, LFT increase. Though I will point out that the dose discontinuation rate was comparable with each of these, around 10% to 11%. And so this had approval in this setting although there was some scrutiny, which we’ll kind of leave out of today’s discussion, about that trial.

The next one I’ll mention is KRYSTAL-12. This is a similar study, but adagrasib versus docetaxel. This time, a 2:1 randomization, again trying to beat PFS, which it did. This time, by 1.7 months from 3.8 to 5.5. A little bit more pronounced benefit in terms of response rate, 9% to 32%. Here, we saw some intracranial responses. Survival is premature here.

At least in my personal experience, I do find adagrasib is a little bit harder in terms of the GI toxicity. And that panned out here. We see more dose interruptions, so threefold higher from 20% to 60%. But less dose discontinuation. And a higher kind of proportion of patients in the oral therapy arm having GI toxicities.

And so, of course, the obvious question then is, if you’re having more GI toxicities, what is the impact on quality of life? So at World Lung, we saw a bunch of instruments read out in terms of quality of life. The punchline is that even with the oral therapy, so here, the adagrasib, less cough, less dyspnea, less fatigue, less pain and less symptom deterioration across various instruments, really kind of suggesting that even if there’s a marginal benefit in terms of PFS, it does help preserve quality of life a little bit better than docetaxel in this setting.

DR LOVE: Why don’t we just keep going and you can talk about some of the newer agents?

DR DAGOGO-JACK: Yeah. So this is the final slide. I think I’ve said it 1,000 different ways that hopefully, we’re not done yet in terms of KRAS G12C. These are our first-generation drugs. We heard from Corey that we’re getting better and better with ALK and ROS1 targeted therapies. We certainly have room to go with KRAS G12C inhibitors. And so these are some of the datasets that were updated at World Lung looking at various drugs. The response rates are bottoming out around the low — high-40’s, low-50% range. The outlier here being divarasib at 59%. And we’re starting to get median PFSes in the 9- to 15-month range. I do want to caution that these are Phase I and Phase II data, and we did see those response rates come down with both adagrasib and sotorasib when we went into larger studies. But this is exciting. And some of these drugs have activity after sotorasib and adagrasib.

DR LOVE: So before we get into your case to conclude here, Corey, can you kind of give us more of a qualitative clinical comparison of the 2 available agents in terms of efficacy and tolerability and how you choose between them?

DR LANGER: The efficacy is virtually identical as far as I’m concerned. Many folks were very disappointed by these trials, but I had no expectation that they would beat docetaxel with respect to survival, and they didn’t. PFS was clearly better. Response rates were clearly better. We do see transaminitis as well which is one of the issues. A lot of times, it comes down to interactions with other drugs in the patient’s medicine portfolio. So I have the benefit of having a dedicated thoracic oncology pharmacist. And we will actually go over the meds and the comorbidities and try to figure out is there a preference one way or the other.

The other issue that’ll come up, particularly as trials go forward, is combinability with the checkpoint inhibitors which work quite well in this disease. Sotorasib does not combine well. Lots of toxicity including hepatotoxicity. Adagrasib is probably better. Some of the newer agents may be better yet. And I don’t want to steal Ibiayi’s thunder here, but these newer agents do look better. Divarasib response rate, granted small numbers, seems to be higher than we’ve seen with the other 2 established agents. And certainly, PFS looks better. So there may be a possibility that the newer agents will displace our “standard.”

And lastly, these patients are common, 30% of our patients have KRAS mutations, half of whom have G12C. It’s almost as common as EGFR.

DR DAGOGO-JACK: Exactly.

DR LOVE: Anything you want to say about this 52-year-old man who, I guess he ended up on adagrasib for 5 months?

DR DAGOGO-JACK: Yeah. I think the main thing I would point out in this particular case, a lot of text, but the key was that he had repeat CNS progressions and he had a poor time on adagrasib. And so I think it’s important as we think about our next-generation KRAS G12C inhibitors, to improve upon the CNS penetration of these drugs.

DR LOVE: Final comment from Corey in terms of brain mets and CNS disease in patients with KRAS G12C.

DR LANGER: No surprise that this patient ultimately succumbed to CNS disease. I’ve seen it myself where the extracranial disease is relatively well controlled. And the median progression — the progression-free survival here was virtually identical to what we’d seen in the Phase III trial. So it’s disappointing. When we hear about oncogenic drivers, we expect EGFR, ALK level benefits. We’re not seeing that with G12C. We’re certainly seeing some benefit, but it’s modest.

DR LOVE: So Ibiayi and Corey, thank you so much for educating us here tonight. Audience, thank you for attending. Come on back tomorrow, same time, same place. I want to see what Drs Garon and Paz-Ares have to say about ivo and a bunch of other things that came out recently. Be safe, stay well and have a great night. Thanks so much, Ibiayi. Thanks, Corey. Have a good one. Take care.