Introduction: Journal Club with Pasi A Jänne, MD, PhD — Part 1

DR LOVE: Good afternoon, everyone. I’m Neil Love from Research To Practice and welcome to Meet The Professor, as today we talk about the current and future management of non-small cell lung cancer in patients with EGFR tumor mutations with Dr Pasi Jänne from the Dana-Farber Cancer Institute in Boston.

We have a great faculty for this series. And later on, we’ll show you the results of a survey we did of the faculty of their usual treatment practices. As always, if you have any questions or cases you’d like to run by us, just type them into the chat room and we’ll talk about as many of these as we have time.

If you could please take the 10-item, 1-minute survey we do before and after this, it really helps us a lot to understand your needs and really be able to do these kinds of programs.

We know a lot of people end up listening to these webinars in their cars and when they workout and raking the leaves. If you’re into audio programs, check out our Oncology Today podcast series, including a recent program with Dr Wakelee talking about adjuvant therapy.

We do webinars all the time. Tomorrow, I’m really looking forward to working with Dr Lonial talking about multiple myeloma. And then on Wednesday, we’re going to be doing a program that’s sort of an outshoot from the Pan Pacific Lymphoma Conference this past summer. We’re going to be talking about CLL. We’re going to be presenting cases by video. It should be a great conference. And then on October 22^nd, we do our annual day-long year in review or clinical implications series with the Florida Cancer Specialists in Orlando. We have 20 investigators coming here. We’re covering many different tumor types over that day. If you happen to be in the Orlando area, come on over. If not, check us out online. Here’s the list of the — what we’re going to be covering during that day. It should be really a great day. I’m really looking forward to it.

And I’m really looking forward to this conference because there’s so many things to talk about. I’m kind of even wondering whether we’re going to get through all that. As always, we have a bunch of cases to present from docs in community-based practice.

We’re going to start out talking about a couple papers from Dr Jänne. Then, we’ll get into some case presentations. Then, the survey. And then, some papers that he’s written.

But just to get started, Pasi, I thought you’d find interesting that last week I was doing a recording with your colleague, Justin Gainor, down the road at MGH. We were doing a program on RET. And he was telling me about a patient who actually got started — had a RET fusion and this was before we had the recent drugs approved. He ended up using chemo. He ended up using cabozantinib, getting the patient through. Finally, we got the 2 drugs, selpercatinib and pralsetinib, the patient got on that and has been on it for the last 4 years. And I was telling him about an idea that Ross Camidge had been talking about a couple weeks before of what he called being in a time capsule, so the idea of trying to move your — keep your patient alive until the next great thing comes along. And I want to just let you know about, I’m sure you’ve seen tons of cases in your practice like that, about this fantastic paper that you did here reviewing the whole history of TKIs. This is an awesome paper for you all to review. It has so much great content in here. I’m going to just sort of click through some of the graphics. But I just want to get your overall global view of where we are today with TKIs. And in addition to all the details and granularity you go through, also whether or not you think they sort of fulfill the promise of what we saw with imatinib in CML or is that really a different situation? Are we ever going to see the kind of outcomes that we’re seeing in CML? Any thoughts?

DR JÄNNE: Thanks, Neil. Yeah, this was a wonderful project that I was involved in to be able to kind of talk about the history of TKIs and what we’ve learned as an oncology community over the last 20 years. And I think the RET example is a beautiful one because there, the cabozantinibs of the world are sort of poor man’s RET inhibitors. They kind of inhibit RET, but we don’t really see the kind of activity that we do if we develop really specific and potent drugs against the target like selpercatinib and pralsetinib are. And there, you see real clinical activity. And I think that’s one of the lessons is that if you have a kinase target, develop a real specific and potent drug against that target and you can see great clinical activity as opposed to repurposing a different kind of drug for that use.

And I think we’ve also learned, of course, about how drug resistance happens, how we can use that to develop next generation TKIs. And that’s true for many different subsets of lung cancer, but other cancers as well. And ultimately, how we can potentially develop combinatorial strategies, how we can potentially inhibit kinases with drugs that are not TKIs using things like drugs that degrade targets or even antibodies or antibody drug conjugates and ultimately, things like allosteric inhibitors. So I think there’s a lot of learnings from the different fields of oncology where TKIs are being used that can inform the future in terms of drug development.

Now to your question about have they fulfilled the promise? I would say partly fulfilled the promise. I think all of us would rather treat our patients with a TKI with the right genetic context as opposed to chemotherapy. On the other hand, we don’t — we’re not curing anyone with advanced cancer with a TKI. We don’t see typically the kinds of imatinib-type of durability of responses where somebody is on it for multiple years. Sometimes we do, but not always. And so I think there’s still room to improve. And whether that’s an improvement in the drugs or whether that’s a better understanding of the biology that then allows us to layer on other therapies onto that, I think, is where the next phases of research and clinical development will move.

DR LOVE: Anyhow. I highly recommend this paper. I don’t know if you’ve ever seen any of these books on tape like Audible, but I’d like to see your paper. It’d probably be about 7 hours for somebody to read it out loud. But I think that’s another way to try to digest the incredible content in this paper.

This is another fantastic paper. Certainly, the most common question you get when you sit down with oncologists is what do you do in the patient who responds and then has disease progression? This is fantastic. A lot of great graphics going into this. Maybe you can just comment a little bit, you’re going to see a lot of the cases, obviously, revolve around that, but what we’ve learned about resistance. And just as I was popping that up, Hassan in the chat room presented a case that I think is relevant. So in addition to commenting on the paper, maybe you can comment on this case of a 55-year-old woman, EGFR 19, gets osimertinib. And after a year, progresses and has a new BRAF mutation. Started on dab/tram. No response for 6 weeks. Then, he adds back osimertinib. Maybe a coincidence, but then dramatic response. Any thoughts about that case? And any comments on your paper and some of the things that you got into in terms of mechanisms of resistance to osimertinib?

DR JÄNNE: Yeah. Just to comment on the mechanisms, many of the mechanisms are new genetic alterations whether they’re an EGFR itself or in other genes like BRAF that was mentioned or MET or other things. But collectively, it only accounts for about 40% of osimertinib resistance. So in less than half of individuals, you find a targetable alteration. That doesn’t mean you shouldn’t look for it, like was presented in this case, because it can have a dramatic affect for the patient if you have the right drug combination. But I think the challenge is then what to do for the other half where you don’t have a targetable alteration. And there are studies looking at things like antibody drug conjugates. And there’s ultimately always, of course, chemotherapy in that situation. But it is a challenge in figuring out how we can develop the most effective strategy at the time of osimertinib resistance. Or should the strategy be enhancing the initial effect of osimertinib to make that durability longer? So I think there are different approaches. And we’ll see which one is clinically more efficacious.

Now back to the BRAF case, right. Yeah, there are a few examples that are published on adding dabrafenib/trametinib. Usually, you need to still keep the osimertinib there just like for MET amplification, you typically add a MET inhibitor to osimertinib. And the same is true here because the osimertinib is doing some things but clearly, not enough because you have the BRAF mutation, but just inhibiting BRAF with dabrafenib/trametinib doesn’t appear to be clinically enough as is highlighted by this case. When you add osimertinib, then you see the effect. I personally haven’t used the 3-drug combination. Toxicity would be a little bit of a concern in my mind but hopefully, that was able to be managed in this particular individual. And it sounds like the patient benefited which is great.

DR LOVE: So I don’t know if in your paper on mechanisms of resistance you got into L792F, but Kenley has a patient who has that in a patient progressing on osimertinib. Is that targetable?

DR JÄNNE: So if it’s after first line osimertinib, meaning that they didn’t have a prior EGFR TKI, it’s potentially targetable with prior generation EGFR inhibitors like erlotinib and afatinib, just switching to one of those agents. And it’s potentially targetable with some of these newer generation agents that are out in clinical development like BLU-945 and others, these sort of so-called fourth generation EGFR inhibitors that are being predominantly tested for the C797S mutation that happens in response to osimertinib, but should potentially work against these others as well.

DR LOVE: So one more case from the chat room from Emily. She doesn’t say that the patient has an EGFR activating mutation, but I’m guessing the patient does. Maybe she can put it in there. But in any event, 52-year-old woman, Stage IB adenocarcinoma of the lung status post lobectomy. I think that IB is kind of interesting. We can talk about that. It was a year ago, so it was after ADAURA. But apparently, this patient didn’t get adjuvant treatment, or at least adjuvant osimertinib. A year later is found to — has dizziness. MRI of the brain, one right cerebellar met. Status post SRS. The rest of the workup, totally negative. Any thoughts about what to do at that point? And would it matter if the tumor was removed surgically? This was treated with SRS.

DR JÄNNE: Yeah. I think you certainly worry a little bit about that is the cerebellar lesion just sort of the tip of the iceberg and that if you wait some time, are you going to see other lesions there appear? And I think to your question about surgery versus SRS, there’s, of course, still a potential that there will be regrowth of the disease after SRS at some point. So I think it is certainly somebody to consider giving osimertinib to because of the high CNS penetration. I don’t know that there’s a right or wrong answer. You could also observe for a little while with serial scans and kind of see what happens. And if there’s any signs or concern about recurrence, then initiate that. Probably also needs good systemic restaging to make sure there’s nothing else going on as well. But a very interesting case.

DR LOVE: Yeah. I feel like — we have another series going on with HER2-positive breast cancer. We just did a program with your colleague, Nancy Lin, just on brain mets. And you get into a lot of these same issues, the same model in terms of systemic therapy, CNS penetration.

Case: An Asian man in his late 60s with adenocarcinoma of the lung and pleural effusion with EGFR amplification (PD-L1 20%) — Jennifer L Dallas, MD

DR LOVE: All right. Let’s make some rounds here. We have some great cases. We’re going to start out with a few cases of some basic issues. This is a patient of Dr Dallas from Charlotte, North Carolina. 67-year-old Asian man who actually has EGFR amplification. So no mutation, just amplification. Here’s her question.

DR DALLAS: I met him earlier in the month in the hospital.

He has underlying cirrhosis, and he presented with a large left pleural effusion. And on the CT imaging there’s pleural thickening in the lung, but not an obvious mass.

He is a current smoker. He underwent thoracentesis, and it showed a poorly differentiated adenocarcinoma.

So my question for this case was he’s originally from Vietnam, so I was hoping for an EGFR mutation. Instead, I found an EGFR amplification. He has a PD-L1 of 20%, should he receive immunotherapy and chemotherapy just as any other non-small cell lung cancer patient?

DR LOVE: So should she basically ignore it or not?

DR JÄNNE: Yeah. So this is not straightforward. So the EGFR amplification is amplification or more copies of the normal form of EGFR. So the kinase domain where drugs like osimertinib bind is wild type. So it’s not a situation where a drug like osimertinib would work. You need a wild type EGFR inhibitor which would be something like afatinib or erlotinib. So if you wanted to go after the EGFR alteration, you would go, you know, you could use medicines like that. On the other hand, probably chemotherapy/immunotherapy would be a very reasonable choice here. It’s a different scenario than having an EGFR mutation.

DR LOVE: So in terms of IOs in patients with EGFR tumor mutation, of course, a huge issue over the last couple of years. Any comment on your thought about why it is that you don’t see very good responses? We hear about patients who are nonsmokers, no tumor mutation burden. And what about, again, a patient with EGFR amplification? Just ignore that in terms of whether to use an IO? You apply the same approach as if the patient didn’t have it or are you less likely to use an IO?

DR JÄNNE: Well I think it’s not clear why IO doesn’t — or current generation IOs don’t work in EGFR mutant cancers. Yes, they have lower tumor mutational burdens because they tend to occur typically in never smokers. And it doesn’t mean that newer generation immune therapeutic approaches won’t ever work in EGFR mutant cancers, but I think it’s pretty clear that the current ones don’t. And when you add them to things like TKIs, you get into real problems with toxicity. So I don’t know that we have enough information in this particular subset. EGFR amplification is fairly uncommon. Oftentimes, you see it in conjunction with a mutation, but to have it by itself in the absence of mutation is pretty uncommon. So I think here, you could do chemotherapy/IO. Or if you — or, as I said, you could use a drug like afatinib or something that is a good wild type EGFR inhibitor that may be effective in this situation. It’s probably doing something important to the cancer. And I think the other question with this patient was that there was a question of cirrhosis. So that may impact your choice of therapies in the first place as well.

DR LOVE: Yeah, that’s a really good point.

Case: A man in his late 50s with metastatic adenocarcinoma of the lung with discordant EGFR testing results and a new mediastinal lesion after therapy with osimertinib — Rohit Gosain, MD

DR LOVE: All right. Here’s another variation of sort of life in the real-world. 58-year-old man presents with metastatic adenocarcinoma of the lung. But interestingly, he’s got an EGFR activating mutation on liquid biopsy and not seen on the NGS on tissue. Here’s Dr Gosain.

So you felt he was progressing. That was after three months, huh?

DR GOSAIN: That is correct. And that’s what was rather surprising and concerning.

DR LOVE: So what are the questions you’d like to hear addressed about this case?

DR GOSAIN: So first of all I was rather surprised with the fact that solid NGS testing was negative from the EGFR mutation testing. Is that something that we tend to do? Or do they see this sort of discrepancy in solid and liquid biopsy at all often? And the other important question will be that, given the progression, would one continue osimertinib in addition to the chemotherapy because the other metastatic lesions were rather stable, except a new lung lesion, of course, and the increase in mediastinal lymph nodes?

DR LOVE: Yeah, I should have mentioned that he actually progressed after 3 months on osimertinib, as you just heard. Obviously, very unusual. And he was wondering is this somehow related to these assay results? First of all, how do you explain the assay results?

DR JÄNNE: It’s a little bit unusual. When there is discordance, it’s often that the mutation is found in the tumor, but not in the ctDNA because the tumor doesn’t necessarily shed enough ctDNA for you to be able to detect it. The converse, as in this case, is more unusual. It’s unlikely that the EGFR mutation is a false positive. Typically, the assays and clinical testing labs have very good criteria when calling something positive. So it’d be unlikely that it’s a false positive. On the other hand, it’s hard to explain. But clinically, it didn’t really behave like an EGR mutant cancer. If it progressed in 3 months, not that it’s impossible to see that. But as you pointed out, Neil, it’s pretty unusual. It’s pretty unusual. So I guess one tiebreaker here is if there really is a new mediastinal mass, could you go after that and biopsy it and sequence to kind of get a more contemporary look at what’s going on while you wait for the results of chemotherapy? Probably, I would have a low threshold of stopping osimertinib here while doing chemotherapy because just the lack of benefit and such a short durability of response.

Case: A man in his late 40s with metastatic adenocarcinoma of the lung and a brain metastasis with an EGFR exon 19 mutation and disease progression after stereotactic body radiation therapy (SBRT) and osimertinib, now with an ALK mutation by RNA testing (PD-L1 0) — Namrata I Peswani, MD

DR LOVE: So here’s another, I was mentioning to you how many of these, I think we’ve done more than 2,000 cases now since the beginning of the pandemic, and I’ve actually heard this scenario a couple of times. The first time I heard it, I’m like does this really happen? 48-year-old man, a patient of Dr Peswani, presents with widespread metastatic disease including a brain met, EGFR exon 19. Gets SBRT to the brain met, osimertinib, responds then progresses. And on progression, there’s an ALK mutation that’s only seen on RNA testing. Here’s Dr Peswani.

DR PESWANI: He’s 48. He’s a nurse practitioner, never smoker. Lung nodule with a solitary brain met and about 3 or 4 areas in his bones. Non-small cell EGFR mutated, exon 19. Got put on first-line osimertinib. SBRT to his brain. Unfortunately, 8 months later he progressed on the osimertinib. I did resistance testing, but I did not find any obvious mutation that explained resistance to osimertinib. But the RNA report showed that he had an ALK mutation.

I was hoping to get some input about that. And also, the other question is, when somebody progresses on osimertinib and they don’t have any resistant mutations or anything else, how would the experts treat this patient?

DR LOVE: Any thoughts about this one?

DR JÄNNE: Yeah. So acquired ALK rearrangements have certainly been seen and previously described even, as you mentioned, with resistance to osimertinib. And there is some data suggesting that targeting that, adding a second drug like alectinib or another drug like that can lead to clinical responses in those patients. In this person with a brain lesion, it may be important to think about a drug that also penetrates the brain.

I think the second question is in terms of what do you do when you don’t find a targetable alteration? I think that is where we don’t have a lot of data. I think the standard of care is chemotherapy, combination platinum-based chemotherapy. But there are other agents being tested in this space. For example, a HER3 antibody drug conjugate called pertuzumab deruxtecan has activity across a broad range of osimertinib resistance mutations, and even in patients who don’t have resistance mutations because most EGFR mutant cancers express HER3. So you’re kind of leveraging this protein that’s expressed in EGFR mutant cancers to deliver a targeted chemotherapy with this antibody drug conjugate. So that’s another approach. And that’s being tested in clinical trials. But I think finding something for this patient population is an important need moving forward.

DR LOVE: So we’re going to get into HER3 later. My eyes were really opened by reading some of the work that you’ve been doing on particularly pertuzumab. That sounds super exciting. We’ll get to that in a second.

Case: A man in his early 50s with Stage III unresectable adenocarcinoma of the lung with an EGFR mutation who receives chemoradiation therapy and consolidation durvalumab, now with metastatic recurrence — Ferdy Santiago, MD

DR LOVE: I want to go through another case. This is another very common scenario I hear all the time, locally advanced, nonresectable. The patient typically would go on durvalumab. And this question has been out ever since the PACIFIC trial was first published. What do you do if the patient has an EGFR mutation? As always, it always plays out a little differently in the real world. This was actually a patient who was incarcerated at the time of the diagnosis, making follow-up a little more challenging. Didn’t quite get all the durvalumab but somehow, they managed to get him through that. Here’s Dr Santiago with his questions about this case.

DR SANTIAGO: He completed I'd say probably at least 2/3 of maintenance. And then when he presented again after he was let out of jail, he definitely had progression of his disease. Due to the fact that he was EGFR mutant, we decided to start him on osimertinib. And he’s done well for the past 2 years on this treatment with overall stable disease with an initial reduction of at least 70% of his lesions. Overall, he has tolerated it relatively well.

DR LOVE: What are some of the questions you think would be interesting to hear them talk about?

DR SANTIAGO: The use of adjuvant osimertinib. This preceded that study coming out. So if this person presented today with Stage III disease along with an EGFR mutation, would we start with chemotherapy, radiation upfront followed by durvalumab, then EGFR maintenance? Or would you switch to an EGFR TKI upfront versus doing the durvalumab maintenance? Or do both?

DR LOVE: Any thoughts?

DR JÄNNE: Yeah. There is a trial that’s trying to address this specifically in the EGFR mutant patients who have locally advanced disease kind of like durvalumab, but instead of durvalumab, they’re getting osimertinib versus placebo as a maintenance therapy. And that would be probably what I would lean towards if I found somebody that had an EGFR mutation and wanted to figure out what to do in terms of the maintenance setting. Probably, I’d lean towards that as opposed to durvalumab. Fortunately, in this individual, it sounds like the time from stopping durvalumab to starting osimertinib was also significant that the patient didn’t run into IO/TKI toxicities. But I’m glad to hear that he’s done well and responded to therapy.

DR LOVE: That is another question you hear a lot from oncologists about they’re very sensitized, they’ve heard a lot about this issue of people who had recent IOs such as a patient like this getting durvalumab who then goes on targeted therapy and the concern about increasing toxicity. They’ve heard stories about pneumonitis with osimertinib and hints that other targeted therapy, maybe you see more complications with recent IOs. Can you comment on what we know about that? And is there an optimal or safe distance between an IO and EGFR TKI?

DR JÄNNE: Yeah, there definitely are reports both in the EGFR and in the ALK field of somebody who would have, for example, gotten chemotherapy/IO and then they were found to have either an EGFR mutation or an ALK rearrangement and they’re switched to TKI and then develop more toxicity, presumably due to this interaction because many of the IO agents being antibodies have very long half-lives and can be in circulation for months. I think if you wanted a real safe window, you probably are talking about a few months at least between the last time you got IO before you start a TKI. Now that’s, of course, not clinically practical always because you need to treat the person in front of you and you want to give them the therapy that will work best for their disease. And if they have the appropriate genetic alteration, that’s often a TKI. So it is a challenge. And how to kind of mitigate against that, I think, remains. You have to be very vigilant about the side effects. If you end up starting someone on a TKI relatively close to when they had an IO, I think they need more frequent monitoring initially to make sure that they’re doing okay.

DR LOVE: We had a really wild case we presented to Lecia Sequist who did the last one of these in this series. A patient, very educated patient in that situation, had just had the durvalumab, but very sick from the disease. They jointly decided to go ahead and try the osimertinib. He sent the patient home with a pulse oximeter and corticosteroids and directions to go to the ER if he got short of breath. And sure enough, the patient actually got pneumonitis, had a fantastic response to osimertinib. Somehow, the doc got the patient through the pneumonitis and the patient is doing great on osimertinib. But what about other TKIs after recent IO? We’re going to talk about some of the drugs for exon 20 insertion, mobocertinib, amivantamab, for example. Again, do you see more toxicity with recent IOs?

DR JÄNNE: I don’t think that for those 2 drugs specifically has been reported, but it wouldn’t surprise me that you would see that. Mobocertinib is an analog of osimertinib, so it wouldn’t surprise me at all if you saw that if someone had previously received or close proximity received an IO. But I think it’s something to, you know, not just our approved drugs, but even those in clinical trials when we enter patients into clinical trials on new TKIs, we’re always aware or try to be keenly aware of when did they last receive IO if that was part of their therapeutic regimen as we evaluate toxicities of the new drug because they could be enhanced because of the IO.

DR LOVE: I’m always wondering whether I’m the last person to hear some of these things, but I don’t remember hearing — mobocertinib is an analog of osimertinib?

DR JÄNNE: Yes. Structurally, it was sort of structurally designed out of mobocertinib to be more of an exon 20 inhibitor. But it has — it shares some of the core structures with osimertinib.

DR LOVE: Yeah, that kind of begins to tie into these next few cases and could help us understand about exon 20 insertion.

Case: A man in his early 70s with Stage IIIC large cell neuroendocrine carcinoma of the lung and an EGFR S768I mutation (PD-L1 1%) — Jarushka Naidoo, MB BCH, MHS

DR LOVE: I’m going to start out with this case of a patient of Dr Naidoo. The thing that was interesting, she said it was an exon 20 insertion point mutation, S768I, I think it is. Anyhow. I’m curious. We’re going to start to get into what exon 20 insertions actually are. But maybe we can start out with this case and this mutation. Here’s Dr Naidoo.

DR NAIDOO: This is a 70-year-old African-American male who is found to have a large, a 10-cm lung mass invading the mediastinum with N3 lymph nodes on PET/CT. The patient’s tumor has an unusual EGFR S768I point mutation, which is an exon 20 point mutation. What is the most appropriate treatment option?

DR LOVE: Any other questions?

DR NAIDOO: Are there circulating biomarkers that will help us to select for patients who may benefit from 1 approach versus another? How are they interpreting those ctDNA studies? There are lots of different ways to quantitate ctDNA. There’s fragmentomics, methylomics, cell-free DNA. Which platform do they think, and which method of analysis do they think, is the most scientifically robust?

DR LOVE: So I don’t know if we’re going to get to some of your papers that get into ctDNA. Everybody is asking about that. But what about this specific mutation? In my naïve eyes, is this more like exon 19 or more like exon 20 insertion?

DR JÄNNE: Yeah, this is a point mutation, so it’s not really an exon 20 insertion and it’s in a slightly different region where the exon 20 insertions happen. This would be classified as an atypical EGFR mutation where there’s data on — or the approved drug in this scenario would be afatinib. Now there is data using osimertinib in some of these atypical mutations that’s starting to emerge. There’s a publication from Korea that’s looked at that. And there is activity of osimertinib against some of these atypical mutations as well. But probably, if you had to pick an EGFR inhibitor in this situation if you’re going to go down that therapeutic path, probably afatinib would be the more tried and true approach here.

In terms of the circulating DNA, I think at the moment, ctDNA is good for noninvasive diagnostics at the time of — molecular diagnostics at the time of presentation or at the time of progression like osimertinib progression. I don’t know — there are studies looking at serial ctDNA studies. And if you clear your ctDNA quickly within 3 or 6 weeks of a therapy, targeted therapy, chemotherapy, IO, that tends to be a better prognosis than if you don’t clear your ctDNA. I’m not sure that that’s standard of care yet to do this every 3 or 6 weeks. And there are trials trying to ask questions of intensifying therapy if you don’t clear your ctDNA. And I think that may be a place where we’ll use this kind of technology moving forward. But I think it’s still in the clinical trial realm as opposed to clinical care.

DR LOVE: I’m not sure if it was this survey or another one, but I remember we had one survey where we asked a bunch of pulmonary investigators what are situations where they would use afatinib? I was curious whether anybody is using it. So have you used afatinib in the last year or 2?

DR JÄNNE: Yeah, in some of these mutations, this and the G719 mutations, sometimes afatinib is used. Again, another atypical EGFR mutation. But it’s not as commonly used. I think a lot of people have sort of, even for these atypical mutations, have substituted using osimertinib with some data, as I mentioned, emerging using them against these atypical mutations. Toxicity is, of course, the issue with afatinib when you compare it to osimertinib.

Case: A man in his early 80s with metastatic adenocarcinoma of the lung with an EGFR exon 20 insertion mutation and disease progression on mobocertinib — Jiaxin (Jason) Niu, MD, PhD

DR LOVE: So we have 2 cases coming up now from Dr Niu of patients with exon 20 insertions. We’ll get into the issue of the new agents that are out there. It’s really interesting how this played out in his practice. He has a lung practice. He’s in a satellite from MD Anderson out in Arizona. But really amazing how he — the kind of practice he has in the community. Let’s start out with this 81-year-old man with metastatic disease who is in his practice.

DR NIU: 81-year-old man. He refused chemotherapy. At that time, I was running a Phase I study on mobocertinib. That’s before the approval of mobo and amivantamab. So I said, “Well, there’s a Phase I study. If you’re interested we can do it.” He actually was enrolled on the study. After 2 years, he clearly developed progression of disease with much worsening cough and shortness of breath. Once again, as expected, he declined chemotherapy. And then, this was the time amivantamab got actually approved. So I actually treated him with ami. He responded. I was quite excited. He had severe fluid retention. He gained 30 pounds on treatment. I had to give him double diuretics.

My question for the faculty is how do we manage the c-MET class side effects with severe fluid retention?

DR LOVE: So any side effects at all with the mobocertinib?

DR NIU: He has mild diarrhea, which is manageable.

DR LOVE: So Phase I trials aren’t the way they used to be. This patient had a 2-year response on a Phase I trial in the community. Really amazing. Another time capsule kind of thing too because he pushed him out so he could get the amivantamab.

DR JÄNNE: Yeah.

DR LOVE: Any thoughts about this case, and particularly the tolerability issues of these 2 agents?

DR JÄNNE: So we have 2 approved agents for exon 20 insertions now, wasn’t the case when this case started, mobocertinib and amivantamab. I don’t think we know what is the right order of these agents to give. Should you start with mobocertinib and then give amivantamab or vice versa? One is an antibody, amivantamab, and mobocertinib is a kinase inhibitor. So it’s unlikely that they have the same mechanisms of resistance just because they bind the receptor in very different parts. So it’s not too uncommon or too surprising that you would see a response after progression on mobocertinib, with amivantamab. And probably, the converse could also occur. But it’s an area where we don’t completely understand the resistance that well.

Now in terms of tolerability, mobocertinib tends to have more GI toxicity. And it sounded like it was the case with this patient as well. Amivantamab has skin toxicity from the EGFR part because it’s a wild type EGFR antibody, so it’s sort of like cetuximab or necitumumab. You get those kinds of toxicities. But then, the edema that comes from the MET portion of it that was mentioned in this case. And this is the most troubling side effect of all MET inhibitors, tepotinib, capmatinib, amivantamab, other MET inhibitors in clinical development. It’s clearly a class effect, but it’s not something that is completely understood as to the mechanism as to why that happens, meaning could you separate the swelling from inhibition of MET or not? And why does the swelling happen at all? So typically, we tend to end up managing them with diuretics, dose interruptions, dose reductions, those sorts of things. But they can be a nuisance. And in a fair number of patients, can be significant. It’s a significant quality of life issue if you’re gaining 30 pounds of fluid weight as was with this patient. So more to be done in that space.

DR LOVE: So actually, I guess, you said it’s an antibody. It’s actually a bispecific antibody. Tomorrow night when we talk about myeloma, that’s super exciting what’s going on in myeloma and lymphoma with bispecifics. Of course, there, it’s more of an immune basis.

DR JÄNNE: Yes.

DR LOVE: Here, you’re bringing in the MET. Any sort of pearls about managing the edema? He was using diuretics. Do diuretics help? What are some of the supportive care issues there?

DR JÄNNE: Diuretics, compression stockings sometimes help, dose interruptions or dose — drug holidays sometimes help. It’s easier with a TKI than a drug like amivantamab which probably is in circulation for a long period of time. But it remains a challenge. It remains a challenge to effectively manage this side effect. And hopefully, something that we as a community can get a better handle on and develop better ways of managing it.

Case: A woman in her mid 70s with adenocarcinoma of the lung and an EGFR exon 20 insertion mutation with new bone and brain metastases after therapy with osimertinib — Dr Niu

DR LOVE: So here’s his other case, a 74-year-old woman. But this one, the issue here was brain mets and CNS penetration, particularly as it relates to these drugs and others. Here’s Dr Niu again.

DR NIU: 18 months after completion of concurrent chemoradiation, she developed progression of disease with newly developed left pleural effusion, shown here, as well as some bone mets.

She was ineligible to be on the trial, and there’s no way I can get off-label use because neither agent was approved at that point. So I talked to her. She’s not really interested in chemotherapy. I said there’s a Phase II study using osimertinib, actually the double dose in a Phase II study. So I started her with osimertinib. She tolerated it very well. She actually had a partial response. Her pleural effusion disappeared, and then her bone lesion was stabilized for a while. Eventually I had to use SBRT.

Ten months later, clearly she had developed progressive disease. One, there’s a new solitary lesion in the brain. Second, she has developed more bone mets. So at that time, mobocertinib became available, so did amivantamab. She picked mobocertinib. She tolerated it very well. And she is highly educated on top of things. Bone lesion actually looks better. She doesn’t have pain anymore, indictive of clinical benefit.

So my question for the faculty is how much do we know about these 2 agents’ activity across blood-brain barrier? And how do we manage brain metastases in this setting?

DR LOVE: So any thoughts about this case? And what do we know about CNS activity of these 2 strategies?

DR JÄNNE: Yeah. The CNS activity of mobocertinib and amivantamab is actually quite poor. And it’s one of the issues of these next generation TKIs for exon 20 insertions as we’d like to find ones that have good systemic activity and also penetrate the brain. And that remains a challenge. And sometimes, the — there is data, as was used for this patient, about using double dose osimertinib that has some activity against exon 20 insertion of non-small cell lung cancer and it has the benefit that it is also CNS penetrant. So that sometimes is used in individuals who progress, let’s say, on mobocertinib with brain metastases, you can switch to double dose osi. In this particular individual with a solitary brain metastasis, that’s also potentially amenable to local therapy such as SBRT. And I’m glad she benefited from — it sounds like clinically benefited from switching systemically to mobocertinib. But there are newer agents, newer exon 20 inhibitors that are out there that are supposed to have CNS activity. And hopefully, we’ll see that in the clinic.

DR LOVE: So we’ll get into a little bit more on that in a second with some papers that you’ve done. And I want to go through a few of those in a second but first, another case from the chat room from Julie who has a patient with a rare EGFR mutation exon 19 insertion, K745-E746ins with extensive CNS mets and leptomeningeal disease. She says afatinib or osimertinib? Or something else, I guess.

DR JÄNNE: Yeah. So these exon 19 insertions are fairly rare mutations, but are definitely seen. And they occur kind of in the same location as the exon 19 deletion. And they are oncogenic EGFR mutations. They do, in general, respond to osimertinib. So I think, especially with CNS disease in this particular individual, that would be probably what I would lean to first. They respond to other EGFR TKIs, erlotinib, afatinib as well, but I think given the CNS disease I’d probably lean to that. And that are data out there showing that there are responses to osimertinib.

DR LOVE: Any update on what we know about the efficacy of osimertinib in people with leptomeningeal disease? A few years ago, there was some case series that were out there. I’m not sure I’ve seen anything more recently. But do you see good clinical responses in leptomeningeal disease?

DR JÄNNE: You do. And I think even at the 80 mg dose, but certainly at the 160 mg dose. I think what remains a challenge is what do you do for somebody who is on 80 mg of osimertinib and then develops leptomeningeal disease? Now there’s some data of doubling the dose there, but the clinical data that exists is — the efficacy is pretty modest in that situation. I think it’s partly because we don’t always understand is it a pharmacologic issue, meaning that the drug doesn’t get in there. Is that why you have progression in the leptomeninges? Or is it more of just like systemic progression, there’s a mechanism of resistance that you can’t target by just increasing the dose of osimertinib? So developing more CNS active drugs for EGFR mutant cancers and other oncogenic subtypes of lung cancer should remain a priority because it can be terribly symptomatic and lead to lots of really terrible side effects for our patients.

Journal Club with Dr Jänne — Part 2

DR LOVE: So we have a couple more cases we’ll get to in a minute, but I want to take a break from the cases and talk about some of the papers that you’ve done. This is another fantastic paper. I always try to figure out what the connection is between HER2 and EGFR. I’ve seen the diagrams. But this paper that you did on 30 years of HER3, I think, is another awesome paper. I really recommend people to check it out. Maybe you can talk a little bit about what HER3 is. I didn’t realize but apparently, HER3 doesn’t have a tyrosine kinase end, so to speak.

DR JÄNNE: It basically has an inactive or doesn’t really have an active kinase domain. But it’s found in — almost all EGFR mutant cancers express HER3. Many HER2-positive breast cancers also express HER3. It dimerizes with EGFR and with HER2 to activate downstream signaling pathways. Mostly, the PI3 kinase signaling pathway. So it has some biologic relevance to both those types of cancers. But, of course, because it’s present on EGFR mutant cancers, it could be used and leveraged for therapeutic purposes now because it doesn’t have a tyrosine — really an active kinase domain, you can’t really develop a TKI against it, so you have to develop an antibody or antibody drug conjugate or other ways of trying to inhibit that. And hopefully, that will then lead to a therapeutic benefit.

DR LOVE: It seems like — there’s an antibody drug conjugate we’re going to talk about in a second, patritumab, that targets HER3 that seems to have a pretty good response rate in patients progressing on osi. I’ll ask you about that. But getting back to this kind of diagram we’ve seen, for example, where does pertuzumab fit in? I know it’s a dimer blocker. But where do the HER2 drugs fit in there?

DR JÄNNE: Yeah. Pertuzumab kind of interrupts HER2 dimerization, so it can disrupt the HER2/HER3 dimerization. We don’t really have a good one. There are some that are being looked at in EGFR as well, but aren’t quite there yet. But there is, as you see in that diagram, a lot of activity still in developing novel antibodies against ErbB family members, EGFR, HER2, HER3. And obviously, they can be naked antibiotics like pertuzumab is a naked antibody. Or they can be conjugated to become antibody drug conjugates like patritumab deruxtecan. And the naked antibody of patritumab was tested and didn’t really do much by itself. It’s only when you use it — you’re using it really in a different way here. You’re using it to bring this antibody drug conjugate to HER3 and then using — internalizing that whole thing and then releasing the cytotoxic payload which is a type of chemotherapy specifically in the tumor cells. So sort of targeted — Trojan horse targeted delivery of chemotherapy to hopefully EGFR mutant cancer cells.

DR LOVE: And you see the patritumab up there in the very top left. It’s kind of like T-DXd to me. It’s like T-DXd for HER3. Is that kind of the way you look at it?

DR JÄNNE: Yes, absolutely.

DR LOVE: I don’t know if that’s too simple, but I’m a simple person. But I’m simple too in terms of seeing response rate. So this trial just presented at ASCO, Phase I study, again, Phase I, amazing, combining with osimertinib. Like 39% response rate. That sounds pretty good. How does that compare to —

DR JÄNNE: So —

DR LOVE: Go ahead.

DR JÄNNE: Yeah. So that trial is a Phase I. That’s a combination of osimertinib and patritumab.

DR LOVE: Right.

DR JÄNNE: The 39% response rate is this one, is the single agent.

DR LOVE: Right, right.

DR JÄNNE: And here, the nice thing about the efficacy is that since most EGFR mutant cancers express HER3, it doesn’t matter what the osimertinib resistance mechanism is. You’re really just using the presence of HER3 to deliver this antibody drug conjugate and the chemotherapy to the tumor cells. So it can be potentially an agnostic — a resistance mechanism agnostic type of approach, and has a certain simplicity associated with that delivering the therapy. And the clinical development is ongoing as a single agent and in combination with osimertinib as well. And hopefully, will be a therapeutic option for patients who progress on osimertinib where you don’t find a resistance mechanism or even if you find a resistance mechanism and you use a targeted combo approach. So it has potential for several different uses in the future. Hopefully, will be part of the armamentarium.

DR LOVE: It kind of looks like the toxicity looks like maybe a lighter form of T-DXd although I don’t know, maybe with more patients, it’ll end up being light. But some chemo side effects. I don’t know if they see alopecia, GI. But also, a little ILD. I don’t think they had any fatal cases. Is that your take, sort of T-DXd-like?

DR JÄNNE: Yeah. There are some chemotherapy toxicities. And the conjugate is the same for the HER2 and the HER3.

DR LOVE: Right. That makes sense.

DR JÄNNE: So you’d anticipate then that perhaps you’d have similar toxicity. So some nausea, some hematologic toxicities, some ILD as well. So similar spectrum of toxicities.

DR LOVE: So as we were talking about before in the patient who responds to osimertinib then has disease progression, I’m not sure if you stated what your usual chemo is, I guess, without an IO. But what is it? And indirectly, how does it compare to patritumab? Would you like — if patritumab were available, would you use it right now rather than chemo in that situation?

DR JÄNNE: Yeah. Typically, carboplatin and pemetrexed. Patritumab would be an option, for sure. I think in some people, we would probably, you know, it is a more targeted approach. And so perhaps, there are certainly individuals who would want that and there’s certainly individuals we’d want that for. There is an ongoing trial that will compare patritumab to chemotherapy after progression of frontline osimertinib to ask that specific question that you just asked. Is there a difference? And in whom would you potentially use patritumab? Meaning that we know that there’s variation in the level of HER3 expression. So far, we haven’t seen that it necessarily correlates with clinical activity although denominator on the number of patients treated so far isn’t huge. And so maybe with larger datasets, we’ll see that if you have high HER3, you benefit rather from patritumab as opposed to chemotherapy and vice versa. So I think those are the important questions moving forward. Which of these therapies would you choose for a patient? And hopefully, the trial will help answer that.

DR LOVE: Really interesting. The chat room is blowing up with all kinds of weird mutations I’ve never heard of. We’ll see if we can get to some of those. Every time I ask you, I’m wondering are you going to know the answer to this? And so far, so good. But there’s a couple in there I certainly haven’t heard of. Anything else you want to say about amivantamab? We put some of the key papers in there. Anything you want to say about the mechanism? We talked about the fact that it’s a bispecific. Anything else you want to say? Any new strategies attempting to address these patients biologically?

DR JÄNNE: Yeah. So there is data on using amivantamab by itself or with lazertinib post-osimertinib. And it can see some activity, especially in patients who have EGFR mediated resistance mechanisms, so a new EGFR mutation, C7I7S or MET amplification since it’s an EGFR/MET antibody. And that development is ongoing. There’s also a frontline trial of amivantamab and lazertinib compared to osimertinib as a frontline treatment approach to see if it would be better. And, again, we’ll wait and see what that data shows. So definitely a lot of activity in that — using amivantamab in the EGFR mutant patients.

DR LOVE: Yeah, we saw the investigators really reacting to this presentation from the ASCO meeting of amivantamab and lazertinib in patients progressing, the CHRYSALIS-2 study. We started to ask people after that, do you want to use this combination in this situation? People were saying yes. Here’s the waterfall plot. Was this enough to get you to want to use this?

DR JÄNNE: I think it’s definitely an option. I think that’s a nice level of activity that you see there. And it certainly would be an option if available. Or hopefully, when available.

DR LOVE: So we talked a little bit about the safety. You can check out the papers and read more. Mobocertinib, also there’s an update that you presented at the ASCO meeting. We’ve seen other papers on mobocertinib. Anything you want to add to what you’ve already said about this? I know there’s another agent, I’m not sure how to pronounce it but it sounds a lot like mobocertinib, that you’ve been doing some work on.

DR JÄNNE: Yeah.

DR LOVE: Where’s all that heading?

DR JÄNNE: Yeah, this is an agent called sunvozertinib. And it is another exon 20 EGFR inhibitor. Has clinical activity comparable if not a little bit better than mobocertinib and amivantamab although it’s a little bit too early to know about progression free survival, but just in terms of response rate. It has less of GI toxicities than mobocertinib has, a little bit more perhaps skin toxicity. But clinical development is ongoing. It also has FDA breakthrough designation. So hopefully, it’ll be available at some juncture for us to use. And how do we sequence all of these different exon 20 inhibitors, I think, is the next set of questions that we need to ask.

DR LOVE: So I want to ask this question. We have another series on mutations in lung cancer outside of EGFR. I never know where to talk about T-DXd or even to talk about it when we do a seminar on chemo because it’s kind of a little bit of each. But I have to ask you about this because in our other series, when we asked this question to the investigators which is, where do you use or do you use T-DXd in people with HER2 mutant lung cancer? We had like half of them that said first line and the other half said second line. Just curious what your thoughts are about T-DXd, both in mutant and overexpressed lung cancer, where you see it fitting in now and in the future.

DR JÄNNE: Well I think at the moment, it’s a second line drug based on the activity and the PFS. And that’s where we typically use it clinically as well. Now there is an ongoing trial comparing frontline T-DXd to chemotherapy. And, of course, we’ll wait and see what that result shows. And there are 2 different doses, the 6.4 and the 5.4. The 5.4 has a similar degree of activity, but less toxicity than the 6.4. So that’s probably the dose to use moving forward. Now it has been tested in HER2 IHC-positive lung cancer. And there, the response rates are sort of 20, 25% with a shorter PFS. So that doesn’t mean that there isn’t any activity, but there is not that much activity there in the IHC-positive patients. And it’s probably because the mutant cancers are more dependent on HER2 mutation. And so when you inhibit it, you get a greater chance of a clinical response. And also, there’s some information to suggest that the mutant receptor internalizes faster than the wild type. And so when you’re binding the drug, you may be just bringing in more drug when you have a mutant receptor because it’s internalizing faster than the wild type. So that may be one of the other reasons as well. But certainly an exciting development and we’ll see if it makes it in the first line space.

Case: A woman in her mid 80s with metastatic adenocarcinoma of the lung with an EGFR exon 21 mutation who switched to erlotinib due to osimertinib-related toxicities, now with recurrence at the primary site (PD-L1 10%) — John Yang, MD

DR LOVE: So let’s finish out with a few quick cases. We have our first case from Dr Yang. Usually, the first line metastatic osimertinib cases start out, the patient did great, had a response and then progressed in a year, year and a half. But this patient did not do too well on osimertinib. She’s 84 years old, a little bit frail. Here’s Dr Yang.

DR YANG: When we started her on osimertinib the lesions on her scans quickly resolved, but she had severe fatigue, severe nausea, and anorexia. I held the drug; she felt better. I then resumed the drug at 40 mg daily. She continued to have fatigue, nausea, and anorexia, but to a lesser extent. She was hospitalized because of shortness of breath. She had a CT scan suggesting pneumonitis without disease progression. I stopped the drug, and the respiratory symptoms improved, and on subsequent imaging the pneumonitis also improved. Earlier this year I started her on erlotinib 100 mg daily. She tolerated the drug much better; mild fatigue, mild nausea. She had a CT scan and she had a new tumor. Actually, at the same site as where her primary tumor was. She had no other sites of disease.

Now in this setting what is the role of radiation to the solitary area of disease progression followed by continuation of the targeted therapy? How would one potentially incorporate immunotherapy in the sequencing of her treatment?

DR LOVE: And I appreciate so much these docs bringing these cases that they really don’t know what to do with. It sounds kind of scary to try erlotinib after somebody had osimertinib pneumonitis. But any thoughts about the case?

DR JÄNNE: Yeah. So they’re structurally divergent drugs. So we’ve definitely seen that same issue that someone can’t tolerate osimertinib for whatever reason or have toxicities and have been switched to erlotinib or even gefitinib and have been able to be on therapy for a long period of time. So I think that that is an option. Depending on the specific toxicity, sometimes the 40 mg dose doesn’t alleviate it like in this case necessitating a drug switch.

In terms of what to do, I tend to, for localized progression of a solitary lesion, I tend to use local therapy such as SBRT followed by then resumption of a TKI, and in this case, erlotinib. So I would certainly favor that if feasible in this situation. I think the challenge for this particular patient will be that erlotinib resistance will likely be EGFR T790M which is where you would normally use osimertinib and she can’t get it and then it’ll be a challenge of what to do at that situation. Maybe some of the new generation drugs would be effective here or maybe chemotherapy. But hopefully, that’s a long time away.

Case: An Asian man in his early 70s with metastatic adenocarcinoma of the lung with an EGFR exon 19 deletion and brain metastases who receives SBRT and osimertinib but develops extracranial biopsy-proven small cell lung cancer progression — Dr Niu

DR LOVE: All right. Let me just see if I can squeeze one more case in because I love this case. Dr Niu is amazing to ask about cases. He actually presented 2 NRG cases to me that we presented in another conference. So incredible what you see in the real world. Anyhow. I love this case too. 70-year-old patient with metastatic adeno of the lung, exon 19 and brain mets. Gets SBRT and osimertinib, but then has systemic and brain progression. He biopsied it and finds there’s small cell transformation. EGFR still there. Here’s Dr Niu.

DR NIU: Metastatic lung adenocarcinoma with multiple brain mets. He’s an engineer. He had some cognitive dysfunction. That triggered the whole thing.

The left-hand panel shows basically baseline. The lower panel shows the left lower lobe lesion with metastases. MRI brain showed multiple brain metastases. So the middle panel, MRI brain showed excellent response to osimertinib, and the same thing happens in his lung. And in January this year, which is right upper-hand panel, which showed a solitary lesion. At that time I thought he had just oligometastasis so he had SBRT. And then, in April, that’s when we did the scan, it also showed regrowth of the left lower lobe lesion. That one was biopsied. It showed small cell lung cancer, and actually EGFR exon 19 deletion is still present.

Start him on small cell lung cancer treatment. Clinically, he responded.

So my question for the investigator in this case is what is the evidence to continue to use osimertinib in this setting? Do we have a role or any study to suggest addition of immunotherapy in this setting, like we would treat de novo small cell lung cancer?

DR LOVE: Any thoughts?

DR JÄNNE: So I think in this situation where the person has had prior CNS disease, my preference and my practice pattern is to add chemotherapy to osimertinib and treat the small cell and then hopefully, also treat the CNS or continue to treat the CNS with osimertinib. There is an ongoing trial, not in small cell, but in non-small cell. Someone who progresses on osimertinib, does not have CNS disease, but progresses systemically on osimertinib randomizing them to chemotherapy versus chemotherapy/osimertinib asking exactly this question, what is the benefit of continuing osimertinib? And maybe we’ll see that in the CNS over a long period of time in terms of CNS recurrence and things like that. But I think if someone has had CNS disease, I tend to keep them on osimertinib when I start the chemotherapy.

DR LOVE: So thank you so much for working with us today. It was so informative. I learned a lot. It was really wild to look at these questions come in the chat room. We talked about a bunch of them. Audience, thank you for attending. Thank you, Dr Pasi Jänne, very much for working with us today. Come on back tomorrow. We’ll see what Dr Lonial says about bispecifics and everything else going on in myeloma. I have a feeling that bispecifics may be coming to practice soon in myeloma. Maybe lymphoma too. Be safe, stay well and have a great night. Thanks.

DR JÄNNE: Thank you so much. Thank you for having me.

DR LOVE: Thank you so much, Pasi.