This transcript has been edited for clarity.
Jacob Sands, MD: Hello. I'm Dr Jacob Sands, thoracic medical oncologist at Dana-Farber Cancer Institute. Welcome to Medscape's InDiscussion Series on Lung Cancer. Today, we'll be discussing biomarkers and targeted therapies for lung cancer. First, let me introduce my guest, Dr Pasi Jänne, director of the Lowe Center for Thoracic Oncology at the Dana-Farber Cancer Institute and professor of medicine at Harvard Medical School. Welcome to InDiscussion.
Pasi Jänne, MD, PhD: Thank you. It's a pleasure to be here, Jacob.
Sands: Now before we get started, I have a question about your journey. How did you end up focusing on lung cancer and on your path to your current position?
Jänne: I trained at the Dana-Farber and was a medical oncology fellow there. During that first year of training where you rotate through all sorts of specific diseases and disease centers, I really got interested in studying lung cancer. I thought it was a disease that was interesting, both from a medical standpoint because it was a very multidisciplinary disease, but also as a disease that unfortunately continues to be the number one cause of cancer death for both men and women in the United States, and was back then as well, and unfortunately one where therapies had not advanced as much as they had, for example, in hematologic malignancies. I thought that there would be potentially an opportunity to do something in this disease. That was another reason I ended up deciding to pursue a path in lung cancer. And then finally, I would say, I found a mentor, Bruce Johnson, who continues to be my mentor today. And that was another big factor in deciding to pursue a career in thoracic malignancies.
Sands: It's a great starting point to highlight the fact that lung cancer has been so deadly because we're going to talk about what incredible advances have happened over the last 10 years. And, of course, you've had a huge impact on both biomarker testing as well as targeted therapies. If we go back to IPASS, which is now about 11 years ago, has it been surprising to you, to now reflect back over the last 10 years and see so many different targets that have been identified with FDA-approved treatments for each of these? Or is this what you envisioned at the time of that early EGFR [epidermal growth factor receptor] work?
Jänne: I don't think we envisioned that we'd find so many other targetable subsets of lung cancer. It's, of course, wonderful to see that we as a group have found that and, of course, the impact that's having for patients with lung cancer. You know, for a lot of the principles of targeted therapy, we still revert back to EGFR-mutant lung cancer because it was the first one around and it's been studied probably the longest, and we've learned a lot from it that has helped, I think, in the development of some of these other subsets of lung cancer with targeted therapies.
Sands: Before we get into testing and treatment, let's start with the basics. What is it that makes a genomic alteration potentially targetable even before drugs are developed? What type of alteration would make something even worthy of looking for or developing drugs to target what makes it targetable?
Jänne: I think in the case of all of the subsets that we have in non-small cell lung cancer and other cancers, these are genetic alterations that turn on proteins in a constitutive fashion. So, for example, EGFR mutations force EGFR to be continuously on, and it's that “continuously on” process that converts a normal cell into a cancer cell. Normally this is a very tightly regulated process of on and off, but these mutations force them into being on all the time and it leads to cell growth because of, again, converting a normal cell into a tumor cell. And because it's so critical in that process, it's really the engine, essentially. It's so big and so critical, it also makes it a good potential therapeutic target if you can develop a therapy against that.
Sands: We're going to jump now into the various testing options. There are different technologies for testing. And I know there's been increasing discussion about next-generation sequencing (NGS) and a push for NGS and we can get to that. But before we do, what are the different ways of testing this from PCR, with NGS, I suppose, being the most common.
Jänne: At the moment when somebody is diagnosed with non-small cell lung cancer, we'd like to test them for all possibilities of targeted therapies. There are seven or so approved different agents for specific targetable alterations at the moment. And you can test them individually: you can test an EGFR mutation and if you don't find that, then you can test for a KRAS mutation or an ALK rearrangement, etc. You can do sequential testing, which I think still happens in some places and used to be more popular, but it takes time and often depletes very valuable tissue resources. Or you can do a more comprehensive single test, which is what next-generation sequencing is; NGS tests comprehensively at the same time for all of these particular alterations. We typically do this from an actual tumor biopsy but, of course, there's technology to do it from circulating tumor DNA as well. These two are often used in a complementary fashion. For me, the standard of care is broad-based testing to look for one of the potential targetable alterations, because we know from the clinical studies that if you find a targetable alteration, getting a targeted therapy as your treatment is the right choice.
Sands: Yes. And I do still see centers, I'm sure you do too, particularly referred in where they've had a handful of tests done and those are often PCR-based tests, which is one-off, as you mentioned. These tend to have historically been done in part due to lower cost and quicker turnaround on the results. But as you point out, NGS testing, the more broad-based testing, really allows you, one, to use less tissue to get all of it and, two, [to find] something that we don't yet know to test but down the line becomes something that's actionable. I have a patient who had a RET fusion that was seen on initial NGS testing. This was before actually having any RET inhibitors available. She'd been through a handful of lines of therapy and was really at the point where we didn't have much more to offer her and we had actually had a discussion with her about hospice. A week later, I found out that we were opening the phase 1 trial of LOXO-292, which ended up being selpercatinib. So, I called her and said, “Hey, we do have a trial that's opening and you qualify.” And the only reason I even had that was due to the NGS testing that had been previously done when we didn't know to test for RET because it wasn't yet something. She was one of the first people on the trial and really did very well on it. And that is now an FDA-approved treatment. So, this is more a statement to the listeners: that even though we have a list of specific alterations — and sometimes I hear people say, “well, they want to just limit the testing to what has approvals” — actually having more broad testing can lead to future options as well.
Jänne: Absolutely. And we can direct individuals to new and novel clinical trials, not just the RET example that you mentioned, but others as well. I do think that there is value in that comprehensive testing. Similarly, I think we will learn that even though we find an actionable genetic alteration — let's say an EGFR mutation — we will continue to learn what the other genetic alterations mean in that NGS report, meaning that there are going to be instances where the other alterations somehow dictate how long someone will benefit from an EGFR inhibitor or they will dictate whether somebody needs an upfront combination strategy vs a single agent. I think there will continue to be value in doing the comprehensive testing not only for identifying new potential therapeutic options, but also [learning] how the genetic alterations may modulate existing therapeutic options.
Sands: Well, that's a perfect transition to now discussing treatment, and there are multiple alterations to discuss. Let's start with the first one being EGFR mutations and that's kind of understood to be sensitizing mutations, but of course, there are some differences. Maybe you can just highlight that when we speak of EGFR mutations, we're talking about targeted therapy for EGFR, and then go into the sensitizing mutations and the multiple drugs that have been developed to this point.
Jänne: One way to think about EGFR mutations is that there basically are three categories of EGFR mutations. There are the most common ones, which are the exon 19 deletion and the L858R mutation, which account for about 85% of EGFR mutations. And this is where we have the vast majority of drugs approved, including osimertinib, which is the standard of care in this situation. Then we have what are sometimes referred to as atypical EGFR mutations. These are mutations in exon 18, like G719X or L861Q, and this is where afatinib has specific regulatory approval. Then there are the exon 20 insertions, which have been to date the most difficult ones to treat, and these account for about 5%- 10% of EGFR mutations. There are two drugs that are specifically approved, amivantamab and mobocertinib, for exon 20 insertions and many others in clinical development. But it's been a tougher subset to treat compared to the more common ones.
Sands: You have, of course, been involved in the development of osimertinib and have spoken at ASCO [American Society of Clinical Oncology] and led some of those publications. I know that's what most in the US tend to use, but there is an array of different options. Can you just go through those?
Jänne: Sure. So, there's osimertinib, there's afatinib, dacomitinib, gefitinib, erlotinib, erlotinib/ramucirumab combination. Osimertinib, as I mentioned, is the standard of care out of all of those for a couple of reasons. One is that in the FLAURA trial, osimertinib was compared to standard of care, EGFR TKIs [tyrosine kinase inhibitors], which were really gefitinib and erlotinib, depending a little bit on which part of the world the trial was being conducted in, and it showed an improvement not only in progression-free survival, but overall survival in that situation. Second, many of our patients unfortunately suffer from brain metastases, and osimertinib is a drug that can effectively cross the blood-brain barrier and pharmacologically treat brain metastases. If you look at the FLAURA trial, where it was compared to the standard of care, EGFR TKIs, there was a lower incidence of developing brain metastases in patients who started on osimertinib compared to standard-of-care EGFR TKIs. I will say it's now also approved in the adjuvant setting once you have effective surgery and/or standard of care afterward, which is chemotherapy. For patients who have EGFR-mutant non-small cell lung cancer, osimertinib had shown an improvement in disease-free survival compared to placebo in the adjuvant setting. So, it's got a couple of different approvals. And as you mentioned, in the US, most patients with the common EGFR mutations today start with osimertinib. Now, having said that, unfortunately, people with advanced EGFR-mutant non-small cell lung cancer are not being cured with osimertinib, so there is an opportunity to build on that success. And there are many clinical trials trying to add a second agent or add chemotherapy to osimertinib. Many of those trials are being conducted at the current time or have completed enrollment. But so far, very limited data exist on anything in terms of efficacy and, for the moment, single-agent osimertinib remains the standard of care.
Sands: At the time of progression, of course, we end up doing genomic testing at that point. Can you go into one, the reason for that genomic testing and two, some of your experiences around how that has impacted treatment?
Jänne: Sure. Well, the reason to do genomic testing at the time of progression on osimertinib is that many of the mechanisms of resistance to osimertinib are also genomic, meaning that there can be a second alteration that could also be targeted. For example, a common one is something called MET amplification, where there are more copies of the normal MET gene, and they can circumvent the need for EGFR inhibition. And if we find that at the time of progression on osimertinib, there are clinical studies showing that adding a MET inhibitor to osimertinib can resensitize that person's cancer to that combination. It's [about] finding things that you can target at the time of osimertinib resistance. I think the bigger challenge that remains is what do you do if you do all that testing and you don't find anything that you can target — what's the right thing to do at that point? Often we revert to chemotherapy at that point, but I think we're looking for the optimal therapeutic approach in that situation. The real reason to do the testing is to find things that you can target, and you can do the testing from a repeat tumor biopsy or blood testing. Repeat tumor biopsy is useful because sometimes these cancers, which are always starting out as adenocarcinomas, can transform into other subtypes of lung cancer, like small cell lung cancer or squamous cell lung cancer. And that dictates specific chemotherapeutic treatments if you find that in the tumor biopsy.
Sands: And often the discussion I have with patients is to say that as long as they're not having a lot of symptoms there's not a rush, to help allay some of the anxiety around wanting to get started immediately. I'll say that we really want to get them on the best therapy, not the first therapy. But if their symptoms start getting worse or if there's some reason we need to get going, we can get them on the first therapy, that being chemotherapy. The point I often make is that if we don't have genomic testing [results] back, then we're doing just the chemotherapy and holding off on immunotherapy until we have full genomic testing and no targeted therapy options. Is that your practice? And do you have reservations about putting people on immunotherapy without yet having the genomics back? What is your thought process around that?
Jänne: Yes. I think many times, there is time to wait to get the genomic testing back, for the reasons you mentioned: to find the best therapy for that individual, not the first therapy. Obviously, there is sometimes a need to begin treatment sooner than the sequencing results are back, which can take a few weeks, and sometimes that time is too long. In terms of the question of immunotherapy, one of the challenges is that the half-life of many of our immunotherapeutic agents is quite long, meaning that even when you're ready for the next treatment, if you measure them in the blood, you potentially still find anti-PD-1 [anti-programmed cell death-1] or PD-L1 [anti-programmed death-ligand 1] antibodies or the drugs there. What we know from the targeted therapy field is that combining targeted therapies — for example, EGFR inhibitors or ALK inhibitors — with immunotherapy has led to a lot of toxicity without a lot of potential benefit. I worry a little bit about starting somebody on chemotherapy and immunotherapy, and then by the time they're ready for their next treatment, you happen to find that they have an EGFR mutation, for example. You want to put them on osimertinib. I worry about that potential interaction with the immunotherapy from the prior treatment. So, I often start them on chemotherapy like you do and then we can always add the immunotherapy later if we don't have a targetable alteration. But I tend not to start with that, especially in someone who I suspect may have a targetable alteration; for example, someone who does not have a background of cigarette smoking or only very limited smoking, where there's a greater than average likelihood of finding a targetable alteration.
Sands: If there are a handful of things to take away from this, this is in there: to not start immunotherapy until you have the genomic testing results, due to the risk of pneumonitis, especially as you've described. To that point then, at the time of progression on osimertinib, if there's not an actionable alteration and you're now going to chemotherapy, what are your thoughts around immunotherapy at that time? And there are different data on this. I don't think there's tons of data in this setting. Some trials have involved EGFR, although I haven't seen the degree to which that's actually sensitizing mutations vs others. But what are your thoughts in that setting? That seems like a setting with a lot less data to go on?
Jänne: I would say the data are pretty clear that our current immune checkpoint inhibitors do not work very well in EGFR-mutant cancers, even if they have a high level of PD-L1 expression; the efficacy tends to be shorter … much more short lived. I think that if someone progresses on osimertinib and you're deciding on chemotherapy, one decision point, which is often a discussion with the patient, is do you continue the osimertinib with the chemotherapy or do you stop the osimertinib with the chemotherapy? There isn't a right or wrong answer here. There is an ongoing trial that's trying to evaluate that approach. If someone has had prior CNS disease and has responded to osimertinib, I think most of us have the tendency to want to continue osimertinib with chemotherapy because we know that chemotherapy doesn't necessarily cross the blood-brain barrier as well as osimertinib does. Also, resistance isn't completely black and white. It's not that everything becomes resistant simultaneously. There may be part of the cancer that's still being kept under control with osimertinib, and taking that off could lead to a flare reaction, where there could be more growth of that disease. It's a little bit of a data-free zone but certainly a discussion with the patient as to what to do at that time. And if you continue osimertinib, then absolutely no immunotherapy because of the potential interaction, as you mentioned. Mostly pneumonitis is the main concern there with osimertinib and, as you know, with other inhibitors, it's liver toxicity, etc., but there is definitely more toxicity if you use a TKI and immunotherapy together.
Sands: EGFR exon 20 insertions have been a real challenge and recently there's been quite a bit of progress in that. As you mentioned earlier, we have two FDA-approved drugs in this setting. There were some data presented at ASCO about another regimen. What is your current practice for EGFR exon 20? What are your thoughts between the two FDA-approved regimens? And then as a follow-up, the recently reported data?
Jänne: The currently approved agents, amivantamab and mobocertinib, are really second-line agents at this point. They don't have quite the degree of efficacy as osimertinib, for example, in the common EGFR mutations, and they really should be used as second-line agents after first-line chemotherapy. I don't think there's a right or wrong answer as to which agent you start with first. You start with amivantamab and then mobocertinib or vice versa. One's an antibody and the other is a small molecule inhibitor. They work by completely different mechanisms. We know very little about if you become resistant to one, whether you can still respond to the other. And we also know very little about the mechanisms of resistance to these two different agents. It's something that we'll hopefully learn about over the next several months to years and how to best sequence these if they're both being used in the second-line setting. There have been a number of agents that have continued to be studied in this space, and there were some data on a few of these at ASCO and they continue to look promising. One of the challenges with the exon 20 insertion agents is toxicity, and they typically have sort of wild-type EGFR toxicity, rash or GI toxicity. Trying to find the osimertinib equivalent for exon 20 insertions remains the Holy Grail. To find something that has a response rate of 60% or 70% with minimal toxicity would be fantastic. I'm not sure that we're there yet, but there's a lot of ongoing effort in that space.
Sands: Well, we've covered a lot today around testing and specifically around EGFR treatment options. Just to quickly go through that as a summary, we discussed different ways of doing genomic testing for actionable alterations, which you defined as essentially the alterations that end up being oncogenic drivers; therefore, shutting them off can then have impacts in treatment. We discussed PCR testing as a quick and less expensive way of doing testing vs NGS, which is a more broad-based testing, and you really highlighted the value of having that broad list of genomic alterations that can guide treatment across all of them, as well as ones that lead to clinical trial enrollment or ones that later on become relevant within trials and are not even necessarily known at the time [of testing]. We also discussed the importance of getting back the genomic testing results before starting any immunotherapy, generally before starting treatment, I'd say. But if you really need to start with treatment immediately, then give just the chemotherapy to reduce the possibility of risks from initiating targeted therapy. Osimertinib and checkpoint inhibitors was the specific combination we discussed that can cause pneumonitis. We also discussed that at progression, it's important to do genomic testing again because this is how we find other actionable alterations that can sometimes be next-line options. But if there aren't any, then chemotherapy without immunotherapy or chemotherapy even with osimertinib, although, Dr Jänne, you highlighted the fact that there's not a ton of data on this, and we discussed some ways of thinking about that next-line treatment. We also discussed exon 20, which has been a real challenge, although recently now has some FDA-approved therapies. There are two FDA-approved therapies, both of which are certainly usable, and there's more research to do. And we didn't go into all of the other actionable alterations, but there are a lot and this is essentially one aspect of a much bigger topic. This has been an exciting decade within oncology, with tremendous progress on treating lung cancer. And with that, I would like to thank our listeners for joining us. This is Dr Jacob Sands for InDiscussion.
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Cite this: Biomarkers and Targeted Therapies for Lung Cancer - Medscape - Aug 11, 2022.