20 years of EGFR research: Ramalingam, Carbone, Politi, Jänne, Govindan reflect

Two decades ago, the discovery of the EGFR mutation transformed lung cancer treatment. The finding led to dramatically improved survival rates and ushered in the era of precision medicine and molecular profiling for lung cancer. 

In a special episode of the new Cancer Letter Podcast, Suresh S. Ramalingam, a lung cancer expert, executive director of Winship Cancer Institute of Emory University, and editor-in-chief of the journal Cancer, moderates a panel of people who played a role in the discovery of the EGFR mutation in lung cancer.

David P. Carbone, of Ohio State University Comprehensive Cancer Center, Katerina Politi, of Yale University, Pasi A. Jänne, of Dana-Farber Cancer Institute, and Ramaswamy Govindan, of Washington University in St. Louis participated in the panel discussion.

During the conversation, the panel members reflected on how lung cancer treatment has changed  from primarily symptom management and palliative treatment to achieving long-term survival since they began their careers.

“I think I’ve been seeing lung cancer [patients] for almost 40 years right now, and in that time, I would say most patients weren’t even treated with therapeutic intent,” Carbone, director of the James Thoracic Center at the Ohio State University Comprehensive Cancer Center, said at the panel discussion. “They had symptom management with palliative radiation and morphine and some of the chemotherapies were even of questionable importance. And we did a randomized trial of chemotherapy versus nothing in first-line lung cancer many years ago and showed a few-week improvement in survival. 

“So, I think the difference between then and now is really remarkable in every way.” 

At that time, Govindan and his colleagues had to argue that it was worthwhile to try to treat lung cancer patients at all. 

“[In] the first few slides in any lung cancer talk would be those slides arguing that it is worth doing something for these patients [rather] than not doing anything at all,” said Govindan, the Anheuser Busch Endowed Chair in Medical Oncology, professor of medicine in the Division of Oncology, and director of the Section of Medical Oncology at Washington University School of Medicine. “And I remember in the early days of designing these trials, I was skeptical. And so were many of our senior colleagues, then—that a pill could help these aggressive cancers.”

Lung cancer treatment was so dismal that Ramalingam’s mentors discouraged him from entering the field. 

“When we all entered—and this would be the same for Pasi, myself, and Katie as well—there were very few treatment options, and our mentors would say, ‘Why do you want to go into lung cancer? There is very little for you guys to do,’” Ramalingam said. 

The discovery of the EGFR mutation changed all that. 

“I think another thing that has happened since the discovery is that many, many more people have been interested in working on lung cancer and studying the disease,” Politi, who is the Joseph A. and Lucille K. Madri Professor of Pathology, scientific director of the Center for Thoracic Cancers, and co-leader of the Cancer Signaling Networks at Yale Cancer Center, said.

“And that has been both in the labs and in the clinic, and I think that has been really important for accelerating the research and has made a difference in how we’ve been able to develop new approaches for treatment and the things that we’ve learned about lung cancer. So, I think that discovery made a big difference there.”

Despite the runaway success of EGFR inhibitors and the introduction of targeted therapy into the management of lung cancer, challenges persist. Researchers are now focused on overcoming drug resistance, refining early detection strategies, and improving access to EGFR mutation and other biomarker testing.

And I remember in the early days of designing these trials, I was skeptical. And so were many of our senior colleagues, then—that a pill could help these aggressive cancers.

Ramaswamy Govindan

Patients can face widely varying outcomes even with the same EGFR mutations, with some experiencing years of disease control while others develop resistance or see limited benefits within a year. These differences in outcomes are due to factors such as co-mutations, the specific type of EGFR mutation, and other biological variations between patients. For example, mutations like L858R, exon 19 deletions and exon 20 insertions all respond differently to treatment. 

“We have a long way to go, but I do see signs,” Govindan said. “I also think the industry has become more energetic in coming up with newer agents, newer targets and keep producing better and better generations of these agents.”

Most patients now receive testing for EGFR mutations and other common genetic changes. However, reflex testing is still lacking, unlike in others cancer types such as breast cancer where it’s routine.

“I think that the importance of finding these mutations really outweighs the urgency that people feel to get started on treatment,” Carbone said. “And more and more people are becoming convinced of that.”

Politi pointed out that mechanisms driving persistence can differ not only between patients but also depending on the site of metastasis. This heterogeneity makes it challenging to develop one-size-fits-all treatment strategies.

Why are EGFR-mutant lung cancers not fully eradicated at baseline despite all tumor cells carrying the mutation? Researchers now focus on drug-tolerant persister cells, which survive initial EGFR inhibition and later drive acquired resistance, the panelists said. 

Studies suggest that these persister cells exhibit unique survival mechanisms, prompting clinical trials that co-target EGFR and pathways like beta-catenin. Researchers are aiming to convert transient responses into durable remissions or potential cures by addressing these resistance pathways early.

I think that the importance of finding these mutations really outweighs the urgency that people feel to get started on treatment. And more and more people are becoming convinced of that.

David P. Carbone

This focus on early intervention is closely tied to efforts to identify patients at higher risk of relapse, Politi said. Understanding which patients might benefit from combination therapies—despite potential toxicity—requires a deeper exploration of both genetic and non-genetic resistance mechanisms. 

Studies show that tumors undergo rapid transcriptional reprogramming and activate alternative survival pathways within days of starting TKI therapy. 

“Are there ways in which we can identify patients who we think are going to have relapses early on in the course of treatment, so that if there are combinations of agents, we can really identify the people who would benefit the most from them? Because there is likely going to be an increase in toxicity when we use these combinations,” Politi said. “So, can we find those patients?”

Researchers are also exploring several new approaches to improve treatment. Politi highlighted the importance of studying how pathway rewiring and epigenetic changes in tumor cells lead to resistance. 

Carbone mentioned bispecific T-cell engagers and cell surface proteins as potential targets to eliminate resistant cancer cells. 

Govindan emphasized the need to understand why some EGFR mutations don’t always lead to cancer and pointed to new therapies like protein degraders and PROTACs. 

“I think there’s hope and I think we’ve all learned from the successes in the last 20 years, and have focused on where currently we have a lack of effective therapies and when there’s a need to develop effective therapies. I think there’s interest both on the academic and on the industry side to develop new therapies,” Politi said. “So, I think the future remains hopeful for our patients with EGFR-mutant lung cancer.”

This panel is available exclusively on The Cancer Letter Podcast—on Spotify, Apple Podcasts, or YouTube. 

This episode was transcribed using AI transcription services. It has been reviewed by our editorial staff, but the transcript may be imperfect.

The following is a transcript of this episode of The Cancer Letter podcast:

Suresh Ramalingam: Hello, everyone. This is Suresh Ramalingam from Winship Cancer Institute of Emory University. This podcast and article is part of a series of articles by The Cancer Letter commemorating the 20th year anniversary of the discovery of EGFR mutations in lung cancer. I have an esteemed panel of colleagues today, Dr. David Carbone from Ohio State University, Dr. Katie Politi from Yale University, Dr. Pasi Jänne from the Dana-Farber Cancer Institute and Dr. Ramaswamy Govindan from Washington University, St. Louis Cancer Institute. David, I want to start this conversation with you. You’re a veteran in this field. You’ve been around in lung cancer for over definitely beyond the two decades we’re talking about. Talk to us a little bit about how it was to take care of patients 20-plus years ago before we had targeted therapy.

David Carbone: I think I’ve been seeing lung cancer [patients] for almost 40 years right now, and in that time, I would say most patients weren’t even treated with therapeutic intent. They had symptom management with palliative radiation and morphine and some of the chemotherapies were even of questionable importance. And we did a randomized trial of chemotherapy versus nothing in first-line lung cancer many years ago and showed a few week improvement in survival. So, I think the difference between then and now is really remarkable in every way.

Suresh Ramalingam: Thank you. Govindan, you also were coming into the field around the same time as systemic therapies were getting better. What are your perspectives on the status of lung cancer at that time?

Ramaswamy Govindan: I agree with David, Ram, and in fact, I remember that study and in my opening slides or [in] the first few slides in any lung cancer talk would be those slides arguing that it is worth doing something for these patients [rather] than not doing anything at all. And I remember in the early days of designing these trials, I was skeptical. And so were many of our senior colleagues then—that a pill could help these aggressive cancers. We are used to putting patients in the hospital. Mind you, these patients were not getting treatment at outpatient centers. They were in the hospital getting intravenous cisplatin and etoposide for a few days and “How can a pill change the whole thing?” and that was the thought. And I have to confess that I had that thought too before we saw any of the early results in the very first early days of IRESSA.

Suresh Ramalingam: And to me, to think that when we all entered—and this would be the same for Pasi, myself and Katie as well—there were very few treatment options and our mentors would say, “Why do you want to go into lung cancer? There is very little for you guys to do.” So, Katie, what inspired you to come into lung cancer?

Katie Politi: Yes, absolutely. I had just started my postdoctoral fellowship at the end of 2003, really at the beginning of 2004, and became interested in studying lung cancer because it was such an important clinical problem and there was an unmet need and was very fortunate to be working in the same bay as William Pao in Harold Varmus’s lab at Sloan Kettering right at the time of the discovery of EGFR mutations. 

So, I was actually planning to do some work in the context of oncogene dependence and understanding oncogene dependence because of our knowledge of KRAS mutations in lung cancer and how oncogenic KRAS alterations could lead lung cells to become dependent on it for its survival.

So, that really was the direction I was heading in and with the discovery of EGFR mutations in lung cancer pivoted to study EGFR mutations, but it is a similar problem; right? How does a cancer cell really become dependent on this oncogenic variant for its survival? I think that it is a fascinating question. And so, that’s how I entered the lung cancer field then.

Suresh Ramalingam: Fascinating. I think it’s fair to say that all of us would remember—at least those of us who were not in the thick and thin of the mutation discovery—where we were when we read the paper that came out in The New England Journal of Medicine and, Pasi, you were in the thick of it all. Talk to us about how this played out. How did the discovery of EGFR mutations come about?

Pasi Jänne: From our end, I was part of the group for the other publication that came out in Science at that time and ours came from three different angles. One was that we were seeing patients treated in the clinic with gefitinib at that time as part of the AstraZeneca Expanded Access Program. And because, as David mentioned, current therapies at that time were toxic and not so effective, there was great hope after the initial results from the gefitinib phase II trials came out that this oral agent would be effective. 

And so, as part of that expanded access trial, we treated something like 200 patients or some large number and saw that there were a number of individuals who had really dramatic responses.

At the same time, Matt Meyerson in our institution was leading one of the first generation efforts of kinase sequencing and they were sequencing cancers from both Caucasian and Asian patients and noted or discovered that there were EGFR genetic variants found in both Caucasian and Asian patients, but they were higher in frequency in the Asian patients. 

And finally, we were performing some laboratory-based analysis studying cell lines that were derived from patients that had the same clinical features as those that responded well to gefitinib in the clinic and noted that there was an outlier there and that outlier when sequenced had an EGFR mutation as well. And so, the common thread between those three observations was EGFR mutation and that’s how it ended up coming together from our side.

Suresh Ramalingam: And the rest is history as we all know it. David, you were also working on this and you had also come across this observation and I remember you talking about a presentation you had made. What’s your perspective? Tell me how you were approaching this problem.

David Carbone: Well, it’s the same as Pasi. We participated, and I was at Vanderbilt at the time, in the phase II studies and we had exactly two patients that had good responses. And I was very interested in doing this expanded access, but Dave Johnson at the time didn’t believe in expanded access programs and refused to let us do it. And in my lab, we actually did sequence one of those patients that had a great response and we found the exon-19 deletion mutation and I presented it at the SPORE meeting in 2003 and then [as an oral presentation] at AACR in 2004. The actual presentation was just weeks before the papers came out.

But we initially thought it was a resistance mutation because we had identified it in the autopsy sample of one of the patients. But then by the time we gave the presentation, we had found that it was present in the pretreatment sample as well and then the papers came out and it really was a turning point in the management of lung cancer in every way. And subsequently, multiple other driver genes with therapeutic potential have been discovered and really it’s made lung cancer treatment exciting.

Suresh Ramalingam: Indeed. Katie, what do you think is the impact of EGFR mutations on how personalized therapies have been applied to treat lung cancer?

Katie Politi: I think, as David was saying, that really this discovery has had such a profound impact on the treatment of lung cancer. I think one of the main things is really the idea that we need to profile tumors and with the profiling then can decide what is the best treatment approach for an individual patient. And I think now that’s the way we think about it. That’s the way we think about lung cancer. The first thing is to make sure that the person has molecular testing of their tumor and that is really a huge shift. I think that there are other things that have changed too since the discovery of EGFR mutations.

I think another thing that happened shortly after the discovery and something that we worked on a lot at Sloan Kettering when I was there, when I was a postdoc, was to work on repeat biopsies. So, the idea was that, if a tumor had an initial response but then resistance was observed, that you actually could get a biopsy if it was safe and then profile that and study that to understand the mechanisms of resistance to the drug. 

That is also something that has been transformative to the field and I’m sure we’ll talk about drug resistance later on in this conversation, but even just the possibility of doing that, of doing those procedures and the importance of doing them so that we can learn things.

I think another thing that has happened since the discovery is that many, many more people have been interested in working on lung cancer and studying the disease. And that has been both in the labs and in the clinic and I think that has been really important for accelerating the research and has made a difference in how we’ve been able to develop new approaches for treatment and the things that we’ve learned about lung cancer. So, I think that discovery made a big difference there.

Suresh Ramalingam: And what a big difference it has been. You mentioned molecular testing for lung cancer as part of routine care now, but we know that not everyone with lung cancer is getting molecular testing. I want to ask the panel as to what the barriers are for molecular testing in lung cancer even in the United States as of today. Maybe we’ll start with Dr. Govindan.

Ramaswamy Govindan: Ram, perhaps I’m wrong here, I do think that gap is narrowing. I rarely see patients with lung cancer who don’t have the EGFR mutation testing for these common alterations. Where I think we are not doing very well is the reflex testing and the reflex testing is not happening as it happens in breast cancer (and other cancers) [where] they do ER [estrogen receptor] testing, PR [progesterone receptor] testing. I think many institutions are struggling with that. And to me, you are right and we need to focus on ensuring on this important aspect that patients do have the tumor tested for molecular alterations. but it’s important to get them done expeditiously as a part of this routine reflex testing. 

Globally, we have a long way to go, but I do see signs. I’m optimistic about this. I see signs of progress in many of these countries. When I go to India, I see many vendors who are doing these testing, and when I get the reports or questions from Indian patients who are treated in India, I do have this comprehensive report often generated. I also think the industry has become more energetic in coming up with newer agents, newer targets and keep producing better and better generations of these agents, not just for EGFR or others.  

Suresh Ramalingam: Thank you. So, let’s talk about where we are in terms of treating patients with EGFR mutations in 2025. David, what are the big wins we’ve had in the treatment of EGFR-mutated lung cancer from your perspective?

David Carbone: Well, I think one of the wins is, as Katie said, focusing of scientists on the problem. And we have seen a real development in optimization of the drugs that we’ve used to target EGFR that have dramatically better brain penetration, and much longer progression-free survival. And so, I think, in terms of the science, there’s been a terrific benefit of this approach, but I also wanted to add as a barrier time and that is that many patients today are diagnosed with metastatic disease and they’re symptomatic and they and their doctors are reluctant to wait the several weeks that this testing usually or often especially in the community takes.

And so, as we get better technologically at detecting these things, I think that barrier will be overcome. And I think that the importance of finding these mutations really outweighs the urgency that people feel to get started on treatment and more and more people are becoming convinced of that.

Suresh Ramalingam: Thanks, David. Now as we take care of patients, Katie, you mentioned acquired resistance. This is a major problem. What do we know about acquired resistance, and I want to hear everyone chime in, and what is being done that you’re excited about to overcome acquired resistance in the research field?

Katie Politi: Perhaps I can start with talking about some of the things that we know about acquired resistance. So, I think some of the things that we’ve learned are that we can have resistance that is due to on-target alterations. These are alterations that are present in the target of the targeted therapy. So, for EGF receptor, that would be for example, mutations in the EGF receptor itself that can affect the efficacy of the targeted agent. We can also get activation of other signaling pathways that bypass the need for EGF receptor signaling and still allow the cancer cell to survive. Those are a couple of the main examples of mechanisms of resistance.

Then we can also have resistance that is due to changes in the histology of the tumor. So, you can go from a lung adenocarcinoma, the histology at baseline and then you can see other subtypes of lung cancer at the time of acquired resistance, like a change to small cell [histology]. So, that’s an example of this histologic transformation in which you lose dependence on that oncogene, that initial oncogene, and the tumor now doesn’t need it to survive. And that is probably one of the most challenging and mysterious mechanisms of resistance. So, those are some of the types of mechanisms. I think one of the things that we know is, with these newer targeted therapies that have been developed, some of the on-target mechanisms of resistance are less common than they were initially with some of the earlier generations of drugs.

[In the case of] EGF receptor, we saw a common resistance mechanism, T790M, come up with erlotinib and gefitinib, early generation drugs. Now when we look with osimertinib, the frequency with which we see on-target alterations is much lower. So, some of these harder-to-target, more challenging mechanisms of resistance to understand seem to be emerging more in the context of the newer drugs.

Suresh Ramalingam: Pasi, your thoughts?

Pasi Jänne: And just to echo on what Katie said and highlight the fact of where re-biopsies are important in that, in order to understand the specific mechanism of resistance, re-biopsying and resampling cancer that’s grown and despite EGFR inhibitor treatment is important as that may dictate what the therapeutic approach is next. If it’s small cell lung cancer, maybe small cell-directed chemotherapy. If there are other genetic alterations, maybe adding such as met amplification and maybe adding a met inhibitor to an EGFR inhibitor. And so, it’s important to continue to study the evolution of the cancer as that not only gives us insights into the biology, but has real therapeutic implications.

And some of the evolution can of course be studied from blood-based testing and sequencing of blood-based tumor-derived DNA, but for example, histologic transformation cannot. And so, tissue-based analysis are still probably better, but it can be supplemented with blood-based testing as well. And that same paradigm exists for the other targeted therapies. And one of the things that since we’ve studied EGFR preclinically and clinically as a community for the last 20 years, it’s also taught us a little bit about what to anticipate and expect for some of the other targeted therapies and how resistance can occur and how those tumors can involve also in the face of being treated with targeted therapies.

Suresh Ramalingam: Thanks, Pasi. One practical problem we all have seen in the clinic is, even with the same mutations, treatment outcomes vary widely. We all have [some] patients who go on for years and years without developing acquired resistance and then there are some patients at the other end of the spectrum who unfortunately don’t even benefit for a year. David, what do we know about why these differences occur in patients?

David Carbone: Well, we’re still learning about this and that’s one of the frustrating things about this type of therapy. We’re very excited about the progress we’ve made. We’ve turned four-month survivals into two or three-year survivals or more, but these patients always relapse. And as you said, there’s a big spectrum [in the duration of benefit]. We’re finding that co-mutations make a big difference in the duration of response in these patients, the type of EGFR mutation, L858R versus exon 19 versus some of the uncommon mutations, exon 20 insertions, they all have different prognoses. But the thing that’s frustrating for patients is they do so well with low toxicity for so long and then [their tumors] become resistant and we start talking about quite toxic second-line therapies.

So, I think we ought to start thinking differently about this disease and really preventing resistance as much as we can rather than trying to tackle the stochastic resistance mechanisms that happen after years of exposure. And so, one of the things that we’ve been studying is why we don’t eradicate the cancer 100% at baseline because every tumor cell has the mutation, but a subset of them become persistent and are not killed and they survive to become resistant. And we currently have a clinical trial co-targeting EGFR and beta-catenin, which we showed was one of the mechanisms of this persistence. And I’m really hopeful that we can transform these responses and these benefits that we’ve seen from transitory into cures in the future by understanding how tumors persist through this initial therapy.

Suresh Ramalingam: Katie, do you want to add to that? 

Katie Politi: Yes, absolutely. I completely agree with David that that’s a very important approach. I think one of the challenges when we think of drug-tolerant persisters is that, even there, there can be quite a lot of heterogeneity in the types of mechanisms that can allow the cells to persist. And some of the things that we are still learning are, “Is there heterogeneity when we think about individual cancers?” but then also in terms of, for example, sites of metastasis, right? So, there might be different mechanisms that are engaged and that allow cells to persist in sites of brain metastasis, for example, or liver metastasis compared in the lung itself.

So, I think we have a lot of work to do in this area and to really understand what are the common pathways that contribute to persistence that can be targeted in the way that David is talking about early on, so that we can prevent relapse. 

And then the other thing I think that is really important to think about is, “Are there ways in which we can identify patients who we think are going to have relapses early on in the course of treatment, so that if there are combinations of agents, we can really identify the people who would benefit the most from them because there is likely going to be an increase in toxicity when we use these combinations. So, can we find those patients?”

And we still have a lot of work to do. Looking at commutations is one thing and there might be some other clinical factors and biological factors, all things that there’s a lot of work happening to understand better.

Ramaswamy Govindan: Yeah, so, I think I would add one more thing that, for too long and quite appropriately, we’ve been focusing on the DNA-centric approach. A lot of it is about DNA sequencing and maybe some transcriptomic sequencing, but one of the things I learned when we were doing the proteomic studies was that how in many instances the copy number alterations are not [transcribed and eventually translated] at the protein level or [the fact that there are important] post-translational modifications. The striking observation in the lung adenocarcinoma proteomics paper from the NCI was that a good number of EGFR mutant patients had the very high levels of the SHP2 at the active site for Y62. If you look at the gene encoding for that, it’s never mutated in lung cancer – PTPN11 – and it is not even amplified. Even the protein is not [present in abundant quantities]. It’s only the post-translational modification that is significantly high. But those were patients untreated before and I’m not proposing that they cause resistance, but I think we are missing some of those alterations that we have not looked at because of this protein at the transcriptomic level. How the immune evasion happens in EGFR mutation is not well studied. So, I think the future studies will focus a lot on that to understand some of these reasons why some people don’t respond well and others do very well.  

Suresh Ramalingam: David?

David Carbone: I just wanted to reinforce that and we’ve learned a lot by sequencing tumors at resistance and we’ve identified many of these acquired resistance mechanisms. But one thing we’ve found is that tumors, if you study the persistent cells just days after starting the TKI treatment, they completely reprogram their transcriptional activity of multiple transcription factors. And I think it’s this reprogramming, if we really understand how that happens and what the key targets are, that really will be the way we’re going to cure this disease or at least reduce the development of resistance. And so, it’s not just genetic alterations that cause resistance, it’s these induced signaling changes.

Suresh Ramalingam: So, I want to pick up on something David had earlier mentioned, which spoke to eradicating all the tumor cells. Earlier, we started treating patients with metastatic disease with TKIs and we know that the results were good but not great. And the expectation was, if you gave it to patients with early stage disease, perhaps we can achieve cures. Now we are in the era of using TKIs for early stage disease. Are we curing patients? How much success are we having? What are the lessons learned from there? I would love to hear, Pasi, maybe you can start us on this.

Pasi Jänne: So, it is exciting to see EGFR and other inhibitors move into the adjuvant space being administered after surgical resection for an early stage EGFR mutant lung cancer or after chemotherapy and radiation for locally advanced EGFR mutant lung cancer. And in both cases, receiving an EGFR inhibitor certainly has substantial improvement in reducing the likelihood of recurrence and following surgery also improves overall survival of individuals with EGFR mutant lung cancer. However, whether that translates to an increase in cure of early stage EGFR mutant lung cancer, I don’t think we know that yet.

We hope that it will. As you point out, you’ve maximally debulked the tumor by surgical resection of the primary tumor and associated lymph nodes, and in that circumstance, there should be very little, if any, disease left, but whether even that small amount can be fully eradicated with just an EGFR inhibitor by itself I think remains to be determined. Now with further followup from these studies, we will be able to I think understand that and it’s nice to see that this is also being looked at in, for example, giving alectinib after surgery for ALK-positive lung cancer and being looked at in other genomic subsets of lung cancer as a way to cure more patients.

But it also gets back to the issue that we discussed earlier that it’s important to test patient’s cancers after surgery or those who are getting therapy for local advanced cancer where testing is less common. It’s been most common in the metastatic setting, but since these agents impact the outcome in patients with earlier stage disease, it’s also important to test those cancers or profile them, do molecular profiling to see if the patient’s tumor has an EGFR or EGFR mutation on ALK rearrangement in 2025 and for many more hopeful targets as more of the studies are being done and completed.

Suresh Ramalingam: Other perspectives on this?

Katie Politi: Can I just add something that I think is something to think about as we think about the future, as these agents are moving into earlier stage disease. , I think one of the other important components of this, and I think there still is a lot of work to do, is to figure out ways in which we can detect lung cancers early in patients even who are maybe not part of the classic screening population. We have a lot of work to do about this, but to reap the most benefit of these agents, also it’s going to have to go hand in hand with early detection. And hopefully, at some point, we can reach that point in which we can have early detection strategies that are safe and effective in a broader population than we can currently.

David Carbone: Just a quick comment on that, I completely agree with that. Lung cancer is most curable when it’s detected early, and the application of these inhibitors after surgery for clinically detected lung cancers, there are some downsides to this and that is that some of these patients are cured with surgery alone and yet we’re giving them years and years of multi-hundred thousand dollars therapy with low toxicity, but real toxicity and people are talking about extending that and giving it forever when people may not need it at all. So, determining who needs it and who does it is important.

I do think there’s a possibility that we’re curing these people, a small fraction of these people that have a small volume of residual micrometastases, and as we all know, not every cancer cell is clonogenic. If you just knock out stochastically the clonogenic cells, you may cure some of these people. But I think we have to take the adjuvant study with a little grain of salt and this is the ADAURA study. If you look in detail at that study, the majority of the patients in the control arm never got the osimertinib therapy [upon relapse]. And we know that, if you don’t treat a patient [with a metastatic EGFR mutant tumor], they’re going to have a worse survival than if you do.

So, the study really didn’t answer the question of, “Is adjuvant therapy better than close followup and appropriate treatment on progression?” And I think we need to think of the data a little bit more in circumspect. The adjuvant alectinib study actually did allow crossover to alectinib. And if you look at the survival in that study, at least so far, there’s no difference. So, we have a lot to learn about who needs it and who doesn’t in this disease and then we’re getting back to the variability and outcomes of different people with this disease.

Ramaswamy Govindan: I completely agree with David and I think really this is an area that I’m worried that won’t be explored because it’s now become the standard of therapy. Hopefully with better technologies, we can try identify the patients who need the therapy and who don’t need, both in the stage 1 and 2 setting following surgery and stage 3 after chemoradiation. The current technology may not allow us to identify the [cell free DNA] because you have to sequence at the high depth, especially there’s a high false negative rate with the predominately intrathoracic disease  

I am quite skeptical at the moment along the lines of what David said, that this improvement that we see may be a way the studies were designed. And I just want to remind both the people here and elsewhere [about the] ALCHEMIST study, which many of us here are part of, randomizing patients after surgery to erlotinib to observation, still we have not had the readout of the survival yet. We’ll see what that shows. The primary endpoint there is overall survival.

Suresh Ramalingam: I want to switch gears to briefly talk about how immunotherapy fares in patients with EGFR mutation. That’s been frustrating because these drugs have been incredibly exciting in certain subsets of lung cancer, but not in EGFR-mutated patients. What do we know about the reasons behind this and what more work remains to be done here, if any, from your perspective? Pasi?

Pasi Jänne: Well, so far we know that certainly single agent immune checkpoint inhibitors, anti-PD-1 or PD-L1 inhibitors are not effective in EGFR mutant cancers. And even when added to chemotherapy after the treatment with an EGFR TKI immune checkpoint inhibitors don’t add to the efficacy of chemotherapy alone. I think we still have some work to do to completely understand the reasons behind this. Many of these cancers do express high PD-L1, but yet there’s no clinical benefit. They tend to be a little bit more immune cold cancers than the ones that tend to respond to immune checkpoint inhibitors.

The lack of response to current immune checkpoint inhibitors doesn’t exclude the possibility that there couldn’t be future immune approaches that could be useful for EGFR immune cancers or many of the other subtypes of lung cancer with genomic alterations like ALK positive lung cancers that also tend not to respond to immune therapy. So, more work to be done in that space for sure.

Suresh Ramalingam: Katie, what do you see as work happening in understanding the biology in the lab with regards to this issue?

Katie Politi: Yes, absolutely. I think there are a couple of things. I think we still do need to do a lot of work to understand the immune response to EGFR tumors. I think Dr. Govindan mentioned that earlier, and in particular, also understanding the role of not only T cells but also other cells in the microenvironment and how they’re contributing to overall immunosuppression that might be present. And so, I think there is quite a lot of work in that area to understand what is happening.

I think another need in the field is the need to really develop and work with models that reflect some of the features of the human tumors that are important to really understand the biology of an immune response to a tumor.

So, we know, for example, in our genetically engineered mouse models that are really amazing for studies of targeted therapies and which we can layer on other mutational alterations as well being in an animal with an intact immune system, we know that, for example, they don’t have very many other mutations, right? And we know that human tumors, even though EGFR mutant tumors might not have many mutations or fewer than some other lung cancers, there still are additional mutations that then can make it more antigenic and are important for studying that immune response.

I think having models where we can study that, whether they be in-vivo models or other in vitro-models that are developed in which you can do co-cultures is really important. I think there’s going to be a lot of work on that coming forward that will help teach us what is happening but also give us ideas of different ways of targeting EGFR-driven tumors. And I think there’s also some promise in some studies of vaccination approaches. So, that’s another area where I think it’ll be interesting to follow in coming years, a lot to learn still.

David Carbone: Just a comment, in addition to that, I think immunotherapy has been the other major revolution in lung cancer therapy and I honestly believe that we are curing people with immunotherapy as opposed to what we talked about with the TKIs. And it’s actually been observed in animal models, Katie, correct me if I’m wrong, but I’ve seen several studies that showed that if you treat an EGFR mutant animal model in an immunocompetent mouse, they tend to have better duration of survival than the same tumor model in an immuno-incompetent mouse. So, the immune system may participate in altering the duration of responses that we see in practice and understanding what those cell types that are engaged in that response are.

They might not be T cells as she said. They might be targeting other epitopes in the tumor, but they also might be NK cells or macrophages or other cells in the tumor microenvironment and we have a lot to learn in that regard.

Suresh Ramalingam: Thank you. I think we’ve covered a lot of ground. As we wrap up, I want to ask every one of you, perhaps we can go around the table, to share your thoughts on, where do you see as the most promising directions in the future when it comes to EGFR-mutated lung cancer? Katie, I’ll start with you.

Katie Politi: Well, I think we’ve covered a couple of the things that I would say. I think one of the things that was mentioned previously was really understanding how pathway rewiring and the vulnerabilities of pathway rewiring in cells that are exposed to treatment. How can we  leverage that and what are those new vulnerabilities? So, I think studying more the signaling and the epigenetics of tumors is going to be very promising for understanding and targeting some of these non-mutational mechanisms of resistance. I think that’s going to be important. I think another thing that will be really interesting to learn in the future is to learn more about the impact of the environment on lung cancer.

That’s an area where there has been some work from Charlie Swanton’s group, for example, and others on particulate matter and its impact on lung cancer. That will be an important area to follow.

Suresh Ramalingam: David?

David Carbone: Well, I would agree with Katie, understanding why we don’t eradicate the tumor at the beginning, that rapid rewiring of pathways that induces this persistence, I would say is most exciting to me and we are actively studying that in the lab. But another exciting development in small cell lung cancer, for example, is this bispecific T cell engager approach. And the other project we have going on in driver mutant tumors is doing a cell surface proteomic discovery of specific cell surface proteins that might be induced by these activated oncogenes that could be an orthogonal type of treatment that might be able to eradicate these persisters as well as targeting [persistence] pathways activation. So, those are the two things that my lab is working on most actively right now and which I’m most excited about.

Suresh Ramalingam: Govindan?

Ramaswamy Govindan: I’m speaking for the field in general, I think one of the interesting observations is that healthy cells, lung cells have EGFR mutation, don’t have cancer and we’ve all taken care of patients who have inherited T790M mutations and they don’t have cancer, they have a nodule. So, what’s really driving these cells after acquisition of this mutation into cancer neoplasia, invasive cancer, I don’t think we understand that well. And second, of course, studying the persisters, using all the newer technologies including single-nuclear sequencing and spatial transcriptomics and then the resistant [cells].

And I also think there is going to be more effort in finding out novel approaches like protein degraders are coming in various thing like PROTACs and others that may be one way to overcome some of the resistance. And I agree with the previous comment that it is not like immunotherapy won’t work. We just know that the PD-1, PD-L1-directed immunotherapy is not the right answer.  How are these cells evading the tumor immune system? I think that’s where I think, in my opinion, it’s where a lot of money is and it’s easier said than done, but that’s an important area.

Suresh Ramalingam: And, Pasi, you have the final words.

Pasi Jänne: I agree with what others have said as well and the good things, there are newer therapies coming. For example, antibody drug conjugates have shown activity in patients with EGFR mutant cancers, the TROP-2 directed antibody drug conjugates, HER3-directed antibody drug conjugates. So, there are new therapies that are coming in how to best incorporate these into how we currently treat our patients with EGFR mutant lung cancer will continue to be important as well as new small molecule inhibitors that new variations of EGFR inhibitors and other agents given in combination with medicines like osimertinib, I think, are entering the clinic and David mentioned a clinical trial that his institution is running.

So, I think there’s hope and I think we’ve all learned from the successes in the last 20 years, has focused on where currently we have a lack of effective therapies and when there’s a need to develop effective therapies. And I think there’s interest both on the academic and on the industry side to develop new therapies. So, I think [the] future remains hopeful for our patients with EGFR mutant lung cancer.

Suresh Ramalingam: Thank you, Pasi. I think this has been a fascinating discussion. It’s been great to go down memory lane and trace back the advances that we’ve made and how the discovery of EGFR mutations have revolutionized the field of not just precision medicine for lung cancer, but for other cancers as well. And I think, decades from now, when people look at major inflection points in the fight against lung cancer, the discovery of EGFR mutations will clearly be among the top of the list. So, I want to thank every one of you for joining in this discussion and sharing your thoughts and wish you all very well for the rest of the day. Thank you.

Pasi Jänne: Thank you.

Katie Politi: Thank you.