Recent advances in non-small cell lung cancer with EGFR mutation — Pasi A Jänne, MD, PhD

DR JÄNNE: Today I’d like to discuss advances in EGFR mutation-positive non-small cell lung cancer.

I wanted to discuss 4 particular topics today. First, first-line therapy for advanced EGFR mutant lung cancer, as this landscape is rapidly changing. Second, resistance to first-line osimertinib and what are our current treatment strategies. Third, EGFR exon 20 mutant lung cancer, a subset of lung cancer for which we don’t have effective EGFR therapies yet. And finally, adjuvant EGFR inhibitor therapy.

The current standard of care for patients with advanced EGFR mutant lung cancer is single-agent osimertinib. This is based on the FLAURA trial which compared osimertinib to standard of care EGFR TKI therapy, either gefitinib or erlotinib. Previously published was the progression-free survival which demonstrated a significant benefit improving that from 10.2 months seen with the standard EGFR TKI therapy to 18.9 months with osimertinib.

More recently and following longer follow up, the overall survival was also published with an improvement in overall survival of 31.8 months with the comparator EGFR TKI to over 38 months with single-agent osimertinib.

Now one of the advantages of osimertinib compared to prior generation EGFR TKIs is the ability to penetrate the brain. Brain metastases, of course, are devastating complications to many of our patients. And having pharmacologic options to treat brain metastases or prevent them from happening in the first place is certainly a welcome advance to solely having radiotherapy.
 
What was analyzed in this trial was the progression-free survival in the brain, seen on the top left in blue, osimertinib, and in yellow is the standard of care EGFR TKI, showing an improvement in brain progression-free survival.

Another way to look at this is cumulative incidence of the development of brain metastases in those individuals who do not have brain metastases over time. And in solid blue, or that with osimertinib, and in solid yellow with comparative TKI, showing a diminished cumulative incidence of brain progression in patients treated with osimertinib.

Finally, on the bottom, were patients who actually had brain metastases where you could measure their response in the brain, on the left-hand side with osimertinib, and on the right-hand side standard of care EGFR TKI. And once again, you can see a greater degree of response, including multiple complete responses in patients treated with osimertinib compared to standard of care EGFR TKI.

Now, more recently, another entry has emerged in the treatment of front-line EGFR mutant lung cancer. And this comes from a randomized clinical trial of erlotinib and ramucirumab compared to erlotinib alone. And this trial randomized patients 1:1 as seen in this schema, with the primary endpoint of progression-free survival. Similarly, to the osimertinib trial, this was limited to patients with the exon 19 deletion or L858R mutations.

The primary analysis demonstrated a significant improvement in progression-free survival from 12.4 months in patients treated with erlotinib alone, compared to 19.4 months in patients treated with erlotinib or ramucirumab. In fact, numbers very similar have been observed with single-agent osimertinib.

This trial is still too immature to know whether the combination of ramucirumab and erlotinib has an impact on overall survival of patients. However, it has been recently approved by the US Food and Drug Administration.

Now one of the challenges we come into with EGFR mutant lung cancer is, of course, the development of resistance. And what we’ve learned from studying resistance over the last several years is that there is more than one way to develop resistance. And in this slide that was obtained from patients that had developed progression after first-line osimertinib therapy demonstrates just that point. In fact, there is no one dominant mechanism of resistance. Resistance can happen in multiple different ways. A few examples include secondary mutations in EGFR itself. MET amplification or HER2 amplification. And/or activation or mutations in some of the downstream signaling pathways.

In addition, not all of the patients develop resistance mechanisms that you can quantify. We’re sometimes left with only finding the EGFR activating mutation and not a clear targetable or identifiable resistance mechanism.

So how do we treat resistance to front-line osimertinib? First of all I think we need to understand the mechanism and that can be done most effectively with a rebiopsy, which can be used to sequence and identify the specific resistance mechanism and/or to rule out the small cell transformation which happens in a minority of individuals.

Cell-free DNA is certainly an alternative if biopsy is not feasible. However, you cannot get information, including histology, from studying cell-free DNA.

In general, our approach has been to target the targetable alterations. If you find a secondary EGFR mutation or a MET amplification, these are ones where we can target those with specific therapies. And these are being tested in trials, including the SAVANNAH trial, which studies MET combination, the ORCHARD trial, which studies multiple different combinations based on that resistance mechanism, and the JNJ6118632 or amivantamab trial, which also studies MET amplification in EGFR secondary mutations as resistance mechanisms.

What if you don’t find a targetable alteration? Well, there are some broader strategies that are being tested, including U3-1402, known as patritumab deruxtecan. And finally chemotherapy plus/minus continuation of osimertinib always remains an option for an individual where you cannot find a resistance mechanism or unable to do a resistance analysis.

These are data from two different clinical trials targeting MET and on the left-hand side are trials targeting MET with a molecule called savolitinib, which is also being tested in the SAVANNAH and ORCHARD trials. And this is for patients that develop resistance to an EGFR TKI and have MET amplification and you can see nice responses in patients treated with the combination of osimertinib and savolitinib.

On the right-hand side is the second approach, again in patients that have developed resistance with high copy number gain or MET IHC expression, here treated with the combination of gefitinib and another MET inhibitor called capmatinib. And again you can see that patients can once again re-respond to therapy.

As I mentioned, EGFR mutant lung cancers also sometimes have expression of the other Erb family members including HER2 and HER3. HER2 amplification is a known resistance mechanism to EGFR inhibitors, but HER3 is often expressed. It's used to activate PI3 kinase signaling, but it's not a known mechanism of resistance to EGFR inhibitors. And one of the potential advantages is to use HER3 as a potential strategy to target EGFR mutant lung cancers when they develop resistance to EGFR TKIs. And this is the concept being tested in this Phase I clinical trial of patritumab deruxtecan or U3-1402, an antibody drug conjugate where you have a HER3 antibody specifically linked to a conjugate. And the idea, the antibody binds the external portion of the receptor. It gets internalized. And then this toxin — topoisomerase-like toxin gets released into the tumor and you can potentially specifically deliver therapy to the tumor, kind of line in a Trojan horse manner. And in this slide in a preclinical study, you can see that in these patient derived xenograft models, those that express HER3, in the middle and on the right, are particularly sensitive to this agent compared to the model on the left that does not express HER3.

And this was taken into a clinical trial, an ongoing Phase I clinical trial where there’s dose escalation of the agent being tested, with the 5.6 mg/kg, as the current dose. And you can see in the early studies, this presented by Dr Yu at the World Lung Cancer conference last year, there’s activity of this agent in patients that have failed EGFR inhibitors and/or oftentimes chemotherapy.

What I did want to point out here was that the activity, the responses, are not limited to one particular type of resistance mechanism, shown on the bottom. So there are patients that respond with MET amplification, with C797S, with no known resistance mechanism, with PI3 kinase mutations. So this could potentially be a broader strategy to treat resistance as opposed to going after known specific resistance mechanisms. I think they’re both complementary approaches and we’ll await to see which one emerges to be a better or a more practical approach.

I’ll switch now to talking about the EGFR exon 20 mutations, which is a subset of EGFR mutant lung cancer where we’ve really struggled to find an effective therapy. This is a subset of about 5 to 7% of all EGFR mutations. They’re located in the same exon of EGFR, where the EGFR T790M, the common erlotinib resistance mutation’s located. But it's not one mutation. It's actually a series of mutations that overlap this portion of exon 20. And that's been part of the struggle to try to develop an effective therapy specifically for these mutations.

However, a couple of agents have emerged over the last few years and I wanted to highlight a few of them. First, amivantamab, or again, the JNJ372, this bispecific EGFR MET antibody. So part of this antibody binds EGFR and part of it binds MET. I’ve already introduced you to the fact that MET is often overexpressed in EGFR mutant cancers, so it sometimes can be amplified as well.

And from this year’s ASCO, Dr Park presented the data specifically on the EGFR exon 20 patients in this group of individuals that was heavily pretreated and had an overall response rate of 36% with a progression-free survival of 8.3 months.

The common side effects of this approach include rash, infusion reactions and paronychia. This agent also has now received breakthrough designation from the FDA.

A second agent which is a tyrosine kinase inhibitor, so more like an osimertinib-like approach, is called mobocertinib or TAK788, a small molecule inhibitor. Also data from ASCO this year and from AACR this year. Similarly, a study of about 30 patients, heavily pretreated with median number of 3 prior therapies with an overall response rate of 43% and the progression-free survival of 7.3 months. Similarly, this agent also has breakthrough designation from the FDA. Slightly different side effect profile, diarrhea, nausea and rash being the more common side effects with this agent.

And finally, at this year’s ASCO we learned about osimertinib, not given at the normal dose, which we give for the patients with exon 19 or L858R mutations, but given a double of a dose at 160 mg dose. And the reason for this is that it’s felt that in order for a drug to be efficacious against exon 20 it has to also be probably around the concentration required to limit wild-type EGFR, which is what you get to with a higher dose. And you can see here a slightly smaller study than the prior study, but similarly a pretreated group of individuals with a response rate of 24% and a progression-free survival of 9.6 months.

Finally, let me turn to the adjuvant setting. Of course we’ve made advances in treating individuals with advanced EGFR mutant lung cancer with us now using third generation EGFR TKIs as first-line therapy with patients seeing an impressive PFS and overall survivals.

However, the question comes what if we added to the adjuvant setting? Can we cure more individuals with early stage lung cancer specifically those with EGFR mutant lung cancer?

At ASCO this year we heard the first data from this ADAURA randomized Phase III clinical trial where patients with Stages IB to IIIA who received appropriate surgery, and in cases adjuvant chemotherapy, were randomized to either osimertinib or placebo. And this was presentation was in fact through an early look at the data based on the Data Safety Monitoring Committee recommendation to unblind the study early due to efficacy.

And in fact, the endpoints were quite stunning. This is disease-free survival endpoints now in patients with Stage II and IIIA disease, which was the primary endpoint. And you can see an impressive improvement in disease-free survival in patients who received osimertinib compared to those treated with placebo, with a hazard ratio of .17 with a highly statistically significant p-value.

If you now look at all stages, including the IB patients and stages II and III here, again you see can improvement, even in the Stage IB patients where we don’t always even give adjuvant chemotherapy, still a hazard ratio of .5, again with a significant improvement in disease-free survival.

As mentioned, these are improvements in disease-free survival, not overall survival. As the data matures on this trial, we anticipate seeing effects on overall survival as well. But certainly, I think this is a stunning example of the use of targeted therapy in the right population in the adjuvant setting and hopefully will inspire other such studies to take place for our other genotype directed therapies.

One last study to mention. At ASCO this year was another adjuvant trial, again in the EGFR mutant patient population, and here a slightly different design. In the US and in the ADAURA trial, specifically adjuvant EGFR TKIs were given after standard of care therapy was completed. Patients could have had chemotherapy, which is the standard of care in the US. However, in this trial, in China, the adjuvant therapy was a randomization to an EGFR inhibitor compared to a chemotherapy, here vinorelbine and cisplatin and the EGFR inhibitor is gefitinib, with the endpoint of disease-free survival.

This is the updated disease-free survival in this study. Again, a highly statistically significant improvement in disease-free survival for patients who were treated with gefitinib compared to chemotherapy. However, when the investigators looked at impact on overall survival, they did not see an improvement in overall survival with gefitinib compared to chemotherapy. Now this trial is much more mature than the ADURA trial. Will we also see the same findings with the ADAURA trial? I think only time will tell, but certainly this trial with gefitinib and chemotherapy, again a slightly different practice strategy than what we are typically used to, demonstrated no improvement in overall survival despite demonstrating an improvement in disease-free survival.

Case: A woman in her mid-50s with metastatic NSCLC with an EGFR exon 19 deletion who receives osimertinib

DR JÄNNE: I wanted to present a few cases to illustrate some of the practice patterns for EGFR mutant lung cancer. This is the first case, a 54-year-old female. Limited former smoker. Presented with progressive cough. Initial CT scan showed a left upper lobe lesion with lymphangitic spread, contralateral lung nodules and thoracic spine lesions. Brain MRI reveals 8 small brain lesions without associated edema. CT-guided biopsy reveals adenocarcinoma and genotyping demonstrates an exon 19 deletion mutation. And you were asked to see her as an initial consult.

She subsequently started on first-line osimertinib and here the thinking was, because of the brain lesions, asymptomatic, no associated edema, with an improved activity of osimertinib in the brain, that this makes sense as a first-line therapy. Her cough improved quickly and disappeared after 2 weeks of treatment. Brain MRI showed resolution of the brain metastases.

She’s doing well and returns for follow up, asking if there’s something more that could be done in addition to osimertinib as a treatment approach. We subsequently decided to continue single-agent osimertinib. Follow-up CT scan demonstrates growth of now the primary left upper lobe lesions and in the bone metastases, the brain MRI is stable. Repeat biopsy of the left upper lobe reveals the original EGFR exon 19 deletion, but no other targetable alterations and now she’s coming back to see you ask what’s her next treatment option.

DR LOVE: So, she was on the osimertinib for 2 years. But you had a question in there that said could you do anything more at that point before she progressed. Can you kind of discuss that?

DR JÄNNE: Yeah. I think most of the time we see partial responses. We don’t see complete responses. And we see some residual disease. And I think this is — I’ve seen a number of people who come and say hey, I’m doing great with osimertinib. I have no side effects. There’s still some cancer in the CT. Yes, it's responded. What more can I do at this point? Should I add something? Should we radiate this? Should I do chemotherapy? And should we do surgery? So this is a question that comes up. And I would say that we don’t know what to do at this point. There are some experimental things being studied such as radiating residual disease. But it is something that comes up.

I would say it didn’t come up so much in the erlotinib days because erlotinib has I think, in general, a little bit more of an associated toxicity, people often dealing with skin side effects or other things, and the thought of adding a second agent wasn’t I think in people’s mind. I think it comes up more now with osimertinib.

DR LOVE: And what are the possibilities that might be considered, for example, a patient who wanted to try something, maybe not completely proven but of interest?

DR JÄNNE: Well I think it depends a little bit to what you see, meaning that if you’ve had all sites of disease disappear with the dominant mass being present, there are studies looking at adding radiation, for example, to treat the sort of residual disease. So I think that's one potential approach. I think if you see multiple sites where you’d be adding a systemic therapy, I think there it's less clear. Of course, there are trials adding things like chemotherapy to osimertinib, but at the time when you’ve had the maximal response and the tumor’s not growing, the cells are also not dividing. So it’s not clear that chemotherapy has the same benefit there than it would, for example, at the time of progression or even at the time of initial diagnosis.

DR LOVE: So a couple of possibilities, at least agents that are approved. I’m not sure many people would necessarily do it outside of a trial, but perhaps could be brought into the discussion. One would be the addition of anti-angiogenic such as bev or ramucirumab. Another might be the addition of chemotherapy. Any thoughts about that? And whether or not you’re more likely to consider that in a patient with exon 19 versus 21?

DR JÄNNE: I think certainly adding bev or ram has activity when you start it from the beginning, when someone starts with osi or someone starts with erlotinib, as we saw from the RELAY trial. Whether that same benefit exists if you add it 6 months later or 4 months later once you’ve been on osimertinib, I don’t know. Part of it is, I don’t totally understand how or what bev or ram are doing to enhance the efficacy of osi or erlotinib for that matter. They don’t enhance the response rate to improve the PFS, but exactly when you do need to do that is not clear to me.

I think chemo, again once you’re 4 months into it or 6 months into it, if the tumor’s not dividing, I worry that chemotherapy is not going to be working because you typically need dividing cells for chemotherapy to be effective. And if osi or erlotinib is arresting it, I think it's less clear. That may be different when you start all of them from the beginning, as we’ve seen with chemo and gefitinib which shows incredible effects compared to gefitinib alone or erlotinib and ram or osi and bev or erlotinib and bev. So I think it's when you start it where the difference is.

DR LOVE: So I guess another issue here I’ve heard people talk about, we even had a case presented, was a patient who you really don’t want to see progress, for example, a patient with a lot of brain mets, and the question of whether or not you’d be aggressive, again in a patient with an exon 21 as opposed to exon 19.

DR JÄNNE: So, interesting, if you look at the front-line osimertinib data, just look at the PFS data, for example. There is an improvement when you take all patients. Now if you break it down by the mutation, the improvement is disproportionally more for the exon 19 deletion patients than the L858R patients. So there may be a higher risk progression population. Now we haven’t thought of them yet clinically that way, meaning that when you diagnose someone with EGFR mutant lung cancer, we treat them same whether or not they have an exon 19 or L858R. I do think that we may be getting to that point in the future where we’re thinking about these as two different populations or one a more aggressive population, for whatever reason, that we need to do more intensified therapy.

I don’t think about that yet or do anything differently yet at the moment, but we could be getting there in the future.

DR LOVE: So let’s continue on with this case.

DR JÄNNE: So here, I think is an example of a situation where a person’s progressed. You don't have small cell transformation. You have the original EGFR mutation, so you know you’re looking at the tumor analysis. You don’t have anything targetable. And I think here’s the next question of what to do.

So, I think here, for me, there’s sort of two possibilities. One is a clinical trial like the U3-1402, which is for broader population of patients who develop resistance and doesn’t require a known resistance mechanism. And the second is chemotherapy and transitioning this individual to chemotherapy.

One of the things in the chemotherapy choice that comes up in someone like this individual who had brain metastases is what do you do with the osimertinib? Do you continue the osimertinib or do you stop it when you give chemotherapy?

Our practice pattern, my own practice pattern especially in someone with brain disease, is often to continue it. I know that that's not everybody’s practice pattern and I know that there’s no clear data to support that. But I think in somebody who’s had brain metastases, it's certainly I think a reasonable thing to continue to do.

DR LOVE: And then in terms of the type of systemic therapy, I guess one key question is what are you going to do in terms of PD-1? And is it going to change based on PD-L1 levels?

DR JÄNNE: Right. So, certainly if I continue somebody on osimertinib I stay away from anti--PD-L1 or PD-1 therapy just because of the concern of interactions between those two.

For systemic therapies, I typically turn to carboplatin and pemetrexed. It's an easy combination to give. Patients don’t develop alopecia or lose their hair and allows one to continue with the osimertinib. I think if you’re going to switch to a regimen like the IMpower regimen of carbo/paclitaxel/bevacizumab/atezolizumab, then I think you need to stop the osimertinib because of that potential concerns for interactions.

I have, in general, been switching people to carboplatin and pem because it allows the flexibility of continuing osimertinib.

DR LOVE: So what happened with this patient?

DR JÄNNE: Ended up getting chemotherapy. And is currently getting chemotherapy and continuing osimertinib. And doing fine. Doing fine.

Case: A man in his mid-40s and a never smoker with metastatic NSCLC with an EGFR exon 20 insertion mutation

DR LOVE: Let’s hear about your next case, this 47-year-old man.

DR JÄNNE: This 47-year-old never smoker presents with 3 months of back pain. MRI of the lumbar spine reveals a mass in L1 extending into the epidural space. Additional imaging demonstrates a right-sided lung mass, liver and adrenal metastases and brain MRI does not reveal metastases.

Biopsy of the lesion is performed which shows adenocarcinoma. It reveals palliative radiation to the lesion. You send the biopsy for NGS but it’s taking the while. The patient would like to start on systemic treatment.

The patient starts treatment with carboplatin and pemetrexed. He has a PR that lasts for 6 months. The genotyping comes back and it reveals an exon 20 insertion mutation. The patient starts on afatinib as a strategy to treat exon 20 insertions, but develops progression within a few months and he returns to see you for consideration of the next treatment.

DR LOVE: So, just to go back to this case. You didn’t mention what the PD-L1 level was in this patient and how you decided upon the therapy.

DR JÄNNE: Right. So, yeah, this one, if I remember correctly, had about 20% PD-L1, so it wasn’t high, but it wasn’t negative. And the reason I started the person on chemotherapy alone was with the knowledge that he was a never smoker. So my thought here was that he was likely to have a targetable alteration and as soon as we found the targetable alteration, we would potentially switch him from systemic therapy to a targetable therapy. And as such, I didn’t want to start with anti-PD-1 or PD-L1 therapy, again for the same reasons as I mentioned previously in the prior case, is that of the potential interaction. That these agents have, in fact, quite long half-lives and even if you stop at 3 weeks or last administer 3 weeks ago an start a TKI now, you can still run into those issues. And the plan was that if he didn’t have a targetable alteration then I could add the PD-L1 or anti-PD-1 therapy at the second or subsequent cycles.

Now, he turned out to have an EGFR exon 20 mutation, which is one obviously that we wanted to discuss here in terms of what the strategy would be and when would the right strategy be.

DR JÄNNE: We decided to continue chemotherapy for 6 months because he was benefiting from it even with the knowledge of the exon 20 mutation, and then he progressed and hence the discussion for what to do next.

DR LOVE: But you conceptually, even though he had an exon 20, you visualized him as somebody who is a non-smoking phenotype type person who maybe won’t benefit from PD-1 therapy?

DR JÄNNE: Yeah, it was both that and then the switching to the drug, right, that if he didn’t have an EGFR mutation maybe he’d have an ALK rearrangement or a ROS or whatnot, that we would have a drug to switch him to. And I was concerned about if I had to do that in a situation where he had just recently received or within 3 weeks received a PD-1 or PD-L1 therapy, was concerned about the toxicity.

DR LOVE: That really ties into an important issue we’ve been trying to bring up which your case really demonstrates which is particularly in a patient who’s a non-smoker, to hold off using PD-1, even in a high PD-L1 situation until you have the NGS for that exact reason. Can you comment on that?

DR JÄNNE: The idea there of course, is that these are individuals — a never smoker is somebody who has at least about a 50+% chance of having some targetable alteration for which we have a targeted therapy, not just EGFR mutations, but ALK or ROS or RET or TRK or MET or many of the others that are out there. And if you start those individuals with chemo and a PD-1 or PD-L1 therapy, the concern really is that if you have to switch, or once you get the NGS back into cycle 2 and you want to switch, that those agents are still around and you could run into toxicity problems in patients who kind of come off of a prior PD-1 or PD-L1 therapy and start, for example, on osimertinib or other agents. And there have been reports that have highlighted this.

And so, waiting for the NGS and if the NGS is negative and then integrating anti-PD-1 or PD-L1 therapy may be a safer approach for the patient. At that point, you will know that you’re going to continue on chemotherapy and not switch to targeted therapy.

DR LOVE: I’m guessing that the afatinib here was used outside a trial setting. It is accessible. Do you think that that's a reasonable option right now or do you think it makes more sense to really, really push hard to get a patient like this on a trial?

DR JÄNNE: I think the trial is a much better choice. Afatinib, when it's been looked at in this patient population, has about a 10% response rate and a relatively short PFS. This was really done I think in order to try something different than moving to docetaxel in somebody who didn’t really have a trial option and they came to see us for a consideration for a trial. And I think if you find somebody like this with an exon 20 insertion, I think it's important to survey and figure out where there potentially is a trial option for this patient population.

And the ones we mentioned are — those are common, but there are others out there too, a little bit early in development, and the hope is that over the next few years we’ll find something that would be hopefully better than chemotherapy for this patient population. Maybe we’ll get to a level of osimertinib for this patient population that have at least a targetable therapy approach for the exon 20 insertion patients.

DR LOVE: For patients who don’t have the option to participate in a trial, do you think, assuming you get it paid for, that increasing doses of osimertinib or higher dose of osimertinib would be a reasonable non-protocol option?

DR JÄNNE: Well, I think that was the first piece of data that was seen in the ASCO presentation there at the 160 mg. There was an earlier presentation done from a Korean group that was presented last year at ESMO I think, where they used 80 mg of osimertinib. And there, there was absolutely no activity. So it clearly seems that the dose is important and there’s activity. There’s about a 25% response rate there. It's better than we know you can get with afatinib. Numbers are small. But I don’t think it's an unreasonable thing if one has access to that agent.

DR LOVE: And I’m guessing from what I’ve seen that you really don’t get much additional toxicity with the increased dose of osimertinib?

DR JÄNNE: I think in that study there wasn’t too much. Again, sample size isn’t huge. In the Phase I osimertinib studies at the 160 mg you start to get more of the wild-type EGFR toxicities. You start to get more skin toxicity, skin rashes, things like that you may see less of at the approved dose of 80 mg.

Case: A woman in her late 40s with Stage IV NSCLC and EGFR L858R and T790M mutations who experiences disease progression during second-line therapy with osimertinib

DR LOVE: Okay, let’s go onto your last case.

DR JÄNNE: A 49-year-old woman with a known Stage IV EGFR L858R mutant non-small cell lung cancer. Here treated with first-line erlotinib/ramucirumab. Had sustained PR but now has progression. Repeat tumor biopsy demonstrates EGFR L858R but no T790M mutation. Plasma NGS reveals EGFR L858R and T790M.

She receives treatment with osimertinib. Has a PR, but develops progression 10 months after treatment and is inquiring about the next line of therapy.

DR LOVE: So, just to be clear, this patient got erlotinib/ramucirumab?

DR JÄNNE: Yes. Yes.

DR LOVE: And then they got osimertinib.

DR JÄNNE: Correct.

DR LOVE: And responded to both.

DR JÄNNE: Yes.

DR JÄNNE: Yes, responded to both. And here, one of the things that I wanted to highlight is that we often talk about pros and cons of tumor biopsies and liquid biopsies and sometimes think it’d be complementary pieces of information. And this is one such example where you biopsied one particular area of the patient but there wasn’t a T790M and just an L858R mutation, but you happened at the same time to send out the plasma for sequencing and it had both mutations and as such, a reason to give this individual osimertinib.

I think it highlights one of the challenges, as we treat patients with sequential EGFR inhibitors and get more different types of resistance mechanisms. You can get more than one way of resistance happening simultaneously and it makes some of the treatment approaches challenging. Fortunately, the person responded to osimertinib here, based on the T790M mutation.

DR LOVE: So what happened at the point that the patient had progression now on osimertinib?

DR JÄNNE: So at this point this individual subsequently ended up getting chemotherapy because they had not received chemotherapy yet. We did do an analysis of the resistance. We did not find anything targetable there and so that person ended up getting chemotherapy. But in that situation where you’re now dealing with post-second line osimertinib, here the resistance landscape is perhaps ever more complex and more diverse than I showed you with first-line osimertinib. Again, there’s many different ways for resistance to happen and it may be difficult to go after each of those mechanisms. And sometimes you need an approach like chemotherapy.