 Today I’ll be presenting the case of a 68-year-old man with metastatic 

-mutant–positive non–small cell lung cancer.

The patient initially presented with recent onset shortness of breath and unintentional weight loss. He didn’t have any nausea, vomiting, or neurologic symptoms.

His past medical history was relatively unremarkable−hyperlipidemia that was controlled by a statin. He had been a former smoker but quit 10 years ago after a 30-pack year of smoking. And his physical exam was notable only for decreased breath sounds, most notably in the left lower lung field on auscultation. In terms of his clinical workup his labs were unremarkable. Pulmonary function was moderately reduced with an FEV1/FVC of 55%, and the DLCO [diffusing capacity of the lung for carbon monoxide] is 65%.

The chest x-ray showed a left lower lobe mass, and on the CT scan it confirmed the presence of a
3.3-cm pulmonary mass involving the left main bronchus, and ipsilateral and subcarinal lymph nodes. In addition, the CT showed adrenal metastases, and CT-core needle biopsy revealed lung adenocarcinoma. An MRI of the brain was negative.

I think every patient with nonsquamous histology and, in fact, I think every patient with non–small cell lung cancer in general should get molecular profiling. And, in this case, this patient had an exon 19 deletion, and 

were all negative. PD-L1 testing showed a TPS [tumor proportion score] of 20%, the other typical mutation being an exon 21 point mutation, and L858R alteration. And if you have any of those typical mutations, an exon 19 deletion, or an L858R point mutation, then treatments for typical 

So, at the end of the day this was a stage IV non–small cell lung cancer.

In terms of his treatment, he was started on erlotinib at 150 mg daily, and ramucirumab at 10 mg per kilogram IV [intravenous] every 2 weeks. After 3 months, imaging showed a partial response with decreased size of the lung metastases and the adrenal metastasis. And imaging at 6, 12, and 18 months showed continued stable disease.

A 68-Year-Old Man With Metastatic EGFR+ NSCLC

What is notable about the case, and what are my initial thoughts about the management? Well, this, in a lot of ways, is a typical patient with 

mutations can happen in nonsmokers, of course, very frequently, but they happen in smokers as well. We often like to say, smoking doesn’t prevent you from getting an 

mutant non–small cell lung cancer, and that’s important because sometimes smokers, or at least former smokers, are not being tested for all these mutations.

I think one important point is that patients, regardless of whether they’re a smoker or not, with lung adenocarcinoma or nonsquamous histology in general, should get molecular testing.

In general, I will test squamous cell carcinomas as well. First of all, sometimes the histology is not recognized as nonsquamous histology; sometimes there’s disagreement about the histology, and patients with squamous histology will sometimes have an 

mutation, or one of the other driver oncogenes.

When I started practicing thoracic oncology a little more than 2 decades ago, the outcome for somebody in this situation would have been a median overall survival of less than a year. In fact, it was on the order of 9 months or 10 months at that point. Fortunately, right now, for somebody [with] newly diagnosed…

mutant non–small cell lung cancer in this situation, the median expected overall survival is somewhere in the area of 40 months, and in fact that number is getting longer and longer as some of our better drugs now are being more wisely used, and we’re developing new tools to be added to the toolbox as well.

The treatment landscape for patients like this has really changed dramatically over the last 2 decades since I started practicing thoracic oncology. In the early 2000s, options for these patients would be really limited to platinum doublet chemotherapy, or a single-agent chemotherapy after that. And the median overall survival of patients in this situation was right around 8 months to 10 months.

If you look at studies like FLAURA and RELAY, the median overall survival is in the range of 38 months or even longer than that. We don’t even have a median overall survival yet for patients treated on the RELAY study. So, this really is remarkable progress. Just think about that, From 8 months to 10 months to now in the area of 40 months and getting longer. So that really is striking.

Now, that progress is coming for a couple of reasons. First of all, we’ve got targeted agents for use in the first-line setting–EGFR inhibitors most prominently for a patient with a typical 

mutation like this. …Patients who develop resistance to first- or second-generation EGFR inhibitors now get a third- generation inhibitor. Our chemotherapy regimens have gotten better with the addition of bevacizumab, platinum doublet chemotherapy. And now with the addition of immunotherapy, that can be used after platinum doublet, although immunotherapy doesn’t tend to be particularly effective for patients with an 

 mutation, but it does remain an option. And for patients who are receiving second-line chemotherapy with agents like docetaxel, we have the addition of ramucirumab. So, if you add together all those changes cumulatively, for patients with 

-mutant non–small cell lung cancer, that amounts to dramatic improvements in the overall survival.

Improved Outcomes for Patients With EGFR+ NSCLC

 What molecular tests should be ordered for a patient with a newly diagnosed non–small cell lung cancer. Well, it’s worth noting that this patient was an ex-smoker, 30-pack-years, so a relatively heavy smoker, and quit 10 years ago. And sometimes I hear that we should only order detailed molecular testing for people that are nonsmokers or very light former smokers. And that really isn’t the case. Anybody with nonsquamous, non–small cell lung cancer should get detailed molecular testing, and I order it in all my non–small cell lung cancer patients, both squamous and nonsquamous. And that’s because sometimes there’s disagreement about the histology, or the histology is obtained with just a fine needle aspirate [FNA], that it can be very hard to see the exact histology. And, as I mentioned before, pathologists will often disagree.

Now what does the detailed molecular testing look like? Well, at a minimum, patients with nonsquamous, non–small cell lung cancer should be tested for 

mutations, because we have FDA-approved drugs for all of those, and now

fusions, because we now have FDA-approved therapies.... And I think in the very near future we can expect a good likelihood there will be agents available for 

fusions. These are changing quickly, and in the near future we may have drugs for HER2 as well. So, when you take all that, there’s a minimum [of] 5 or 6 assays that need to be done. And really we advocate for broader profiling here at MD Anderson Cancer Center with next-generation sequencing where you get an entire panel that covers not only the alterations for which we have FDA-approved drugs right now, but other alterations [for] which we have active drugs that are currently in clinical testing.

That’s why I really think the next-generation sequencing with broader profiling is more appropriate. In addition, PD-L1 testing is commonly done. Now, that may have less of a role in patients with 

mutations, but it is something that should be broadly done as well.

A question arises when you have a patient there in the office, do you start treatment right away and then change later if the results come in and suggest the new agents. Or, do you wait for the results to come? Unless the patient is really in extremis, unless they have something, for example, like an airway obstruction or are really highly symptomatic, I try to wait until the molecular testing comes back and of course try to get it done as quickly as possible.

The reason we recommend against starting immunotherapy up front before you know the results of this is because if somebody gets immunotherapy, there’s some evidence that with a TKI like erlotinib or osimertinib, you may have a higher rate of pneumonitis down the road.

Secondly, it’s better not to start therapy and then immediately stop it afterwards. I advocate for testing and waiting for the results, unless, as I said, there’s some impending issues that really force you to treat early.

Now practically speaking in the clinic, what most often prompts doctors to get the treatment started before the test results are back are patient concerns or anxiety, the desire to get going quickly. And that’s entirely understandable that the patient would want to get treatment started quickly.

I try to let them know this cancer has likely been around for a couple of years, and all that’s really changed in the recent weeks from a patient’s perspective is their awareness of the cancer. Waiting an extra two weeks in the vast majority if it is not likely to make a big difference in outcome, and it could lead to a more appropriate therapy. In general, we want to get patients on the right therapy in the first line setting and not be sending off test results and then starting chemotherapy or chemotherapy with immunotherapy and then changing it when the results come back.

So, when at all possible, I certainly advocate for waiting for test results to come back before starting therapy and explaining to patients that this is unlikely to make a difference given that the cancer has been around in most cases for years.

Molecular Testing for Newly Diagnosed NSCLC

 Now what are the treatment options for this patient? Well, first of all, I’ll note that the patient has a typical 

mutations are the exon 19 deletion or L858R which is in exon 21. And if you have those 2 different alterations, you have got several treatment options. You have first- and second-generation drugs that are still FDA approved. That’s gefitinib or erlotinib as first-generation drugs, or afatinib as a second-generation drug.

Recently, based on the results of the FLAURA study, which was a first-line study that compared osimertinib versus first-line drugs, erlotinib and gefitinib, osimertinib has become a first-line option as well. And given that it was superior in that study to the other drugs, I think many people, including myself, will often use osimertinib in the study.

Now the RELAY results actually offer another potential option for patients as well, assuming this is FDA approved and recently the RELAY results have led to a favorable ruling from ODAC which often precedes an FDA approval for a regimen.

Now the RELAY results were as follows. It was a study comparing erlotinib and ramucirumab versus erlotinib alone, or erlotinib with a placebo. And that showed a significantly improved progression-free survival, which was the primary endpoint of the study. The PFS in that study was 19.4 months as compared to 12.4 months for erlotinib alone. That’s a 7-month improvement in PFS. Now, it’s worth nothing that in the FLAURA study, osimertinib as monotherapy had an 18.9-month PFS. That’s slightly shorter than was seen in the RELAY study. If you look head-to-head with erlotinib and ramucirumab versus osimertinib, that frontline PFS results are really comparable between the 2.

Now, this brings up the question, why would one take an IV drug, ramucirumab in combination with erlotinib when you could just start with osimertinib? Well, starting with osimertinib is unquestionably still a reasonable treatment option. But I think a lot of people would consider erlotinib and ramucirumab, including myself, in good performance status patients who do not have CNS metastases because you still have the ability to use osimertinib later. So, in other words, if you start with erlotinib and ramucirumab, just about half of the patients then subsequently develop at the time of resistance, a T790M secondary mutation. And T790M mutations can be successfully treated with osimertinib. That was the original FDA label for osimertinib.

So if you start with erlotinib and ramucirumab one can then move on to osimertinib later, whereas if you start with osimertinib at the time of resistance, currently there are no FDA approved targeted regimens for resistance mechanisms that might emerge for osimertinib. Those resistance mechanisms are diverse, one from our group and a number of other groups, have shown that patients with osimertinib, who are receiving osimertinib, can develop resistance by a host of different mechanisms that include 

 mutations and so forth. In fact, there is a whole variety of different resistance mechanisms, and in a lot of cases the resistance mechanisms can’t be seen by a genetic profiling. The reason why we may start with erlotinib and ramucirumab is at least open the option of osimertinib later if T790M alterations develop, whereas if you start with osimertinib, you don’t have the option of erlotinib and ramucirumab later.

How does PD-L1 status factor into the decision making here? Well I noted that the PD-L1 level, the TPS score was 20%. And for a patient who doesn’t have a driver alteration, with a TPS of 20%, you certainly may think about immunotherapy as an option.

But I think it’s important to note that patients with EGFR mutations do not typically have good responses to immunotherapy. In fact, in retrospective studies, the response rates for EGFR-mutant patients to single-agent immunotherapy is typically on the order of 5% to 10%, as compared to a targeted agent, if you’ve got a typical EGFR mutation where the response rates are in the range of 60% to 70% typically.

mutation between a PD-1 or a PD-L1 inhibitor or a targeted agent, the targeted agent is always the way you want to go to start with. And we typically reserve the immunotherapy further down the line after chemotherapy for patients with 

So, if you put those factors together, in fact there was a typical 

 mutation, and brain metastases were not present, I think the choice of erlotinib and ramucirumab would be a very reasonable treatment option here.

Other reasonable treatment options would include osimertinib and the other older EGFR inhibitors is afatinib, gefitinib, and erlotinib are still FDA approved. But given the recent results of the RELAY study, as well as the FLAURA study, I would usually think of adding osimertinib first or erlotinib with ramucirumab if that regimen is approved.

Treatment Options for EGFR+ NSCLC

: The RELAY study compared erlotinib and ramucirumab versus erlotinib with placebo.

What’s the preclinical rationale for the RELAY study? Well, it’s been known for some time that tumors with 

 mutations upregulate VEGF and the VEGF pathway. This appears to be, at least in part, through something called the HIF pathway. HIF stands for hypoxia-inducible factor.

Normally when cells have low oxygen, they turn on this HIF pathway, and that turns on all these factors that help the cells survive. In fact, the Nobel Prize in Physiology or Medicine this past year was awarded for understanding the mechanisms underlying this HIF pathway. It was awarded to Bill Kaelin, MD at Dana-Farber Cancer Institute, as well as Peter John Ratcliffe, FRS, FMedSci and Gregg Semenza, MD, PhD, who’s at Johns Hopkins Medicine for showing how this mechanism works.

 mutation, when you turn on this HIF pathway, that leads to VEGF getting upregulated. They’re highly dependent on the VEGF pathway for these tumors to survive. And that’s why we believe that 

mutated tumors are particularly vulnerable to VEGF inhibitors like bevacizumab or ramucirumab. And this has been observed now in a number of different studies.

Early on, the BeTa study was conducted, that was erlotinib with bevacizumab, and that was in unselected patients. But it was noted that the patients with 

mutations were really the group that got the most benefit from adding a VEGF inhibitor. Building on those results, the RELAY study was designed testing erlotinib and ramucirumab, a VEGF receptor-2 blocker, as compared to erlotinib and placebo.

Now, it is worth noting in that study, the patients had to have a typical 

 mutation, either exon 19 deletion or the L858R mutation. And this patient in this case had an exon 19 deletion, and would certainly be suitable for it. They had to have a good performance status and then did not have untreated brain metastases, as this patient did not have. Now, in this regimen, there were 449 patients who were randomized, 224 in one arm, 225 patients to the other, the 2 arms were pretty well balanced. And overall, the study showed that progression-free survival [PFS] was significantly improved with the ramucirumab plus erlotinib combination. The progression-free survival on the treatment arm was 19.4 months versus 12.4 months in the control arm, so that’s a 7-month improvement in PFS. Seven months is really a remarkable difference. If you think back of all the studies with EGFR-targeted agents, typically we were seeing just a couple of months difference, even if you compared, for example, gefitinib or erlotinib versus chemotherapy. Here you’re comparing an active regimen, an EGFR inhibitor, erlotinib, versus the combination, and you’re still improving on erlotinib by 7 months in terms of PFS. So really a striking difference.

What about this patient’s response to erlotinib plus ramucirumab? Well, the response I think in many ways is a typical one, with initial regression and tumor shrinkage. More shrinkage, it seems, with patients with typical 

mutations does happen in the first 8 to 12 weeks. Patients often get rapid benefit, and then it’s often followed there by sustaining stable disease for a long time. This patient we saw at 18 months. The patient still had stable disease after the initial partial response, and that’s typical. Again, the median progression-free survival for patients with this regimen is 19.4 months, and I’ve seen patients with regimens like this going on for years in many cases. I think prolonged benefit and good tolerability are the hallmarks of first-line regimens for 

-mutated non–small cell lung cancer now. So in that sense, this patient’s response is really a typical one.

Practical Implications of the RELAY Trial in EGFR+ NSCLC

: What about the toxicities of this regimen? There were more adverse events noted in the ramucirumab arm, but overall these toxicities were, as expected, based on what we already knew about ramucirumab, and readily managed. In particular, patients treated with ramucirumab had higher rates of hypertension, and hypertension is a well-known class effect with drugs blocking the VEGF receptor. And that’s typically managed with antihypertensives as well. There was increased risk of proteinuria, and proteinuria is something that is picked up on laboratory tests and also happens with the VEGF receptor inhibitors. It’s not something that patients can typically notice. It really just has to do with their laboratory testing.

There were some adverse events of special interest. There was a bit more bleeding. Most of this was epistaxis, or nosebleeds that would happen. This is an adverse effect that also happens with VEGF inhibitors, thought to be related to the mucus membranes getting dried out a bit in the nasal canal. Again, this is not something that’s limiting, and it’s typically readily managed. But those were the primary adverse events that occurred at an increased rate in the ramucirumab arm. There were slightly higher rates of diarrhea, acne, and myelosuppression, but none of those were clinically significant differences between the 2 arms. Overall, the adverse events were as expected, readily managed, and something that we had experience dealing with because ramucirumab is a drug that’s been FDA approved for a long time, and we have a lot of experience with these adverse effects.

In fact, my experience with ramucirumab has been consistent with what’s been seen in the RELAY study. I have a lot of experience using it for years in combination with docetaxel, based on its earlier FDA approval. And I find that patients can be readily managed. Hypertension does occur occasionally, and sometimes we have to start additional antihypertensive regimens. I commonly use calcium channel blockers or β-blockers in this situation, but in general, patients do very well. And it’s exceedingly rare, at least in my hands and in the RELAY study, that I would have to stop the ramucirumab because of adverse events. That’s the safety and adverse events, and I think in general the RELAY regimen was well tolerated overall and readily managed with predictable and known adverse events. There was an increased rate of adverse events in the treatment arm, but again, in the context that it dramatically improved overall outcomes, I think a favorable benefit versus risk ratio in that setting.

What about the safety and efficacy of other treatments out there? Well, the other treatment that I would use most commonly would be osimertinib based on the first-line FLAURA study. Osimertinib is a very good drug in the first-line setting for patients with typical 

 mutations. The median progression-free survival [PFS] with osimertinib by itself is 18.9 months, compared with the 19.4 months in the RELAY study. Compared to erlotinib or the first- or second-generation drugs against which it was tested in the FLAURA study—erlotinib or gefitinib—osimertinib has a favorable safety profile. It’s got slightly lower rates of acne. It still does have diarrhea, but the rates are a little better overall. And in general, patientsdo very well with osimertinib. I think in particular the lower rates of skin toxicity make this a particularly appealing option.

Osimertinib absolutely remains an option, and I would typically go with one of those 2 regimens, osimertinib, or if FDA approved, erlotinib and ramucirumab, compared to the other regimens. I would particularly go with osimertinib with patients who present with brain metastases in the beginning because of the well documented efficacy in the CNS [central nervous system] for osimertinib, based on a number of studies. That would be an option that would push me toward osimertinib as opposed to erlotinib and ramucirumab, but I would certainly discuss both options with a vast majority of patients who present with the typical 

I mentioned already that ramucirumab adds significant efficacy on top of erlotinib as seen in the RELAY study. Would it add similar efficacy if we combined ramucirumab with osimertinib and really put those 2 things together? And I certainly think that’s an extremely promising regimen. As part of RELAY, they have opened an arm C where they’re looking at that combination. In my group, we’ve opened a multi-center study. This is led by Xiuning Le, MD, at The University of Texas MD Anderson Cancer Center, testing ramucirumab and osimertinib versus osimertinib. There we’re using every-3-week ramucirumab. And there are similar studies testing VEGF inhibitors with osimertinib, for example, bevacizumab with osimertinib is also being studied in randomized trials. I think both the preclinical rationale and all the clinical data so far strongly support that VEGF inhibitors can offer benefit in patients with 

-mutated non–small cell lung cancer. And the RELAY trial is the first randomized phase 3 that achieved its primary end point in terms of PFS and showed a really striking benefit.

Is there going to be an overall survival benefit? Well, the overall survival data thus far are not mature, so certainly we’re waiting to see the results of that. But the results we have seen so far really do show a striking magnitude of benefit, 7-month improvement in progression-free survival with ramucirumab plus erlotinib compared to erlotinib alone. From my perspective and given that patients who start with that regimen often then go on to osimertinib later, so you can have 2 lines of EGFR-targeted therapy. Certainly, from my perspective, this becomes an appealing first-line option that I would offer to the vast majority of patients who present with an

 exon 19 deletion or an L858R exon 21 point mutation, so-called typical mutations.

Manageable Adverse Effects Associated With Treatments for EGFR+ NSCLC

: What happens at the time of progressive disease for patients like this with a typical 

mutation who were treated with a first-line regimen? Well, if the patient has progressive disease that can be readily biopsied, I typically will try to get a tissue biopsy. If not, I’ll order a liquid biopsy. Liquid biopsies have the benefit that of course it’s less invasive getting a blood test than a tissue biopsy. They have the drawback that they don’t always detect the alterations. Typically, for 

 mutations, most studies show that they detect somewhere between 85% and 90% of an 

 mutation. I think our experience is consistent, so they’re very good, just not perfect for picking up alterations. I think it’s reasonable to start with either option.

I do think it’s important to test at the time of progressive disease for patients with 

 mutations because there are alterations that can occur that are targetable. What are some of those alterations? Well, if somebody is getting a drug in the first-line setting, a first- or second-generation drug like erlotinib, then they have close to a 50% chance of developing T790M, a secondary alteration. And in the RELAY study, whether patients got erlotinib alone or erlotinib with ramucirumab didn’t seem to really impact the resistance mechanism. In both cases, T790M was detected in roughly half the cases, and that was just by liquid biopsy. And if they did have T790M, then osimertinib would be indicated.

Now, what if you start with osimertinib? If you start with osimertinib, we don’t have any FDA-approved regimens, but we do have a number of good clinical studies for patients who have progressive disease. For example, if you developed a 

amplification, we have a number of studies now testing MET inhibitors combined with EGFR inhibitors that show promising activity. Some of the MET inhibitors that are in clinical testing right now include savolitinib, capmatinib, and tepotinib, and they all showed promising results in this setting. It’s possible to get additional

 alterations, and some of those additional 

alterations may actually be responsive to other EGFR inhibitors.

I do think it’s important to do testing. There have even been reports, there’s one from Zosia Piotrowska, MD, and colleagues at MGH [Massachusetts General Hospital] where they showed 

fusions coming out in patients with EGFR inhibitor resistance. And there was a response subsequently to RET inhibitors. And we’ve also seen 

 fusions arise in the setting of EGFR inhibitor resistance as well. I do think that it’s really important for patients to undergo molecular testing at the time of progressive disease. I think the good news is that more treatment options are coming out for patients who do have progression after EGFR inhibitors. Right now, the most common one for someone who starts with erlotinib will be osimertinib if you had T790M. But I’m expecting in the near future there will be a lot more options emerging.

What other treatment options are there for patients who progress after an EGFR inhibitor? Well, if they don’t have a targetable alteration, then chemotherapy certainly remains an option. Personally, I always try to incorporate a VEGF inhibitor with chemotherapy. For example, the ECOG 4599 regimen with carboplatin/paclitaxel, and bevacizumab, or the IMpower150 regimen, or find some way to use bevacizumab with platinum doublet chemotherapy, just because we know that patients with 

mutations depend on the VEGF pathway so much.

The KEYNOTE-189 study, which had tested platinum doublet with pembrolizumab, did not include patients with 

mutated non–small cell lung cancer, the KEYNOTE-189 regimen is not FDA approved. I typically would use a platinum doublet regimen. I try to include bevacizumab wherever possible as long as the patient didn’t have a contraindication to bevacizumab. And I reserve immunotherapy for after platinum doublet chemotherapy, unless the patient had very high PD-L1 levels. If the patient had a PD-L1 level of greater than 50%, I might consider doing immunotherapy first, but it’s very rare for patients with 

 mutations to have a PD-L1 level that high. Typically, they have low PD-L1 levels. A platinum doublet would usually be the next regimen and then considering immunotherapy, or docetaxel, or docetaxel with ramucirumab after a platinum doublet.

We really want to stretch out the time for which patients are on an EGFR inhibitor, and I think this is an important concept. I think patients being treated for 

mutated non–small cell lung cancer really think of their time on EGFR inhibitors as where their quality of life is usually very good, really dealing with some mild and manageable adverse effects from the EGFR inhibitor. And then when they stop on the EGFR inhibitor and move to chemotherapy, that’s often where the quality of life can be compromised by the treatment to a significant extent. The treatment is still worth carrying out, but I and I think most oncologists, really try to stretch out that period on EGFR inhibitors for as long as possible.

Let me mention 1 other option for people treated with a first-line EGFR inhibitor who only have progression at a couple of sites, we call that oligoprogression, I’ll often recommend local therapy to those sites. For example, let’s say this patient subsequently had progression, and there was only 1 bone metastasis, or bone metastasis and 1 spot in the lung, I would commonly radiate those 2 spots. And then if the patient had a T790M, switch over to osimertinib. If they didn’t have a T790M, I’d often continue the treatment that I was using.

We recently reported, for patients on osimertinib, that if you consolidated them at the time of progression with radiation, they could go on for another year on osimertinib. This shows you that even after progression with consolidative radiotherapy, you often can get durable benefit afterward. I think you want to be as creative as possible at figuring out how to keep using EGFR inhibitors for as long as it’s clinically indicated, either by finding alterations that can be targeted with the combination, like T790M, or consolidating the sites of progression, if it’s only a couple, and continuing the regimen.

Repeat Testing at Progression of EGFR+ NSCLC

: To give a summary about the changing landscape of

mutated non–small cell lung cancer, I think this is a really exciting time, and we’re seeing clear advances. And the survival in these patients has gone from less than a year not very long ago to now more than 3 years, heading toward 4 years. A lot of patients have a much more durable benefit than that. A way to think about the landscape now, these are for typical 

 mutations, the exon 19 deletion, or the L858R, in the first-line setting we now have third-generation inhibitors, like osimertinib, that are clearly better than the first- and second-generation inhibitors.

But we also have the option of adding a drug like ramucirumab, assuming this regimen is FDA approved from the RELAY study, to a first-generation inhibitor and then using the third-generation inhibitor later in the treatment paradigm. I think these are 2 ways the landscape is shifting, either starting with a third-generation inhibitor or starting with a first- or second-generation inhibitor with the addition of a VEGF pathway inhibitor like ramucirumab.

What about at the time of resistance? Well, we’re developing more and more tools to tackle resistance. Right now, if there’s a T790M mutation as the mechanism of resistance, we can switch to osimertinib. There are a lot of clinical studies underway to look at targeting, for example, 

amplification as a resistance mechanism. There are some other atypical mutations that can emerge as resistance mechanisms to EGFR, like C797S, or mutations at L718 in 

 or L792 where we may have EGFR inhibitors in the near future that are effective.

I think what’s going to be developing over the next few years is more and more treatment options for smaller subgroups of resistant 

-mutated disease. Then after that we still have chemotherapy and we still have immunotherapy. Immunotherapy is not particularly effective for patients with 

-mutated disease, but occasionally it can provide benefit. I think our group and many others are working on ways to activate the immune system to get immunotherapy to work better for these patients. I think over the next few years, you’re going to see better regimens for targeting resistance in EGFR-mutated disease and more ways to activate the immune system for this group of patients.

A 68-Year-Old Man With Metastatic EGFR+ NSCLC

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