Managing EGFR+ Metastatic NSCLC

Rasheda Persinger: This is managing EGFR+ metastatic non-small cell lung cancer patients. We've already went through this. We know the faculties, disclosures, planning committee information. Our learning objective, to evaluate efficacy and safety data, supporting the use of targeted and immune checkpoint inhibitor therapy used to treat non-small cell lung cancer. And as before we'll start with the question, do you want to ...

Beth Eaby-Sandy: Which EGFR mutation ... Oh, before I read the question, can I just make sure everybody votes. It's the only way that we get our metrics, and that's how we get funding for the conferences, is to see if people are voting and how they're voting. So even if you're not sure and you don't know the answer, just answer unsure. Believe me, none of it's tied back to your name or who you are, so it's okay. Just please vote. So which EGFR mutation is not usually sensitive to EGFR inhibitors? Is it Exon 19 Deletion, the L858R, the G719X, the Exon 20 Insertion, or I'm unsure?

Rasheda Persinger: Right, exactly.

Beth Eaby-Sandy: And remember you can ask questions through the iPad, though it might take forever to type them so I'm happy with you just asking them as we go, with raising the hand or whatever. Okay, according to this group, pretty much all of them are. So we will talk about that. And then for a patient needing treatment for an EGFR+ tumor, which would you choose based on its designation as the NCCN guidelines preferred first line agent. Is it afatinib, erlotinib, osimertinib, or none, they are all FDA approved for first line EGFR+ non-small cell lung cancer, or I'm unsure? Okay. All right, so we'll talk about that as well, Rasheda.

Rasheda Persinger: All right, let's go ahead and dive in. So EGFR and non-small cell lung cancer, overwhelming majority of EGFR mutations found in adenocarcinoma type of non-small cell lung cancer, rare in squamous but they can happen, which we spoke about earlier, and also rare to have two different mutations. But remember if that is, that they are usually mutually exclusive.

Beth Eaby-Sandy: Yeah, so meaning it would be really uncommon to have EGFR and ALK.

Rasheda Persinger: Yeah.

Beth Eaby-Sandy: It's happened, it's less than 1% of the time that you would have two different mutations. And obviously that gets hard to then determine which drug should treat, which.

Rasheda Persinger: I think not more common, but it may be possible you see it a little bit more often is that if you have a mutation, such as the EGFR and [inaudible 00:03:02], and then maybe squamous cell or a different histology [crosstalk 00:03:07]. Sensitizing mutations in normal cell lung cancer, we've seen this before. It adds in the method, was not on the previous slide, as well as the end track. So this is just a diagram to kind of give us the epidermal growth factor-induced signal transduction and tumorigenesis. Just to kind of get us how the mechanism is working and what is the mechanism working on. Epidermal growth-factor receptor is a tyrosine kinase growth factor receptor, activated by binding of natural lichens. Activation of EGF linked with increased cell proliferation, angiogenesis, metastasis, and EGFR expression correlates with poor response to treatment, disease progression and poor survival.

Beth Eaby-Sandy: And that would be obviously with our standard treatments, before we had EGFR inhibitors, which obviously work much better. And I think the take home message here on this slide, this is a driver mutation. So when you hear that term, if you have an EGFR mutation, this is a part of your tumor cell that is turned on because of this mutation and it drives your cancer growth. So obviously our treatment strategy should be to stop that driver mutation.

Rasheda Persinger: So epidemiology of EGF-mutated non-small cell lung cancer, just shows us what we've kind of already talked about thus far. EGF mutation most common; females, never in minimal smokers, Asian ethnicity. Study of 3026 lung adenocarcinomas, EGFR was found in 43% of never smokers and 11% of smokers. Mutation frequency and distribution in Asian and Caucasian population. Graph A and B is just showing the mutations frequency of the difference, EGFR, KRAS, ALK and so forth. Graph C and D is breaking down EGFR in their particular mutations and showing you the comparison. Which you see, though it is more known in Asia, when you break down the EGFR, the Exon 19 versus Exon 21 is kind of similar [crosstalk]

Beth Eaby-Sandy: It is, it is. I mean there's slightly more, I mean there's more L858R, which is the Exon 21 in Asians and Caucasians, but otherwise it's somewhat of a 50/50 split.

Rasheda Persinger: Exactly.

Beth Eaby-Sandy: But you can see, if you are of Asian ethnicity, you have about a 50% chance of having an EGFR mutation. So if you have that patient, and you get a negative result, I might keep looking. You know, really have a high suspicion in those patients with lung cancer, especially if you're never a smoker.

Rasheda Persinger: So uncommon EGFR mutations. One thing that we know, that there's a driver mutation too, is the T790M. The other mutations, do you want to speak on there?

Beth Eaby-Sandy: Well, I mean, the two most common types that you're going to see is Exon 19 and 21, but you can see that there's a lot of other uncommon EGFR mutations. And some of these are responsive to EGFR inhibitors and some not, and I think that Insertion 20 is usually not sensitive. And when I talk later on about clinical trials, there is actually drugs now in clinical trials to look at that resistant form. Some of these other ones are sensitive to EGFR therapies and we're going to talk about those.

Rasheda Persinger: Yes, mm-hmm (affirmative). So how do we test for EGFR mutation? We kind of talked about it earlier. Tissue wise; DNA sequencing panel, NGS, not an "expression", not found on IHC or FISH, takes time due to NGS sequencing. And just again, it's just reiterating that take home point, that not 100% sensitive. Why? Poor specimen quantity based off of lung cancer being heterogeneous. Those are the things of why it's not 100% sensitive. Same with blood. We've talked about it before. Reason why it's not 100% sensitive is because it depends on how much it's being shed in the ... How much of the DNA is being shed in the blood. Who do we test for EGFR mutations? You can never treat with EGFR inhibitors if you have never found the EGFR mutation, just reiterating that.

            NCCN guidelines, we spoke about it before. All patients with non-squamous metastatic non-small cell lung cancer, and in squamous patients we just want to look at the clinical picture. Consider testing EGFR. This is a breakdown of the different TKI's that are approved for EGFR mutated non-small lung cancer. It tells you the administration schedule, the indication and the dosing of them. So now we're just going to kind of go through each of them, kind of briefly reiterate some points that most of us probably have either heard of, or familiar with. And if not, hopefully educating you a little bit more. So gefitinib was the first drug on market, approved around 2004 for metastatic non-small cell lung cancer. Second line, because we were still trying to figure it out. What is EGFR?

Beth Eaby-Sandy: We didn't know what EGFR was at the time.

Rasheda Persinger: Pull from market due to fertility over chemotherapy at the time in general population, re-approved in the US many years later for only EGFR mutated patients. Was found to be inferior to afatinib in a head-to-head first line study. Causes less rash than most EGFR inhibitors.

Beth Eaby-Sandy: So, Rasheda, do you have anybody on gefitinib?

Rasheda Persinger: No.

Beth Eaby-Sandy: Yeah, I don't anymore either. This was the first drug that was approved, and I remember when it was approved, we did not know what EGFR was at the time. No, not even when it was approved, but when we had it in a clinical trial at Penn, it was in 2003 and I will never forget ... This Asian female never smoker came in. Wheelchair, oxygen, she was dying. It was really sad. She was only like ... she's was maybe 38 years old, her little kid was on our lap, and we decided to enroll her in this study. It was expanded access at the time, and two weeks later she walked in with no oxygen. And I was like, "Oh my gosh." I had never seen anything like that. I mean all we had was paclitaxel and carboplatin back then.

            And, you know, it took us a while to figure out ... And I never confirmed that she had an EGFR mutation. Obviously now, looking back, I assumed that she did. And she did very well for a long period of time, but it took another couple of years, even after gefitinib was approved, for the lab and scientist to realize, oh it's because of this EGFR mutation. And that's why these patients are responding well. So it was almost like this was the first drug approved, not knowing that. And then we worked backwards, and it got pulled from the market because it wasn't better than chemo in the general population. Well of course it wasn't, it was only better in that sub-select EGFR mutated population. So it was an interesting story of drug being approved, but kind of for the wrong reasons on response rates, initially, until the confirmatory trials. And figuring out who is the targeted population.

Rasheda Persinger: And I will correct myself is that, we've had a couple that have come in with, or been on this drug, and one particular one that I can think of more recently where we have switched them to osimertinib, not that we did the testing to see if they had the T790 mutation. They were on the gefitinib for, I would say, at least four years, but have this slow growth. And so because of that, and they were Asian descent, we highly knew that if we did the tissue biopsy we probably would get negative T790M and if we did, if we did a liquid plasma, it's not shedding much in the DNA so it would probably be negative. So we made the clinical judgment of proceeding with osimertinib and there was a response.

Beth Eaby-Sandy: Yeah. And I think the feeling, and not to belabor gefitinib, we can move on, but I think the feeling was this is probably the less potent EGFR inhibitor in the first generation.

Rasheda Persinger: Yeah. So erlotinib was the second EGFR inhibitor approved, initially similar to gefitinib, in second line setting of all metastatic non-small cell lung cancer. Once we figured out EGFR mutation, it was only approved in this setting where it was clearly superior to chemotherapy. Caused more rash than gefitinib, however, was the mainstay of EGFR first line therapy for years. Afatinib, the third EGFR inhibitor approved, causes significantly more rash and diarrhea than either of its predecessors. Superior to gefitinib in head-to-head studies, has niche approval in second line squamous and first line for uncommon EGFR mutations. And I'll go back to the second line, squamous, because for some that may be like, really?

Beth Eaby-Sandy: Yeah, I know.

Rasheda Persinger: So there was a study that looked at, after they had progressed, and I'll let the pharmacists in the room to correct me if I'm misspeaking, but after they had progressed off of a platinum-base, after four cycles, and then they were noted to try ... Or they, in this trial, they used the afatinib and they compared it to afatinib and erlotinib in this study. And in this study it showed that afatinib had superior to erlotinib when looked at this subset, and the median overall survival was 7.9 months versus 6.8 when they compared the two.

Beth Eaby-Sandy: Yeah, so not earth shattering data, but remember we talked about in the beginning that lung cancer is commonly overexpressed EGFR. And I think afatinib is a pretty, is very potent. It's a pan-HER inhibitor, so EGFR is HER1. So it does seem to cover more than just EGFR and HER1, and my personal reason for thinking it works a little bit in squamous is because they overexpress EGFR a lot. And while it's not targeting a mutation, it still is having some antitumor benefit, is my kind of thought process. I don't think a lot of people use it. I don't know that I've ever used it. I just wanted to say it has that approval and it's been studied there. And then those are the other uncommon EGFR mutations. Afatinib is the only one that has approval for these uncommon, and they're really uncommon, but they do Harbor some sensitivity to EGFR inhibitors. So if you had any of those uncommon EGFR mutations, you could use afatinib. It has shown to work for some of those.

Rasheda Persinger: Now let me ask you, Beth, I know here recently we had a patient who harbored ... They started on osimertinib and then they progressed, did a biopsy, and found one of these uncommon mutations. And we put her back on, or put her on, afatinib.

Beth Eaby-Sandy: Yeah, that's a reasonable treatment strategy. I mean, these are not necessarily ... I mean they can be, as resistance mutations, but a lot of times these are de novo. They're found upfront, they're just uncommon. So they're probably less than 5% of EGFR inhibitors, or mutations, that are found upfront.

Rasheda Persinger: So osimertinib is the fourth EGFR inhibitor to be approved initially for T790M resistance mutated positive in the second line setting. However, after the FLAURA trial, now the preferred first line treatment for EGFR mutated non-small cell lung cancer, per the NCCN guidelines. FLAURA significantly improvement in the progression-free survival over either gefitinib or erlotinib in the first line setting. Also causes less rash than prior EGFR inhibitors.

Beth Eaby-Sandy: Dacomitinib.

Rasheda Persinger: Thank you. We don't use this at all. Fifth EGFR inhibitor approved in 2018, is more toxic than most EGFR inhibitors. High rate of rash. Head-to-head was superior to gefitinib in first line setting for overall survival, with a median overall survival of 34.1 months versus 26.8 months. Again, I have no really personal experience, clinical experience, with using this drug.

Beth Eaby-Sandy: Neither do I. This was the most recent drug to be approved, and again, it is a pan-HER inhibitor, so it does kind of cover a broader base. But there's no head-to-head data in osimertinib, or afatinib for that matter, that are the more recent generation. And this drug is toxic. I've had patients on it in clinical trial. So I don't think this is a drug that's being commonly used very often, but presenting it because it was the most recent EGFR inhibitor approved.

Rasheda Persinger: So which drug to use in first line setting of metastatic EGFR mutated non-small cell lung cancer? So this is just multiple trials that look at this comparison; chemotherapy with different EGFR mutation, and it just speaks to the fact that patients with EGFR mutated non-small lung cancer, that they benefit more with EGFR targeted medication versus chemotherapy.

Beth Eaby-Sandy: Yep. It's always better. It's always better for your targeted therapy first over chemotherapy.

Rasheda Persinger: So this is the FLAURA study, design first line osimertinib trial versus gefitinib. I always bring, to your point in terms of inclusion criteria, that included those with CNS mets. You know, I think that's very important in what we do because most of our patients present to us in more stage four, probably a lot of brain mets, And so it's important to know that some of these trials are including that population. But it is key to note that it has to be stable CNS metastasis allowed, which means no steroid, if I'm not mistaken.

Beth Eaby-Sandy: Usually they should not be on steroids anymore, for stable.

Rasheda Persinger: And so, generally, because I won't break it down as much, but the end points of this study was; progression free survival based on investigator assessment. The study had 90% power to detect a hazard ratio of 0.71 at two sided alpha level of 5%, and the secondary endpoint was objective response rate, duration of response, disease control rate, depth of response, overall survival and patient reported outcomes. As you can see it was stratified into, based off of the Exon 19 Deletion, you were to osimertinib versus EGFR, either gefitinib or erlotinib, is what the two arms were. And crossover was allowed for patients in the standard of care arm who could receive open label osimertinib upon central confirmation of progression in T790M positivity. So this is the investigator assessed, progression free survival, which you can clearly see the widen graph there, where it show that the progression free survival was 18.9 months versus 10.2. Which is huge.

Beth Eaby-Sandy: This was another fall off my seat in my chair. I remember, in clinic, this data was presented at ESMO a couple of years ago and this was huge. At this time we were using erlotinib for everyone first line. And to see that this drug that we had been using, the second line setting almost doubled the progression free survival, was like, "Oh my gosh, what have we been doing? This is what we need to be doing first line." So it's very clear why the NCCN guidelines has this as your preferred first line treatment.

Rasheda Persinger: And so the overall survival data not reached, but apparently has been reached, and will be presented in late 2019. Stay tuned. As you can see, though, you can still see the osimertinib kind of plateaus and just kind of ... Still, there's some benefit with osimertinib than versus [crosstalk 00:18:08]

Beth Eaby-Sandy: And there's a hazard ratio of 0.63, so we know that it appears to be better statistically. We just don't know what the median is yet and I think they're going to present that at ESMO soon.

Rasheda Persinger: So the mechanism of acquired resistance in EGFR; multiple possibilities, many can be detected on blood tests, can and should also re-biopsy if possible. Blood will not detect small cell transformation, we said that earlier, other than small cell lung cancer. Other resistance mechanisms; hard to manage outside of clinical trial, and C797S is common tertiary resistance mechanism to EGFR T790M. Toxicities of EGFR inhibitors, we kind of mentioned, but we'll kind of dig into it a little bit more here. Why does EGFRs inhibitor rash occur? The epidermis relies on the EGF. The keratocytes located in the basal layers of the epidermis express elevated levels of EGF.

            Inhibition of EGF will result in negative effects on cell growth in this layer of the epidermis. This results in thinning, which decreases the ability of skin to hold in moisture. The damage also causes a recruitment of the immune system response, and thus a pustular eruption. Meta-analysis on EGFR rash and clinical benefit. Liu and colleagues reviewed 33 studies of the EGFR TKI's, which reported rash and clinical benefit. Rash was a significant predictor of clinical benefit for non-small cell lung cancer patients receiving EGFR inhibitor therapy. Rash predicted overall response rate, longer progression free survival, and longer overall survival. My question to you, Beth, though-

Beth Eaby-Sandy: [inaudible] of the study.

Rasheda Persinger: Yeah, right, because with osimertinib we don't [crosstalk] see a lot of rash.

Beth Eaby-Sandy: So that's why I want to be clear with this, is this was reported in 2013. But since then, with osimertinib, which causes virtually very minimal rash, we have not seen that correlation. So just because they're not getting a rash from osimertinib doesn't mean they're not responding. As a matter of fact, they respond often to osimertinib without rash. So this was based on more the first and second generation EGFR inhibitors.

Rasheda Persinger: So rash incidents by drug. You see this here, any grade rash versus the grade. You'll see when we started with gefitinib versus osimertinib in grade three, four, as well as when you compare that with erlotinib and afatinib. Such a decrease in seeing that grade three, four. And I know in our clinic, I can count, maybe on one or two hands, any type of rash. If anything it's the dry nails or something like that.

Beth Eaby-Sandy: Exactly.

Rasheda Persinger: [crosstalk] Definitely not a rash, yeah. So this is the FLAURA trial adverse events. Just further talking about the dermatitis effects. When you look at osimertinib compared to the standard of care, meaning the other EGFR drugs that were used prior to that. I will tell, pay attention to ... Because, osimertinib doesn't come with some side effects, which is the elevated liver function tests that we see with all the EGFR drugs, and so, just something to kind of keep an eye on and to monitor. So grade two EGFR rash, here's a picture here. Moisturize. What do we do? Moisturize. Thick cream, no fragrance or dyes. Topical, either clindamycin gel or fluocinonide 0.05% cream, may add oral doxycycline or minocycline. Not recommended is vitamin K cream or acitretin, but I will say, again, in osimertinib I have never had to use this thus far. I don't know about your experience.

Beth Eaby-Sandy: Right, all of these patient ... Well actually, it's funny, just yesterday the physician I work with texted me that somebody did have some rash on their face for osimertinib and she was like, "What do you use because we haven't treated this a long time." So that's what I told her, topical clindamycin gel. If it's a little bit worse, maybe some oral doxycycline, 100 milligrams twice a day. All of these recommendations that you're about to see for dermatologic and other toxicities are in the paper that you can see there. Which I can't believe was that long ago now, but 2011 was the mask skin toxicity guidelines, which I was part of that study group. So we really put a lot of time and effort into the literature. Mostly derm literature, to be honest with you, because oncologists aren't that into treating rashes, but that paper does a very thorough review of what is recommended, what's not recommended.

Rasheda Persinger: And again, I think we see this more with afatinib, patients that are still on afatinib and so forth like that. Again, grade three, four rash so you could see the appearance, what you're looking for there. For grade three or four rash, moisturize, sun protection, which I still tell patients even on osimertinib. Sun protection, minimize exposure to heat and hot water, whole drug and likely dose reduce, topical clindamycin or higher potency steroid creams. Alclometasone, fluocinonide, betamethasone, oral doxycycline 100 milligrams bid or minocycline 100 milligrams daily. Be aware of photosensitivity on these antibiotics as well. Systemic steroids are not recommended and MASCC-

Beth Eaby-Sandy: The MASCC paper.

Rasheda Persinger: MASCC paper, sorry, however at times have been used for inflammation.

Beth Eaby-Sandy: Yeah, and this is where I consult with my clinical pharmacist a lot, because I don't know these high medium potency steroid creams. Some of them are not covered by patients' insurances, so I would really talk with your clinical pharmacist about some of these steroid creams. And this goes for IO toxicity rash as well. And they have rules on these high-end, medium potency steroid creams is; you're not supposed to use them so long, you should pulse them. Don't use them on the face. So that gets a little over my head sometimes. So really talk with your multidisciplinary team or dermatologist, pharmacist.

Rasheda Persinger: Paronychias, hands and feet, not just the feet. I always tell patients that, those patients that are on afatinib still. Remember, we're looking at the hands, the toenails and the fingernails. Very diluted bleach soaks; approximately one fourth cup, bleach to three gallons of water. Prevent: keep nails trimmed and clean, loose fitting shoes, biotin. Topical steroids or antibiotics. If you're treating it, systemic antibiotics, nail avulsion and silver nitrate. I don't know for, with osimertinib, obviously I don't see this, but in fact I think we've had a few cases where we've actually sent them to podiatrists because they were just a little bit above what we were used to treating.

Beth Eaby-Sandy: Yeah. So paronychias is really hard because topical and oral antibiotics don't often work. It's just a hard place for you to get systemic, you know, absorption of anything oral. Really, prevention is the key for these, for the most part. But nail avulsion is cutting off the nail, or cutting it out partially. And a lot of times that's what we end up doing with the paronychias on the feet and having dermatologists do that to the fingernails if it becomes a real issue. The most problems we had is on the feet, I don't know. But paronychias actually happened quite a bit with osimertinib as well. It is one of the more common dermatologic toxicities of that.

Rasheda Persinger: I know it's in the literature, but I have not seen it at all.

Beth Eaby-Sandy: I definitely have, and again, it's more ... This woman, I remember her very well. I mean, she died a long time ago, but I mean she loves ... She's like me, and she definitely wore those tight pointy shoes and boots and she loved them, but she used to get these recurring paronychias all the time. So I think some of it is EGFR inhibitor, but some of it is definitely lifestyle and what you're wearing. We see so much less of them in the summer with flip flops and sandals. But a lot of it does end in nail avulsion, unfortunately, in my practice.

Rasheda Persinger: Scalp rash, I think this is important to mention. I'm glad you had this in your slide because sometimes we overlook the scalp, and so, when patients come in and they say, "I just have some itching here," or, "Something just feels like it's discomfort," I always, you know, I have, because I've gotten screwed before of not looking there or catching it early on. I have a habit now of making sure I ask directly, "Are you having any itching? Are you having any soreness to your scalp?" Or something like that, because they may not think to tell you. So moisturizing shampoos with selenium, brands that are sold for dandruff, topical solutions, either in shampoo form or liquid solution, that you apply and leave in. [crosstalk]

Beth Eaby-Sandy: Fluocinolone solution, we've actually gone more to the solution. The shampoo's really expensive, but they make it just in a liquified solution, I don't know how else to explain it, and our dermatologists says, "Just squirt it on the scalp." Like ladies, if you're at the hair salon and they do a glaze or something, you know the same thing. Just put it on the scalp after you've washed it and leave it in, and that can kind of penetrate and get to the scalp easier is what we're told. As opposed to the shampoo, which-

Rasheda Persinger: And it works, it does. It works very well.

Beth Eaby-Sandy: I think so, yeah.

Rasheda Persinger: Again, I've gotten screwed before so that's how I know that it does work there. Fissuring. Prevent: wear gloves, prevent exposure, thick moisturizer, liquid glues to seal cracks, steroid tapes.

Beth Eaby-Sandy: Liquid glue [crosstalk 00:27:12], yeah, Super Glue those babies closed. We're not allowed to put super glue because it's a brand name up there. But I said it. But I mean, literally, you can use it. They make liquid bandaid, also a brand name that we're not supposed to say, but they make these ... So, liquid glues, but just liquid bandaid or super glue and super glue is sterile. It's fine. You can seal cracks, just even people with dry skin use it to seal cracks closed and it just prevents infection. So it may sound weird, but that's the recommendation.

Rasheda Persinger: Hypertrichosis, trim lashes carefully. Again, I've seen this really with afatinib, and to see the ophthalmology for this.

Beth Eaby-Sandy: That totally happens, less with osimertinib, but sometimes.

Rasheda Persinger: Other EGFR inhibitor toxicities, this is just a graph to kind of show you the comparison based off of the grades in comparison to the standard of care. Diarrhea, similar across agents, about 50% more in ceritinib. I have not seen this in osimertinib often. Maybe here and there. They may have a bout of it, but it's not a consistent thing. I'm not for sure if you're seeing something different.

Beth Eaby-Sandy: Yeah, [crosstalk] through ceritinib, which is an ALK inhibitor that we'll get to later. But it was more in afatinib, in the EGFR toxicities. But usually, especially with osimertinib, the main drug we use now, this is pretty easily managed. About half people get it, but with over the counter Loperamide, usually pretty easily managed. So not a lot of dose reductions.

Rasheda Persinger: Not at all.

Beth Eaby-Sandy: Grade three was to 2%? No, 6%? And no grade four severe, life threatening. So, yeah.

Rasheda Persinger: Other EGFR inhibitor toxicities; ILD and pneumonitis, uncommon, but a class effect of EGFR TKI's. In the range of 1% to 4%, however, can be fatal. I think Tyler had mentioned earlier the word of caution, recent data shows that osimertinib given in a short time period after immunotherapy causes significantly increased rate and severity of pneumonitis. I don't think anyone has defined what that wash out period should be, so it's probably just based in, kind of depending on the institution that you work at.

Beth Eaby-Sandy: Yeah. And a rule of thumb for us, we would not want to give osimertinib after immunotherapy within three to six months, and probably more on the six months side.

Rasheda Persinger: Really?

Beth Eaby-Sandy: So this really stresses the importance of knowing if they have an EGFR inhibitor upfront. Because if you start them on immunotherapy, and this just happened recently to a patient we saw as a second opinion. Went back, we were doing the molecular testing, but she went back and she started on chemo immunotherapy with her community oncologist. When I called the oncologist to say we found an EGFR mutation, the patient had already started on immunotherapy. So I said, "At this point, we would not recommend you starting the osimertinib anytime soon." Now I will tell you, in that study, the other EGFR inhibitors did not seem to have the severity of pneumonitis. Now the numbers were small, so I don't know if you can extrapolate that. But that being said, you saw the data for how much better osimertinib is than the gefitinib and erlotinib.

            So I really would still want the osi, what we recommended to that oncologist is to drop the immunotherapy, continue with the chemotherapy at that point, because you've already started it, and stop the immunotherapy. When the patient progresses, if it's within six months, we would not consider starting the osimertinib, and hopefully the patient will get some time from the chemotherapy benefit before. But if the patient is declining, you may have to take that risk. I'm trying to remember the exact rates. I think it was about 50%, so it wasn't severe. It wasn't like 80 or 90% pneumonitis, but when you consider that it's only like 4%, it was way more than that. I want to say it was around 40 or 50% pneumonitis, right?

Rasheda Persinger: So we have a different practice. We don't wait three to six months ... Again, we've got those patients that have come in from outside, because as I mentioned earlier, at our institution we have difficulty in getting immunotherapy approved if we do not have the molecular testing back. And so in patients that we have switched over because they've come to us in second opinion, we don't wait to three to six months. We've waited to ... four weeks, I think is the longest that we've waited. Definitely more than two weeks to give our false wash out period and we proceed. We've gotten screwed before, initially, before all this data came out and information was being known.

Beth Eaby-Sandy: I think the one concern, though, is if you ... if you say, "Okay, I'll take the risk." So the EGFR inhibitors are different than immunotherapy. The pneumonitis is severe and you can never re-challenge, like we re-challenge with immunotherapies. So I think our concern would be if you say, "Well you might get pneumonitis but we can treat it," but then you can never give them osimertinib ever again. The drug that is going to make them live a long time. So our feeling is, wait as long as you possibly can to minimize that risk of pneumonitis before you start the OSI. Because if you start it and they get pneumonitis, you can never use it again. Nor any of the drugs in that class. And then you're really in trouble.

Rasheda Persinger: Clinical pearls can't treat EGFR mutation if you never find it. Must test. Reiterating. It's being said in almost every slide, so don't forget that. Several drugs available; osimertinib is the preferred first line treatment based on current data. And several toxicities, usually many are manageable. And I think we're going to the questions. So which EGFR mutation is not usually sensitive to EGFR inhibitors? Exon 19 Deletion, L858R, G719X, Exon 20 Insertion or unsure? And remember, we just want you to answer even if you're not for sure, just so it can help with the data intake.

Beth Eaby-Sandy: Okay, great. Yeah, so Exon 20 is the one. And like I said, I'm going to talk later about a drug in particular that's in clinical trials for this that has some promise. So that's good.

Rasheda Persinger: For a patient needing treatment for an EGFR+ tumor, which would you choose based on this designation, as the NCCN guidelines prefer a first line agent? Afatinib, erlotinib, osimertinib, none, they are all FDA approved for first line EGFR+ non-small cell lung cancer, or unsure?

Beth Eaby-Sandy: Yay.

Rasheda Persinger: Good.

Beth Eaby-Sandy: So osimertinib certainly is the preferred first line treatment because of that FLAURA trial that we saw that almost doubled the progression free survival. Okay. So thank you very much, Rasheda. Any questions? I guess we could take any questions. We do have a little bit of time, on EGFR inhibitors.

Attendee: So should we just throw away [inaudible 00:34:18]?

Beth Eaby-Sandy: I know. I know, you know, there's still some patients that are on the other EGFR inhibitors. And of course we don't take them off, but going forward, this is ... And one thing we didn't talk about either, is the fact that the osimertinib actually has much better cranial ... intercranial penetration and brain met responses, than the other ones. So there's actually several reasons why it's preferred. It's better intercranial response, it's overall response, it's better tolerated.

Rasheda Persinger: But I will say in a community setting, you will still find that physicians are using erlotinib upfront because, in their thinking process is that, why not get as much use as you can for the erlotinib before you go to [crosstalk 00:35:03].

Beth Eaby-Sandy: Erlotinib, yeah.

Rasheda Persinger: I mean erlotinib, before you go to osimertinib. But the argument is that some patients don't make it to osimertinib, and so you miss a population with the opportunity to get the benefit from osimertinib.

Beth Eaby-Sandy: Yeah.