This is a woman who&rsquo;s a fairly young woman of Chinese descent who is a never-smoker, and she has fairly recent onset of pulmonary symptomscough, chest pain&mdash;and has had several years of recurrent bronchitis. But because of her new symptoms, she went to her doctor and underwent a chest CT where she was found to have a lung mass as well as pleural disease. And she had a biopsy that showed lung adenocarcinoma. A mutation testing was done and it showed an

mutation. What was interesting about that mutation is that it was an uncommon mutation. It was a

Because this woman was a never-smoker, one might think that she&rsquo;s not at risk for lung cancer. But there are patients who have never smoked or have smoked a very small amount in the past who can get lung cancer. Much more commonly, patients who have smoked are at greater risk of lung cancer. But such as this woman, there are patients who have never smoked who can get lung cancer, and mutations such as

are more common in patients who have never smoked.

As I mentioned, what&rsquo;s interesting about this case is that she does have a rare mutation in

mutation. And so, this mutation, while it is uncommon, we do sometimes see it in lung cancer. And it does lead to a sensitivity of the EGFR inhibitor, so it is very important to note that that is present in her cancer. And so, her cancer may have been able to be caught at an earlier stage if imaging was done earlier.

What&rsquo;s challenging in patients like this is that they don&rsquo;t commonly undergo imaging because if they have bronchitis or they have pulmonary symptoms, lung cancer is not usually on the forefront of doctors&rsquo; minds, or a patient&rsquo;s mind, because they&rsquo;ve never smoked. So it&rsquo;s not thought to be a possibility in patients like this, and actually that&rsquo;s probably for a good reason because lung cancer is not common in never-smokers. So, lung cancer screening can be done in patients, but again, not typically in patients who are never-smokers because of the very low risk in those patients.

Recommendations for lung cancer screening currently are patients who are between the ages of 55 and 80 who have a history of smoking 30 pack years or greater and either are current smokers or have quit in the last 15 years. So, those are patients who are at the greatest risk of having a lung cancer, and that&rsquo;s why they&rsquo;re included in the recommendations. There was a trial that looked at patients who fell into that group, and those patients were screened using a low-dose CT scan looking for abnormalities. And it was found that if you did a low-dose CT scan that you could find abnormalities that then potentially could lead to the diagnosis of lung cancer and decrease the risk of lung cancer death. And so, that now is the recommendation to screen patients with those factors. So, you can see that this patient would not have fallen into that; she had no history of smoking at all. And so, that&rsquo;s why she did not get a lung screening and she only underwent a CAT scan once she developed symptoms.

Case Overview: EGFR-Positive NSCLC

mutation, so it&rsquo;s not at all unexpected that she&rsquo;s wild-type for

. In general, we do test for many mutations at the diagnosis of advanced or stage 4 NSCLC, specifically lung adenocarcinoma. And looking for

are 2 of the most important genes to look at because we have targeted therapies that can work very well for those. There are other genes that are very important to look for mutations in, including

is an interesting one to talk about because we don&rsquo;t have targeted therapies for

. One important reason to check it might be that typically if there&rsquo;s a mutation in

, the other ones are usually negative, although sometimes you can see multiple alterations in genes. But typically, if one is positive, the others are negative if they&rsquo;re mutually exclusive. So, again, in this patient, it&rsquo;s not surprising that since she does have an

mutations that are, by far, the most common in NSCLC, specifically lung adenocarcinoma. That&rsquo;s the exon 19 deletion and the L858R point mutation in exon 21. So, those 2 types of mutations make up, again, the vast majority of

mutations, probably around 90% of the mutations. When we see a patient with an

mutation, that&rsquo;s typically what we see. And those 2 types of mutations typically make the cancer very sensitive to EGFR inhibitors. And so, when we find that, it&rsquo;s usually a very good thing for the patient because we have drugs that can work very, very well for their treatment.

There are several drugs that we have now that are EGFR inhibitors that are options for patients, but those are the common mutationsthat&rsquo;s what they&rsquo;re typically called, the common

mutationsand they are sensitizing as well, meaning they sensitize the cancer to the EGFR inhibitors.

mutations can be in this rare category, or uncommon category. About 10% of them fall into that category. And this patient has one of them, the

mutations that fall into uncommon category. And what&rsquo;s important to note about the uncommon

mutation is that some of them still are sensitizing. So, uncommon doesn&rsquo;t necessarily mean that the drugs won&rsquo;t work, the EGFR inhibitors won&rsquo;t work. Uncommon can be sensitizing to the drug, and that&rsquo;s the case with this patient&rsquo;s mutation. This is the type of mutation that is uncommon; it&rsquo;s rare in

but still can make the cancer sensitive to the EGFR inhibitors.

Mutation Testing in NSCLC

This patient has a point mutation in exon 18 actually, the

mutation. And again, this mutation, although uncommon, does result in sensitivity to afatinib. That&rsquo;s the drug that specifically has been studied in this uncommon mutation as well as other uncommon point mutations.

There was a recent retrospective analysis of several large randomized and actually nonrandomized trials. So, there were several trials of afatinib that then, at the time, included these uncommon

mutations. Whereas other trials did not include these uncommon mutations but several afatinib trials did include them. So, the authors of this retrospective study were able to go back to those prospective trials and retrospectively look at the data from the uncommon mutation. And they found that 32 patients had these uncommon mutations, and they were able to see how they did with afatinib.

And impressively, they found that the outcomes were very similar to patients who have the common mutation, who have what we&rsquo;re used to seeingthe exon 19 deletions and the L858R point mutations. But with these uncommon mutations, such as with the one this patient has, the data looked very similar. So, the response rate was in the high 70s, the progression-free survival was around 10 months, and overall survival was around 19 months. So, again, the data looked very similar with these uncommon mutations as with the common mutations, which I think fully support the use of afatinib with these uncommon mutations.

What we don&rsquo;t know is, what about the other EGFR inhibitors? Those have not been nearly as well studied with these uncommon mutations because these mutations were not included in those trials. So, we really just don&rsquo;t know about their effectiveness with these mutations. Most other trials really just included the common mutation. So, potentially they could work. We just really don&rsquo;t know as much about them.

I think that afatinib is a very good option for this patient, and we now have good data showing that it does sensitize the tumor to afatinib. Again, we just know a lot less about the other drugs with this and other uncommon mutations. Potentially, they could work. Potentially, osimertinib could be effective as well. Again, it&rsquo;s just because the trials excluded those mutations, we just don&rsquo;t know as much. So, I think afatinib is a very reasonable option for this patient.

mutations that make the tumor not sensitive to EGFR inhibitors, and that includes afatinib or really any of the other first- or second-generation EGFR inhibitors. And those mutations include the de novo

is typically something that arises after treatment with EGFR inhibitors. But occasionally, we can see it at baseline at diagnosis. So, that would be one situation where we&rsquo;ve seen, in this retrospective study I was describing earlier, those patients don&rsquo;t typically benefit from afatinib treatment.

exon 20 insertion mutations. Those tumors also tend to not respond very well to afatinib. Or in the instance where they do respond, the duration of response or the progression-free survival is fairly short. We also learned that from the retrospective analysis of the afatinib trials.

So, those are the 2 instancesthe de novo

and the exon 20 insertion mutations in EGFR. Although those are

mutations, those don&rsquo;t tend to respond well to afatinib, and so I would not use the drug in those patients.

Afatinib in Patients With Uncommon EGFR Mutations

Afatinib is, of course, an EGFR inhibitor, and so EGFR inhibitors as a class have very common side effects that we see across the board. And so, those include diarrhea, rash, sometimes nausea and fatigue, also other skin-type changes that include the nails or hair, eyelashes. But really, I would say the main ones with afatinib that are common with patients, that I always tell my patients to expect to some degree, are rash and diarrhea. They can sometimes be very mild. I&rsquo;ve had patients where they&rsquo;re barely noticeable at all and sometimes really significant. And so, I always will tell my patients that that&rsquo;s something to be aware of and to always contact me if it happens to a severe degree that we need to deal with it. This patient had significant diarrhea and that actually required holding the drug.

Fortunately, with these side effects, they&rsquo;re usually easy to manage by either providing supportive care or we sometimes do need to hold the drug and lower the dose. But with those 2 measures, we almost always are able to continue treatment. So, supportive management of diarrhea is typically with antidiarrheal agents that you can sometimes get over the counter or by prescription, and that can commonly work very, very well for patients. We find certain foods affect patients and can lead to diarrhea. Sometimes fresh fruits and vegetables affect patients, and so I&rsquo;ll often tell patients to keep track of what they&rsquo;re eating and see if they can link anything to when the symptoms occur and they should try to avoid those foods.

But sometimes, those measure are just enough and so I will sometimes have to hold the drug until the diarrhea improves, or if it&rsquo;s the case of a rash, I&rsquo;ll have them hold the drug until the rash improves. And once it&rsquo;s either gone or very minimal, then I&rsquo;ll restart the drug usually at a lower dose. So, if a patient is started on the standard dose of afatinib at 40 mg a day, I&rsquo;ll usually lower the dose to 30 mg a day. And that can often be very, very effective and a patient won&rsquo;t have recurrence of symptoms or maybe just mild symptoms. And typically, that can work very, very well and they&rsquo;re able to continue the drug.

There are many patients who do have to lower the dose of afatinib because of side effects. It&rsquo;s actually pretty common that the drug has to be lowered. Interestingly, there has been some research looking at trials of afatinib in patients who&rsquo;ve had to lower the doseand the effectiveness of afatinib seems to be about the same&mdash;and whether the dose has to be lowered or not. So, that has always been reassuring to me that if I have to lower the dose for side effects, it&rsquo;s fine and we should do it to give our patients good quality of life and allow them to continue on the treatment.

Side Effect Management With Afatinib

Although EGFR inhibitors, including afatinib, can be very effective and this patient has a high chase of benefitingand hopefully for a long time&mdash;we know that these drugs are not curative and eventually the cancer progresses. And so, at the time of progression, I always have to ask myself, how is the patient doing clinically? Because sometimes on scans we can see tumor progression but the patient&rsquo;s actually doing quite well still, and if the progression is minimal, we might be able to continue treatment for a period longer. So, that&rsquo;s really the first question: Do I need to actually switch therapies right then?

So, at the time when I feel that there is clinical progression and I do need to switch treatment, I will plan to get a biopsy of the tumor. And that&rsquo;s to look for a secondary mutation or the mechanism of resistance. After first- and second-generation EGFR inhibitorsafatinib being a second-generation inhibitor&mdash;we do see the development of

in EGFR about half of the time. And so, at that point, we&rsquo;re able to use a third-generation drug, like osimertinib, which can be very effective for patients.

I would consider that a standard of care at this point is assessing the tumor for

at the time of resistance. You could do that either by a tumor biopsy of a progressing lesion or you could also consider a plasma biopsy or a liquid biopsy when they do the blood test. Sometimes I do both. So, in a patient who has an easily accessible lesion, I&rsquo;ll consider a tissue biopsy. If it&rsquo;s difficult to do that, I&rsquo;ll get liquid biopsy with blood. They can be complementary, so I&rsquo;ll sometimes do both. If the blood is negative, I&rsquo;ll definitely really consider getting a tissue sample because blood can have a false-negative rate. But it&rsquo;s very important to know if a

is present because osimertinib can be a very effective treatment, and especially if

There are other mechanisms of resistance, and there are clinical trials assessing whether a treatment can work for those. But in cases where

is negative, typically I would consider chemotherapy for patients after progression on a first- or second-generation EGFR inhibitor.

Treatment of NSCLC With Uncommon EGFR Mutations

Case Overview: EGFR-Positive NSCLC

Mutation Testing in NSCLC

Afatinib in Patients With Uncommon EGFR Mutations

Side Effect Management With Afatinib

NSCLC: Clinical Decision Making at Progression