GRACE :: Lung Cancer

never-smoker NSCLC

Molecular Markers in Lung Cancer

Dr West

Is immunotherapy the wrong choice for some lung cancer patients?


Amidst all of the glowing reports about immunotherapy for lung and many other cancers, it would be understandable for patients and physicians to be tempted to rush toward prioritizing immunotherapy as the first treatment strategy to pursue. In fact, a highly publicized trial called KEYNOTE-024 was just presented at the ESMO meeting in Copenhagen and demonstrated a significant improvement in progression-free and overall survival over standard chemotherapy doublet treatment as the first line approach for patients with high level expression of the PD-L1 protein on their tumor (about 30% of patients).  But there is also converging evidence that some patients are consistently less likely to benefit from immunotherapy — specifically, those patients with an EGFR mutation and perhaps others with another “driver mutation” such as an ALK or ROS1 rearrangement.  This is an important issue to know, because I and some other lung cancer specialist colleagues see patients with one of these highly targetable lesions sometimes being mistakenly recommended immunotherapy over the optimal targeted therapy for their cancer, or patients deflect a recommendation for an EGFR or ALK inhibitor in favor of immunotherapy based largely or completely on the hype around the latest new idea in cancer treatment.

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Lung Cancer Risk Factors

GRACE Cancer Video Library - Lung



Dr. Jared Weiss, UNC Lineberger Comprehensive Cancer Center, discusses smoking, asbestos, radon and other risk factors for lung cancer.

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I’m going to speak to you today about lung cancer risk factors.


Of course we cannot ignore that smoking is the dominant risk factor for lung cancer.


Eighty-five percent or so of our patients have smoked at some point in their lives. However we cannot ignore as well that 15% of so of our patients have never smoked, and about 45% have long since quit.

What to do with this data? In my opinion, we need to really focus on smoking cessation.


So at top left you see that smoking cessation at any time is worthwhile. Immediately upon quitting smoking, the lung cancer risk falls. This risk falls over time. Stated another way: it’s worth quitting cigarettes at any time point, but the sooner the better.

This effect on health is not just lung cancer. At the bottom left, you can see other cancer mortality declines because lung cancer is not the only smoking-related cancer. Cardiovascular disease competes with cancer for the leading cause for death in Americans — actually I think it edges it out, and you can see that risk declines with quitting smoking. Again, the sooner the better, and for total mortality, shown at the bottom right, the same effect holds.


Lung cancer can affect anyone, regardless of age. On the far left of this table you can see that lung cancer can strike very young people — I’ve taken care of some of them. However you can also see in looking at the far right side of this curve that age is a legitimate risk factor. Our median age of presentation is about 71, and so this risk does go up with chronologic age.


There are other risk factors for lung cancer and we need to spend some time particularly on those that are preventable. Asbestos is an important risk factor. This risk varies by fiber type, it also varies by the nature of the exposure. It turns out that occupational exposure, working in a factory on asbestos is a much greater risk factor than environmental exposure, meaning like having asbestos in the walls of the building you live in or something like that. It’s also worth noting that there’s a strong interaction factor here with smoking. Asbestos is bad, smoking is bad — put them together and you have something truly deadly.


Radon is another major risk factor and also important because it is preventable. This one has a great difference in incidence by geography, shown here, and it’s important to talk about radon because you can do something about this risk.


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There are kits that can detect radon in your home, and if it’s found it can be mitigated.


Cooking fumes are a major risk factor, particularly in developing countries and this risk varies by the type of coal used. It turns out that bituminous coal (I didn’t know that word before making this podcast) is the kind that makes a lot of smoke and this dramatically increases the lung cancer risk. In contrast, cleaner coals like anthracite coal seem to be a bit safer. European studies have shown that diesel exhaust contributes to lung cancer risk, but the relative risk increase is somewhat small.

The best data on radiation comes from Hodgkin’s disease and breast cancer, where radiation to the lung roughly triples the risk of later lung cancer.

In terms of pulmonary diseases like COPD, it’s a little hard to tease apart the component caused by smoking because smoking does cause both these diseases as well as lung cancer and the part caused by the actual pulmonary disease, but these pulmonary diseases are inflammatory and it makes common sense that they probably do increase the lung cancer risk a little bit.

Dietary factors are huge in the public consciousness. If you search the web, if you Google, you would think they were the only risk factor and that you can mitigate your lung cancer risk substantially by diet. In particular there was an idea out there that diets high in fruits and vegetables would lower the lung cancer risk. I wish this were true because this is the kind of diet that also prevents some other cancers and helps prevent cardiovascular morbidity and mortality, but the best data available points out that it’s probably just not true.  There’s also a big idea out there that beta carotene supplementation might decrease the lung cancer risk. The best data out there on this shows that not only does it not help, but it might actually increase the lung cancer risk. Again, these may not be the findings that we were looking for, it may not be consistent with all of the stuff in the popular press, but we have to go where the actual data leads us.

There’s real data out there that combined estrogen and progesterone hormones may increase the lung cancer risk a bit — for those more interested in this, Dr. West did an excellent post on this a few years ago that to my mind is still quite current.

The only other cancers that I treat other than lung cancer are cancers of the head and neck. In the tonsils and the base of the tongue, it is clear now that the human papillomavirus, the same one that can cause genital warts, and its high risk forms cause cervical cancer, can also cause cancers of the tonsil and base of tongue. These viruses can also be found in the upper respiratory passages, so there was an idea that perhaps they’re causing cancer there. It’s an interesting idea, it’s still undergoing further research, but to my mind the best available data on this don’t convince me that it’s actually true.

The final subject is genetics. We’re talking here about heritable genetics, the kind that you receive from your parents and that you can potentially pass on to your children, not the molecular changes that we talk about so often on GRACE. This is actually a rather rare risk factor. Lung cancer is one of the least heritable of the cancers, and if you want more information on this, this will be the subject of another podcast.

I thank you for your attention.


Do Clinical Characteristics Alter Your Enthusiasm for Immune Checkpoint inhibitors?




Drs. Leora Horn, Ben Solomon, & Jack West assess whether clinical factors such as being a never-smoker or having a driver mutation (EGFR, ALK, etc.) reliably predict minimal benefit from immunotherapy agents.

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Dr. West:  We’re starting to see some early results suggesting that never-smokers and patient with driver mutations, like EGFR, or an ALK rearrangement, or ROS1, are particularly unlikely to have very good responses to these agents, the immune checkpoint inhibitors. Even if PD-L1 testing isn’t required, do these clinical characteristics matter to you, in terms of whether you’re less likely to recommend an immune checkpoint inhibitor as an early therapy in patients with no smoking history, or a driver mutation, are you thinking that this is really not likely to work, or are patients or clinicians so eager to use them that it’s really the first opportunity, no matter what the patient characteristics are?

Dr. Solomon: Yes, so I think the data so far haven’t been that exciting in patients, certainly with EGFR mutations, and probably also patients with ALK rearrangements, and why that is, I think, remains to be sorted out. Like you were suggesting, maybe it has to do with the mutational load, within tumors. So, I think — we want patients to receive the most effective treatments early on, and certainly, I don’t think there’s a role outside of clinical trial of using these inhibitors before therapy with an ALK or an EGFR inhibitor. I think there are some really interesting studies that look at using concurrent EGFR or ALK inhibitors with a PD-1 inhibitor, and I think it will be really interesting to see whether that increases response rates in these populations.

Dr. West:  What are your thoughts about the role for immune checkpoint inhibitors in never-smokers, and patients with driver mutations?

Dr. Horn:  I completely agree with what Ben said, you know, and many of those patients have been excluded from the first line trials, if you’re EGFR or ALK positive, because there are such great options for those patients. There was a little hint of — maybe we’re going to see some responses with the community study that was presented with nivolumab, where they showed around a 10-11% response rate in those patient populations — very small numbers, so maybe there are a group of patients that will respond, but I agree that the combination therapies look really, really interesting. The difference is that EGFR inhibitors — they’re incredibly effective, but at some point, they’re failing the patients, whereas, if a PD or PD-L1 inhibitor is working, they really have these long, durable responses that are often measured beyond just one year of therapy.


Differences Among Specific EGFR Mutations

GRACE Cancer Video Library - Lung



Medical oncologist Dr. Greg Riely, MSKCC, discusses evidence for whether there are clinically significant differences among specific EGFR mutations that should lead to differences in management.

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Within the overview of EGFR mutations, there’s several different types — the two most common are EGFR exon 19 deletion and EGFR L858r; together, these represent more than 80% of EGFR mutations. In addition to these two common types, there are some uncommon types, but some of these are related to responsiveness to EGFR tyrosine-kinase inhibitors, so rarer ones like G719A, L861, these are rare, but we have pretty good evidence that they lead to response to drugs, just as those patients who have L858r or exon 19 deletion.

There are patients who have exon 20 insertions — in general, EGFR exon 20 insertions are associated with resistance to EGFR tyrosine-kinase inhibitors like erlotinib, gefitinib and afatinib, and so, as a consequence, that’s not our first line therapy for those patients with EGFR exon 20 insertions.

Going back to the two most common EGFR mutations, exon 19 deletion and EGFR L858r, since these are the most common ones, we have more data on patient outcomes for these two mutations. When we look at a broad variety of data, typically with afatinib, we see that afatinib may actually be more effective for those patients with EGFR exon 19 deletions than it is for patients with EGFR L858r.

There has been similar data reported for patients treated with gefitinib and erlotinib as well. Though the data is not quite as clear cut, it does seem that those drugs also work a bit better for patients with EGFR exon 19 deletions.

Now what the consequence of those differences is, is quite controversial. I think that, in general, I still recommend treatment with an EGFR tyrosine-kinase inhibitor — and I don’t prefer one or the other, for patients with EGFR exon 19 deletions, EGFR L858r, as well as the rarer ones like G719A or L861Q.


Should Avastin be Added to EGFR TKI Therapy for EGFR Mutation-Positive NSCLC?

GRACE Cancer Video Library - Lung



Dr. Jack West, medical oncologist, reviews evidence in favor of adding Avastin (bevacizumab) to the EGFR inhibitor Tarceva (erlotinib) for patients with lung cancer that harbors an activating EGFR mutation.

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The historical standard of care over the last several years for patients with advanced non-small cell lung cancer, whose tumor has an activating EGFR mutation, has been single-agent oral EGFR tyrosine-kinase inhibitor therapy. That is a pill like Iressa (gefitinib), or Tarceva (erlotinib), or Gilotrif (afatinib), and these agents are associated with long responses that typically will last 9, or 12, or sometimes more months, but unfortunately, in almost every case, will demonstrate progression after some period of time — and we would always like that to be longer.

One of the big questions that we’ve wanted to know is, if we could add something to this therapy and do better than that — and one of the key questions has been about adding an anti-angiogenic agent, something that blocks the tumor’s blood supply, which is a drug like Avastin (bevacizumab), which is used in other cancer settings, and in some cases, for lung cancer, in combination with chemotherapy. In lab-based studies there is evidence that adding a blood supply blocker, an anti-angiogenic agent, to one of these EGFR inhibitors can more effectively suppress cancer cells, and for longer, but we haven’t seen clear evidence that this is beneficial for patients in the real world. In fact, there have been a couple of large studies that have asked the question about adding Avastin to a drug like Tarceva — these trials, however, have only been in broad populations that are called molecularly unselected, not looking specifically at patients with an EGFR mutation or any other feature, but just really taking all comers.

One of the key studies is called BeTa, and this was a study where all the patients had receive first-line chemotherapy, and were getting, now, a second-line treatment, after progression, and they were either getting Tarceva alone, or the combination of Tarceva with Avastin.


The study, overall, did not show a significant improvement in survival, but when they looked at the different subgroups of patients, based on various clinical characteristics, you can see that a couple of subgroups of patients did particularly well with the combination.


Specifically, when they looked at patients who were Asian or Pacific Islander, or never-smokers — those patients really seemed to skew more toward greater benefit with the combination of Avastin and Tarceva.


They also looked at a small subgroup of patients, whom they had tumor tissue on and were known to have an EGFR mutation, and those patients also trended clearly toward a better effect with the combination of Avastin and Tarceva.

So, that’s provocative, but that’s just one study. What’s interesting as well, though, is that a remarkably similar study was done where patients received either Tarceva alone, or Tarceva and Avastin, as a maintenance therapy. So, they had not progressed, but they had already received first-line therapy, and then went on to get Tarceva, or Tarceva and Avastin.


This study also showed no significant improvement in the overall population — this was, again, a molecularly unselected population, but when they looked at the different subgroups, based on their clinical characteristics, it was the same subgroups who got the benefit, in terms of overall survival, from the combination.


So, again, it is the Asian and Pacific Islander patients, and the never-smokers — the two groups who we know are most enriched for having an EGFR mutation. So, this is really a bit more compelling evidence that, maybe, there’s really something there.

The question was asked more directly in a study done in Japan and just published in Lancet Oncology not too long ago.


This trial had about 150 patients, all with an activating EGFR mutation, who were randomized to receive Tarceva, or Tarceva and Avastin, as a first-line therapy. The study was designed to look for a significant improvement in progression-free survival, the time before at least half the patients had demonstrated significant progression of their cancer, on this combination that they started with, or the single agent.


What they found was a significant improvement in progression-free survival in the patients who received the combination. In fact, the difference in median time to progression, the time when half the patients in each group had progressed, was over six months longer in the patients who got the combination.


When we look at overall survival — most of the patients are still alive, so it’s too early to really say much, but the trend is in the direction of favoring the patients who received the combination.

The other side of the coin, beyond efficacy, is tolerability, and the combination was associated with more side effects, as you’d expect — although, there were no treatment-related deaths with the combination. In the Japanese experience, there were more patients who had significant problems and needed to come off of the drugs, specifically Avastin, than we’ve typically seen with this combination in other studies. 40% or so of the patients had to discontinue the Avastin because of side effects, usually high blood pressure, or leaking protein into the urine, something called proteinuria; whether that is because these patients just had been on these agents for longer than they usually are in other studies, or there is something about the Japanese patients, or EGFR patients, who were more susceptible, we don’t know. But, at the end of the day, it was still a tolerable regimen, and more of the patients did well and did not progress for much longer when they received the combination.

So where does this leave us? We have a more than six month improvement in the median time to progression with the combination, but this is only one study, done in Japan, and sometimes we see differences in studies done in one part of the world, versus another. Overall, I would say that, to me, these data are quite compelling, and it’s enough to lead me to favor the combination for my patients if an insurer will cover the Avastin, which is not, at this point, a clear standard of care. To many investigators and general oncologists, the combination is not yet their preferred regimen — they would like to see more evidence, larger studies, and ideally, work from other parts of the world to corroborate what we saw out of Japan. In fact, there are studies being done, one in Europe and one in North America, that are asking the same question, so we’ll hope to get more information soon, but this is certainly a very promising lead, and enough to lead me to favor the combination for my patients who have an EGFR mutation.

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