We’re recognizing more and more that lung cancer in never-smokers (LCINS) is a distinct disease, with different patterns of who gets it, how the cancer behaves, and it responds to treatments. But this recognition is still a work in progress, coming from a background in which the party line has been that NSCLC is treated the same regardless of the histologic type (squamous, adenocarcinoma, large cell, or other), smoking history, or other factors. In fact, it’s fair to say that it’s still appropriate to treat never-smoking patients with the same approach that I described in other posts about NSCLC patients in general. But I do think of never-smokers a little differently because of its apparently distinct biology, and this does modify my practice recommendations. To me, the guiding point, based on what we know right now, is that never-smokers have a high likelihood of receiving a significant benefit from oral EGFR tyrosine kinase Inhibitors (TKIs) like tarceva and iressa (see prior post). While the LCINS population isn’t as likely to have a significant response to EGFR TKIs as a population defined by the presence of an EGFR gene mutation (around 30-50% for never-smokers vs. 60-80% for EGFR mutation-positive patients) , they are a readily identifiable group of patients who consistently have a higher magnitude of benefit with EGFR inhibitors than we’re used to seeing with chemo. But there are absolutely other factors, since some studies corroborate my own clinical observations treating the LCINS population really demonstrates that Asian never-smoking women are clearly more likely to respond than some other groups, such as Caucasian never-smoking men.

Several clinical studies have shown that LCINS patients are a subset that receives the greatest clinical benefit in positive EGFR TKI trials, and they’re a group that benefits even when the overall trial is negative. They experienced a doubling of survival with tarceva as a single agent, and they were the group that showed a similar benefit when tarceva was added to carbo/taxol as first-line chemo. A clinical trial is currently being done in current or remote former light smokers that is testing tarceva vs. carbo/taxol/tarceva, so that will help us understand whether tarceva should be added to chemo (summary here). I haven’t favored that approach because several studies have suggested a detrimental effect of giving standard chemo and an EGFR TKI concurrently, but I hope and expect we’ll have a real answer in the next year or two. In the meantime, what do I do? First, I do think that it’s completely reasonable to use the same strategy for never-smoking NSCLC patient that you would recommend for a current or former smoker. We have evidence that EGFR TKIs are unusually effective in the LCINS population, but we have almost no information about how never-smokers do with standard chemo. The TRIBUTE trial of carbo/taxol with or without tarceva showed that never-smokers receiving placebo had a very ordinary median survival of about 10 months (abstract here), but there have been a few suggestions in other trials that never-smokers may do a bit better. Overall, though, we don’t have enough information to say much about how standard chemo agents perform in never-smokers, except to say that thus far there hasn’t been any signal that they consistently have a high probability of a major benefit, in contrast with the EGFR TKIs. So I offer the same standard therapy I’d give to a current or former smoker, but I also talk about potentially starting with an EGFR TKI, on or off of a trial. As a non-standard approach, my preference would be to do this under the auspices of a clinical trial, such as the SWOG trial that I’m leading that pairs tarceva and avastin for never-smokers (link here). This option isn’t for everyone, either because they are found to have brain metastases or another reason to be ineligible for avastin, or because they aren’t inclined to accept the risk even if they are technically eligible. In those cases, I think it’s definitely appropriate to consider tarceva as a single agent, off protocol, as a first line therapy. There’s no other treatment we know about for which we can say that LCINS patients have such a high probability of success, not only in terms of both likelihood of a major response, and (more importantly, I’d say) also duration of response/non-progression that can extend into years. For patients who receive standard first line therapy, I just want to ensure that every LCINS patient receives an opportunity to see how well they might do with tarceva (the EGFR TKI commercially available in the US, and the only one proven to improve survival vs. placebo thus far), preferably as early as feasible. We see that likelihood of benefit with any cancer treatment, whether targeted therapy or standard chemo, is lower in patients with a poor performance status, so I don’t want to wait until these patient s become debilitated before offering them an EGFR TKI. Beyond that, I have a series of trials for LCINS patients (see prior post). I believe that because they tend to have a genetically simpler cancer (without the accumulation of dozens of tobacco-induced mutations over many years), LCINS patients have a greater likelihood of having a profound response to other agents if the treatment effectively targets the Achilles’ Heel of the tumor. Finally, there is some overlap between never-smokers and patients with bronchioloalveolar carcinoma (BAC), about 1/3 of whom never-smoked. Without enough evidence to say anything definitive, my sense is that smoking status is the more dominant factor than BAC histology, but further studies will tell us more

. The special case of BAC, when it applies, is that it can be a very indolent cancer, and I think that situation merits special consideration, which I’ll cover separately.