Several trials have recently opened up for never-smokers with any lung adenocarcinoma or those with BAC (or adeno/BAC mix, invasive adenocarcinoma with BAC features) with any smoking status. Both of these groups have only recently gained recognition as likely being a distinct clinical entity with a different natural history (clinical behavior outside of treatment) and pattern of responsiveness to treatments that is different from other types of lung cancer.
The Southwest Oncology Group (SWOG) has just recently activated a pair of trials that I wrote and will lead, each giving the combination of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) tarceva and the anti-angiogenic (attacking tumor blood supply) avastin at current standard doses to patients who we think may fare very well with this combination as an early, potentially first-line therapy. These are single arm phase II trials, so every patient will know what they are receiving, and there is no randomization or placebo treatment. SWOG trial 0635 will give this combination to patients with BAC or adeno/BAC, whether they have smoked or not, while SWOG trial 0636 will give this combination to never-smokers with invasive adenocarcinoma or BAC (never-smokers with BAC will preferentially be enrolled to SWOG 0636 if both are available at an institution). Tumor tissue is also built into these trials, so that we can have the tumor reviewed by expert pathologists in one central place, and so that we can check molecular variables like EGFR gene amplification by FISH, mutation analysis for FISH and RAS, and several other potentially relevant makers that we can then correlate with how individual patients did.
While any patients who have not received either an EGFR inhibitor or avastin can enter these trials, we anticipate that this will be a first line therapy for the majority of the 80 planned patients on each trial. Essentially, this is because we have gained an increasing amount of evidence suggesting that EGFR TKIs are consistently highly effective in never-smokers (prior post here) and those patients with BAC (prior post here). While EGFR inhibitors like tarceva are not considered a standard first-line treatment comparable to chemotherapy for the overall population, there are many (but certainly not all) experts who consider EGFR inhibition to be comparable to or better than standard chemo and might recommend this approach as a first treatment. At the same time, we also have evidence that avastin improved survival when given combined with first line chemo (prior post here) and that avastin and tarceva can also be combined with safety comparable to and perhaps more favorable than the combination of avastin/chemo, with a suggestion that avastin/tarceva may also be a particularly active combination (prior post here). Since tarceva works primarily against the tumor itself while avastin may work more against its blood supply, this combination may provide a particularly effective 1-2 punch:
(Click to enlarge)
Basically, these trials look at two groups of lung cancer patients who we think may do so well with tarceva that it becomes an attractive early (often first line) treatment, and since avastin improves outcomes with chemo in eligible lung cancer patients, perhaps avastin will improve results with tarceva as well. It’s important to mention, however, that some patients would not be eligible for these trials because of the avastin, including patients with brain metastases, those on full dose blood thinners, and patients who have coughed up blood, among other factors. Nevertheless, these trials are now available at my institution and are becoming activated and approved at a growing list of SWOG-affiliated institutions across the US. I sincerely hope and expect that we’ll move the field forward, potentially identify a very promising treatment option for other never-smokiing patients and those with BAC in the future. And the collection of tissue will teach us not only about how to predict the best candidates for these treatments but also more about the molecular causes of these tumors.
A couple of additional trials are available at my own institution, Swedish Cancer Institute (SCI) in Seattle, for never-smokers or patients with BAC. Unlike the SWOG trials, each of these is likely to be primarily pursued by patients after they have received several other treatment approaches. One trial features single agent sutent (sunitinib) (contact info here), and the other is of single-agent nexavar (sorafenib) (contact info here), both oral multi-targeted inhibitors of angiogenic activity. While both of these drugs are approved anticancer therapies outside of lung cancer and have some evidence for activity in previously treated NSCLC (limited evidence for sutent described in prior post here and for nexavar described in prior post here), it is not at all clear whether never-smokers or patients with BAC might represent a subset of patients who do extremely well or perhaps similarly or even possibly worse than other NSCLC patients who receive these agents. At the same time, while the previous trials of sutent and nexavar in previously treated NSCLC are only a few years old, those earlier patients had not received prior treatment with the anti-angiogenic drug avastin, so it’s possible that even the modest activity seen thus far with these agents would be lost if patients had already been treated on avastin, as most eligible patients will have been today before moving to 3rd of 4th line treatment or beyond.
Although both BAC and never-smoker populations have really been the subject of dedicated studies only over the past couple of years, I hope and expect that trials like these will lead to a much greater understanding of these cancers, and more importantl to more effective treatment options, for the people affected by them.
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