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Dr. Jack West is a medical oncologist and thoracic oncology specialist, and Executive Director of Employer Services at the City of Hope Comprehensive Cancer Center in Duarte, CA.

Second Line Treatment for NSCLC: Choosing Among Several Options
Thu, 01/24/2008 - 18:05
Please Note: While this is Still Excellent Background Info, New Treatments and Procedures Have Emerged Since this Original Post
Howard (Jack) West, MD, Associate Clinical Professor, Medical Oncology, Executive Director, Employer Services, Founder, President and CEO of GRACE

Member Sandra recently asked the question that several other people have asked in one form or another: how do we choose among the treatment options for second line therapy in NSCLC. I've covered in several posts and a huge number of responses in the Q&A Forum the leading options we generally consider for second line therapy for NSCLC. I've consistently stated that there are three agents that are most commonly used -- taxotere, alimta, and tarceva -- because they've all been pretty well studied, and they're all approved by the US FDA for this setting based on the evidence available. Moreover, they also have what appears to be very comparable activity: taxotere and alimta have been compared head to head and shown to have remarkably similar efficacy, and while we don't have data yet for direct comparisons of tarceva vs. one of these chemo options, we do have data from the large INTEREST trial (post here) that showed that iressa, which the preponderance of evidence would say is the slightly weaker EGFR inhibitor vs. tarceva, had the same efficacy as taxotere in a huge worldwide trial.

So we've got these three leading options (and it's also reasonable consider others, even if they aren't as well studied), and how do we choose among them? My first question is whether I'm inclined to recommend chemo or an EGFR inhibitor as second line therapy. And the two leading factors I'd consider are prior response to chemo in first line, and smoking status. To me, they both count pretty similarly. The main principles are that if someone responded well to chemo in first line, they're more likely to respond well to second line chemo. On the other hand, someone who progressed after the first two cycles is not someone I'd be especially optimistic about for a better response to second line chemo. So the better the first line outcome with chemo, the more inclined I'd be to recommend more chemo; conversely, the more disappointing the outcome, the more inclined I'd be to recommend EGFR inhibitor therapy with tarceva, although in this case I'm selecting it as the "not more chemo" choice more than because it's an EGFR inhibitor. I'd consider it more of a wild card, and a wild card is good when you're expecting a bad outcome with what you've already got (for instance, more chemo), but it's less appealing if you're expecting a good outcome with what you're holding.

The second big factor is smoking status. We've spoken mostly about never-smokers, and as I've mentioned all over the website, never-smokers appear to have a distinct biology (post here) and are consistently more likely to do well with EGFR inhibitors like tarceva (post here). So in my mind, never-smokers should receive tarceva early: many experts consider it to be an appropriate first line treatment (I'd consider myself in that camp), but if not used first line, I'd almost always advocate to use it second line. And I wouldn't wait for someone to have major progression on first line chemo. If a never-smoker's scans looked convincingly worse, even if the difference didn't technically meet criteria for progressive disease, I'd almost certainly move them to tarceva ASAP. But the important point is that while that's a neat answer for the 10-15% of lung cancer patients who never smoked, what about the other 85-90%? And the point is that it isn't ALL or NOTHING, ever-smoker or never-smoker. People who smoked relatively little (say, less than an average of a pack per day for 10 or 15 years) and who quit smoking 20 or 30 years before diagnosis often have the molecular and treatment characteristics of the never-smoker population (as described in one of the referenced posts above, on different response to treatment in never-smokers). Some of our current trials on smoking status also include remote, light smokers in addition to never-smokers. We don't know if they will do as well as never-smokers, but in the real world, the less a person has smoked and the longer they've been off of tobacco, the more likely I think it is that they'll get an impressive benefit from tarceva. However, I don't want to completely overstate this association. There are never-smokers who don't benefit, and there are smokers who do well with tarceva as well. Smoking status is just a useful predictive tool, not a guarantee.

So putting this together, I'd definitely advocate chemo for someone who responds well to first line chemo and has a significant smoking history. And I'd strongly favor tarceva second line for someone who either has a minimal/remote smoking history or progressed quickly through chemo. What is someone is a remote and/or light prior smoker AND responded pretty well to chemo? Either choice is very reasonable, so I talk with the patient about whether they'd prefer IV chemo or an oral targeted therapy, discuss the different side effect profiles, and then make a decision or flip a coin (kidding -- hasn't happened yet). And most of the time, whichever we didn't do second line is going to remain a feasible third line option, so it's more choosing the order of treatment than which treatment they'll get. We don't need to burn bridges, unless a person declines too quickly to tolerate more therapy.

In terms of which chemo, either is very appropriate, but I and many other oncologists have come to clearly favor alimta. If patients haven't lost their hair, most would prefer not to lose it (which occurs far more commonly on taxotere). Alimta was approved by the US FDA based on its modestly more favorable toxicity profile overall vs. taxotere, and although the differences weren't striking, my clinical experience, and that of many of my oncology colleagues, is that the toxicity of alimta is appreciably less than taxotere, overall. Of course, there are patients who have a hard time with it, just as with any cancer medication.

In patients who are strong enough for long enough, it's possible to give first line therapy and then all three of these agents at some point, and sometimes more. But beyond these general principles, I largely individualize my treatment plans with patients, as most oncologists do.

I'd be interested in learning how Dr Laskin approaches second line therapy. She may have a similar approach, or she may have a different perspective, working in a system that, from my vantage point, has more rigid guidelines in place. There's plenty of lattitude for differing views, but at the present time, this is how I approach my patients after they have completed first line therapy.

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