GRACE :: Lung Cancer

Third-line therapy and beyond

Who Benefits from Third-line Treatment for Advanced NSCLC?

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The Benefit of Zactima: Damning with Faint Praise

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Member Neil Berch just wrote a nice summary of the four large randomized clinical trials being done with Zactima (vandetanib), an oral targeted therapy that can block both the VEGF (angiogenic) and EGFR pathways. In fact, the name vandetanib comes from blocking V and E. In the single agent studies, one comparing Zactima to Tarceva (erlotinib) and the other to a placebo (in patients with advanced NSCLC previously treated with an EGFR inhibitor like Tarceva), the Zactima dose was 300 mg, which is a dose thought to block both pathways. In the chemotherapy trials, the daily dose of Zactima was 100 mg, which the lab work would suggests is enough to block angiogenic activity but probably not block the EGFR pathway. Why? A prior, preliminary trial of the chemo agent Taxotere (docetaxel) with either placebo or Zactima at 100 mg or 300 mg daily actually demonstrated clearly better results with Zactima at the lower dose, a finding that I suspect may be because blocking the EGFR pathway while also giving chemotherapy could well be detrimental. In any event, we can’t presume that a higher dose would lead to better results with chemo in the current large trials.

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Stable disease is just fine, thank you.

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At the 1st ESMO-IASLC Lung Cancer Conference in Geneva last week I saw a presentation that I thought would interest this general readership. The study, presented by Dr Grossi, from Italy, is a retrospective review of 61 patients with advanced NSCLC of all subtypes treated with either Tarceva (erlotinib) or Iressa (gefitinib) in the 1st or 2nd line setting.

The groups were similar, remember this was not a randomized prospective study; the median age was 65 for those receiving Tarceva and 74 for those on Iressa. About 26% of the whole group were never/former smokers. They all were pretty physically fit (ECOG PS of 0 or 1), and most of them (55-58%) had adenocarcinoma.

There were no complete responses and the rate of partial response was 6% and stable disease of 26% for the people on Tarceva and 13% partial response and 29% stable disease for those on Iressa. These figures, although low, are entirely in keeping with previous study results for both drugs given to unselected patient populations.

What was interesting was that for the people who had a partial response the median survival was 9.7 months, but it was 9.1 months for those who had stable disease, and only 3.7 months for those who progressed on treatment. This was a trend noted in other studies and one I certainly see in my clinic, but it was reassuring to see it reproduced. And hopefully reassuring to anyone who might have “only” stable disease. Dare I say “size isn’t everything”?


Clinical Trials with Sutent (Sunitinib) in NSCLC

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One of the novel agents being studied in lung cancer is sutent (sunitinib), a multi-targeted oral anti-angiogenic drug that I’ve described in a prior post. While I’ve mentioned a small study I’m leading at my own institution with this agent in advanced NSCLC patients with bronchioloalvelar carcinoma (BAC) or who have never smoked (information here), I wanted to describe a couple of larger studies that are being run by Pfizer, the company that is developing sutent, in lung cancer. Their development program is a series called the SUN trials, for Studies to UNderstand Sunitinib, another acronym that is a bit of a stretch in order to be memorable.

These trials are based on the combination of sutent/tarceva, which has been studied in a limited trial in kidney cancer (abstract here), and another one in NSCLC is being conducted at the University of Wisconsin (information here).

The largest trial is SUN-1087, which is an international phase III randomized trial of the combination of sutent and tarceva (erlotinib) compared to a current standard for previously treated patients with advanced NSCLC of tarceva with a placebo. The SUN-1087 trial is ongoing and will plan to enroll 956 patients in the second or third line setting, and it patients with any kind of NSCLC (adenocarcinoma, squamous, or less common subtypes). It will look at potentially important variables such as whether enrolled patients received prior avastin (bevacizumab), whether they are a never-smoker, ex-smoker, or current smoker, and also their EGFR status (I believe my looking at immunohistochemistry, the levels of EGFR protein on tumor cells. These factors will be monitored and compared between the two arms so that neither arm receives far more never-smokers, prior recipients of avastin, etc. – a balancing act called stratification. The tarceva will be given at the standard starting dose of 150 mg daily, with sutent at 37.5 mg daily, and the trial will treat all patients until they develop either progressing cancer or prohibitive toxicity. The goal of the study will be to see whether the tarceva/sutent provides a significant overall survival (OS) advantage over tarceva alone (with tarceva). Further information on this trial, including participating sites, is available here.

A smaller trial known as SUN-1058 has a very similar design of tarceva/sutent vs. tarceva alone, but it doesn’t have a placebo included. It is enrolling essentially the same population of previously treated patients with advanced NSCLC (second and third line), with any NSCLC subtype, but will only enroll a total of 126 patients and will be looking at progression-free survival (PFS) as the primary endpoint. Further information on this trial, including participating sites, is available here.

You might ask yourself why a company would conduct two trials with such similar designs – it’s not a typical approach, and I’m still not sure why the company would do this. However, I speculate that the reason for running a small trial at the same time as a large trial is a strategy to obtain early feedback from a small trial looking at PFS (a quick endpoint) that could potentially lead to changes or an early termination of the larger trial looking at the longer-term endpoint of OS before having invested far more millions into the larger trial. Continue reading


Second Line Treatment for NSCLC: Choosing Among Several Options

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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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