The question of whether we should routinely have advanced NSCLC patients with a response or stable disease after four cycles of first line chemotherapy transition to immediate maintenance therapy or be watched during a treatment break has been the subject of several clinical trials and debates in the lung cancer community over the past couple of years. But now, with chemotherapy and the EGFR inhibitor tarceva (erlotinib) showing a survival benefit in clinical trials, we may be reaching a tipping point where the question is no longer whether to do maintenance therapy, but rather which agent or agents are the best maintenance therapy strategy. We also need to reconcile the idea of starting a new maintenance therapy with the concept of continuing a treatment from the first line setting. The Eastern Cooperative Oncology Group (ECOG), one of the main networks of cancer centers doing collaborative cancer research together in the US, is moving ahead with a trial that aims to address some of these questions. ECOG is the network that conducted the important clinical trial (called ECOG 4599) that established the combination of carboplatin/taxol (paclitaxel) with avastin (bevacizumab) as a potential pace-setting regimen in the US after it was shown to lead to a significantly longer survival than carbo/taxol alone for patients with non-squamous advanced NSCLC. This approach entails continuing the avastin as a single agent after a fixed number of cycles of avastin with chemotherapy, typically 4-6 cycles (in the absence of progression or prohibitive side effects). At the same time, the trial of maintenance alimta (pemetrexed), previously summarized, showed a very impressive survival benefit from having patients switch to alimta after four cycles of chemo if they hadn't progressed and were doing well.

So with a couple of competing possible standards of care, should we have patients continue with avastin, switch to alimta, or (stop me if you've heard this one...) combine the two together? Yes, this means we're talking about two very pricey medications instead of (just) one, but we've also seen that tarceva significantly improves progression-free survival combined with avastin compared with avastin alone. This shows me that avastin alone isn't necessarily the ceiling of what we can do for patients. In addition, earlier work has shown that the alimta/avastin combination is generally very manageable for patients and looked favorable as a second line regimen, so this is essentially just shifting that a little earlier. The trial, designated ECOG 5508, is being run by my friend Suresh Ramalingam, who is the Director of the Lung Cancer Program at Emory University in Atlanta. It's just getting final approvals and will enroll nearly 1300 patients with previously untreated non-squamous advanced NSCLC to receive carbo/taxol/avastin for up to four cycles. Those who haven't progressed (estimating about 900) will then be randomized equally to one of the three arms: 1) maintenance avastin (just like the older ECOG 4599 trial) 2) maintenance alimta (like the "JMEN" trial of maintenance alimta), or 3) maintenance alimta/avastin (is more better? can avastin improve alimta, and alimta improve avastin?)

E5508 Trial Design

(click to enlarge)

Note that there isn't an arm here that receives observation or a placebo. We'll see if American oncologists are disinclined to enroll onto this trial because they just don't believe that maintenance therapy is valuable, but I suspect that it will accrue readily. It will be years before this trial is completed and reported, but in the meantime, I think that the range of options being offered here suggests that the shift toward maintenance therapy will continue and that the debate will move from whether to give maintenance therapy to what agent or agents are the best choice for maintenance therapy.