The oral EGFR inhibitors Iressa and Tarceva both have activity in advanced NSCLC, with proven responses in a minority of patients and improvements in cancer-related symptoms as well. While Iressa ultimately did not prove to have a significant survival advantage over a placebo in previously treated advanced NSCLC patients (ISEL trial abstract here), and is therefore no longer used in the US outside of trials or in patients who have already shown a response, Tarceva did show a significant survival benefit compared to placebo (BR.21 trial abstract here) and is one of our more commonly used agents in previously treated advanced NSCLC.

Patients and physicians have noted that in the advanced/metastatic NSCLC setting, the potential improvements are limited. While some fortunate patients have a very prolonged response or non-progression, the average improvement in survival on the major tarceva trial was two months. If we turn to earlier stage, potentially curable NSCLC, can we add EGFR inhibitors to actually improve the cure rates? The studies thus far have been limited but have at this point mostly highlighted how much we still need to learn about these agents.

A single trial gives us information about maintenance Iressa after aggressive treatment with chemo and radiation for unresectable stage III NSCLC. After an earlier preliminary study showed very encouraging results for treating with cisplatin and etoposide with chest radiation at the same time, all followed by three cycles of "consolidation" taxotere (SWOG 9504 abstract here), a larger trial was initiated in which all of the patients were to be treated with this combination of chemo and concurrent radiation followed by consolidation taxotere. Then the patients who got through that treatment were divided into two groups, one that received maintenance Iressa, and another that received maintenance placebo instead. The design of this complex trial, known as SWOG 0023, is shown here:

(clieck to enlarge)

The trial was closed early a couple of years ago, in the wake of the negative trial of Iressa in the advanced NSCLC setting. An early evaluation of the SWOG 0023 trial by an independent data monitoring committee led to a recommendation to close the trial early, because the review of the evidence showed there was no way that the Iressa maintenance arm would show a survival benefit compared to placebo. Dr. Karen Kelly, world leader in lung cancer who recently left the University of Colorado to head the program at the University of Kansas, presented a very early analysis of the trial at ASCO, the big US-based oncology conference, a couple of years ago (abstract here, which really doesn't describe the updated data presented at the meeting). At that time, she showed that the overall survival for the entire trial was pretty encouraging, averaging about 19 months, but the surprising result was that the survival for recipients of Iressa looked WORSE than the group that got a placebo:

What?! More patients appeared to be dying on iressa than a placebo? Let me tell you, nobody expected that. We really felt that even on a bad day, Iressa would perhaps not show a benefit, or a small benefit that wasn't statistically significant (as was seen in the advanced disease ISEL trial). Interestingly, it wasn't that these patients were dying of side effects like lung inflammation. The only real difference between the two arms was in the number of patients who were developing recurrent lung cancer.

Now, the data Dr. Kelly presented was very early, and the two survival curves were not statistically significant (which means that there was a reasonable possibility the differences were just by chance, rather than a real harmful effect of Iressa. Perhaps with longer follow-up, the two curves would drift together and there wouldn't be any real difference. No benefit, but no clear harmful effect.

Wrong again. Dr. Kelly recently presented an updated version and has shown that 18 months after the initial presentation of the trial, the Iressa arm has continued to show a much worse survival than the placebo arm, and the difference is now quite statistically significant, which means it's very likely to be real. And the difference in survival appears to be entirely due to a higher liklihood of lung cancer recurring in Iressa recipients, not greater toxicity from Iressa. Why? We don't know, and it's hard for us to even think of a plausible explanation. It doesn't make sense, but that's what we saw.

So that's pretty humbling, and it's an important message about any of us, physicians or patients, presuming we know that a new treatment will help or that no harm can come of adding something new without testing it. Even a non-believer wouldn't have suggested we'd find a harmful effect from Iressa. So it makes me more cautious about being a cowboy and adding a new anticancer therapy without the evidence to back it up. Better to try new things in a clinical trial where we can learn what works and what doesn't, and move the field forward in the process. If a new approach works, we have a better treatment for the world. If not, we at least learn from that and keep others from making the same mistake. Doing something new outside of a trial means that we don't learn from the experience and we don't get a new option or learn about a poor choice.

Now, this trial gave Iressa to a group of patients who were NOT selected as those who might be most likely to do well with an EGFR inhibitor. It's quite possible that the results would be very different if we only treated patients with EGFR mutations or EGFR FISH positive tumors or never-smokers or otherwise restricted to a group most likely to benefit. But maybe not. It's an open question, but with the only evidence we have showing the treatment is detrimental as maintenance therapy in locally advanced NSCLC, I wouldn't recommend it outside of a clinical study.

And while this trial was done with Iressa and not tarceva, it would be hard to be enthusiastic about recommending tarceva instead, since tarceva at standard dosing seems to be essentially a stronger version of iressa at standard dosing of 250 mg per day. So a stronger version of this iressa effect wouldn't be very appealing.

Turning to earlier stage, surgically-treated NSCLC, all we have is a half-completed study that has no results available yet. A trial by the National Cancer Institute of Canada, known as BR.19, looked at treating early stage patients who had surgery, possibly chemo post-operatively, and then randomized patients to receive up to two years of Iressa or placebo. The schema is as shown below.

The trial was slated to accrue over 1200 patients to answer the question of whether mainenance Iressa after surgery for resected NSCLC, but after the negative results with Iressa in advanced disease came out, this trial was also closed with about 500 patients enrolled. Unfortunately, it will be a couple of years before we get any information from this trial, because the follow-up needs to be longer for earlier stage patients than for later stage patients, who tend to show progression over a shorter period of time. So this remains an open question. The RADIANT trial is currently open and asking the question of whether tarceva in a targeted population of patients with EGFR-positive tumors by immunohistochemistry (IHC) or fluorescence in situ hybrodization (FISH) will be helpful compared to a placebo in post-surgical patients (see my prior post describing this trial here).

So that's what we know, and what we don't know, about EGFR inhibitors in the potentially curative treatment settings for NSCLC. We don't have evidence that giving EGFR inhibitors outside of advanced disease improves cure rates, and there is some evidence that they can be harmful in some circumstances. We have no results of studies where this targeted therapy was given to a targeted population who might be expected to do best, but for now, it is hard to recommend using maintenance EGFR therapy based on the cautionary findings of the SWOG 0023 trial.