We've recently received a series of questions on the question of whether it makes sense to give an oral EGFR inhibitor like Tarceva (erlotinib) or Iressa (gefitinib) concurrently with radiation. This is really a poorly studied question, but a paper just published in the Journal of Thoracic Oncology describes a clinical trial that helps to address this question. Unfortunately, for reasons that aren't very clear, the results didn't look very favorable overall. But let's explore this in more detail.

The Cancer And Leukemia Group B (CALGB), one of the three main cancer cooperative groups in the US, noted that EGFR inhibitors were apparently active for at least some patients with NSCLC and with often modest side effects, most typically rash and a tendency toward diarrhea. The investigators from CALGB started trial 30106 to ask a slightly different question in two different clinical populations:

1) For patients with a good performance status (PS) and unresectable stage III NSCLC, does adding daily Iressa to initial chemo followed by concurrent chemo/radiation lead to more favorable results than would be expected from this approach without Iressa?

2) For patients with a marginal PS and unresectable stage III NSCLC, does adding daily Iressa to initial chemo, giving Iressa with radiation instead of chemo/radiation lead to favorable results?

The trial enrolled patients with stage III NSCLC and either PS 0/1 (good) or 2 (marginal) to start in all cases with two cycles of carbo/Taxol (paclitaxel) every three weeks, with Iressa at 250 mg daily. Patients with a good performance status then started daily radiation up to 66 Gray (a standard amount that went over about 7 weeks), switched to weekly lower dose carbo/Taxol, and continued daily Iressa. After the end of the seven weeks, patients continued on Iressa daily until progression. The only difference for the patients with a marginal PS is that the weekly carbo/Taxol during radiation wasn't included. They continued daily Iressa through the radiation and then beyond that time, until progression.

The trial was designed to accrue 72 patients in each of these two groups, but it closed early, after the initial reports in 2005 emerged that the SWOG 0023 trial was negative for any benefit from addition of maintenance Iressa after chemo/radiation for stage III NSCLC, and perhaps even detrimental: the longer-term follow up actually demonstrated a statistically significant worsening of survival with Iressa maintenance therapy after chemo/radiation and consolidation Taxotere (docetaxel). The final enrollment was 60 eligible patients in total: 39 more fit patients and 21 marginal PS patients.

The overall results were pretty disappointing, and perhaps most surprising was the fact that the poor PS population did better than the better PS patients. For those with a PS of 2, the median progression-free survival (half progressing, half not) was 13.4 months, and the median overall survival was 19.0 months. Though this group of patients is very understudied for this setting, these numbers are comparable to what we typically see for better performance status patients getting standard chemo and concurrent radiation.

The results with the better performance status patients were pretty discouraging: a median progression-free and overall survival of 9.2 and 13.0 months, respectively, which is really worse than we would expect to see for similar patients getting chemo and radiation today. These disappointing results weren't from increased side effects: aside from an increased probability of rash and diarrhea, toxicities with Iressa weren't increased compared with what you'd expect to see in other trials, in either the good or more marginal PS groups.

The investigators also did EGFR and KRAS mutation testing for as many patients as they could get tissue samples of. Among the surprises were that 25% of the patients tested actually had an EGFR mutation, even though very few were never-smokers. This number is really more than we would expect, and the authors suggested that it could be related to differences in technique for testing in different trials and clinical settings. Regardless, what was really surprising was that the patients with an EGFR mutation didn't do better than the patients who didn't have an EGFR mutation, and the people with a KRAS mutation actually seemed to do better than those with a KRAS mutation. The numbers are small, though, so this work can't be taken as an absolute truth.

What can we say about these results? The trial was stopped early, with less than half of the intended population, so we are definitely limited in our ability to draw conclusions, but one clear point is that more is not better. These results were pretty terrible for good PS patients, for unclear reasons. Given the fact that Iressa was also associated with a significant harmful effect as a maintenance therapy in the larger SWOG trial noted above, even though it didn't overlap with other treatments, it raises the question that there really may be harmful interactions of EGFR inhibitors with radiation that we may not understand. I don't think these results are clear enough to raise alarms, but it certainly suggests that we should be cautious about presuming that combining treatments is definitely a fine idea. It was one of the pieces of evidence that made me concerned that combining chemo and EGFR inhibitors concurrently may be a detrimental combination, though other studies haven't clearly supported this idea.

The results in the poorer risk, more frail patients look fairly encouraging, albeit in a small number of patients. The CALGB is actually planning to start a larger trial specifically for PS2 patients with locally advanced NSCLC that will look at this overall strategy in more patients, and I certainly support that.

In the meantime, I think this small, aborted trial highlights that we can't get too confident: here, the more frail patients did better than the patients with a better performance status, patients with a KRAS mutation did better than patients with an EGFR mutation on an EGFR inhibitor, and an often effective therapy in one NSCLC setting appeared to lead to considerably worse outcomes than expected. There's still plenty more for us to learn...