GRACE :: Lung Cancer

Beyond the SWOG 0023 Trial: Are Iressa and/or Tarceva Harmful after Definitive Concurrent Chemoradiation (CRT)?

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In 2008 the SWOG 0023 trial was published, which looked at the question of maintenance Iressa (gefitinib) after definitive chemoradiation in patients with locally advanced (Stage III) NSCLC. The trial randomized patients who had not progressed after completing CRT with concurrent cisplatin and etoposide chemotherapy followed by consolidation Taxotere (docetaxel) to either Iressa or placebo. Patients were then followed until progression or death. In a result which still confounds lung cancer oncologists, it appeared that the arm which received Iressa had a significantly WORSE survival than those who received placebo, with a median survival that was 12 months shorter (23 months in the Iressa arm vs. 35 months with placebo).0023-survival

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No one has put forth an adequate explanation of why Iressa, a drug used widely now in NSCLC patients for almost a decade, would be harmful (instead of merely ineffective) in these patients. It did not appear that more patients on Iressa died of toxic side effects from the drug, which would have been a convenient explanation. Instead it appeared that the patients receiving Iressa had faster progression of their lung cancer than those on placebo. Some have hypothesized that EGFR inhibition actually stimulates the cancer to progress in this specific population. As a result, this study has been held up as a cautionary tale about how we need to understand that our treatments have the potential to harm patients, not just help or do nothing. I have no bones with this concept in general, but…

I have never been convinced about this conclusion that EGFR inhibition caused harm, although I had no more evidence one way or the other than anyone else. Luckily, before the results of 0023 became known, several other studies testing the concept of maintenance EGFR therapy after chemoradiation were initiated. One such study, presented for the first time at the World Conference on Lung Cancer this past month, was the “Dartmouth Protocol”, presented by Dr. James Rigas at Dartmouth Medical School. Offical name: Maintenance Erlotinib versus Placebo in Patients with Unresectable Stage III NSCLC following Concurrent Chemoradiation.

In this randomized clinical trial, 243 patients with unresectable stage III NSCLC were treated with concurrent CRT with weekly carboplatin and docetaxel, and then were randomized to either erlotinib or placebo, a design very similar to the SWOG 0023 trial. The primary endpoint was progression-free survival (PFS). One key difference was that patients were randomized at diagnosis to one or the other arm prior to CRT, while in the SWOG trial patients were randomized if they had not progressed after CRT. For this reason, only 63% of originally randomized patients received the Tarceva or placebo as many progressed or were too sick to proceed.

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In contrast to SWOG 0023, however, Dr. Rigas showed in his talk that the patients on the erlotinib arm had a significantly delayed time to progression of the cancer. There was not a significant prolongation of either DFS or overall survival (OS) with the addition of maintenance erlotinib, but neither was there any trend towards WORSE survival in these patients either, in direct contrast to SWOG 0023. The curve below is the OS in the two groups based upon who actually received the Tarceva or placebo, with only a trend towards better survival in the Tarceva group but no suggestion of harm.

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In addition, my own group at the Cleveland Clinic presented the final results from a single arm phase II trial of concurrent chemoradiation incorporating surgery, and then followed by 2 years of maintenance erlotinib. While a single arm study cannot show that maintenance is better or worse than no maintenance, our patients had quite good outcomes compared to what one might expect in this high risk population, with no hint of problems during the maintenance erlotinib phase.

What does this mean? I think this provides some evidence that perhaps the poor survival in the 0023 Iressa arm was more a statistical fluke than true harm with Iressa treatment. Of course, there is no evidence SUPPORTING the use of maintenance EGFR inhibitors in this setting either (in contrast to the results of the SATURN trial in patients with metastatic NSCLC), but should such a strategy be investigated in another setting I do not think it should be dismissed from the results of only one trial. As with most trials of this nature, the indiscriminate testing of targeted agents in populations of patients who have not been preselected for the target of interest is more likely to leave us with more questions than answers.


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