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Dr. Jack West is a medical oncologist and thoracic oncology specialist, and Executive Director of Employer Services at the City of Hope Comprehensive Cancer Center in Duarte, CA.

Longterm Survival with Iressa in BAC
Wed, 06/25/2008 - 21:22
Author
Howard (Jack) West, MD, Associate Clinical Professor, Medical Oncology, Executive Director, Employer Services, Founder, President and CEO of GRACE

One of my earliest posts when I started OncTalk was on the use of oral inhibitors of the epidermal growth factor receptor (EGFR), one of the growth signals that is often over-active in cancer cells, against advanced bronchioloalveolar carcinoma (BAC), a unique subtype of lung cancer that tends to grow within the lungs, sometimes slowly, and not progress elsewhere. These EGFR inhbitors like iressa (gefitinib) and tarceva (erlotinib) have certainly been well studied in NSCLC in general, but both of these drugs have been a focus of particular attention as a treatment for BAC. In fact, the largest trial that has yet been conducted in advanced BAC is one that I led, called SWOG 0126, that gave iressa at 500 mg by mouth daily (actually twice the dose that was eventually settled on, but possibly a more effective dose) to 135 eligible patients with advanced BAC. My colleagues and I published the results of this trial a couple of years ago (abstract here), but this year at ASCO I presented the results with longer-term follow up (abstract here), which yielded some interesting findings.

Obviously, the response rates and side effects didn't change with a couple of years of longer-term follow up. Nor did the median progression-free and overall survival numbers, since those reflect the point at which half of the patients will have demonstrated progression or have died:

S0126 Efficacy Update

It's worth noting that while this study enrolled both patients who had never been previously treated and some other patients who had received prior chemotherapy, both the chemo-naive and previously treated patients had the same progression-free and overall survival results, as shown in the superimposed curves shown above.

As we saw in the initial reports, there were major differences by clinical variables, including far better results in never-smokers compared with current/former smokers, those who developed a rash compared with those who didn't, in women vs. men, and in patients with a good performance status compared with those with a marginal performance status. Here are the differences in survival that emerged:

S0126 clinical variables

But the most interesting issue isn't what happened for the majority of people, but how remarkably well a few patients did. We identified six patients who went more than four years without progression, including three who continue on the study without progressing at this time. To my knowledge, this is the first time that we've seen published documentation that patients who continue to do well on an EGFR inhibitor for this far out (as if they were some mythical creature that we heard exists but never actually encounter). And you can see various clinical and molecular features of these patients:

S0126 Longterm Survivors

So here are some important points to glean from the table above. These patients aren't only female never-smokers, although three of the six never smoked. These aren't only patients who have EGFR mutations or have EGFR gene amplification as measured by "fluorescence in situ hybridization" (FISH) -- tissue was available from just a few of these patients, and this work suggested that the major benefits aren't only seen in patients who have molecular predictors of a good response to EGFR inhibitors. Finally, none of these patients met the strict criteria for a response. Instead, they all had stable disease only, although some had good minor responses, and then went years and years and years without progressing on iressa.

I think these results are very important to serve as an illustration of how well people can do on an EGFR inhibitor, and also that you don't need to have the clinical or molecular predictors of major benefit to be not only a beneficiary, but even a huge beneficiary who shows no progression over 4 years or more. To me, these patients also highlight why I don't think we're ready to routinely use molecular testing to shape our clinical decisions in whether and when to use EGFR inhibitors. Some people might see someone like patient D in the table, a former smoker without an EGFR mutation and negative by EGFR FISH, and decide that they don't have a real chance of getting a benefit from an EGFR inhibitor. And they'd pass up a treatment on which she's shown no progression over more than five and a half years, and still counting.

More on the great debate about the pros and cons of molecular testing for EGFR soon.

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