The issue of population-based differences in response to lung cancer treatments was essentially introduced with the EGFR inhibitors, so it’s appropriate to introduce racial differences overall with this work. Mention of more favorable results with EGFR inhibitors iressa and tarceva emerged with the earliest clinical studies and have since become a well established truism. Let’s explore what we know now and how we got here.

The first demonstration of more favorable results in Asian patients came with the phase II Iressa single anent dosing studies called IDEAL-1 (conducted largely in Japan and Europe) and IDEAL-2 (conducted largely in the US) (see review post of this work). The response rate in IDEAL-21 was in the 18-20% range, approximately twice that seen in IDEAL-2. One hand-waving argument was that the eligibility requirements were slightly different between the two trials: the trial that included Asian patients required only a single line of prior therapy for advanced NSCLC, while the US-based trial required two or more lines of therapy. So while you could argue that the less extensively treated patients in the IDEAL-1 trial would be expected to have a higher response rate, this doesn’t explain the difference in response rate within IDEAL-1 of 27.5% vs. 10.4% (p = 0.0023) for Asian vs. non-Asian patients, all on the same trial and with the same eligibility requirements. And the same trend was seen in the BR.21 trial with tarceva, in which the response rate was 18.9% vs. 7.5% for Asian vs. non-Asian patients, respectively (p = 0.02), with everyone sharing the same eligibility and receiving the same treatment. Similarly, although the ISEL trial of iressa vs. placebo in patients with refractory advanced NSCLC was negative overall, there was a three month difference in survival that was statistically significant in the pre-specified subset analysis of Asian vs. non-Asian patients (9.5 vs. 5.5 months, p = 0.01).

Of course, the explanation for this difference came from the groundbreaking work on the activating mutations of the EGFR molecule that exist right in the part of the target protein where iressa and tarceva bind and where the subsequent signal cascade is activated.

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That story broke in the spring of 2004, and shortly after that it was demonstrated that collections of tumor tissue showed a frequency of EGFR mutations from Asian patients that was 2-3 times that in Caucasian patients. Since then, I and other experts have described how many of the clinical factors identified with favorable response to EGFR inhibitor therapy has really been largely due to the tight correlation of these variables with the frequency of EGFR activating mutations in patients with particular clinical characteristics, such as a higher frequency of EGFR mutations (which themselves appear to be closely associated with higher likelihood of response to EGFR inhibitors) among Asians vs. non-Asians, women vs. men, never-smokers vs. current or prior smokers, and/or patients with adenocarcinomas (including bronchioloalveolar carcinoma (BAC) tumors) vs. squamous histology tumors.

It's clear that these clinical and molecular factors overlap: below is a table I made a couple of years ago in order to highlight the frequency of EGFR mutations, as well as K-ras mutations, in relation to smoking status. At the time, I also noted how striking it was to see how many of these surgical series that describe a high frequency of EGFR mutations, along with a high proportion of never-smokers, were from Asia (6 of 8 trials that described tissue from a single country):

At the ASCO meeting last year, Dr. Pasi Janne from Dana Farber Cancer Center presented this important summary slide that highlights how, regardless of the other clinical variables involved, Asian populations have a remarkably higher frequency of EGFR mutations:

Importantly, I need to underscore that response rate on EGFR inhibitors isn't the whole story of clinical benefit. I believe that there are very large proportions of patients who don't have a real "response" on EGFR inhibitors but live longer than they would have otherwise, so response is not the same as survival. But it's clear that the biology is different, and Asian patients are far more likely to have EGFR as a driving factor for their lung cancer.

At this point, the oncology community has come to understand and expect that trials of EGFR inhibitors done in Asia will likely demonstrate more favorable results than trials of these agents done elsewhere, and that we can’t necessarily generalize findings from Japanese patients receiving EGFR-based therapies for the US or many other parts of the world.

Are there population differences in response to chemotherapy? We’ll cover this question next.