Are There Significant Differences Among EGFR Mutations?

Howard (Jack) West, MD, Founder and President

Since we've come to appreciate the presence of distinct activating EGFR mutations associated with a very high probability of responding to an oral EGFR inhibitor, the question has emerged about whether there are significant differences in outcomes between the two most common ones, which are a deletion in exon 19 and a "point mutation" in exon 21. Some retrospective work in smaller aggregated series has suggested that patients with an exon 19 deletion tend to do best, but other work has suggested no difference between these two most common mutations. The recently reported trio of prospective trials of patients with an EGFR mutation receiving first line chemo or an EGFR inhibitor provide a good opportunity to evaluate this question.

The studies are actually pretty consistent in conveying that there is a modest trend toward the most favorable progression-free survival (PFS) in people with an exon 19 vs. an exon 21 mutation, but the differences aren't great. Here are the PFS curves directly comparing the two main types of mutations in the Japanese trials with Iressa (gefitinib):

pfs-by-type-of-egfr-mutation (Click on image to enlarge)

So while the curve for exon 19 deletion is on top by a small margin, both activating mutations appear to follow a very similar trajectory overall, with no significant difference.

The Chinese OPTIMAL trial of standard chemotherapy vs. Tarceva (erlotinib) in patients with an EGFR mutation also presented results for PFS by EGFR mutation subtype, though the presentation included separate curves for each mutation compared to the standard chemotherapy arm:

optimal-pfs-by-type-of-egfr-mutation Here, again, there is a very striking, clinically significant difference in PFS favoring Tarceva for both groups (don't be put off by the fact that the differences aren't statistically significant in these two trials, since the power to do so is very reduced in subgroups half the size of the main trial). Though the difference is a little greater with an exon 19 deletion vs. an exon 21 mutation, with a median PFS 15.3 and 12.5 months respectively, the general principles hold up, and clearly both major EGFR mutation subtypes show the same effect of clear benefit for EGFR inhibitor therapy.

Practically speaking, there may be a tendency toward the most favorable results in patients with an exon 19 deletion, but clearly the patients with an activating EGFR mutation in exon 21 also show the same profound PFS benefit with an EGFR inhibitor compared with standard chemo, so I don't think there's any practical distinction to be made. We can say that with increasing confidence as we do more studies that specifically focus on populations of patients with an EGFR mutation.

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