Several years ago, we learned that EGFR tyrosine kinase inhibitors (TKIs) were not a very helpful strategy for an unselected population of frail patients in the US, clearly inferior to standard chemotherapy (see prior posts here and here). This work was in patients who hadn't been tested for molecular markers like EGFR mutations, and our interpretation of the previous US-based trial left us with the conclusion that an EGFR TKI like tarceva (erlotinib) or iressa (gefitinib) was an inferior chemotherapy alternative and apparently ineffective treatment for the majority of patients with a marginal performance status, but it could still be an effective option for patients selected to be especially likely to benefit from this class of agents, like patients with an EGFR mutation.

This was the subject of pure speculation until now. A manuscrupt by Inoue and colleagues (abstract here) has just been published that describes the experience of treating patients with an EGFR mutation and who are either elderly or have a poor performance status or both with an EGFR TKI (iressa at the standard 250 mg/day) as first line therapy. Specifically, they enrolled 30 patients who either had a poor performance status (3 or 4 on a scale of 0 to 5 where 0 is asymptomatic and 5 is dead: details here), or were 70 or older with a marginal performance status (2 -4) or 80 or older with any symptoms (1-4). It's worth noting that there are relatively few studies that include patients with a performance status of 2, and almost none that have included patients with a performance status of 3, who spend more than half of their day in bed and can't take care of many of their activities of daily living.

The exciting thing that they found was that these patients responded to gefitinib (response rate of 66%, right in line with the typical results for a population with an EGFR mutation) and had a much more favorable median survival, 18 months, than you'd expect for patients with a marginal or poor performance status (likely in the 2-6 month range). In the curves below, the yellow one shows the survival of a comparable group of Japanese frail patients who didn't have an EGFR mutation but also received iressa as first line therapy:

(Click to enlarge)

What was also impressive was that this very favorable response rate and median survival was associated with a very significant improvement in performance status for two thirds of the patients, as shown here (downward lines are favorable, since a lower performance status is more independent and less symptomatic):

It's important to highlight that his was a Japanese study and that we've seen major differences between Asian and North American populations in lung cancer outcomes, especially with regard to EGFR inhibitors. However, thus far it has really appeared that the differences are due primarily to differences in the molecular markers of tumors, so it's very likely that patients with the EGFR mutation positive tumors have a similar response to EGFR TKIs everywhere. Consequently, it seems likely that the previously noted unimpressive results with an EGFR inhibitor apply to the majority of poor performance status patients in North America, since only about 10% would be expected to carry an EGFR mutation. But for those who do have one, this study out of Japan would suggest that they have a high probability of a good response and improvement in symptoms, along with a prolonged survival, from early administration of an EGFR inhibitor.

The key appears to be in separating the major beneficiaries from the ones who won't benefit and may even be harmed from this approach. But this work provides the hope of treating certain elderly and/or very frail patients with an EGFR TKI and getting dramatic results.