The European Society for Medical Oncology (ESMO) Congress, similar to ASCO but based in Europe, has been going on in Stockholm, where the results of a study called the First Line Iressa versus Carboplatin/Paclitaxel in Asia Study (taking some liberties to force it into the acronym "IPASS") was presented in the Presidential Symposium by my friend and Hong Kong-based colleague Tony Mok. This study, as shown in the schema below, randomized 1217 Asian patients with advanced NSCLC who had not received prior systemic therapy to either the oral EGFR inhibitor iressa (gefitinib) or the standard chemotherapy carboplatin/taxol (paclitaxel):
It was conducted in 7 countries throughout Asia, and by including only Asian never-smokers or light former smokers (less than 10 "pack-years", the product of number of years smoked x packs per day; and must not have smoked in last two years), it was able to use clinical factors to heavily enrich for patients with EGFR mutations, who are known to have a high probability of responding to oral EGFR "tyrosine kinase inhibitors" (TKIs) like iressa and tarceva(erlotinib). In fact, Dr. Mok noted that there was a great practical advantage in being able to use clinical variables rather than molecular markers that required tissue: only 683/1217 (56%) of patients provided tissue for detecting the mutation, of whom mutation work could be completed in only 437 (36%). This highlights an important challenge in trying to use tissue markers to guide treatment decisions.
Progression-free survival (PFS) was the primary endpoint, and it showed a significant difference favoring iressa overall. Among patients receiving iressa, 25% showed no progression after one year on treatment, compared with only 7% on chemotherapy alone. The overall "hazard ratio" (HR), a measure of improvement in progression-free survival over the entire course of treatment, was 0.74, corresponding to a 26% improvement on iressa vs. standard chemo. However, the results were very different for EGFR mutation-positive vs. EGFR mutation-negative patients. The patients with the mutation showed a more than doubling in progression-free survival with iressa (HR 0.48), while those without mutations did nearly three-times better in terms of PFS with chemo (HR 2.85).
It wasn't surprising to see a response rate (RR) of 71.1% among EGFR-mutation positive patients who received iressa, or that it was remarkably higher than the RR of 1.1% seen in EGFR mutation-negative patients. What was interesting and somewhat surprising to see was that the patients with EGFR mutations also had a significantly higher RR on standard chemotherapy (47.3% vs. 23.5%). I'm actually not blown away by this, since we had already seen that patients with EGFR mutations on the TRIBUTE trial of carbo/taxol with either tarceva or placebo not only had a remarkably long survival on the tarceva arm, but they also had a significantly longer survival if assigned to chemo and placebo:
The important point in the figure above is that the two hatched lines travel together: patients with EGFR mutations showed the same superior survival, whether they received the EGFR inhibitor or not. In the IPASS study, the median overall survivals of the two arms are very similar: 18.6 months with iressa, and 17.3 months with chemo. This isn't a statistically significant difference, although more definitive survival results won't be available for another year or two.
Finally, the investigators also included a qualify of life analysis that was more favorable in the recipients of iressa than those on chemo (p = 0.0148).
What can we take from this? First, it's clear that in a selected population, EGFR inhibitors can perform as well or better than chemotherapy. In terms of which EGFR inhibitor, iressa is still widely used and potentially relevant in Asia, but outside of Asia tarceva has appeared to be more active in a broader population. I would find it nearly unfathomable that tarceva wouldn't look as good or better and would therefore extrapolate these results to the family of EGFR inhibitors. I'm not confident that iressa would perform as well in a broader population.
I have already written that I do feel comfortable offering an EGFR inhibitor as a first line alternative to chemo in patients who have never-smoked and/or have a known EGFR mutation (see prior post). The results of this trial certainly corroborate my prior interpretation that this was acceptable. Is it optimal? Perhaps, but overall survival appears to be comparable between the two arms, and it may well be that there's no real practical difference between starting with chemo and then following with an EGFR inhibitor vs. starting with the EGFR inhibitor first line (I'd expect it to really be six of one, a half dozen of the other). If quality of life is better with the EGFR inhibitor, it's really just a question of whether they get it as first or second line treatment.
Importantly, I wouldn't extrapolate these results to be applicable outside of a narrowly selected patient population. EGFR mutation is probably the purest version, and never- or minimal-smoking status along with being Asian help get you there. I would not expect these results to apply to a broader population, as illustrated by the response rate difference of 71% vs. 1% for Asian patients with vs. without EGFR mutations. Run this trial in North America and the results could be very different.
Finally, it's quite interesting to see that patients with EGFR mutations not only had a superior survival even with chemo alone (as noted in the TRIBUTE trial, figure above), but now also show a much higher response rate with standard chemo. Unlike survival, which could be affected by patients just getting an EGFR inhibitor after chemo, the response rate to chemo is not affected by EGFR inhibitor therapy, so it shows that patients with activating EGFR mutations really have a different, more responsive form of lung cancer.
We'll discuss this further in my next post, about a trial focusing exclusively on patients with EGFR mutations.