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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.

ASCO Preview on TORCH Trial: Treatment Order Matters
Sat, 05/22/2010 - 16:39
Howard (Jack) West, MD, Associate Clinical Professor, Medical Oncology, Executive Director, Employer Services, Founder, President and CEO of GRACE

Despite the fact that many of the most anticipated ASCO abstracts are still being withheld until the meeting itself, there is certainly a lot of information in the released abstracts that provide a tantalizing preview and already hint at some important new conclusions. I'll try to provide some ongoing thoughts leading into the meeting coming up in two weeks.

The first I want to highlight is the TORCH trial, an international study being presented by Italian lung cancer leader Cesar Gridelli. This study looks at the question of whether the order of therapy matters: patients in this phase III study were randomized to cisplatin/gemcitabine as first line therapy, followed by the EGFR inhibitor Tarceva (erlotinib) on progression, or the reverse of first line Tarceva followed by cisplatin/gemcitabine at progression. A total of 760 patients, not selected for particular histology (55.5% hadadenocarcinomas), smoking status (20.6% never-smokers), race (3.2% East Asian), or EGFR mutation status (not tested), were enrolled. This is in a population that we must presume is likely to have only a small minority of patients as EGFR mutation positive.

The results demonstrate that the order of therapy matter and that there are consequences of giving the less optimal treatment first. Specifically, at the time of a planned interim analysis of the ongoing results, the differences in survival were striking enough, 40% worse for those who started with Tarceva, that the trial was closed for further enrollment. The difference in median overall survival is 10.8 months vs. 7.7 months, favoring initial chemotherapy: a statistically and clinically significant difference, to be sure.

The results of the IPASS study illustrate convincingly that patients who don't have an EGFR mutation are better served by receiving initial chemotherapy than an EGFR inhibitor, at least in terms of the striking difference in progression-free survival, though the difference in (preliminary) overall survival wasn't statistically significant at times the IPASS results have been presented thus far. Frankly, my presumption has been that if patients cross over to the best therapy for them, regardless of whether it's first or second line therapy,they'd end up with a very comparable overall survival.

We don't know yet whether most of the people enrolled successfully crossed over to the second line treatment option. Perhaps the inferior survival with first line Tarceva was related to many patients not getting the opportunity to benefit from chemo -- and perhaps there wouldn't be any real differences if a more tolerable carboplatin-based doublet were used (I can imagine that patients progressing and having a worse performance status would have more success with a second line carboplatin combination than with cisplatin/gemcitabine).

It should also be underscored that these results don't negate the very consistent results thus far that have shown that patients with a known EGFR mutation do exceptionally well with first line oral EGFR inhibitor therapy. The TORCH trial included a very different population.

We've certainly got much more to learn than is contained in this abstract, and much will be revealed in the actual oral presentation in a couple of weeks. But based on the synopsis available now, I need to revise my general presumption that "it'll all come out in the wash", as my grandfather used to say. It may not be feasible to have everything come out the same whether you start with option 1 or option 2. Instead, these results from the TORCH trial raise the ante for ensuring that patients get the optimal treatment strategy for them at the earliest opportunity. It directly counters the concept that it's just as good to start with an EGFR inhibitor based on clinical features or a desire to avoid chemotherapy-related side effects. That appears to be an ill-conceived idea unless you know a person has an EGFR mutation.

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