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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.

Differences in Never-Smoker vs. Current/Ex-Smokers Receiving Chemo
Mon, 01/12/2009 - 07:31
Howard (Jack) West, MD, Associate Clinical Professor, Medical Oncology, Executive Director, Employer Services, Founder, President and CEO of GRACE

A quick point on the importance of biology over treatment. Years ago, I highlighted the results in the TRIBUTE trial of chemo with placebo or combined with erlotinib (tarceva) at the same time (biomarker study abstract here), which showed that patients with EGFR mutations had a much better survival whether they received an EGFR inhibitor or not:

Eberhard EGFR Mutation and OS on TRIBUTE (Click to enlarge)

Here, biology was the prevailing factor. We’ve also recently seen that the patients on the IPASS trial of Asian never-smokers or light former smokers who were then randomized to first line chemo or an EGFR inhibitor had a far better survival if their tumor had an EGFR mutation compared to those who did not (see prior post). Similarly, the IPASS trial also showed that patients with EGFR mutations had nearly double the response rate to chemotherapy that patients without EGFR mutations demonstrated. So maybe the benefit of unique biological factors applies to standard chemotherapy as well as “targeted therapies”. Chemotherapy is also targeted and only benefits a subset of patients: we’re just further behind at understanding the relevant targets and discriminating the beneficiaries from others with standard chemo than with agents like EGFR inhibitors.

The recently published trial of cisplatin/alimta (pemetrexed) vs. cisplatin/gemzar (gemcitabine) (abstract here) showed an interesting result among enrolled never-smokers, who comprised 14-15% of the patients on the 1725 patient trial overall. Although we think of never-smokers as doing especially well with EGFR inhibitors, this trial also showed that never-smokers had a markedly longer median overall survival in both chemotherapy arms compared to current or former smokers (15.9 vs. 10.0 months in the cis/alimta arm; 15.3 vs. 10.3 months for the cis/gem arm).

What’s not clear is whether this favorable result in never-smokers is related to doing better with chemo or largely because of benefit from subsequent oral EGFR inhibitor therapy. A little over 50% of the patients on each chemo arm received some form of second line therapy, and about a quarter of the patients on each chemo arm received a subsequent EGFR inhibitor. These may have preferentially been the never-smokers. It’s not possible to say how much of the prolonged survival in never-smokers is from chemo having more benefit, EGFR inhibitors being particularly helpful, a slower progression of the underlying cancer, and/or fewer other medical problems contributing to worse tolerance of treatment. There’s a strong chance it’s a combination of all of these factors. But this is compatible with some other studies that have also shown an improved survival for never-smokers compared with smokers in a range of settings. But as the IPASS trial suggests, the population of never-smokers with lung cancer includes several different subpopulations that we don’t yet understand. We’ll need to learn more about the biology, for which the designation of never-smoker provides only an approximation, in the coming years.

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