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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.

Tarceva Dose Escalation in Current Smokers: Could Higher Doses Improve Results?
February 4, 2009, 10:44 PM
Howard (Jack) West, MD, Associate Clinical Professor, Medical Oncology, Executive Director, Employer Services, Founder, President and CEO of GRACE

We have long noted that there is a clear association of smoking history with effectiveness of oral EGFR tyrosine kinase inhibitors (TKIs). Part of this is because never-smokers have a high incidence of carrying activating EGFR mutations, but also potentially because current smokers actually metabolize EGFR TKIs faster (see prior post). We've seen a consistent association of rash development with better outcome (see prior post), and current smokers have been disproportionately likely to develop little or no rash. A recent study just coming out in the Journal of Clinical Oncology from a group in the UK has studied blood levels with dose escalation of tarceva (erlotinib) among current smokers (abstract here) and suggests a possible value in giving higher than standard tarceva dosing among current smokers, so that they can achieve the same blood levels as never-smokers or former smokers. Will this lead to better results for these patients?

The clinical trial enrolled patients who smoked at least 10 cigarettes per day and first escalated the dose of tarceva from 200 to 350 mg daily and carefully assessed side effects. While the standard "maximum tolerated dose" with tarceva in a general population is 150 mg/day, this population of current smokers reached the level of frequent rash and diarrhea and fatigue at 300 mg/day. One thing this work demonstrated was that escalating the dose could bring current smokers to the side effect severity and frequency more typical of never-smokers or prior smokers.

The trial then entered another phase that enrolled 35 current smokers to receive either the standard dose of 150 mg/day or 300 mg/day. Looking at the blood levels in patients, the higher dose translated to higher blood levels, which are comparable to the levels of people who don't smoke:

erlotinib PK in Smokers (click to enlarge)

Interestingly, the patients who received the higher dose of tarceva had a median pverall survival of 9.56 months, compared with 5.45 months for current smokers who received tarceva at 150 mg/day (pretty similar to the median overall survival of 6.1 months in the larger BR.21 trial of tarceva vs. placebo (abstract here).

However, we need to keep the results of this small trial in perspective. This trial had just a few dozen patients, so comparison of very small groups is only provocative, not conclusive at all. It suggests that there is a value in asking the question of whether escalating dose in current smokers might be benefcial. But the BR.21 trial didn't show a better result in former smokers (median overall survival 5.5 months) than current smokers, and the former smokers shouldn't be metabolizing tarceva faster and getting lower blood levels: interestingly, the package insert for tarceva says that doctors might consider giving a higher dose than the standard 150 mg to current smokers, but we just don't have much evidence to guide us here. And at about $3500/month for tarceva at the standard dose, I can imagine many insurers balking at doubling that cost based on something that is a mere hypothesis waiting to be tested more thoroughly. But at least the little work done thus far suggests that we might improve outcomes for smokers receiving tarceva by re-evaluating whether they're receiving the best dose right now.

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