Erlotinib Prolongs Survival in Never Smokers With NSCLC

NEW ORLEANS—Subgroup analysis of data from the TRIBUTE trial indicates that erlotinib (Tarceva), when given in combination with carboplatin (Paraplatin) and paclitaxel, provides a survival benefit to never-smoking patients with previously untreated advanced non-small-cell lung cancer (NSCLC). Vincent A. Miller, MD, of Memorial Sloan-Kettering Cancer Center, presented the results at the 40th Annual Meeting of the American Society of Clinical Oncology (abstract 7061). In contrast, the combination of erlotinib and chemotherapy did not provide any survival benefit to the entire population of NSCLC patients enrolled in the trial (abstract 7011).

Erlotinib is a selective inhibitor of the tyrosine kinase (TK) domain of the epidermal growth factor receptor (EGFR), currently being investigated in a number of cancers; data from the BR21 trial showed a significant survival benefit of erlotinib monotherapy in advanced refractory NSCLC (abstract 7022).

In the phase III TRIBUTE study, patients received six cycles of chemotherapy, together with either oral erlotinib 150 mg/d or placebo. There was no selection for tumor expression of the EGFR; altogether 1,059 patients were enrolled.

In the trial as a whole, the addition of erlotinib resulted in no difference in overall survival, objective response rate, or time to disease progression. These data were subjected to further analysis on the basis of prespecified subgroups, including cancer stage (III or IV), tumor measurability, weight loss greater than 5% in the previous 6 months, age, sex, race, tobacco history, baseline ECOG score, prior radiotherapy, prior cancer-related surgery, histology, and presence or absence of EGFR expression.

In all but one of these subgroups, the inclusion of erlotinib conferred no survival benefit; it should be noted, however, that many of these categories were too small to provide sufficient statistical power to detect a treatment effect. The single exception was the 10% of patients (64 in the erlotinib arm, and 41 in the placebo arm) who classified themselves in the behavioral factors questionnaire as never having smoked. When compared with former/current smokers, these never smokers tended to be younger (age 58 vs 64), female (60% vs 37%), and to have adenocarcinoma (82% vs 58%).

While median overall survival of never smokers on placebo was similar to that of current or former smokers on placebo (approximately 10 months), never smokers on erlotinib had a median survival of 22.5 months. Never smokers on erlotinib also had improved median time to disease progression—6 months vs 4.3 months for never smokers on placebo.

The degree to which these correlations will ultimately assist in targeting treatment remains to be determined. The correlation between never smoking and deriving survival benefits from the EGFR inhibitors is likely an obverse reflection of the variety of molecular insults that are delivered by nicotine and other carcinogens in tobacco smoke. Since a never-smoking history implies fewer possible mechanisms of transformation to the cancerous phenotype, the probability is enhanced that one specific molecular pathway such as EGFR may be involved, and targeting it has a correspondingly greater likelihood of success.

In recent work (Proc Natl Acad Sci 101:13306-13311, 2004), William Pao, MD, of Memorial Sloan-Kettering Cancer Center, and his colleagues reported that EGFR gene mutations are common in lung cancers from never smokers (fewer than 100 cigarettes in their lifetime). The researchers looked at tumors from 96 lung cancer patients, 15 of whom were never smokers. About half of the never smokers were found to have EGFR mutations, compared with only 5% of the current or former smokers. The investigators also showed that such mutations are found in tumors responsive to erlotinib. Others have previously detected such mutations in tumors sensitive to the EGFR inhibitor gefitinib (Iressa).

Dr. Pao concluded that "adenocarcinomas from never smokers comprise a distinct subset of lung cancers, frequently containing mutations within the TK domain of EGFR that are associated with gefitinib and erlotinib sensitivity."