NEW ORLEANSSubgroup 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
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 progression6
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
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
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