Lay Summary: Tarceva is experimental together with chemotherapy but studies in specific subgroups are being conducted.
Four front-line randomized chemotherapy combination trials with gefitinib (INTACT 1 and 2) and erlotinib (TALENT and TRIBUTE) have definitely shown no benefit to adding the EGFR inhibitor to standard combination chemotherapy in patients with NSCLC. I describe the best trial in some detail.
The TRIBUTE trial was a phase III study involving patients with advanced NSCLC who had yet to be treated with chemotherapy. Most patients in the study had advanced, stage IV disease.
Between July 2001 and August 2002, researchers with the trial randomly assigned 1,079 patients to one of two groups. One group (539) was treated with a standard chemotherapy regimen of paclitaxel (Taxol®) andcarboplatin, plus a daily erlotinib pill. The other group (540) received the same chemotherapy treatment plus a dummy pill (placebo).
The trial was primarily designed to determine whether patients taking the erlotinib combination did better in terms of overall survival. However, based on encouraging results from earlier studies, the researchers also designed the trial to see if a particular subgroup of patients – those who had never smoked – did better on erlotinib.
A related analysis was done on tumor samples provided by 274 of the 1,079 patients. Drawing on the results of previous tissue sample studies, researchers looked for the presence of certain EGFR mutations in this group of NSCLC patients and whether they were associated with better or worse survival and other outcomes.
The clinical trial team was led by Roy S. Herbst, M.D., Ph.D., of the University of Texas M.D. Anderson Cancer Center in Houston (see the journal abstract). The tissue study team was led by David A. Eberhard, M.D., Ph.D. of Genentech, Inc. in San Francisco, Calif. (see the journal abstract). Both reports were published in the same journal issue.
Erlotinib did not help patients live any longer overall. The median survival for patients taking erlotinib was 10.6 months compared to 10.5 months for the placebo group. Both groups of patients also experienced about the same “time to progression” (the time it took for their cancer to get worse): 5.1 months for the erlotinib group, 4.9 months for the placebo group.
Erlotinib failed to make any difference among most of the subgroups analyzed, including those defined by age, gender, race, and the level of EGFR expression. However, erlotinib did help the subgroup which had never smoked. The 72 “never smokers” in the erlotinib group survived 22.5 months; the 44 never smokers in the placebo group lived 10.1 months. This amounted to a 51 percent reduction in the risk of dying for the erlotinib group.
Never smokers on the erlotinib combination also did better in terms of time to progression (6.0 months) when compared to never smokers in the standard chemotherapy group (4.3 months) – a 50 percent reduction in risk of progression.
As for side effects, all patients in both groups experienced about the same level of toxicity, though those taking the erlotinib combination experienced more instances of rash and diarrhea. These particular side effects are known to be associated with EGFR inhibitors such as erlotinib.
In the related tissue sample analysis, researchers reported that certain EGFR mutations were found in 13 percent of the samples provided. (The rest of the tumors expressed what researchers call the “wild type” form of EGFR.) Patients with EGFR mutations tended to live longer, regardless of whether they were taking the erlotinib combination or just the standard chemotherapy. Among the never smokers, those in the erlotinib group tended to have more of these mutations than those in the chemotherapy-only group.
A number of other patterns were noted about patients with EGFR mutations, leading the researchers to suggest that the mutations may help doctors determine which advanced NSCLC patients are most likely to benefit from treatment with or without erlotinib. Studies that stratify patients based on their EGFR status are ongoing.
nccn.org, nonsmall cell lung cancer
S Tort, D Gallardo, FR Macbeth, MC Pallarès, I Solà Erlotinib for advanced non-small cell lung cancer Cochrane Database of Systematic Reviews 2008 Issue 1