Erlotinib (Tarceva®) Plus Chemotherapy Fails to Improve Overall Survival in Non-Small Cell Lung CancerKey Words
Non-small cell lung cancer, erlotinib (Tarceva®), epidermal growth factor receptor (EGFR) inhibitor. (Definitions of many terms related to cancer can be found in the Cancer.gov Dictionary.)
Summary
In a phase III trial testing a new approach to treating non-small cell lung cancer, patients receiving standard chemotherapy plus the drug erlotinib (Tarceva®) did not live any longer than those on chemotherapy alone. However, there was a significant survival benefit for one subgroup of patients taking the erlotinib combination: those who had never smoked were 51 percent less likely to die than never-smokers who didn’t receive erlotinib.
Source
Journal of Clinical Oncology, released online July 25, 2005, published Sept. 1, 2005 (links to the journal abstracts, below).
Background
In 2005, an estimated 163,510 deaths from lung cancer will occur in the United States, accounting for about 29 percent of all cancer-related deaths in the nation. Most cases (80 percent) are non-small cell lung cancer.
Researchers have been testing agents that interfere with a protein called the epidermal growth factor receptor (EGFR). EGFR, which helps cells to divide, is found at abnormally high levels on the surface of many types of cancer cells, including non-small cell lung cancer. Examples of these experimental EGFR inhibitors are gefitinib (Iressa®), cetuximab (Erbitux®), and erlotinib (Tarceva®).
In 2004, several phase III clinical trials involving patients with non-small cell lung cancer (NSCLC) reported that patients receiving standard chemotherapy plus an EGFR inhibitor (gefitinib or erlotinib) did no better than patients receiving chemotherapy alone. However, that same year researchers with a phase III Canadian trial reported that erlotinib helped NSCLC patients whose cancer was no longer responding to chemotherapy to live about two months longer than those taking a placebo (see the related story).
The Study
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®) and carboplatin, 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.
Results
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.
Limitations
“The TRIBUTE trial suggests that certain subsets of patients may benefit from combined treatment” with erlotinib plus standard chemotherapy, noted Janet E. Dancey, M.D., of the National Cancer Institute’s Cancer Therapy Evaluation Program. “However, these are
retrospective analyses on small subsets of patients, and thus cannot be viewed as definitive. Further studies would be required to confirm the potential beneficial effects of concurrent treatment with EGFR inhibitor and chemotherapy in these patient subpopulations.”
Comments
In an accompanying editorial, David R. Gandara, M.D., and Paul H. Gumerlock, Ph.D., of the University of California Davis Cancer Center wrote: “While certainly not conclusive, these data…suggest that for patients with [wild-type] EGFR, who make up the vast majority of the NSCLC population in the United States, caution should be observed in recommending such a combination strategy outside” of a clinical trial. More studies are needed before doctors and patients can know whether combinations of chemotherapy and EGFR inhibitors have any merit. In the meantime, they say, “the jury is still out.”
From Dancy’s point of view, the jury may have rendered its verdict. The TRIBUTE trial, she noted, is the latest of four trials to report negative results for erlotinib or the other EGFR inhibitor, gefitinib, in patients with advanced, previously untreated lung cancer. “When given daily and combined with standard chemotherapy,” she said, “the addition of these agents do not provide benefit to patients.”
Other approaches, such as giving an EGFR inhibitor before or after chemotherapy, may provide benefit, she said. “However, such alternative schedules require further evaluation in clinical trials.”
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