CHICAGO – Second-line treatment with docetaxel led to significantly better outcomes than with erlotinib in a head-to-head comparison among patients whose non–small cell lung cancer did not have a mutation in the epidermal growth factor receptor.
Progression-free survival, response, and disease control rates all favored docetaxel (Taxotere) in the phase III TAILOR (Tarceva Italian Lung Optimization Trial) study, investigators reported. "TAILOR does not support the use of erlotinib over docetaxel in patients with EGFR wild type," Dr. Marina C. Garassino said at the annual meeting of the American Society of Clinical Oncology.
Dr. Marina C. Garassino
TAILOR is the only prospective trial to select patients with non–small cell lung cancer (NSCLC) carrying the epidermal growth factor receptor (EGFR) in its wild-type form for a direct comparison of docetaxel with erlotinib (Tarceva), a tyrosine kinase inhibitor (TKI) targeting EGFR. TKIs are well established in the treatment of patients harboring EGFR mutations, but their role continues to be debated in EGFR wild type, which accounts for about 85%-90% of NSCLC cases.
Investigators randomized 222 patients who had an ECOG (Eastern Cooperative Oncology Group) performance status of 0-2 and had advanced or recurrent disease after prior treatment with a platinum-based doublet. They were assigned to erlotinib 150 mg daily or to either of two doses of docetaxel: 75 mg/m2 on day 1 every 21 days, or 35 mg/m2 on days 1, 8 and 15 every 28 days until disease progression or unacceptable toxicity. Three patients were not included in the intent-to-treat analysis because of major protocol violations, according to the late-breaking abstract.
About three-fourths of the patients had adenocarcinoma histology, were current or ex-smokers, and carried wild-type KRAS. EGFR and KRAS mutational status was determined by a central lab and was cross-validated in two independent labs. The patients’ median age was about 66 years.
The investigators noted the following findings:
• The median time to progression was 3.4 months with docetaxel and 2.4 months with erlotinib (hazard ratio, 0.69; P = .014). At 6 months, 29% of patients who were given docetaxel were free of progression, compared with 17% on erlotinib, said Dr. Garassino of the medical oncology department at Fatebenefratelli and Ophthalmic Hospital in Milan.
• The disease control rate (defined as complete and partial responses and stable disease) was doubled in the docetaxel arm at 41.5% vs. 22.8% in the erlotinib arm (P = .007).
• Responses in the erlotinib arm were "rare and almost unseen" (2.2% vs. 14%; P = .004), she said. No erlotinib patients had a complete response, whereas 4.3% did with docetaxel. During a discussion of the study, this finding was questioned as being unusual for single-agent docetaxel in second-line use. Although no independent review was conducted, Dr. Garassino replied that the data were trustworthy.
A progression-free survival subgroup analysis favored docetaxel over erlotinib, regardless of age, sex, performance status, and smoking status, although the interactions were not statistically significant. Patients with and without KRAS mutations also benefited from docetaxel (HR, 0.84 and 0.65, respectively; P = .237), with median progression-free survival also similar in these patients at 2.6 months and 2.4 months (HR, 0.91; P = .558).
KRAS mutation does not seem to be a predictive or prognostic factor in second line, said Dr. Garassino, who remarked that a possible negative predictive and prognostic role has been suggested for KRAS.
Overall survival, the study’s primary end point, will be evaluated after the required 199 deaths have occurred.
Toxicity was as expected, with treatment-related adverse events leading to dose modifications in 22% of the docetaxel and 29% of the erlotinib arms. Data on rash have not been analyzed for correlation with progression or response.
Five randomized trials have compared chemotherapy vs. EGFR TKIs in previously treated NSCLC patients, but they were all were conducted in unselected patients, and only two trials reported outcomes by EGFR mutational status for a minority of patients in unplanned analyses. The hazard ratio for progression-free survival in TAILOR is consistent with the retrospective analyses from the recent TITAN (Lancet Oncology 2012;13:300-8) and INTEREST (Lancet 2008;372:1809-18) trials, suggesting benefit of chemotherapy over EGFR TKIs in EGFR wild-type patients, said discussant Benjamin Solomon, Ph.D.
"Although we await the survival data, in the second-line setting, as we know already in the first-line [setting], outcomes are better with chemotherapy (docetaxel) than EGFR TKIs, (erlotinib) in patients with EGFR wild-type non–small cell lung cancer," said Dr. Solomon of the lung cancer service at Australia’s Peter MacCallum Cancer Centre in East Melbourne, Victoria.
The one caveat, he added, is that EGFR wild-type patients are not a homogeneous population, and thus clinicians should still test for ALK gene rearrangements and other potentially actionable genetic alterations.