Study Finds No Disease-Free Survival Improvement With Adjuvant Erlotinib in EGFR-Expressing NSCLC
In the phase III RADIANT trial reported in the Journal of Clinical Oncology, Kelly et al found no disease-free survival improvement with adjuvant erlotinib (Tarceva) vs placebo in patients with EGFR-expressing stage IB to IIIA non–small cell lung cancer (NSCLC). However, there was evidence of erlotinib benefit among patients with activating EGFR mutations.
Study Details
In this double-blind trial, 973 patients with completely resected disease from 204 sites in 19 countries were randomly assigned 2:1 between November 2007 and July 2010 to receive erlotinib 150 mg once daily (n = 623) or placebo (n = 350) for 2 years. EGFR expression/amplification was determined by immunohistochemistry or fluorescence in situ hybridization. Stratification factors were stage, histology, previous adjuvant chemotherapy, smoking status, EGFR amplification status, and country.
The primary endpoint was disease-free survival in the intent-to-treat population. Secondary endpoints included overall survival and disease-free and overall survival in patients with tumors harboring EGFR-activating mutations. Secondary endpoints were to be statistically tested only if the primary disease-free survival analysis showed a significant effect favoring erlotinib.
The erlotinib and placebo groups were generally balanced for age (median 62 years in both), sex (59% and 60% male), race/ethnicity (80% white in both, 17% Asian in both), Eastern Cooperative Oncology Group performance status (0 for 62% and 60%, 1 for 37% and 38%), never smokers (21% and 20%), histology (adenocarcinoma in 59% and 60%, squamous cell carcinoma in 32% in both), stage (IB in 53% and 48%, IIA in 7% in both, IIB in 25% and 28%, IIIA in 15% and 17%), primary surgery (pneumonectomy in 13% and 11%, lobectomy in 79% and 82%), adjuvant chemotherapy (51% and 57%), and EGFR mutation status (activating mutation in 16% and 17%, wild type in 74% and 70%).
No Disease-Free Survival Benefit
After a median follow-up of 47 months, there was no significant difference in median disease-free survival between the erlotinib group and the placebo group (50.5 vs 48.2 months, hazard ratio [HR] = 0.90, 95% confidence interval [CI] = 0.74–1.10). There were no differences between groups by stratification factors. Overall survival data are immature; at the current analysis, there was no difference in overall survival (HR = 1.13, 95% CI = 0.881–1.448).
EGFR Mutation Subgroup
Among the 161 patients (102 in the erlotinib group and 59 in the placebo group) with EGFR-activating mutations, erlotinib was associated with prolonged disease-free survival (median 46.4 vs 28.5 months, HR = 0.61, 95% CI = 0.38–0.98), but the difference was not statistically significant due to the hierarchical testing procedure. A similar effect was observed in a post hoc exploratory analysis correcting for stage, previous chemotherapy, age, sex, smoking status, EGFR-mutation type, and tumor size (HR = 0.60, 95% CI = 0.362–0.978). Analysis by EGFR-mutation type showed similar effects in del19 (HR = 0.68, 95% CI = 0.36–1.28) and L858R (HR = 0.55, 95% CI = 0.27–1.12) subgroups. Overall survival data in the mutation subgroup were immature; at the time of analysis, there was no difference in overall survival (HR = 1.09, 95% CI = 0.545–2.161).
Adverse Events
The most common adverse events of any grade in the erlotinib group were rash (86% vs 32% in placebo group), diarrhea (52% vs 16%), and pruritus (26% vs 15%). The most common grade ≥ 3 adverse events were rash (22% vs < 1%) and diarrhea (6% vs < 1%). Adverse events led to dose reduction in 22% vs 2%, dose interruption in 22% vs 7%, and discontinuation of treatment in 30% vs 5%.
The investigators concluded: “Adjuvant erlotinib did not prolong [disease-free survival] in patients with EGFR-expressing NSCLC or in the EGFR [activating mutation]-positive subgroup. Further evaluation of erlotinib is warranted in the EGFR [activating mutation]-positive subgroup.” A phase III U.S. intergroup trial of adjuvant erlotinib in patients with EGFR-activating mutation-positive NSCLC currently is enrolling patients.
Karen Kelly, MD, of the University of California, Davis, Comprehensive Cancer Center, is the corresponding author of the Journal of Clinical Oncology article.
The study was supported by Astellas Pharma Global Development, F. Hoffmann-La Roche, and Genentech. For full disclosures of the study authors, visit jco.ascopubs.org.
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