First-Line Cetuximab Monotherapy in KRAS/NRAS/BRAF Mutation-Negative Colorectal Cancer Patients.

BACKGROUND: Colorectal carcinomas (CRCs) are sensitive to treatment by anti-epidermal growth factor receptor (EGFR) antibodies only if they do not carry activating mutations in down-stream EGFR targets (KRAS/NRAS/BRAF). Most clinical trials for chemo-naive CRC patients involved combination of targeted agents and chemotherapy, while single-agent cetuximab or panitumumab studies included either heavily pretreated patients or subjects who were not selected on the basis of molecular tests. We hypothesized that anti-EGFR therapy would have significant efficacy in chemo-naive patients with KRAS/NRAS/BRAF mutation-negative CRC. METHODS: Nineteen patients were prospectively included in the study. RESULTS: Two (11%) patients experienced partial response (PR) and 11 (58%) subjects showed stable disease (SD). Median time to progression approached 6.1 months (range 1.6-15.0 months). Cetuximab efficacy did not correlate with RNA expression of EGFR and insulin-like growth factor 2 (IGF2). Only one tumor carried PIK3CA mutation, and this CRC responded to cetuximab. Exome analysis of patients with progressive disease (PD) revealed 1 CRC with high-level microsatellite instability and 1 instance of HER2 oncogene amplification; 3 of 4 remaining patients with PD had allergic reactions to cetuximab, while none of the subjects with PR or SD had this complication. Comparison with 19 retrospective KRAS/NRAS/BRAF mutation-negative patients receiving first-line fluoropyrimidines revealed no advantages or disadvantages of cetuximab therapy. CONCLUSIONS: Cetuximab demonstrates only modest efficacy when given as a first-line monotherapy to KRAS/NRAS/BRAF mutation-negative CRC patients. It is of question, why meticulous patient selection, which was undertaken in the current study, did not result in the improvement of outcomes of single-agent cetuximab treatment.

Survival Outcomes in EGFR Mutation-Positive Lung Cancer Patients Treated with Gefitinib until or beyond Progression.

BACKGROUND: Discontinuation of gefitinib treatment is often accompanied by a disease flare. Some studies have demonstrated a benefit of the use of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) beyond progression; however, long-term results of these investigations remain limited. PATIENTS AND METHODS: We observed 70 patients with EGFR-mutated (EGFR-M+) non-small cell lung cancer (NSCLC) receiving single-agent gefitinib in a routine clinical setting; 56 patients were experiencing RECIST progression at the time of the analysis. RESULTS: There was a significant increase (p = 0.00001) in overall survival (OS) in patients continuing on gefitinib beyond progression (n = 21; median duration of continued gefitinib use: 4.2 months; median OS: not reached; expected OS: 29.7 months) as compared to those who stopped gefitinib treatment upon disease progression (n = 35; median OS: 14.0 months). The association between extended gefitinib use and improved OS remained true in multivariate Cox regression analysis (hazard ratio = 4.49, 95% confidence interval 1.25-16.09; p = 0.021). Patient selection bias constitutes an essential limitation of this clinical observational study, given that patients with a more favorable disease course and/or high initial tumor sensitivity to TKI treatment were more likely to be considered for prolonged gefitinib use. CONCLUSION: This study confirms that continued administration of gefitinib beyond progression is a viable treatment option for some patients with EGFR-M+ NSCLC, in particular those who cannot be rescued by novel EGFR mutation-specific inhibitors such as osimertinib.