A prospective biomarker analysis for the phase III SATURN (Sequential Tarceva in Unresectable NSCLC) trial in non–small-cell lung cancer (NSCLC) patients taking erlotinib (Tarceva) as maintenance therapy shows that those with activating epidermal growth factor receptor (EGFR) mutations had extended progression-free survival (PFS) compared with patients with KRAS mutations. The results were reported online first in Nature Reviews Clinical Oncology.
Large-scale, prospective biomarker trials that look at tumor mutations’ response to specific cancer treatments are needed to find patient populations that will derive the greatest benefit from targeted therapies. But so far, these types of studies have been the exception and not the norm.
In the trial reported in Nature Reviews Clinical Oncology, 889 patients provided tumor samples, which were then tested for EGFR protein expression, EGFR gene copy number, and EGFR and KRAS mutations. A predictive effect of erlotinib on PFS was seen in EGFR mutation–positive patients (P < .001) even though the study was not powered to test for interactions, confirming that the EGFR mutation status is predictive of greater clinical benefit with erlotinib compared to wild-type EGFR.
A benefit in PFS was also seen with wild-type EGFR, while a KRAS mutation was a significant negative prognostic factor for PFS. This suggests that regardless of treatment, outcomes are worse in patients with KRAS mutated tumors.
Of the 18% of patients who had a mutated KRAS gene, 11% had an EGFR mutation. Erlotinib provided a PFS benefit in the KRAS wild-type subgroup (hazard ratio [HR] = 0.7, P < .001) while no benefit was seen in the KRAS mutation group. Erlotinib also reduced the risk of progression or death by 90% in patients with EGFR-mutant tumors (HR = 0.10, P < .001). Patients with wild-type EGFR tumors also derived a PFS benefit.
There was no interaction between treatment and EGFR expression level, suggesting that the effect of erlotinib was independent of EGFR protein expression. EGFR gene copy number did not influence PFS outcome in this maintenance erlotinib trial. Erlotinib treatment among patients who did not have a high gene copy number reduced the risk of death by 23%. The authors attribute this reduction in the risk of death to subsequent treatments.
While the PFS benefit seen with erlotinib in patients with EGFR-mutated tumors did not translate into an overall survival benefit, the authors believe that this may be due to confounding factors such as the small number of patients with EGFR-mutated tumors in the trial and the high level (67%) of crossover from the placebo group to second-line EGFR tyrosine kinase inhibitor (TKI) therapy, as well as a lack of data maturity.
How well patients with various EGFR and KRAS mutations respond to EGFR TKIs need to be studied further with large-scale progressive studies. Genetic profiling of tumors for other mutations will also be important in order to gauge the effect of EGFR TKI response in the context of other potentially interacting mutations.