Dr. O'Byrne presented the retrospective analysis of the data from FLEX trail to identify the molecular and clinical predictors of outcome for cetuximab in NSCLC . In this study, 1125 patients with advanced NSCLC and positive EGFR staining by immunohistochemistry (IHC) were randomized to cisplatin and vinorelbine with or without cetuximab. Patients remained on maintenance therapy until disease progression. A statistically significant difference in OS was found, with improvement from 10.1 months to 11.3 months (p = 0.0441). The RR was also superior in the cetuximab group (29% vs. 36%, p = 0.012). However, PFS was identical at 4.8 months in each group. In a subgroup analysis, patients with squamous cell histology retained survival benefit. Subgroup analysis of Asian patients included in the study (n = 121) did not show an improvement in survival with the addition of cetuximab (median OS, 17.6 months for chemotherapy plus cetuximab vs. 20.4 months for chemotherapy alone, not statistically significant). However, on disease progression, the Asian subgroup that received cetuximab also received fewer EGFR TKIs (50% vs. 73%). The lack of this may have had a negative effect on their outcomes .
Patient selection with positive IHC of EGFR might not be the right selection criteria in this study. Most cetuximab studies have not clearly shown an association between EGFR expression and response. However, the results from SWOG 0342 study have shown that the amplification of EGFR gene copy number, determined by fluorescent in situ hybridization (FISH), might predict an improved survival for EGFR TKI therapy . Among FISH-negative patients, median OS was 10.6 months with chemotherapy and cetuximab compared to 10.0 months with chemotherapy alone (HR, 0.91). In FISH-positive patients, median OS was 11.6 months in the cetuximab arm while it was 9.9 months in the control arm (HR, 0.85). Similarly, PFS and RR by FISH status failed to indicate response to cetuximab therapy. KRAS mutation status did not affect OS, PFS, or RR in either subgroup. The KRAS and EGFR-biomarker data are congruent with those from the smaller BMS-099 trial, in which cetuximab was added to a taxane and carboplatin in the first-line treatment of NSCLC .
The most important finding of the analysis was the first-cycle rash, which might help to identify patients with improved survival with cetuximab. The median overall for survival was 15.0 months in patients that developed an acnelike rash of any grade within 21 days of treatment with cetuximab and chemotherapy in comparison to 8.8 months for those without a rash after cetuximab treatment (HR 0.63; p < 0.001). The survival was 10.3 months in the chemotherapy-alone arm. The median OS was 15.0 months in 290 patients with a grade 1-3 rash and 14.7 months in 120 patients with a grade 2-3 rash. It might indicate that the development of a rash is important predictive factor than the specific grade of the rash. The data depicted the OS to be far more superior when cetuximab was added to the standard first-line chemotherapy regardless of histology or KRAS mutation and EGFR gene copy number status. An important question to consider is: if the first-cycle rash is a predictive clinical biomarker, should we continue with cetuximab in patients with no signs of rashes? Overall, the findings suggest that the optimal selection strategy for treatment with cetuximab remains to be defined.
SWOG 0536 was a phase II study that evaluated the effectiveness and safety of utilizing combinations of bevacizumab, paclitaxel, carboplatin, and cetuximab in patients with advanced-stage NSCLC . Bevacizumab and cetuximab were continued after 6 cycles of chemotherapy till progression of disease. In this study, 104 patients with newly diagnosed stage IIIB or IV NSCLC were treated. Overall, this 4-drug combination was shown to be active with favorable efficacy. An analysis of molecular biomarkers showed that neither KRAS nor EGFR mutations were predictive of outcomes. In addition, although there was a trend toward improved tumor response and disease control rate in patients with EGFR-positive tumors by FISH, no significant differences were noted in PFS or OS. Further analysis of other translational studies such as, EGFR status by FISH, cytokine and angiogenic factor profiling, and proteomics are still ongoing.
The SWOG 0536 study met its primary tolerability endpoint. This combination may also have an additive rather than a synergistic effect. However, the synergistic benefit may be seen in a subset of patients. The positive results of this trial warrant the continued investigation of this 4-drug combination in the phase III SWOG 0819. This study, with a planned enrollment of 1,545 patients, will compare initial therapy (paclitaxel/carboplatin plus bevacizumab with or without cetuximab) followed by maintenance therapy (bevacizumab with or without cetuximab). The primary endpoints are OS in entire study population and PFS in EGFR FISH positive patients.