DENVER (FRONTLINE MEDICAL NEWS)This is why clinical trials are conducted.

Results from a randomized clinical study show that adding cetuximab (Erbitux) to platinum doublet chemotherapy with or without bevacizumab (Avastin) in patients with advanced non–small cell lung cancer (NSCLC) did not improve overall survival (OS).

But the results also point to a survival benefit with cetuximab in patients with squamous cell histology NSCLC whose tumors express high levels of the epidermal growth factor receptor (EGFR) on fluorescent in situ hybridization (FISH), as well as a significant benefit for other patients who are not candidates for bevacizumab, Dr. Roy S. Herbst of the Smilow Cancer Hospital at Yale–New Haven (Conn.) reported.

The findings support those of the recently published SQUIRE trial , which showed an OS benefit for adding necitumumab, an investigational anti-EGFR monoclonal antibody, to chemotherapy with gemcitabine and cisplatin in patients with advanced squamous cell carcinoma, Dr. Herbst said at a world conference on lung cancer.

“These data, along with the recent SQUIRE results suggest a role for EGFR FISH in selecting patients for EGFR antibodies, either cetuximab, perhaps necitumumab, perhaps others, especially when bevacizumab is not used,” he said.

Dr. Herbst and colleagues had previously found evidence to suggest that four or more EGFR gene copies detected by FISH could be a biomarker to identify patients most likely to benefit from therapy with cetuximab, a chimeric monoclonal antibody that targets the EGFR receptor.

To test this hypothesis, investigators in the trial, designated S0819, enrolled 1,313 patients with newly diagnosed or recurrent (after prior surgery and/or radiation) stage IV NSCLC into a randomized clinical trial comparing chemotherapy with carboplatin and paclitaxel with or without bevacizumab and with or without cetuximab. Patients with controlled brain metastases were eligible for the trial, which included patients with both adenocarcinoma and squamous cell histologies.

The investigators hoped to see a progression-free survival (PFS) benefit in EGFR FISH–positive patients, and an OS benefit among the entire study population. The study did not meet either of these coprimary endpoints, however.

The hazard ratio for overall survival among the entire study population was 0.94 (P = .34). Similarly, there was no significant difference with or without cetuximab in the entire population (HR 0.98; P = .68).

There were also no differences among EGFR FISH–positive patients in the overall study population, although the OS for this subgroup trended toward significance, Dr. Herbst noted (HR for OS, 0.83; P = .10; HR for PFS, 0.91; P = 0.37).

Among so-called bevacizumab-appropriate patients (that is, those with no bleeding or squamous cell histology), there were also no significant differences in OS with or without cetuximab.

But among the overall subgroup of bevacizumab-inappropriate patients (that is, those with squamous cell NSCLC or for whom bevacizumab was considered to be clinically contraindicated), there was a trend toward significance (HR for OS, 0.88; P = .12), and among 234 EGFR FISH–positive bevacizumab inappropriate patients, ­there was a significant overall survival benefit (HR, 0.75; P = .048)

An exploratory analysis showed that the strongest benefit of adding cetuximab was among 111 patients with FISH-positive squamous cell carcinoma, with a HR for OS of 0.56 (P = .006), compared with squamous cell FISH-positive patients who received only carboplatin and paclitaxel.

“So you can see that the biomarker selection by FISH does appear to have some effect in this group of patients,” Dr. Herbst said at the conference sponsored by the International Association for the Study of Lung Cancer.

In an interview, Dr. Herbst noted that while he was pleased that he and his colleagues were able to recruit more than 1,300 patients with NSCLC, they had originally planned to enroll 1,546, but had to slightly scale back the size and statistical power of the study because they were unable to obtain sufficient tumor tissue (a study requirement) from more than 200 patients.

Dr. Robert Pirker, professor of medicine and program director for lung cancer at the Medical University of Vienna, the invited discussant, said that the results of the SWOG 0819 trial dovetail with the results of the FLEX phase III trial, which showed that the addition of cetuximab to first-line chemotherapy for patients with advanced NSCLC significantly improved overall survival, compared with chemotherapy alone. In a separate analysis of data from FLEX, Dr. Pirker and colleagues developed an EGFR expression score based on immunohistochemistry, and found that high EGFR expression predicted the survival benefit of cetuximab, and suggested that it could serve as a biomarker for treatment selection.

“Patients with advanced NSCLC deserve access to these therapeutic advances. Our purpose is not just doing just research for the sake of research, but we also have to implement the research,” he said.

The SWOG S0819 trial was supported by the National Institutes of Health and Bristol-Myers Squibb. Dr. Herbst disclosed consulting with the company. He is also a member of the Oncology Report editorial board. Dr. Pirker disclosed receiving honoraria, speaker’s fees, and consulting with various companies, not including Bristol-Myers Squibb.