Results of cetuximab in advanced non-small cell lung cancer

Results of cetuximab in advanced non-small cell lung cancer

13 Sep 2015

Adding the EGFR inhibitor cetuximab (Erbitux) to chemotherapy failed to improve survival in patients with advanced non-small cell lung cancer, a multicenter randomized trial showed.

The primary analysis showed a median overall survival of 10.9 months compared with 9.4 months, a difference that did not achieve statistical significance. The trial also failed to demonstrate improvement in progression-free survival for patients with EGFR-positive disease, the co-primary endpoint.

However, cetuximab led to a 25% reduction in hazard ratio among patients who had EGFR-positive tumors by fluorescence in situ hybridization (FISH) and were not candidates for bevacizumab (Avastin), a prespecified secondary endpoint. An exploratory analysis showed that patients with EGFR-positive, squamous-cell tumors lived almost twice as long with cetuximab as with chemotherapy alone.

"The biomarker selection of patients by FISH does appear to have some effect in this group of patients," said Roy Herbst, MD, PhD, of Yale Cancer Center. "These data, along with [other recent results] suggest a role for EGFR FISH in selecting patients for therapy with EGFR antibodies, cetuximab, perhaps necitumumab, perhaps others, especially when bevacizumab is not used."

Data from more than 1,000 patients

Herbst reported data from the Southwest Oncology Group (SWOG) S0819 trial, which represented the culmination of work that started with several negative trials of small-molecule EGFR tyrosine kinase inhibitors. The addition of gefitinib (Iressa) or erlotinib (Tarceva) to platinum-based chemotherapy showed no benefits in unselected patients with NSCLC. Whether monoclonal antibodies against EGFR behaved differently remained unclear.

Another SWOG trial, the 0342 trial, suggested that patients with EGFR-positive tumors by FISH analysis might benefit from cetuximab, as both overall response and disease control rates improved significantly in FISH-positive patients who received cetuximab in addition to chemotherapy versus patients who were EGFR negative. The S0536 trial then demonstrated the safety of adding cetuximab to bevacizumab to chemotherapy for patients with advanced non-squamous NSCLC.

The S0819 trial involved 1,333 patients with advanced NSCLC and adequate tissue specimens for biomarker analysis. The patients were randomized to paclitaxel-carboplatin chemotherapy with or with cetuximab. Patients who met the safety criteria for hemorrhage risk in S0536 also received bevacizumab.

Disappointing results of the clinical trials

The primary endpoints of the trial were progression-free survival (PFS) in EGFR FISH-positive patients and overall survival in the total population. Secondary endpoints included PFS and overall by patient appropriateness to receive bevacizumab. About 550 patients were deemed appropriate to receive bevacizumab with or with cetuximab.

After S0819 began, results of the another trial, the SQUIRE trial, were reported, showing that the addition of necitumumab to chemotherapy improved survival in patients with advanced squamous NSCLC. Investigators in S0819 added an exploratory analysis for overall survival in patients with EGFR FISH-positive squamous NSCLC. The study population included about 400 patients with EGFR-positive tumors.

For the most part, the results were disappointing, which did not come as a surprise to many of the investigators, after data from other trials became available, said Herbst. The trial failed to show a benefit of cetuximab for:

• Overall survival (as 10.9 vs 9.4 months)
• PFS
• Overall survival (EGFR+) (as 13.4 vs 9.8)
• PFS (EGFR+)( as 5.4 vs 4.8)
• Overall survival, bevacizumab appropriate (as 12.7 versus 11.6)
• PFS, bevacizumab appropriate (EGFR+) as 15.5 versus 13.2
• Overall survival, bevacizumab inappropriate  (as 9.2 versus 8.2)

Similar adverse events rates

Investigators found a glimmer of hope in the analysis of overall survival among the bevacizumab-inappropriate, EGFR-positive subgroup, said Herbst. Patients treated with cetuximab had a median survival of 11.2 months versus 8.7 months for the control arm who received only chemotherapy. The difference translated into a 25% reduction in the hazard ratio.

The exploratory analysis involved a small number of patients (111 total) but showed a clear survival benefit among patients with EGFR-positive, squamous NSCLC. Patients treated with cetuximab lived almost twice as long with cetuximab as with chemotherapy alone.

Adverse event rates were similar in the cetuximab and control groups, including the comparison of patients who received bevacizumab with or without cetuximab.

Source: MedPage Today