EGFR-Positive Squamous NSCLC Survival Improved by Cetuximab

Roy S. Herbst, MD, PhD

When cetuximab (Erbitux) was added to chemotherapy, the risk of death was reduced by 44% for patients with advanced squamous non-small cell lung cancer (NSCLC) whose tumors test positive forEGFRgene amplification, according to results from a clinical trial that were presented at the 2015 World Conference on Lung Cancer.¹

Those findings, which emerged from a subgroup analysis of the large phase III SWOG S0819 trial, suggest a promising therapeutic strategy for this hard-to-treat malignancy, as well as a potential assay that could be used to select patients for antibody therapies that targetEGFRin this patient population, said lead investigator Roy S. Herbst, MD, PhD, during a press conference.

“This was the most compelling finding of the study,” said Herbst, Ensign Professor of Medicine and chief of medical oncology at Yale Cancer Center and Smilow Cancer Hospital at Yale-New Haven. “It’s a very difficult group to treat. There have been very few drugs for this group in the last decade. Here you can see a very significant result.”

The median overall survival (OS) was 11.8 months for 55 patients with squamous NSCLC and positiveEGFRcopy score, treated with cetuximab plus chemotherapy, compared with 6.4 months for 56 patients who received chemotherapy alone (HR, 0.56; P= .006). Herbst said there were not any significant safety differences between the two groups.

EGFRpositivity, measured by fluorescence in situ hybridization (FISH) testing, was defined as one of three values: (1) >40% of cells displaying >4 copies of the EGFR signal; (2) >2 EGFR to CEP7 chromosome ratio on scored nuclei; (3) gene clusters (>4 spots) or >15 copies of EGFR signals in >10% of tumor cells.

Broad Goals of SWOG S0819 Trial

The results in the squamous subtype marked the strongest positive signal to emanate from the trial, which randomized 1333 patients to paclitaxel plus carboplatin and if appropriate, bevacizumab (Avastin), with or without cetuximab.

Bevacizumab is not appropriate for patients with squamous histology or for individuals who are experiencing bleeding, Herbst indicated; in this trial, 554 of the study participants received the drug. The angiogenesis inhibitor is approved for the treatment of patients with nonsquamous NSCLC, in combination with carboplatin and paclitaxel for the first-line treatment of patients with unresectable, recurrent, locally advanced, or metastatic disease.

The study was conducted at more than 700 centers throughout the United States and launched in 2009 in an effort to establish whether cetuximab, a monoclonal antibody that inhibitsEGFRactivity, would be a beneficial addition to chemotherapy, in a general population of patients and in a biomarker-driven group. Cetuximab is approved for head and neck and for colorectal cancers.

Prior studies resulted in “promising but inconclusive data" signals for cetuximab, including when findings were analyzed with the use of an EGFR immunohistochemistry assay for patient selection.²As a result, researchers chose to use a FISH scoring criteria for EGFRpositivity developed at the University of Colorado.

The trial recruited patients with primary stage IV NSCLC of any histology that was either newly diagnosed or recurrent after previous surgery and/or radiation.³No prior chemotherapy for any stage of NSCLC or previous therapies targetingEGFRor VEGF were permitted.

The primary endpoints of the trial were OS for the entire study population and progression-free survival (PFS) in theEGFR-positive patients.

For the entire study population, the addition of cetuximab did not translate into a statistically significant improvement in median OS (HR, 0.94;P= .34). Similarly, there was no median PFS benefit with cetuximab for the broadEGFR-positive population (HR, 0.91;P= .37).

Herbst noted that “we did see some signs of life” when analyzing median OS among the entire study population ofEFGR-positive patients who received cetuximab. In this group, the 199 patients in the cetuximab arm achieved a median OS of 13.4 months compared with 9.8 months among the 201 patients in the control arm (HR, 0.83;P= .10). That result was “approaching statistical significance,” Herbst said.

Among patients who received bevacizumab along with chemotherapy, the addition of cetuximab proved less beneficial, with a median OS of 12.7 months for the 279 patients in the experimental arm versus 11.6 months for the 275 participants in the control arm (HR, 1.04;P= .70). Similarly, there was no benefit among patients who received the bevacizumab-containing regimen plus cetuximab and were EGFR-positive (HR, 0.97;P= .88).

At the same time, there was an indication of an OS benefit for the addition of cetuximab among the broader population of patients who were not appropriate candidates for bevacizumab therapy and wereEGFRpositive (HR, .75; P= .048).

“if you don’t select, if you don’t pick the right patients, this is probably not a therapy you should give,” said Herbst, regarding one of the messages of the trial that concerned the addition of cetuximab.

He said the data, when combined with other emerging research, suggest a role for EGFR FISH testing in selecting patients for anti-EGFR therapy, particularly if bevacizumab is not used.

Moving forward, Herbst and colleagues are anticipating advances for the treatment of patients with squamous NSCLC as a result of the biomarker-driven Lung-MAP trial that began recruiting patients last year.⁴

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References

1. Herbst RS, Redman MW, Kim ES, et al. A randomized, phase III study comparing carboplatin/paclitaxel or carboplatin/paclitaxel/bevacizumab with or without concurrent cetuximab in patients with advanced non—small cell lung cancer (NSCLC): SWOG S0819. Presented at: 2015 World Conference on Lung Cancer; September 6-9, 2015; Denver, CO. PLEN04:01.
2. Redman MW, Crowley JJ, Herbst RS, et al. Design of a phase III clinical trial with prospective biomarker validation: SWOG S0819 [published online May 16, 2012].Clin Cancer Res. 2012;18(15):4004-4012.
3. NIH Clinical Trials Registry. www.ClinicalTrials.gov website. Identifier: NCT00946712.
4. NIH Clinical Trials registry. www.ClinicalTrials.gov website. Identifier number: NCT02154490.