Clinical Findings

According to Dr Nilsson, “each of the trials we utilized had unique information available for our analyses — the ZEST trial allowed us to validate preclinical findings that high IL-6 is associated with worse response to EGFR inhibitors.”

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In the phase 3 ZEST trial, 209 pretreatment plasma samples from patients with platinum-refractory NSCLC receiving erlotinib demonstrated that high levels of IL-6 were significantly associated with shorter overall survival (P < .0001) and progression-free survival (PFS; P = .0092) compared with lower levels of IL-6.

“The BATTLE clinical study allowed us to determine whether β-blocker use was associated with lower levels of IL-6,” Dr Nilsson said.

Circulating levels of IL-6 were significantly lower among patients receiving incidental pan β-blockers compared with patients who were not taking beta blockers during the BATTLE trial (P = .02).

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“Our preclinical data further indicated that the effect of stress hormones may be most pronounced in EGFR-mutant NSCLC, so we evaluated data from the LUX-Lung3 study, which included only patients with NSCLC with EGFR mutations,” Dr Nilsson said.

In the phase 3 LUX-Lung3 trial, patients who were incidentally taking β-blockers experienced a greater benefit with afatinib compared with patients who did not use β-blockers. Among patients who did not use β-blockers, afatinib resulted in a median PFS of 11.1 months compared with 6.9 months with chemotherapy (hazard ratio [HR], 0.60; P = .001). Among patients who used β-blockers, afatinib resulted in a median PFS of 13.6 months compared with 2.5 months with chemotherapy (HR, 0.25; P = .0001).