1175 - HER3 ligand heregulin expression and clinical implication in patients with epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer treated with EGFR-tyrosine kinase inhibitors

Background

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) improve the prognosis of EGFR-mutant non-small cell lung cancer (NSCLC). However, other human epidermal growth factor receptor (HER) families contribute to EGFR-TKI resistance. The HER3 ligand heregulin is aberrantly expressed in NSCLC. Previously, heregulin genomic induction in an EGFR-mutant NSCLC cell line caused EGFR-TKI resistance, except against 2^nd-generation EGFR-TKIs, which uniquely blocked the pan-HER family. However, the clinical relevance of heregulin is unclear in EGFR-mutant NSCLC. Here, we aimed to explore the implication of heregulin in patients with EGFR-mutant NSCLC treated with EGFR-TKIs.

Methods

Soluble heregulin was immunologically measured in the plasma of patients with EGFR-mutant NSCLC. Cut-off values were determined via 1-year progression-free survival (PFS) receiver operating characteristic curve. Relationship between soluble heregulin and PFS, after EGFR-TKI therapy, was analyzed using a Cox proportional hazards model.

Results

Seventy-six patients were enrolled, of which 44 were treated with 1^st-generation, 29 with 2^nd-generation, and 3 with 3^rd-generation EGFR-TKIs. Soluble heregulin levels were found to vary (range: 274–7,138 pg/mL, median: 741.5 pg/mL). Among patients treated with 1st- and 3rd-generation EGFR-TKIs, those with high heregulin (n = 22, > 800 pg/mL) had a shorter PFS than those with low heregulin (n = 25, < 800 pg/mL) levels; median PFS of 322 and 667 days were, respectively, observed. Cox proportional hazards model indicated a trend toward resistance (HR: 1.797, 95% CI: 0.833–3.877), except with 2^nd-generation EGFR-TKIs (HR: 0.879, 95% CI: 0.325–2.376).

Conclusions

Results showed soluble heregulin to potentially correlate with EGFR-TKI resistance, though not so for 2^nd-generation EGFR-TKIs, in patients with EGFR-mutant NSCLC. Therefore, 2^nd-generation EGFR-TKIs warrant comparative clinical examination regarding their anti-cancer efficacy in heregulin-expressing NSCLC.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Boehringer Ingelheim.

Disclosure

K. Yonesaka: Honoraria (self), Research grant / Funding (institution): Boehringer ingelheim. E. Iwama: Research grant / Funding (institution): Boehringer Ingelheim. H. Hayashi: Honoraria (self), Research grant / Funding (institution): Boehringer Ingelheim. S. Suzuki: Research grant / Funding (institution): Boehringer Ingelheim. R. Kato: Research grant / Funding (institution): Boehringer Ingelheim. S. Watanabe: Research grant / Funding (institution): Boehringer Ingelheim. T. Takahama: Honoraria (self), Research grant / Funding (institution): Boehringer Ingelheim. J. Tanizaki: Honoraria (self), Research grant / Funding (institution): Boehringer Ingelheim. K. Tanaka: Research grant / Funding (institution): Boehringer Ingelheim. M. Takeda: Honoraria (self), Research grant / Funding (institution): Boehringer Ingelheim. K. Sakai: Research grant / Funding (institution): Boehringer Ingelheim. K. Azuma: Honoraria (self), Research grant / Funding (institution): Boehringer Ingelheim. Y. Chiba: Research grant / Funding (institution): Boehringer Ingelheim. S. Atagi: Honoraria (self): Boehringer Ingelheim. K. Nishio: Research grant / Funding (self), Research grant / Funding (institution): Boehringer Ingelheim. I. Okamoto: Honoraria (self), Research grant / Funding (self), Research grant / Funding (institution): Boehringer Ingelheim; Honoraria (self), Research grant / Funding (self), Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (self), Research grant / Funding (self), Research grant / Funding (institution): AstraZeneca. K. Nakagawa: Honoraria (self), Research grant / Funding (self), Research grant / Funding (institution): Boehringer ingelheim; Honoraria (self), Research grant / Funding (self), Research grant / Funding (institution): AstraZeneca; Honoraria (self), Research grant / Funding (self), Research grant / Funding (institution): Bristol-Myers Squibb.