Abstract PD3-12: PIK3CA alterations and benefit with neratinib after trastuzumab-based adjuvant therapy in early-stage HER2+ breast cancer: Correlative analyses of the phase III ExteNET trial

Background: Neratinib is a pan-HER tyrosine kinase inhibitor that blocks the PI3K/Akt and MAPK signaling pathways downstream from HER2. The international, randomized, placebo-controlled phase III ExteNET trial showed that a 1-year course of neratinib after trastuzumab-based adjuvant therapy significantly improved 2-year invasive disease-free survival (iDFS) in early-stage HER2+ breast cancer (HR 0.67; 95% CI 0.50–0.91; p=0.0091) [Chan et al. Lancet Oncol 2016]. Furthermore, the effects of neratinib on iDFS were shown to be durable at 5 years9 follow-up (HR 0.73; 95% CI 0.57–0.92; p=0.008) [Martin et al. ESMO 2017]. PIK3CA alterations are common in HER2+ breast cancers, and in general are associated with a worse prognosis. We sought to assess the prognostic and predictive significance of PIK3CA alterations in an exploratory substudy of the ExteNET trial. Methods: ExteNET is an international, multi-center, randomized, double-blind, placebo-controlled phase III trial (Clinicaltrials.gov: NCT00878709). Patients received oral neratinib 240 mg/day or placebo for 1 year. Of the intent-to-treat (ITT) population (n=2840), primary formalin-fixed paraffin-embedded (FFPE) tumor specimens were available from 991 patients for PIK3CA mutation testing by RT-PCR for two hot-spot mutations in exon 9 (E542K, E545K/D) and one hot-spot mutation in exon 20 (H1047R). 702 FFPE tumor slides underwent FISH analysis for PIK3CA amplification with a ratio of ≥2.2 considered as amplified. Primary endpoint: iDFS. iDFS events were tested by 2-sided log-rank tests, and HR (95% CI) were estimated using Cox proportional-hazards models. Data cut-off: March 2017. Results: Baseline demographics and disease characteristics between treatment arms of the correlative cohort (n=1201) were balanced. Overall, 21.2% (n=210) of primary tumors harbored one of the specified PIK3CA mutations, and 8.7% (n=61) were PIK3CA FISH-amplified. Patients with PIK3CA -altered tumors (i.e. PIK3CA mutations or FISH-amplified) had fewer iDFS events with neratinib compared with placebo (HR 0.41; 95% CI 0.17-0.90, p=0.028). The interaction test was not significant (p=0.1842). Results of the various correlative analyses within treatment arms are shown in the table. Conclusions: One year of neratinib treatment after trastuzumab-based adjuvant therapy significantly improves iDFS after 5 years in patients with early-stage HER2+ breast cancer. From this modest-sized exploratory cohort, it appears that PIK3CA may be a biomarker for differential sensitivity to neratinib after 1 year of trastuzumab in the adjuvant setting.These exploratory results should be validated in a larger subset. Citation Format: Chia SKL, Martin M, Holmes FA, Ejlertsen B, Delaloge S, Moy B, Iwata H, von Minckwitz G, Mansi J, Barrios CH, Gnant M, Tomasevic Z, Denduluri N, Separovic R, Kim S-B, Hugger Jakobsen E, Harvey V, Robert N, Smith II J, Harker G, Lalani AS, Zhang B, Eli LD, Buyse M, Chan A. PIK3CA alterations and benefit with neratinib after trastuzumab-based adjuvant therapy in early-stage HER2+ breast cancer: Correlative analyses of the phase III ExteNET trial [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD3-12.