PIK3CA alterations and benefit with neratinib: analysis from the randomized, double-blind, placebo-controlled, phase III ExteNET trial

Background:Neratinib is an irreversible pan-HER tyrosine kinase inhibitor that inhibits PI3K/Akt and MAPK signalingpathways after HER2 receptor activation. The ExteNET study showed that neratinib significantly improved 5-yearinvasive disease-free survival (iDFS) in women who completed trastuzumab-based adjuvant therapy for early breastcancer (EBC). We assessed the prognostic and predictive significance ofPIK3CAalterations in patients in ExteNET.Methods:Participants were women aged≥18 years (≥20 years in Japan) with stage 1–3c (modified to stage 2–3cin February 2010) operable breast cancer, who had completed (neo)adjuvant chemotherapy plus trastuzumab≤2years before randomization, with no evidence of disease recurrence or metastatic disease at study entry. Patientswere randomized to oral neratinib 240 mg/day or placebo for 1 year. Formalin-fixed, paraffin-embedded primarytumor specimens underwent polymerase chain reaction (PCR)PIK3CAtesting for two hotspot mutations in exon 9,one hot-spot mutation in exon 20, an fluorescence in situ hybridization (FISH) analysis forPIK3CAamplification.The primary endpoint (iDFS) was tested with log-rank test and hazard ratios (HRs) estimated using Coxproportional-hazards models.Results:Among the intent-to-treat population (n= 2840), tumor specimens were available for PCR testing (991patients) andPIK3CAFISH (702 patients). Overall, 262 samples werePIK3CAaltered: 201 were mutated (77%), 52(20%) were amplified, and 9 (3%) were mutated and amplified. iDFS was non-significantly worse in placebo-treatedpatients with altered vs wild-typePIK3CA(HR 1.34; 95% CI 0.72–2.50;P= 0.357). Neratinib’s effect over placebo wassignificant in patients withPIK3CA-altered tumors (HR 0.41; 95% CI 0.17–0.90,P= 0.028) but notPIK3CAwild-typetumors (HR 0.72; 95% CI 0.36–1.41;P= 0.34). The interaction test was non-significant  (P=0.309). Conclusions: Although there was a greater absolute risk reduction associated with neratinib treatment of patients with PIK3CA-altered tumors in ExteNET, current data do not supportPIK3CAalteration as a predictive biomarker ofresponse to neratinib in HER2-positive EBC.