Biomarker analysis of the GATSBY study of trastuzumab emtansine versus a taxane in previously treated HER2-positive advanced gastric/gastroesophageal junction cancer

Abstract

Background Prespecified exploratory biomarker analyses of the phase II/III GATSBY study (NCT01641939) assessed whether patient subgroups experienced a survival benefit from trastuzumab emtansine (T-DM1) versus taxane therapy, and to advance understanding of HER2-positive advanced gastric/gastroesophageal junction cancer (AGC) disease biology. Methods Adults with HER2-positive AGC whose disease progressed during/after first-line therapy were enrolled and randomized to receive T-DM1 [Stage 1: 3.6 mg/kg q3w, 2.4 mg/kg qw, or taxane (docetaxel/paclitaxel); Stage 2: 2.4 mg/kg qw or taxane]. Primary efficacy endpoint was overall survival (OS). Prespecified exploratory biomarkers included HER2, HER3, PTEN, PIK3CA mutation status, FcγR, and cMET. Tumor samples from patients who received 2.4 mg/kg T-DM1 (n = 228) or taxane (n = 117) were included. Results Median OS was longer in subgroups with HER2 immunohistochemistry (IHC) 3+ [9.5 versus 8.3 months for T-DM1 versus taxane; hazard ratio (HR) 0.99 (95% CI 0.68-1.43)] versus HER2 IHC 2+/in situ hybridization-positive [5.2 versus 9.2 months for T-DM1 versus taxane; HR 1.53 (95% CI 0.94-2.50)] tumors. Trends towards increased median OS were also observed in subgroups with > versus ≤ median HER2 mRNA expression, higher versus lower HER2 gene copy number, HER2 gene ratio and H score, and homogenous or nonfocal HER2 IHC staining. T-DM1 was not associated with superior OS versus taxane in any subgroup. Conclusions Patients with previously treated HER2-positive AGC with higher HER2 expression experienced a better treatment effect from T-DM1 than those with lower HER2 expression and may derive comparable survival benefits from T-DM1 and taxane therapy. Clinical trials registration NCT01641939 (https ://clini caltr ials.gov/ct2/show/NCT01 64193 9).

ERBB2 mRNA Expression and Response to Ado-Trastuzumab Emtansine (T-DM1) in HER2-Positive Breast Cancer

“…Moreover, benefit associated with the use of post-neoadjuvant T-DM1 as compared to trastuzumab in the KATHERINE trial appeared to more marked in HER2 3+ than in HER2 2+ tumors [ 19 ]. Greater benefit to T-DM1 in HER2 3+ tumors has also been reported in the KATE2 trial [ 20 ] and other cancer types [ 21 , 22 ].…”

“…Furthermore, the impact of ERBB2 mRNA levels on T-DM1 benefit has been reported in other cancers beyond BC. A translational study [ 21 ] evaluating gastric cancer samples of the GATSBY trial [ 17 ] demonstrated more benefit to T-DM1 in terms of PFS in patients with tumors with higher ERBB2 mRNA levels [ 21 ].…”

Epidermal Growth Factor Receptor Family and its Role in Gastric Cancer

“…A multicenter adaptive phase II/III of TDM-1 recruited patients with HER2-positive advanced gastric cancer in progression after first-line treatment (http://www.clinicaltrials.gov/show/NCT0164tab1939). In particular, patients with higher HER2 expression experienced a better treatment effect from TDM-1than those with lower HER2 expression (101).…”

Systemic therapy for advanced gastroesophageal cancers: progress and pitfalls

“…Notably, neither this study nor the aforementioned studies (TyTAN, LoGIC, JACOB) reached their primary endpoint of improved OS. A biomarker analysis of the GATSBY study investigated if there was any correlation with HER2 expression and the efficacy of T-DM1 (25). Importantly, confirmation of continued HER2 overexpression prior to starting second line therapy was not assessed in the prespecified biomarker analysis as fresh tumor biopsy was not mandatory for enrollment in the study.…”