Quantitative assessment of diagnostic markers and correlations with efficacy in two phase II studies of trastuzumab-DM1 (T-DM1) for patients (pts) with metastatic breast cancer (MBC) who had progressed on prior HER2-directed therapy.

Abstract

1016 Background: The antibody-drug conjugate T-DM1 has shown encouraging efficacy in two phase II studies (4258g and 4374g) for pts with HER2-positive (HER2+) MBC who had progressed on prior HER2-directed therapies. Assays to quantify HER2 and PTEN expression and to assess PI3K mutation status were conducted; results were correlated with responses to T-DM1 therapy. Methods: Both trials were single-arm, with 3.6 mg/kg T-DM1 IV q3w. HER2 status was centrally retested using archival tissue. HER2 expression by qRT-PCR, PI3K mutation status by PCR-based assay, and PTEN expression by immunohistochemistry (IHC) were also assessed. Exploratory analyses of objective response rates (ORR) and progression-free survival (PFS) by independent review were conducted for biomarker-defined pt subgroups. Results: The Table summarizes ORR and median PFS based on biomarker data for pts in 4258g and 4374g (∼12 and 6 mos minimum follow-up, respectively). Conclusions: In this retrospective analysis, HER2+ status by central retesting correlated with better responses to T-DM1. HER2 expression by qRT-PCR may identify pts more likely to benefit from T-DM1 therapy. No consistent trend in T-DM1 activity was observed in pts with activating PI3K mutations and/or decreased PTEN. Future trials are needed to validate these findings. 4374g 4258g n ORR% (95% CI) n ORR% (95% CI) mPFS, mos (95% CI) Efficacy evaluable pts 107 33.6 (24.8, 43.4) 108 26.9 (19.2, 35.8) 4.6 (3.9, 8.6) Centrally retested HER2 status +a 74 40.5 (29.3, 52.3) 74 33.8 (23.2, 44.9) 8.2 (4.4, NR) Normal 14 21.4 (6.1, 50.0) 21 4.8 (<1.0, 21.8) 2.6 (1.4, 3.9) HER2 RT-PCRb ≥ Medianc 26 50.0 (29.9, 70.1) 25 36.0 (18.5, 56.9) NR (4.6, NR) Median 38 31.6 (17.5, 48.6) 25 28.0 (12.1, 47.5) 4.2 (2.7, 6.8) PI3K Mutationb Wild type 34 29.4 (15.1, 46.5) 42 35.7 (21.6, 51.9) 9.8 (4.9, NR) Mutant 8 25.0 (4.6, 65.1) 9 22.2 (4.1, 55.8) 3.9 (2.0, NR) PTEN by IHCb Normal 38 36.8 (22.6, 53.5) 30 36.7 (20.5, 56.0) 4.6 (3.1, 8.9) Decreased 3 33.3 6 16.7 (0.9, 59.8) NR (NR, NR) Abbreviation: NR, not reached as of data cut. a FISH+ and/or IHC3+. b Among pts with centrally retested HER2+ status. c Median was based on 4258g data. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech Genentech Roche Genentech Genentech