IMMUNOGENICITY OF TRASTUZUMAB INTRAVENOUS AND SUBCUTANEOUS FORMULATIONS IN THE PHASE III HANNAH STUDY

Abstract

Background HannaH demonstrated non-inferiority of the fixed-dose subcutaneous (SC) formulation of trastuzumab (H) to the intravenous (IV) formulation, based on pharmacokinetics (Ctrough) and efficacy (pathological complete response [pCR]) (Jackisch et al, EBCC 2012). We report on efficacy and safety in relation to immunogenicity (anti-drug antibodies [ADAs]). Methods Blood samples for ADA testing were drawn at baseline (BL), then day 1 of cycles 2, 5 (pre-surgery), 13 and 18 (post-surgery) and at months 3, 6, 12, 18 and 24 following last H dose. Screening for ADAs to H and rHuPH20 was by bridging immunoassays. Positive (pos) samples were re-tested, with confirmed pos patients (pts) then tested for neutralizing antibodies (abs). Relationship between ADAs (against H and/or rHuPH20) with respect to, efficacy (pCR) and safety (infusion-related reactions, IRRs) was investigated. Results The median follow-up (FU) (including ADA testing) was ∼12.3 months. At BL, 5.9% of pts (17/290) in the IV arm and 4.2% of pts (12/287) in the SC arm were pos for ADAs to H. Post-BL (treatment and FU), 3.4% (10/295) and 6.8% (20/295) pts in IV and SC, respectively were pos for ADAs to H. One pt was confirmed pos twice (non-consecutive time points). At BL, 7.6% of pts (22/290) in the SC arm were pos for ADAs to rHuPH20. Post-BL, the rate was 11.5% (34/295). Titer ranges post-BL were similar to those observed pre-BL. One pt was pos for ADAs to both H and rHuPH20. No neutralizing ADAs to H or rHuPH20 were seen. The pCR rate did not differ significantly between Anti-H ab (AHA)-pos (30% [IV n = 10], 55% [SC n = 20]) and AHA-neg (36.5% [IV n = 10], 41.6% [SC n = 20]) pts. Anti-rHuPH20 status did not correlate with pCR rates (41.2% [pos n = 34] vs 41.7% [neg n = 254]) in the SC arm. In pts given H SC or H IV, occurrences of IRRs were similar in AHA-neg (46.3% [SC n = 255] 37.6% [IV n = 263]) and -pos (40% [SC n = 20] 25% [IV n = 10]) pts. The incidence of pts with an IRR was similar in both anti-rHuPH20 status groups (SC arm only; neg 44.5% [n = 254], pos 41.2% [n = 34]). Conclusion Using a highly sensitive assay, ADAs against both H (IV/SC) and rHuPH20 (SC only) were observed transiently and were of no relevance in terms of efficacy or safety. Immunogenicity monitoring in the study is ongoing.