Development of a Subcutaneous Fixed-Dose Combination of Pertuzumab and Trastuzumab: Results From the Phase Ib Dose-Finding Study

Abstract

Adding pertuzumab to trastuzumab (both monoclonal antibodies targeting human epidermal growth factor receptor 2 [HER2]) has proven survival benefits when combined with chemotherapy for patients with HER2-positive breast cancer. The combination of pertuzumab and trastuzumab together in 1 vial for subcutaneous (SC) administration is being developed as a ready-to-use formulation to reduce the treatment burden on patients while improving healthcare efficiency. An open-label, 2-part, phase Ib dose-finding study (NCT02738970) was undertaken in healthy male volunteers (part 1) and female patients with HER2-postive early breast cancer who had completed standard (neo)adjuvant treatment (part 2). This study aimed to identify an SC pertuzumab dose given with recombinant human hyaluronidase that results in comparable exposure to that of the intravenous (IV) pertuzumab dose, based on pertuzumab serum trough concentration and area under the serum concentration-time curve. Pharmacokinetics (PK), safety, and tolerability of a single dose of SC pertuzumab given alone or in a fixed-dose combination (comixed or coformulated) with trastuzumab were also assessed. A maintenance dose of 600 mg for SC pertuzumab resulted in an equivalent exposure to that of IV pertuzumab, and no new safety signals were identified for SC pertuzumab or trastuzumab. A loading dose of 1200 mg for SC pertuzumab was selected based on approximate dose proportionality. The PK and safety results support further development of a fixed-dose coformulation combination of pertuzumab and trastuzumab for SC administration, which will be investigated in an upcoming phase III trial in patients with HER2-positive early breast cancer.

Keywords: HER2-positive; breast cancer; dose-finding; pertuzumab; population pharmacokinetics; subcutaneous; trastuzumab.

© 2018, The American College of Clinical Pharmacology.

Figures

Figure 1

Study design. arHuPH20 concentration = 2000 U/mL. brHuPH20 concentration = 667 U/mL. cCalculated to deliver a similar exposure to a 420 mg IV dose. dOnly if coformulated FDC is not feasible. FDC indicates fixed‐dose combination; IV, intravenous; PK, pharmacokinetics; rHuPH20, recombinant human hyaluronidase PH20; SC, subcutaneous.

Figure 2

Mean serum pertuzumab concentration–time profiles (A), and geometric mean dose‐normalized serum pertuzumab concentration–time profiles (B) for pertuzumab with and without concomitant trastuzumab by cohort in healthy male volunteers (part 1). arHuPH20 concentration = 667 U/mL only. bCohorts 1, 3, and 4 (n = 18). cCohorts 6 and 7 (n = 12). Error bars represent the 95%CIs of the mean. GM indicates geometric mean; IV, intravenous; rHuPH20, recombinant human hyaluronidase PH20; SC, subcutaneous.

Figure 3

Phase III clinical trial simulations of SC/IV GMR and 90%CI estimates using part 1 data. Circles represent the GMR (SC/IV) Ctrough point estimates; horizontal solid lines represent the 90%CIs. Each circle/horizontal line represents a unique clinical trial simulation. Only 100 of the 400 clinical trial simulations are shown for clarity. Vertical dashed lines represent GMR 0.8–1.25. Ctrough indicates trough serum concentration; GMR, geometric mean ratio; IV, intravenous; SC, subcutaneous.

Figure 4

Mean serum pertuzumab concentration–time profiles following 420 mg IV (part 1, cohort 1) and 600 mg SC doses in female patients with early breast cancer (part 2, cohort B) (A), and geometric mean dose‐normalized serum pertuzumab concentration–time profiles for pertuzumab comixed (part 2, cohort B) or coformulated (part 2, cohort C) as an SC fixed‐dose combination with trastuzumab in female patients with early breast cancer (B). Error bars represent the 95%CIs of the mean. GM indicates geometric mean; IV, intravenous; rHuPH20, recombinant human hyaluronidase PH20; SC, subcutaneous.