FDA Accepts BLA for Subcutaneous Fixed-Dose Pertuzumab/Trastuzumab in HER2+ Breast Cancer | OncLive

FDA Accepts BLA for Subcutaneous Fixed-Dose Pertuzumab/Trastuzumab in HER2+ Breast Cancer

February 25, 2020

The FDA has accepted a Biologics License Application for a fixed-dose combination of pertuzumab and trastuzumab with hyaluronidase, administered by subcutaneous injection in combination with intravenous chemotherapy, for the treatment of eligible patients with HER2-positive breast cancer.

The FDA has accepted a Biologics License Application (BLA) for a fixed-dose combination (FDC) of pertuzumab (Perjeta) and trastuzumab (Herceptin) with hyaluronidase, administered by subcutaneous (SC) injection in combination with intravenous (IV) chemotherapy, for the treatment of eligible patients with HER2-positive breast cancer.1

The BLA is based on data from the phase III FeDeriCa study, in which an SC FDC of pertuzumab and trastuzumab demonstrated noninferiority to intravenous formulations of the 2 drugs with respect to pharmacokinetics, clinical activity, and safety.2

The 500-patient study met the primary end point, demonstrating noninferiority on the basis of predose cycle 8 serum Ctrough for the pertuzumab component of the FDC, with a mean value of 93.7 versus 78.5 µg/mL for IV pertuzumab. Geometric means were 88.7 and 72.4 µg/mL, respectively (geometric mean ratio [GMR], 1.22; 90% CI, 1.14-1.31).

The trial also demonstrated noninferiority for the predose cycle 8 serum Ctrough for the trastuzumab component of the FDC compared with IV: 62.9 versus 48.1 µg/mL. Geometric means were 58.7 and 44.1 µg/mL for the SC and IV formulations of trastuzumab (GMR 1.33; 90% CI, 1.24-1.43).

Total pathologic complete response (tpCR) in the breast and axilla and safety also were similar between the 2 treatment regimens.

“For more than two decades, our medicines have redefined the standard of care for people with HER2-positive breast cancer,” Levi Garraway, MD, PhD, chief medical officer and head of Global Product Development, Genentech (Roche), said in a statement. “Today’s acceptance builds upon our commitment by potentially offering patients a faster way to administer Perjeta and Herceptin. We’re working with the FDA to bring this treatment option to patients as quickly as possible.”

IV pertuzumab plus IV trastuzumab and chemotherapy have been shown to improve outcomes in patients with HER2-positive breast cancer, as compared with IV trastuzumab plus chemotherapy. A first-ever SC FDC combines the 2 monoclonal antibodies with recombinant hyaluronidase in premeasured single-use vials. The FDC is administered subcutaneously in the thigh over 5 to 8 minutes.

The dose of trastuzumab and hyaluronidase-oysk (Herceptin Hylecta) was established in the phase III HannaH trial,3 and the dose of SC pertuzumab was determined in a phase Ib dose-finding study.4

To compare the SC FDC with conventional IV treatment, investigators at 122 sites enrolled patients with newly diagnosed stage II-IIIc HER2-positive breast cancer in the trial of neoadjuvant therapy. The patients were randomized to 4 cycles of doxorubicin and cyclophosphamide chemotherapy followed by 4 cycles of docetaxel administered with randomized therapy: IV pertuzumab and trastuzumab or the SC FDC.

Following surgery, patients received adjuvant therapy with the same pertuzumab-trastuzumab formulation they received in the neoadjuvant setting. The primary analysis for the trial occurred before the start of adjuvant therapy.

The patients had a median age of about 50, 80% had stage II-IIIa disease, and 61% were hormone-receptor positive.

The comparison of predose cycle 8 Ctrough values for IV pertuzumab and trastuzumab versus the individual components of the FDC produced GMRs that fell within the 90% confidence intervals for noninferiority.

The 2 treatment arms had almost identical rates of tpCR (defined as ypT0/Tis, ypN0): 59.5% with the IV drugs and 59.7% with the SC FDC.

The safety analysis showed that incidences of the most common adverse events (AEs) were similar between the 2 arms, including alopecia, nausea, diarrhea, anemia, and asthenia. Rates of specific AEs to monitor also were comparable, including diarrhea, neutropenia/febrile neutropenia, cardiac dysfunction, infusion/administration-related reactions within 24 hours of anti-HER2 therapy, interstitial lung disease, serious rash/skin reactions, serious mucositis, and pregnancy/neonatal-related AEs.

References

  1. FDA Accepts Genentech’s Biologics License Application for Fixed-Dose Subcutaneous Combination of Perjeta And Herceptin For HER2-Positive Breast Cancer. Genentech. Published February 24, 2020. https://bit.ly/38TtXKp. Accessed February 25, 2020.
  2. Tan AR, Im S-A, Mattar A, et al. Subcutaneous administration of the fixed-dose combination of trastuzumab and pertuzumab in combination with chemotherapy in HER2-positive early breast cancer: primary analysis of the phase III, multicenter, randomized, open-label, two-arm FeDeriCa study. Presented at: 2019 San Antonio Breast Cancer Symposium. Poster PD4-07.
  3. Ismael G, Hegg R, Muehlbauer S, et al. Subcutaneous versus intravenous administration of (neo)adjuvant trastuzumab in patients with HER2-positive, clinical stage I-III breast cancer (HannaH study): a phase 3, open-label, multicentre, randomised trial. Lancet Oncol. 2012;13(9):869-78. doi: 10.1016/S1470-2045(12)70329-7.
  4. Kirschbrown WP, Wynne C, Kagedal M, et al. Development of a subcutaneous fixed-dose combination of pertuzumab and trastuzumab: results from the phase Ib dose-finding study. J Clin Pharmacol. 2019 May;59(5):702-716. doi: 10.1002/jcph.1362.

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