New Subcutaneous Monoclonal Antibodies
Michelle Gardiner, PharmD BCOP CPP
Chapel Hill, NC
Since their development more than 20 years ago, the targeted monoclonal antibodies (MABs) rituximab and trastuzumab have treated multitudes of patients. Newly developed subcutaneous (SC) formulations of these ubiquitous monoclonal antibodies may improve patient care while increasing the efficiency of infusion clinics. SC Herceptin Hylecta and Rituxan Hycela significantly reduce the treatment burden for patients because they eliminate the need for accessing central lines or placing peripheral intravenous lines before treatment, and administration requires only a few minutes.1,2 Other monoclonal antibodies may soon be reformulated for SC administration, including an SC daratumumab product expected to become available in the near future.3
Recombinant Human Hyaluronidase
The administration of such large volumes via the SC route is made possible by recombinant human hyaluronidase PH20 (rHuPH20).4 SC rituximab, SC trastuzumab, and SC daratumumab are all coformulated with rHuPH20.1-4 Hyaluron is a large glycosaminoglycan that is responsible for forming a gel-like substance with water in the skin, which creates resistance to bulk fluid flow. RHuPH20 temporarily degrades hyaluron, allowing large volumes to be administered into the SC space. The effect of rHuPH20 remains localized and temporary. Within 24 hours of administration, normal SC structure and function are restored.4
The U.S. Food and Drug Administration (FDA) approved Herceptin Hylecta in February 2019. This is a new SC formulation of trastuzumab 600 mg and hyaluronidase-oysk 10,000 units per 5 mL. This standard non-weight-based dose is for all patients and does not require a loading dose. Currently, Herceptin Hylecta is approved by the FDA for use in the adjuvant and metastatic breast cancer settings,1 and it has been studied in the neoadjuvant setting as well. The National Comprehensive Cancer Network (NCCN) guidelines for treating breast cancer (Version 1.2019) indicate that Herceptin Hylecta is also appropriate for use in the preoperative setting.5 Approval was based on the HannaH and SafeHER clinical trials.1
The SafeHER study was a prospective two-cohort non-randomized trial that assessed the safety and tolerability of SC trastuzumab. Cohort A (n = 1,864) received the Herceptin Hylecta formulation from a single-dose vial through a hand-held syringe. Cohort B (n = 709) received a bioequivalent formulation of SC trastuzumab via a single-use injection device with an option for patient self-administration.6 The FDA considered the safety outcomes of the patients in cohort A.1 Within cohort A, 88.6% of participants experienced 1 or more adverse events (AEs) of any grade, and 7.8% of participants experienced AEs grade 3 or higher. In the study, 7.8% of patients experienced blood or lymphatic system disorders; 3.1% experienced infections and infestations; and 1.1% experienced respiratory, thoracic, or mediastinal AEs. Cardiac AEs were observed in 1.1% of participants, with 0.4% experiencing congestive heart failure.6 Conversely, cardiac failure occurred in 2% of patients receiving 1 year of treatment with intravenous (IV) trastuzumab.7
The HannaH trial enrolled 596 women with HER2-positive early breast cancer in a prospective phase 3 non-inferiority trial. Participants were assigned 1:1 to receive either SC trastuzumab hyaluronidase-oysk 600 mg/10,000 units or IV trastuzumab (loading dose, 8 mg/kg; maintenance dose, 6 mg/kg) every 3 weeks. Trastuzumab was administered concurrently with 8 cycles of chemotherapy (4 cycles of docetaxel, followed by 4 cycles of fluorouracil, epirubicin, and cyclophosphamide [FEC]) in the neoadjuvant setting. Following surgery, the study groups continued treatment with either IV trastuzumab or SC trastuzumab every 3 weeks for an additional 10 cycles of single-agent anti-HER2 therapy. Both treatments showed similar efficacy at the clinical cutoff, with a median duration of follow-up of 5.9 years in the SC trastuzumab group and 6 years in the IV trastuzumab group. The 6-year event-free survival (EFS) rates were comparable: 65% in both study groups (hazard ratio [HR], 0.98; 95% confidence interval [CI], 0.74–1.29). Six-year overall survival (OS) rates were also similar, at 84% in both study groups (HR, 0.94; 95% CI, 0.61–1.45).8
Rituxan Hycela (SC rituximab and hyaluronidase) received FDA approval in June 2017.2 Clinical trials showed its safety and efficacy when used for indications related to multiple malignancies. It is available in two strengths: 1,400 mg rituximab/23,400 units hyaluronidase per 11.7 mL single-use vial and 1,600 mg rituximab/26,800 units hyaluronidase in 13.4 mL. These are standard non-weight-based doses.2 The NCCN clinical practice guidelines for B-cell lymphoma indicate that SC rituximab may be substituted for IV rituximab in all regimens with one exception: SC rituximab may not replace IV rituximab when used in combination with ibritumomab tiuxetan.9 NCCN guidelines for chronic lymphocytic leukemia (CLL) and small lymphocytic leukemia (SLL) also endorse substituting SC rituximab for IV rituximab.10 Approval was based on the results of the SABRINA, MabEase, and SAWYER trials.2
The two-stage phase 3 randomized controlled SABRINA trial compared SC and IV rituximab in previously untreated CD-20-positive follicular lymphoma of grades 1, 2, and 3a. Participants (N = 410) were randomized in a 1:1 ratio to receive either 1,400 mg SC rituximab or 375 mg/m2 IV rituximab in combination with either 6–8 cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or 8 cycles of cyclophosphamide, vincristine, and prednisone (CVP); the chemotherapy regimen was chosen at the discretion of the study center. Patients in both arms then received maintenance rituximab IV or SC every 8 weeks. In the IV group, 84.9% of patients achieved an unconfirmed (CRu) or confirmed complete response (CR) or a partial response (PR) during induction compared to 84.4% in the SC group. Overall response rate (ORR) at the end of maintenance was 78.1% (95% CI, 71.3–83.9) in the IV group and 77.9% (95% CI, 71–83.9) in the SC group. The safety profile of both formulations was considered similar, with patients experiencing one or more AEs or AEs grade 3 or higher in comparable frequencies in both the IV and SC treatment arms.11
The phase 3 MabEase trial randomized treatment-naive patients with diffuse large B-cell lymphoma in a 2:1 ratio to receive either SC rituximab 1,400 mg or IV rituximab 375 mg/m2 in combination with either CHOP-14 or CHOP-21 regimens. This was a descriptive study designed to assess major differences in efficacy between treatment arms. In the intention-to-treat population, rates of CRu or CR were 50.6% (95% CI, 45.3%–55.9%) and 42.4% (95% CI, 35.1%–49.7%) in the SC and IV groups, respectively (p = .076). PR and progressive disease rates were similar between treatment arms. CR/CRu rates for all randomized patients were 45.7% (40.7%–50.7%) for SC rituximab and 38.5% (31.6%–45.3%) for IV rituximab (p = .099). At 24 months of follow-up, progression-free survival was 75% (69.9%–79.4%) in the SC group and 81.5% (74.7%– 86.6%) in the IV group (p = .175), and EFS was 68.6% (63.3%–73.4%) and 73.4% (66%–79.4%), respectively (p = .456). Safety profiles were similar between arms.12
The phase 1b randomized controlled SAWYER study compared SC rituximab 1,600 mg trough serum concentrations to those achieved with IV rituximab 500 mg/m² in 176 patients with CLL. Patients received SC rituximab or IV rituximab, plus fludarabine and cyclophosphamide (FC), every 4 weeks for up to 6 cycles. Geometric mean trough serum concentration at cycle 5 showed non-inferiority in the SC rituximab group, with 97.5 mcg/mL in the SC group and 61.5 mcg/mL in the IV group, yielding an adjusted geometric mean ratio of 1.53 (90% CI, 1.27–1.85).13
Subcutaneous Daratumumab on the Horizon
Results of phase 1 studies have shown SC daratumumab 1,800 mg to be a tolerated dose in relapsed or refractory multiple myeloma.14 The Danish company GenMab A/S announced in a press release in February 2019 limited results of the phase 3 COLUMBA trial. Both the reported ORR and the geometric mean of Ctrough for patients treated with SC daratumumab met the specified non-inferiority criteria.11 ORR was 41.1% (n = 263) for the SC daratumumab group compared to 37.1% in patients treated with IV daratumumab (n = 259). The Ctrough for patients treated with SC daratumumab was 499 mg/mL (n = 149) versus 463 mg/mL in patients treated with IV daratumumab (n = 146). GenMab A/S plans to submit applications for drug approval with regulatory agencies in multiple countries.3
Patient Perspective and Clinic Experience
SC formulations decrease the time it takes for patients to receive their treatments and may improve overall infusion clinic efficiency by decreasing the healthcare provider time required per patient because of reduced administration time. A few studies have evaluated patients’ experience or clinic efficiency. MabEase assessed patient satisfaction using the Rituximab Administration Satisfaction Questionnaire (RASQ). Mean RASQ scores were higher across all areas for SC rituximab versus IV rituximab. Impact on activities of daily living mean scores were 83.8 (standard deviation = 16.1) and 57.4 (19.2) for the SC and IV groups, respectively. A majority (90.8%) of patients in the SC group specified a preference for SC over IV. The median administration time (cycles 2–8) was substantially shorter for SC rituximab (5–7 minutes) compared to IV rituximab (range: 2.6–3 hours). For each cycle beginning with cycle 2, a higher proportion of patients who received SC administration spent less than 2 hours in a chair or bed receiving rituximab than those who received IV rituximab (27%–56% SC vs. <1%–5% IV).12 Likewise, an Irish study compared the cost of administering IV trastuzumab with that for administering SC trastuzumab. The study calculated substantial cost savings to institutions in the following areas: fewer materials used to prepare patients for the medication (e.g., IV placement), fewer materials used to compound SC versus IV trastuzumab, and less healthcare provider time required for patient supervision.15 If SC rituximab and SC trastuzumab become more widely used, their proven efficacy and efficiency may encourage future development of more SC oncology medications.
- Herceptin Hylecta [package insert]. April 2019. San Francisco, CA: Genentech, Inc.; 2019.
- Rituxan Hycela [package insert]. April 2018. San Francisco, CA: Biogen and Genentech; 2018.
- GenMab A/S. Company Announcement no. 08 CVR no. 2102 3884. LEI Code 529900MTJPDPE4MHJ122. Copenhagen, Denmark. Accessed May 27, 2019.
- Locke KW, Maneval DC, LaBarre MJ. ENHANZE® drug delivery technology: a novel approach to subcutaneous administration using recombinant human hyaluronidase PH20. Drug Deliv. 2019;26(1);98-106. Available at https://doi.org/10.1080/10717544.2018.1551442
- National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Breast Cancer. Version 1.2019 (March 14, 2019). Available at https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf
- Gligorov J, Ataseven B, Verrill M, et al. Safety and tolerability of subcutaneous trastuzumab for the adjuvant treatment of human epidural growth factor receptor 2-positive early breast cancer: SafeHer Phase III study’s primary analysis of 2573 patients. Eur J Cancer. 2017;82:237-246. Published online June 16, 2017. Available at https://doi.org/10.1016/j.ejca.2017.05.010
- Trastuzumab [package insert]. November 2018. San Francisco, CA: Genentech, Inc.; 2018.
- Jackisch C, Stroyakovskiy D, Pivot X, et al. Subcutaneous vs intravenous trastuzumab for patients with ERBB2-positive early breast cancer: final analysis of the HannaH phase 3 randomized clinical trial. JAMA Oncol. 2019;5(5):e190339 (published online ahead of print April 18, 2019). Available at https://jamanetwork.com/journals/jamaoncology/fullarticle/2730632
- National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. B- Cell Lymphomas. Version 3.2019 (May 6, 2019). Available at https://www.nccn.org/professionals/physician_gls/pdf/b-cell.pdf
- National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Chronic Lymphocytic Leukemia/Small Lymphocytic Leukemia. Version 5.2019 (May 23, 2019). Available at https://www.nccn.org/professionals/physician_gls/pdf/cll.pdf
- Davies A, Merli F, Mehaljevic B, et al. Efficacy and safety of subcutaneous rituximab versus intravenous rituximab for first-line treatment of follicular lymphoma (SABRINA): a randomised, open-label, phase 3 trial. Lancet Haematol. 2017;4(6):e272–e282 (published online ahead of print May 2, 2017). Available at https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(17)30078-9/fulltext
- Lugtenburg P, Avivi I, Berenschot H, et al. Efficacy and safety of subcutaneous and intravenous rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in first-line diffuse large B-cell lymphoma: the randomized MabEase study. Haematol. 2017;102(11):1913-1922.
- Assouline S, Buccheri V, Delmer A, et al. Pharmacokinetics, safety, and efficacy of subcutaneous versus intravenous rituximab plus chemotherapy as treatment for chronic lymphocytic leukaemia (SAWYER): a phase 1b, open-label, randomised controlled non-inferiority trial. Lancet Haematol. 2016;3(3):e128–e138. Available at https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(16)00004-1/fulltext
- Chari A, Nahi H, Mateos M-V, et al. Subcutaneous delivery of daratumumab in patients (pts) with relapsed or refractory multiple myeloma (RRMM): PAVO, an open-label, multicenter, dose escalation phase 1b study. Blood. 2017;130(suppl 1):838.
- O’Brien GL, O’Mahony C, Cooke K. Cost minimization analysis of intravenous or subcutaneous trastuzumab treatment in patients with HER2-positive breast cancer in Ireland. Clin Breast Cancer 2019. Published online ahead of print February 6, 2019. Available at https://www.ncbi.nlm.nih.gov/pubmed/308533