Changes in Biologics Dosing May Help Keep Patients Safe From COVID-19

Coronavirus Disease 2019 (COVID-19) has forced physicians worldwide to reconsider acute treatment in the face of uncertainty about the virus’ spread and the risk it presents to patients with compromised immunity, especially those with cancer. Since the pandemic began, visits to doctor’s offices and infusion centers dramatically declined in an attempt to reduce patient exposure to the virus, which led to delays in the delivery of certain therapies in the oncology setting.

One strategy for limiting exposure that emerged was the use of biologics with different dosage frequencies or administration routes. Notable changes in the administration of 2 prominent anticancer agents, pembrolizumab (Keytruda) and daratumumab (Darzalex), and 1 combination regimen, pertuzumab (Perjeta) plus trastuzumab (Herceptin), came at a time when they were needed most, presenting the possibility of reducing the number of office visits or time spent at each appointment. In April, the FDA approved a new dosing regimen of pembrolizumab that allowed patients to be treated with 400 mg every 6 weeks versus 200 mg every 3 weeks.¹ Following on its heels, the sub-cutaneous formulation of daratumumab plus hyaluronidase-fihj (Darzalex Faspro) was approved in May across several indications in multiple myeloma, reducing the administration of the CD38 antibody from a several-hour infusion to a simple 5-minute injection.² And in June, the FDA approved the fixed-dose combination of pertuzumab and trastuzumab plus hyaluronidase–zzxf (Phesgo) as a subcutaneous injection.³

Less Frequent Pembrolizumab Dosing

Trial data supporting the approval of the amended dose of pembrolizumab were supported by results of cohort B of the phase 1 KEYNOTE-555 trial (NCT03665597) in patients with advanced melanoma.¹

At the American Association for Cancer Research Annual Meeting 2020, preliminary pharmacokinetic, efficacy, and safety analyses were presented from this cohort to validate a consistent benefit-risk profile for the doses given every 6 weeks versus every 3 weeks.⁴

“This offers convenience and flexibility to both patients and providers, the need for which is particularly exemplified by the current COVID19 pandemic,” said Mallika Lala, PhD, senior scientist for the quantitative pharmacology and pharmacometrics group at Merck, the developer of the agent, in a plenary session at the meeting.

The National Comprehensive Cancer Network was proactive in its response to these changes and issued guidance for the treatment of patients with melanoma, non–small cell lung cancer, and colorectal cancer that included recommendations for the every-6-week dosing strategy to reduce patient exposure during the COVID-19 pandemic.⁵

Subcutaneous Dose of Daratumumab and Phesgo

The formulation of daratumumab that allows for subcutaneous administration was approved based on the phase 3 COLUMBA trial (NCT03277105), which demonstrated the noninferiority of this particular formulation versus intravenous daratumumab. The objective response rate (41.1% vs 37.1%, respectively) and the geometric mean ratio for the comparison of the 2 formulations (108%; 90% CI, 96%-122%) supported the noninferiority of subcutaneous daratumumab.²

“The subcutaneous dose [of daratumumab] will definitely reduce patient time in the office,” said Ola Landgren, MD, PhD, chief of Myeloma Service at Memorial Sloan Kettering Cancer Center, in an interview with Targeted Therapies in Oncology following the initial approval. “I predict that we will loosen up on these rules and procedures going forward. To begin with, we will probably have the patient [in the office] for a few hours. After the first cycle, I could see it [changing to a] short visit.”

The initial approval of subcutaneous daratumumab was for 4 indications in patients in the frontline and relapsed multiple myeloma settings. In November, an application was submitted to the FDA to expand its use in combination with pomalidomide (Pomalyst) and dexamethasone for patients with relapsed/ refractory disease after at least 1 prior therapy.⁶

Pertuzumab and trastuzumab for subcutaneous injection was approved for 2 indications: neoadjuvant therapy for HER2-positive early breast cancer and adjuvant treatment of HER2-positive early breast cancer with a high recurrence risk.³

Efficacy was confirmed in the phase 3 FeDeriCa trial (NCT03493854), in which patients who received neoadjuvant chemotherapy were administered concurrent Phesgo or the intravenous formulation of the same regimen. The subcutaenous formulation was shown to be noninferior to the intravenous dose by serum trough concentration, meeting the trials primary end point.

Additional Strategies to Reduce Patient Exposure

Given the success of these new administration strategies, reduced dosing frequencies and agents with more convenient modes of delivery may be used even more to meet the needs of patients across settings.

For example, other pembrolizumab dosing strategies have been proposed to reduce patient exposure, including a weight-based dosage of 4 mg/kg every 6 weeks, with a 400-mg cap.⁷

“While we have used pembrolizumab as an exemplar, there is little doubt that the principles used here apply to many checkpoint inhibitors, and indeed to many monoclonal antibodies in therapeutic use,” wrote Daniel L. Goldstein, MD, and colleagues in an article about weight-based dosing of pembrolizumab.⁶

Time will tell if widespread adoption of these alternative strategies occurs, but the potential for positive impact on patient care has been established and may be considered in patients who present with treatment challenges due to COVID-19.

_References:

_{1. FDA approves new dosing regimen for pembrolizumab. FDA. Updated April 29, 2020. Accessed November 13, 2020. https://bit.ly/2Usfq2C}

_{2. FDA approves daratumumab and hyaluronidase-fihj for multiple myeloma. FDA. May 1, 2020. Accessed November 13, 2020. https://bit.ly/3ltoBfi}

_{3. FDA approves combination of pertuzumab, trastuzumab, and hyaluronidase-zzxf for HER2-positive breast cancer, June 29, 2020. Accessed December 7, 2020. https://bit.ly/3lTGEuu}

_{4. Lala M, Akala O, Chartash E, et al. Pembrolizumab 400 mg Q6W dosing: first clinical outcomes data from KEYNOTE-555 cohort B in metastatic melanoma patients. Clin Cancer Res. 2020;80(suppl 16):CT042. doi:10.1158/1538-7445.AM2020-CT042}

_{5. Coronavirus disease 2019 (COVID-19) resources for the cancer care community. National Comprehensive Cancer Network. Accessed November 13, 2020. https://bit.ly/3pqlJSL}

_{6. Janssen submits applications in the U.S. and EU seeking approval of Darzalex Faspro (daratumumab and hyaluronidase-fihj)/Darzalex (daratumumab) subcutaneous (SC) formulation in combination with pomalidomide and dexamethasone for patients with relapsed or refractory multiple myeloma. News release. Janssen Pharmaceutical Companies of Johnson & Johnson. November 12, 2020. Accessed November 12, 2020. https://prn.to/35n742y}

_{7. Goldstein DA, Ratain MJ, Saltz LB. Weight-based dosing of pembrolizumab every 6 weeks in the time of COVID-19. JAMA Oncol. 2020;6(11):1694-1695. doi:10.1001/jamaoncol.2020.2493}