Commercial specifications for a new biotherapeutic product are a critical component of the product's overall control strategy that ensures safety and efficacy. This paper describes strategies for setting commercial specifications as proposed by a consortium of industry development scientists. The specifications for some attributes are guided by compendia and regulatory guidance. For other product quality attributes (PQAs), product knowledge and the understanding of attribute criticality built throughout product development should drive specification setting. The foundation of PQA knowledge is an understanding of potential patient impact through an assessment of potency, PK, immunogenicity and safety. In addition to PQA knowledge, the ability of the manufacturing process to consistently meet specifications, typically assessed through statistical analyses, is an important consideration in the specification-setting process. Setting acceptance criteria that are unnecessarily narrow can impact the ability to supply product or prohibit consideration of future convenient dosage forms. Patient-centric specifications enable appropriate control over higher risk PQAs to ensure product quality for the patient, and flexibility for lower risk PQAs for a sustainable supply chain. This paper captures common strategic approaches for setting specifications for standard biotherapeutic products such as monoclonal antibodies and includes considerations for ensuring specifications are patient centric.

Background: Amivantamab, an epidermal growth factor receptor (EGFR)-MET bispecific antibody, is approved for patients with advanced EGFR exon 20 insertion non-small cell lung cancer after progression on platinum-based chemotherapy. First-dose intravenous (IV) delivery leads to infusion-related reactions (IRR) among 66% of patients, resulting in dose interruptions and slower infusion restart rates (infusion duration ranges 2-4 hours) and necessitates splitting of the dose over 2 days (Park Ann Oncol 32[suppl_5]:S981). Subcutaneous (SC) administration of amivantamab, which could simplify and accelerate administration, is being investigated in an ongoing phase 1 study (PALOMA; NCT04606381). Preliminary safety (including IRR) and pharmacokinetics (PK) of SC formulations of amivantamab ± recombinant human hyaluronidase (rHuPH20) for enhanced absorption were evaluated. Methods: PALOMA is an ongoing phase 1 dose escalation study of amivantamab SC in patients with advanced solid tumors who may derive benefit from EGFR or MET-directed therapy. Eligible patients must have progressed after standard-of-care therapy for metastatic disease, be ineligible for, or have declined current standard therapies. The study objectives were to evaluate the feasibility of administration, safety, and PK of a low concentration formulation, 50 mg/mL of amivantamab ± rHuPH20 (Part 1) and a high concentration formulation, 160 mg/mL of amivantamab ± rHuPH20 (Part 2). Patients in Part 1 and Part 2 received the currently approved dosage of amivantamab, 1050 mg (1400 mg for bodyweight ≥80 kg) SC (weekly for the first 4 weeks and every other week thereafter). This study also evaluated administering the full dose of amivantamab on the first day. Results: The full safety, PK, bioavailability, and receptor occupancy data of patients enrolled in Part 1 (n=16) and Part 2 (n=17) will be presented. Compared to IV administration, initial SC experience demonstrates the co-formulation of high concentration amivantamab with rHuPH20 shortened the needed infusion time to less than 5 minutes, with initial bioavailability of approximately 65% of IV administration. Saturation of soluble free EGFR and MET was achieved after the first SC dose. The incidence of IRRs was 18.2%, with all events of grade 1-2 severity. The full amivantamab SC dose was safely given at first administration to 14 patients, potentially obviating the need for split dosing. Conclusions: Initial SC amivantamab ± rHuPH20 was well tolerated with improvements in time and ease of administration and associated with a meaningful reduction in IRRs, eliminating the need for split dosing compared with IV administration. Higher SC dose levels and alternative dosing schedules are being explored. Citation Format: Matthew G. Krebs, Melissa L. Johnson, Byoung Chul Cho, Se-Hoon Lee, Rachel Kudgus-Lokken, Donna Zemlickis, Anna Mitselos, Eileen Berkay, Joshua M. Bauml, Roland E. Knoblauch, Peter Hellemans, Anna Minchom. Subcutaneous delivery of amivantamab in patients with advanced solid malignancies: Initial safety and pharmacokinetic results from the PALOMA study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT198.

9126 Background: Ami, an EGFR-MET bispecific antibody, is approved for pts with advanced EGFR exon 20 insertion non-small cell lung cancer after progression on platinum-based chemotherapy. Intravenous (IV) delivery is associated with infusion-related reactions (IRRs) in 67% of pts, requiring splitting the first dose over 2 days (Park Ann Oncol 2021;32[suppl_5]:S981). PALOMA (NCT04606381) is an ongoing phase 1b dose escalation study of subcutaneous (SC) ami ± rHuPH20 (a hyaluronidase that aids SC agent absorption) in pts with advanced solid tumors who may benefit from EGFR- or MET-directed therapy. Preliminary results showed SC ami was well tolerated, improved time and ease of administration, and meaningfully reduced IRRs (Krebs Cancer Res 2022;82:12_Supplement, CT198). We present updated safety results and identification of the recommended phase 2 dose (RP2D) for ami SC Q2W administration. Methods: PALOMA enrolled pts with various advanced solid tumors. Objectives were to evaluate administration feasibility, safety, and PK of low and high concentration formulations of ami SC (50 mg/mL ami ± rHuPH20 [Part 1; Cohorts 1a/b] and 160 mg/mL ami ± rHuPH20 [Part 2; Cohorts 2a/b, Cohort 3a, Cohort 5a]). Cohorts 1a/b and 2a/b received 1050 mg (1400 mg, ≥80 kg), Cohort 3a received 1600 mg (2240 mg, ≥80 kg), and Cohort 5a received 2560 mg (3360 mg, ≥80 kg). Cohorts 1-3 were dosed weekly for the first 4 weeks and Q2W thereafter. Cohort 5a was dosed weekly for the first 3 weeks and Q3W thereafter. Results: As of Jan 3, 2023, 81 pts were enrolled (16 pts in Part 1, 65 pts in Part 2) and majority had NSCLC (71; 88%). Median age was 64 years, 44 (54%) pts were female, and most pts were White (44; 54%) or Asian (34; 42%). Across all doses, IRRs were reported by 13 (16%) pts; all of grade 1-2. The most frequent manifestations of IRRs were chills (7%), pyrexia (7%), and asymptomatic tachycardia (4%). Treatment-emergent AEs (TEAEs) of rash were reported by 59 (73%) pts, with no grade ≥3. In total, 3 (4%) pts discontinued ami SC due to toxicity (2 pneumonitis, 1 asthenia). Grade ≥3 related TEAEs were reported by 3 (4%) pts (hypoalbuminemia, lymphopenia, hypertension). Full ami SC dosing on day 1 was feasible (≤7 min), obviating the need for split dosing. PK analysis confirmed that ami SC 1600 mg (2240 mg, ≥80 kg) Q2W resulted in similar exposure to the approved IV dose (1050 mg [1400 mg, ≥80 kg] Q2W). Compared to IV, ami SC resulted in lower Cmax and equal or higher Ctrough and AUC0-336h at Cycles 2 and 4. Based on these data, ami SC 1600 mg (2240 mg, ≥80 kg) was selected as the RP2D for ami SC Q2W administration. Conclusions: Ami SC was well tolerated with meaningful reductions in administration time and TEAEs. Ami SC provided a quantitative and qualitative improvement in the symptoms of IRRs vs historical IV rates. The identified RP2D for ami SC on the Q2W schedule achieved similar exposure as the approved IV dose. Clinical trial information: NCT04606381 .