A phase 1 study to evaluate the safety, pharmacokinetics (PK), and pharmacodynamics (PD), and to determine the recommended phase 2 dose (RP2D) of subcutaneous (SC) cetrelimab (CET) in patients (pts) with advanced solid malignancies.

person Piotr Rutkowski Maria Skłodowska-Curie National Institute of Oncology Center, Warsaw, Poland info_outline Piotr Rutkowski, Dariusz Kowalski, Victor Moreno, Aitana Calvo, Fiona Thistlethwaite, Elizabeth Ruth Plummer, Kevin Tianxiang Han, John Loffredo, Jenna Carcione, Daniel Jonathan, Vinod Philip, Mahadi Baig, Peter Hellemans, Iurie Bulat

Authors person Piotr Rutkowski Maria Skłodowska-Curie National Institute of Oncology Center, Warsaw, Poland info_outline Piotr Rutkowski, Dariusz Kowalski, Victor Moreno, Aitana Calvo, Fiona Thistlethwaite, Elizabeth Ruth Plummer, Kevin Tianxiang Han, John Loffredo, Jenna Carcione, Daniel Jonathan, Vinod Philip, Mahadi Baig, Peter Hellemans, Iurie Bulat Organizations Maria Skłodowska-Curie National Institute of Oncology Center, Warsaw, Poland, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland, Medical Oncology, START Madrid-FJD, University Hospital Fundación Jiménez Diaz, Madrid, Spain, Gregorio Marañón University General Hospital, Madrid, Spain, The Christie NHS Foundation Trust, Manchester, United Kingdom, Newcastle University, Newcastle upon Tyne, United Kingdom, Janssen Research & Development LLC, Titusville, NJ, Janssen Research & Development, Spring House, PA, Janssen (A Pharmaceutical Company of Johnson & Johnson), Montclair, NJ, Janssen Research & Development LLC, Malvern, PA, Janssen Research and Development LLC, Raritan, NJ, Janssen Research and Development LLC, Beerse, Belgium, Oncological Institute, Chisinau, MA, Moldova, The Republic of Abstract Disclosures Research Funding Janssen Pharmaceuticals, Inc Background: In part (P) 1 and P2 of LUC1001 (NCT02908906), the RP2D of intravenous (IV) CET was established as 240 mg IV once every 2 weeks (Q2W) or 480 mg IV Q4W, and the PK/PD characteristics, safety profile, and clinical activity were consistent with known and approved PD-1 inhibitors (Felip et al. Cancer Chemother Pharmacol 2022). CET administered SC was investigated in P3 and P4 of LUC1001. Methods: In P3 and P4 of LUC1001, safety, PK, PD, and clinical activity of low- (30 mg/mL [CET-LC]) and high- (150 mg/mL [CET-HC]) concentration SC CET formulations, respectively, were evaluated. Key entry criteria were advanced or refractory solid tumors, previous receipt of or ineligibility for standard treatment, and being anti-PD-1/PD-L1/2–naïve. In P3, SC CET-LC injection was administered at a dose level of 600 mg with a 6-week dosing interval between doses 1 and 2, then Q3W dosing after dose 2. In P4, SC CET-HC injection was administered as a single loading dose of 900 mg, followed by 600 mg Q3W. Results: Among 30 enrolled pts (P3: n = 11; P4: n = 19), median age was 54.5 years; 17 (57%) were male; most (29 [97%]) were White and heavily pretreated, with a median of 3 (range, 1-8) prior lines of therapy. Most common tumor types were colorectal cancer (6 [20%]), breast cancer (4 [13%]), cholangiocarcinoma and NSCLC (3 [10%] each). Most commonly reported adverse events (AE) were fatigue (11 [37%]), ALT increased (7 [23%]), abdominal pain, constipation and AST increased (6 [20%] each). Overall, 20 (67%) pts had CET-related AEs, 1 (3%) of which led to CET discontinuation. Eight (27%) pts had ≥1 CET-related ≥Grade 3 AE. Immune-related AEs were reported in 9 (30%) pts. No pts experienced systemic-administration–related reactions, and 2 (6%) pts experienced Grade 1 administration-site reactions. No CET-related serious AEs were reported. Durable responses were observed in 2 (7%) patients (cholangiocarcinoma in P3 and thymoma in P4). Stable disease ≥24 weeks was observed in 4 (13% [P3, 0 (0%); P4, 4 (21%)]) pts. According to PK data, the 900-mg SC CET loading dose followed by 600-mg SC CET Q3W would likely result in comparable exposure as observed at steady state with IV RP2Ds. No differences in PK, including absorption, were observed between CET-LC and CET-HC formulations. Maximum PD-1 receptor occupancy was achieved, consistent with historical IV and SC data. Incidence of anti-CET antibodies (P3, 3/11 [27%]; P4, 0/13 [0%]) was low, and no neutralizing antibodies (0/24 [0%]) were detected. Conclusions: SC CET demonstrated a safety profile similar to IV CET. Based on safety, PK, and PD data, the RP2D of SC CET was established as a loading dose of 900 mg followed by 600 mg Q3W. Studies are planned to further evaluate the safety and efficacy of SC CET in combination with other agents. Clinical trial information: NCT02908906.

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