RYBREVANT FASPRO, RYBREVANT - PALOMA Study

SUMMARY

• RYBREVANT (amivantamab-vmjw) is a low fucose, fully human immunoglobulin G1 (IgG1)-based bispecific antibody with immune cell-directing activity that targets epidermal growth factor receptor (EGFR) mutations and mesenchymal-epithelial transition (MET) mutations and amplifications in non-small cell lung cancer (NSCLC).¹
• RYBREVANT FASPRO (amivantamab and hyaluronidase-lpuj) for subcutaneous (SC) administration is a coformulation of amivantamab with recombinant human hyaluronidase PH20 (rHuPH20).²
• PALOMA (NCT04606381) is a phase 1, open-label, multicenter, 2-part study evaluating the pharmacokinetics (PK), safety, and efficacy of amivantamab SC as low- and high- concentration formulations with and without rHuPH20 in patients with advanced solid malignancies. The study also determined the recommended phase 2 dose (RP2D) for every 2 weeks (Q2W), every 3 weeks (Q3W), and every 4 weeks (Q4W) SC administration.^3,4 
  • The cycle (C)2 trough concentration (C_trough)and area under the curve (AUC_𝜏) for the SC Q2W dose (1600 mg; 2240 mg if body weight ≥80 kg) were consistent with those of the reference intravenous (IV) Q2W dose.
  • The C2 C_trough and AUC_𝜏 for the SC Q3W dose (2560 mg, 3360 mg if body weight ≥80 kg) were higher than those of the reference IV Q3W dose. The SC Q3W dose was adjusted to a lower dose of 2400 mg (3360 mg if body weight ≥80 kg).
  • The C2 C_trough and AUC_𝜏 for the SC Q4W dose (3200 mg; 4320 mg if body weight ≥80 kg) were consistent with those of the reference IV Q2W dose, with a lower C_trough at steady state. The SC Q4W dose was adjusted to a higher dose of 3520 mg (4640 mg if body weight ≥80 kg) to better match the reference IV Q2W steady-state C_trough, with the predicted SC Q4W steady-state maximum concentration (C_max) not exceeding 125% of the reference IV Q2W C_max.
  • Grade ≥3 treatment-related adverse events (TRAE) with administration of amivantamab SC were reported in 12 (8%) patients.
  • Infusion-related reactions (IRR) were reported in 15% of patients receiving amivantamab SC vs 67% receiving RYBREVANT IV.
    • No increased risk of IRR was observed with full dose amivantamb SC administration on C1 day (D)1 vs split-dose amivantamab SC administration (18% vs 20%, respectively), therefore subsequent cohorts received full dose administration of amivantamab SC on C1D1.

PRODUCT LABELING

• RYBREVANT FASPRO (amivantamab and hyaluronidase-lpuj) [Prescribing Information]. Horsham, PA: Janssen Biotech, Inc.; https://www.jnjlabels.com/package-insert/product-monograph/prescribing-information/RYBREVANT+Faspro-pi.pdf.
• RYBREVANT (amivantamab-vmjw) [Prescribing Information]. Horsham, PA: Janssen Biotech, Inc.; https://www.jnjlabels.com/package-insert/product-monograph/prescribing-information/RYBREVANT-pi.pdf.

CLINICAL DATA

PALOMA Study

Study Design/Methods

• Phase 1, open-label, multicenter, 2-part study of amivantamab SC in patients with advanced solid tumors. The study also determined the RP2D for Q2W, Q3W, and Q4W SC administration.³ 
• The study design is shown in Figure: PALOMA Study Design.
• In part 1, the feasibility of SC administration of amivantamab was assessed using a low-concentration formulation (50 mg/mL) at the RP2D level for IV administration, admixed with (cohort 1a) and without (cohort 1b) rHuPH20.³ 
• In Part 2, dose escalation was evaluated using a high-concentration amivantamab formulation (160 mg/mL), co-formulated with (cohorts 2a, 3a, 4a, 5a, and 6a) and without (cohort 2b) rHuPH20.³ 

Results

Patient Characteristics

• Overall, 158 patients across 8 cohorts were enrolled from November 2020 to April 2024. Patients received a median of 3 (range, 1-8) prior lines of anticancer therapy.³ 
• Baseline characteristics are presented in Table: Baseline Demographics and Disease Characteristics.
• At the clinical data cutoff date of July 11, 2024, 31 (20%) patients remained on study treatment, while 111 (70%) patients discontinued treatment due to disease progression.³ 
• The median duration of study treatment was 2.8 months (range, 0.03-39.2 months), and the median follow-up duration was 3.8 months (range, 0.1-39.2 months).³ 

Formulation Selection

• More rapid absorption and higher bioavailability were observed with amivantamab SC plus rHuPH20 (cohorts 1a/2a) compared with the formulation without rHuPH20 (cohorts 1b/2b).³ 
•  In cohorts 3a, 4a, and 5a, amivantamab SC was administered at a single injection site in approximately 5 minutes, with a few exceptions that needed longer administration times.³ 
• In cohort 6a, where higher doses from C2D1 onward required 2 injection sites, amivantamab SC was administered in approximately 10 minutes.³

PK and RP2D Selection

• PK data analyses from cohorts 1 and 2 identified the SC Q2W dose of 1600 mg (2240 mg if body weight ≥80 kg), the Q3W dose of 2560 mg (3360 mg if body weight ≥80 kg), and the Q4W dose of 3200 mg (4320 mg if body weight ≥80 kg) to be evaluated in cohorts 3a, 5a, and 6a, respectively.³ 
• The C2 C_trough and AUC_𝜏 for the SC Q2W dose were consistent with those of the reference IV Q2W dose³ (Table: PK Parameters for Amivantamab SC vs RYBREVANT IV at Q2W Dosing).
  • The RP2D for amivantamab SC Q2W administration was 1600 mg (2240 mg if body weight ≥80 kg) weekly for C1 and then Q2W thereafter.
• The C2 C_trough and AUC_𝜏 for the SC Q3W dose (2560 mg; 3360 mg if body weight ≥80 kg) were higher than those of the reference IV Q3W dose³ (Table: PK Parameters for Amivantamab SC vs RYBREVANT IV at Q3W Dosing).
  • The RP2D for amivantamab SC Q3W administration was adjusted to 1600 mg (2240 mg if body weight ≥80 kg) on C1D1, followed by 2400 mg (3360 mg if body weight ≥80 kg) on C1D8 and C1D15 and Q3W from C2D1 onwards. The lower dose on C1D1 is to reduce the risk of IRRs, which generally occurred during the first dose.
• The C2 C_trough and AUC_𝜏 for the SC Q4W dose (3200 mg; 4320 mg if body weight ≥80 kg) were consistent with those of the reference IV Q2W dose, with a lower C_trough at steady-state.³ 
  • The RP2D for amivantamab SC Q4W administration was adjusted to 1600 mg (2240 mg if body weight ≥80 kg) weekly in C1, followed by 3520 mg (4640 mg if body weight ≥80 kg) Q4W from C2D1 onwards. The SC Q4W administration dose was increased to better match the reference IV Q2W steady-state C_trough, with the predicted SC Q4W steady-state C_max not exceeding 125% of the reference IV Q2W C_max.

Safety

• Adverse events (AE) with amivantamab SC were consistent with those reported with RYBREVANT IV in the CHRYSALIS study.³  The most common AEs with amivantamab SC vs RYBREVANT IV are presented in Table: Safety Profile for Administration of Amivantamab SC vs RYBREVANT IV.
• Venous thromboembolism (a grouped term including pulmonary embolism and deep vein thrombosis) was reported in 11% of patients with amivantamab SC.³ 

• Grade ≥3 TRAEs were reported in 12 (8%) patients³ (Table: Grade ≥3 TRAEs With Administration of Amivantamab SC).
• Treatment-related serious AEs were reported in 5 (3%) patients.³ 
• Treatment-related dose reductions occurred in 23 (15%) patients and were primarily associated with management of skin or nail toxicity; 4 patients discontinued treatment due to treatment-related AEs (pneumonitis, n=2 [grade 1-2]; asthenia, n=1; dermatitis acneiform, n=1).³ 
• One patient in cohort 6a reported grade 3 dermatitis acneiform that qualified as a dose-limiting toxicity. No dose-limiting toxicities were reported in other cohorts.³ 

• In cohorts 1a and 2a, no increased risk of IRR was observed with full dose amivantamb SC administration on C1D1 vs split-dose amivantamab SC administration (18% vs 20%, respectively). Therefore, subsequent cohorts received full dose administration on C1D1, which confirmed reduced risk of IRRs with amivantamab SC.³ 
• IRRs were reported in 15% of patients receiving amivantamab SC vs 67% receiving RYBREVANT IV in the CHRYSALIS study³ (Table: IRRs With Administration of Amivantamab SC vs RYBREVANT IV).

• All IRRs were grade 1 or 2 and occurred only with the first dose, with a median onset of 2.5 hours (range, 0-10.7); 15 patients required medications to control their symptoms (62.5% of patients with IRRs or 9.5% of the total population; Table: IRR Symptoms With Administration of Amivantamab SC vs RYBREVANT IV).³ 
• No IRR event led to interruption or discontinuation of study drug administration.³ 

• The most frequently reported infusion-site reactions (ISR) were grade 1 erythema and induration, both of which resolved within 1 day.³ 
• No ISR event led to interruption or discontinuation of study drug administration.³ 

Immunogenicity and Pharmacodynamics

• No antidrug antibodies were detected in any cohort of patients who received amivantamab SC.³ 
  • Of the 131 evaluable patients, treatment-emergent anti-rHuPH20 antibodies were detected in 10 (8%) patients, with no impact on amivantamab exposure levels.
• Mean serum EGFR and c-MET concentrations decreased substantially after the first full dose of amivantamab SC and remained suppressed throughout treatment in all cohorts.³ 

Efficacy

•  Of the 122 patients with EGFR‑mutated NSCLC, the confirmed overall response rate (ORR) was 17% (95% confidence interval [CI], 11–25) and the clinical benefit rate (CBR) was 48% (95% CI, 39–57).³ 
• All confirmed responses (n=20) were partial responses, with a median duration of response of 7.6 months (95% CI, 5.5-not estimable).³ 
• No confirmed responses were observed in the 21 patients with other solid malignancies.³
• Durable stable disease (≥11 weeks) was observed in 5 out of 13 patients with colorectal cancer, 3 patients with triple-negative breast cancer, and 1 patient with duodenal carcinoma.³ 

Literature Search

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File (and/or other resources, including internal/external databases) was conducted on 14 March 2026.