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
• PALOMA (NCT04606381) is an ongoing, phase 1, open-label, multicenter, 2-part study evaluating the safety, pharmacokinetics (PK), and efficacy of subcutaneous (SC) RYBREVANT as low- and high-concentration formulations with and without recombinant human hyaluronidase (rHuPH20) in patients with advanced solid malignancies.²
  • Initial safety and PK results of SC RYBREVANT from part 1 (cohorts 1a and 1b) and part 2 (cohorts 2a and 2b) are reported.³
    • A reduced delivery time (<5 minutes) with the high-concentration formulation of RYBREVANT (160 mg/mL) with rHuPH20 was observed.
    • Grade ≥3 adverse events (AEs) were reported in 27.3% of patients who received SC RYBREVANT.
    • Overall, 6 (18.2%) patients reported infusion-related reactions (IRRs) with SC RYBREVANT and were all grade 1-2 in severity.
    • Preliminary estimate of bioavailability was 65%.
  • The updated safety results from all dosed cohorts and PK results from part 2 (cohorts 3a and 5a) of the study are also reported.⁴
    • Grade ≥3 treatment-emergent AEs (TEAEs) were reported in 32 (39%) patients who received SC RYBREVANT.
    • Overall, 13 (16%) patients reported IRRs with SC RYBREVANT and were all grade 1-2 in severity.
    • Compared to the reference intravenous (IV) every 2 weeks (Q2W) RYBREVANT dose, the SC Q2W RYBREVANT dose (1600 mg; 2240 mg if body weight ≥80 kg) demonstrated a similar exposure (cycle 2 [C2] trough concentration [C_trough] and area under the curve [AUC_𝜏]), whereas the SC every 3 weeks (Q3W) dose (2560 mg; 3360 mg if body weight ≥80 kg) demonstrated a higher exposure. Accordingly, the SC Q3W dose was adjusted to a lower dose of 2400 mg (3360 mg if body weight ≥80 kg).

CLINICAL DATA

PALOMA Study

Study Design/Methods

• Phase 1, ongoing, open-label, multicenter, 2-part study of SC RYBREVANT in patients with advanced solid tumors.^{2, 3}
• The study design is shown in Figure: PALOMA Study Design.
• In part 1, the feasibility of SC administration of RYBREVANT using the available IV formulation (50 mg/mL) at the recommended phase 2 dose (RP2D) level for IV administration, with and without rHuPH20, will be assessed.²
• In part 2, dose escalation will be evaluated using a high-concentration formulation (160 mg/mL) of RYBREVANT, with and without rHuPH20.²

Krebs et al (2022)³ reported the initial safety and PK results of SC RYBREVANT treatment from part 1 (cohorts 1a and 1b) and part 2 (cohorts 2a and 2b) of the PALOMA study.

Results

Patient Characteristics

• A total of 33 patients received treatment with SC RYBREVANT across part 1, cohort 1 (n=16; 8 patients each in cohorts 1a and 1b) and part 2, cohort 2 (n=17; 9 patients in cohort 2a and 8 patients in cohort 2b).³
• Baseline characteristics are presented in Table: Baseline Demographics and Disease Characteristics.

• In cohort 2a, SC administration reduced the needed infusion time to <5 minutes for the high-concentration formulation of RYBREVANT (160 mg/mL) with rHuPH20.³

Safety

• SC RYBREVANT showed a similar safety profile (excluding IRRs) as that of IV RYBREVANT. The most common AEs are presented in Table: Adverse Events.³
• Grade ≥3 AEs were reported in 27.3% of patients and most were single events.³
  • One single grade 3 event was considered treatment related (hypokalemia).
• Dose reductions for treatment-related rash events (grade 2) were required in 3 patients (9.1%). No treatment-related AEs led to discontinuation of treatment.³
• Two patients (6.1%) had transient injection site reactions (grade 1) that did not affect subsequent dosing.³

• Overall, 18.2% of patients who received SC RYBREVANT reported IRRs compared with 67.3% of patients who received RP2D of IV RYBREVANT across the CHRYSALIS study (Table: IRRs With SC vs IV Administration of RYBREVANT).³
• Type and incidence of IRR symptoms were also reduced with SC vs IV RYBREVANT (Table: IRR Symptoms With SC vs IV Administration of RYBREVANT).³
• All IRRs with SC RYBREVANT were grade 1-2 in severity.³
• IRRs with SC RYBREVANT were associated with the first dose in cycle 1 (C1) and did not occur with subsequent doses or cycles.³
• A total of 14 patients received the full SC dose of RYBREVANT safely at first administration on C1 day 1 (D1), thereby potentially eliminating the need for split dosing with IV RYBREVANT.³
  • No increased risk of IRR was observed with the full initial RYBREVANT dosing. IRR was reported in 3 of 14 patients (21%) who received the full dose (C1D1) and 3 of 19 patients (16%) who received a split dose (C1D1 and day 2 [D2]).

PK, Pharmacodynamics, and Immunogenicity

• Maximum concentration was achieved within 2-3 days after SC administration.³
• Higher exposure was obtained with rHuPH20.³
  • The preliminary estimate of bioavailability with SC administration using formulations with rHuPH20 was approximately 65%.
• In all cohorts, the saturation of soluble free EGFR and MET was achieved after the first full dose (C1D1 and C1D2).³
• No anti-drug antibodies were detected in any patients.³

Minchom et al (2023)⁴ reported the updated safety results from all dosed cohorts and PK results from part 2 (cohorts 3a and 5a) of the PALOMA study.

Results

Patient Characteristics

• At the data cutoff date of March 13, 2023, 83 patients received treatment with SC RYBREVANT across part 1 (cohort 1, n=16) and part 2 (cohort 2, n=17; cohort 3a, n=25; cohort 5a, n=25).⁴
• Baseline characteristics are presented in Table: Baseline Demographics and Disease Characteristics in the Updated Analysis.

Safety

• Adverse events reported with SC RYBREVANT (excluding IRRs and IRR-related symptoms) were consistent with what was previously reported with IV RYBREVANT.⁴ The most common AEs (≥10%) are presented in Table: Safety Profile of SC vs IV Administration of RYBREVANT.
  • The cumulative incidence of rash (grouped term) for SC vs IV administration was 76% (grade ≥3, none) vs 76% (grade ≥3, 3%).
• SC RYBREVANT was well tolerated at the site of administration. The only reaction observed was brief erythema without induration.⁴
• Grade ≥3 TEAEs occurred in 32 (39%) patients, with 2 (2%) events considered treatment related (hypoalbuminemia and pulmonary embolism, n=1 each).⁴
• Treatment-related dose reductions (n=8, 10%) occurred due to dermatitis acneiform and rash (n=2 each) and fatigue, peripheral edema, bone marrow edema syndrome, paronychia, arthralgia, and pulmonary embolism (n=1 each). Treatment-related discontinuations (n=3, 4%) occurred due to pneumonitis (n=2) and asthenia (n=1).⁴

• Overall, 16% of patients who received SC RYBREVANT and 67% of patients who received RP2D of IV RYBREVANT reported IRRs (all grades). See Table: IRRs With SC vs IV Administration of RYBREVANT).⁴
• The type and incidence of IRR-related symptoms were also reduced with SC vs IV RYBREVANT. See Table: IRR-Related Symptoms With SC vs IV Administration of RYBREVANT).⁴
• All IRRs were associated with the first dose and did not occur with subsequent doses. Full-dose administration on C1D1 was not associated with an increased risk of IRRs, confirming that split-dose administration was not required.⁴
  • Of the 13 patients who experienced IRRs, the time of IRR onset was between 15 minutes and 7 hours postdose, with supportive medications provided to 9 patients.
  • For the selected RP2D doses, the injection time with RYBREVANT 160 mg/mL coformulated with rHuPH20 varied between 3.3 minutes (1600 mg) and 7 minutes (3360 mg).

PK and Immunogenicity

• Based on the PK data from cohorts 1 and 2, the projected SC Q2W dose (1600 mg; 2240 mg if body weight ≥80 kg) and SC Q3W dose (2560 mg; 3360 mg if body weight ≥80 kg) were evaluated in cohorts 3a and 5a, respectively.⁴
• The C2 C_trough and AUC_𝜏 for the SC Q2W dose were similar to those of the reference IV Q2W dose.⁴
• The C2 C_trough and AUC_𝜏 for the SC Q3W dose were slightly higher than those of the reference IV Q3W dose. The SC Q3W dose was refined to a lower dose of 2400 mg (3360 mg if body weight ≥80 kg).⁴
• No antidrug antibodies were detected in any cohorts of patients who received SC RYBREVANT.⁴
• The geometric mean ratios (GMRs) demonstrated similar exposures for SC and IV administration of RYBREVANT.⁴ GMRs for the selected RP2D SC Q2W and Q3W doses compared with their corresponding IV doses are presented in Table: Simulated GMRs for SC vs IV Administration.

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 18 May 2023.