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.^2,3
  • Initial safety and PK results of SC RYBREVANT from part 1 (cohorts 1a and 1b) and part 2 (cohorts 2a and 2b) are reported.⁴
    • 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, all of which were 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.⁵
    • 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, all of which were grade 1-2 in severity.
    • Compared with the reference intravenous (IV) RYBREVANT every 2 weeks (Q2W) dose, the SC RYBREVANT Q2W 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).
  • The safety and PK results of SC RYBREVANT every 4 weeks (Q4W) from part 2 (cohort 6a) of the study are also reported.⁶
    • Grade ≥3 treatment-related AEs (TRAEs) were reported in 3 patients who received SC RYBREVANT Q4W.
    • Overall, 3 (16%) patients reported IRRs with SC RYBREVANT Q4W, all of which were grade 1-2 in severity.
    • The SC Q4W dose was increased to 3520 mg (4640 mg if body weight ≥80 kg) to allow the SC Q4W predicted steady-state maximum concentration (C_max) to match the reference IV Q2W steady-state C_trough.

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.^2-4
• 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)⁴ reported the initial PK and safety 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).⁴
• 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 rHuPH20.⁴

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.⁴
• Grade ≥3 AEs were reported in 27.3% of patients and most were single events.⁴
  • 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 TRAEs led to discontinuation of treatment.⁴
• Two patients (6.1%) had transient injection site reactions (grade 1) that did not affect subsequent dosing.⁴

• 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).⁴
• Type and incidence of IRR symptoms were also reduced with SC vs IV RYBREVANT (Table: IRR Symptoms With SC vs IV Administration of RYBREVANT).⁴
• All IRRs with SC RYBREVANT were grade 1-2 in severity.⁴
• IRRs with SC RYBREVANT were associated with the first dose in cycle 1 (C1) and did not occur with subsequent doses or cycles.⁴
• 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.⁴
  • 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

• C_max was achieved within 2-3 days after SC administration.⁴
• Higher exposure was obtained with rHuPH20.⁴
  • 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).⁴
• No antidrug antibodies were detected in any patients.⁴

Minchom et al (2023)⁵ reported the updated PK results from part 2 (cohorts 3a and 5a) and safety results from all dosed cohorts 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).⁵
• Baseline characteristics are presented in Table: Baseline Demographics and Disease Characteristics in the Updated Analysis.

Safety

• AEs reported with SC RYBREVANT (excluding IRRs and IRR symptoms) were consistent with what was previously reported with IV RYBREVANT.⁵ 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.⁵
• Grade ≥3 TEAEs occurred in 32 (39%) patients, with 2 (2%) events considered treatment related (hypoalbuminemia and pulmonary embolism, n=1 each).⁵
• 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).⁵

• 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).⁵
• The type and incidence of IRR symptoms were also reduced with SC vs IV RYBREVANT. See Table: IRR Symptoms With SC vs IV Administration of RYBREVANT).⁵
• 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.⁵
  • 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.⁵
• The C2 C_trough and AUC_𝜏 for the SC Q2W dose were similar to those of the reference IV Q2W dose.⁵
• 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).⁵
• No antidrug antibodies were detected in any cohorts of patients who received SC RYBREVANT.⁵
• The geometric mean ratios (GMRs) demonstrated similar exposures for SC and IV administration of RYBREVANT.⁵ 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.

Leighl et al (2024)⁶ reported the PK and safety results of SC RYBREVANT Q4W treatment from part 2 (cohort 6a) of the PALOMA study.

Results

Patient Characteristics

• At the data cutoff date of December 18, 2023, 19 patients received treatment with SC RYBREVANT Q4W in part 2, cohort 6a.⁶
• Baseline characteristics are presented in Table: Baseline Demographics and Disease Characteristics.

Safety

• AEs reported with SC RYBREVANT Q4W were consistent with previous reports of SC RYBREVANT. The most common TEAEs (≥15%) are presented in Table: Safety Profile of SC Q4W Administration of RYBREVANT.⁶
  • The most common TEAEs were related to EGFR and MET inhibition and were primarily of grade 1-2 in severity.
  • Grade ≥3 TEAEs with SC RYBREVANT Q4W occurred in 9 (47%) patients, of whom 3 had TRAEs (dermatitis acneiform, n=2; paronychia, n=1).⁶
• The cumulative incidence of all-grade rash (grouped term, including dermatitis, dermatitis acneiform, rash erythematous, and rash maculopapular) after SC RYBREVANT administration was 79% (n=15).
• Dose reduction due to TRAEs was required in 3 patients.⁶
• TEAE-related discontinuations reported in 2 patients were not treatment related.⁶

• Overall, 16% of patients who received SC RYBREVANT Q4W and 67% of patients who received IV RYBREVANT Q2W reported IRRs (all grades). See Table: IRRs With SC Q4W vs IV Q2W Administration of RYBREVANT.⁶
  • IRRs with SC RYBREVANT were grade 1-2 in severity.
  • In the 3 (16%) patients who experienced IRRs with SC RYBREVANT, the time of IRR onset was 3, 11, and >24 hours after dosing.
• IRR symptoms with SC RYBREVANT Q4W were chills, pyrexia, pruritus, and urticaria, each reported in 5% of patients. See Table: IRR Symptoms With SC Q4W vs IV Q2W Administration of RYBREVANT.⁶
  • For the treatment of pruritus, 1 patient received diphenhydramine and clotrimazole.
  • No recurrent IRRs occurred with the subsequent administrations.

PK and Immunogenicity

• The SC RYBREVANT dose in C1 was administered (manually pushed into the abdomen over 7-10 minutes) weekly for the first 4 weeks (1600 mg; 2240 mg if body weight ≥80 kg), followed by Q4W (3200 mg; 4320 mg if body weight ≥80 kg). The SC Q4W dose was evaluated in cohort 6a.⁶
  • Compared with the reference IV RYBREVANT Q2W dose, the SC Q4W dose at C2 demonstrated a lower C_max, an equal or higher C_trough, and a noninferior area under the concentration-time curve from time 0 to 672 hours (AUC_0-672h).
• The SC Q4W dose was increased to 3520 mg (4640 mg if body weight ≥80 kg) to allow the SC Q4W predicted steady-state C_max to match the reference IV Q2W steady-state C_trough.⁶
• No antidrug antibodies were observed in patients who received SC RYBREVANT.⁶

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 21 March 2024.