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
• LAZCLUZE (lazertinib) is a third-generation EGFR tyrosine kinase inhibitor (TKI).²
• SKIPPirr (NCT05663866) is an ongoing, phase 2, global, open-label study evaluating the potential of 4 independent prophylactic strategies in reducing the incidence and severity of RYBREVANT-associated infusion-related reactions (IRRs) in patients with EGFR-mutated (Exon 19 deletion [Exon19del] or Exon 21 L858R substitution) advanced or metastatic NSCLC with disease progression on or after sequential osimertinib and doublet platinum-based chemotherapy (N=68). Prior to the administration of intravenous (IV) RYBREVANT and lazertinib orally (PO), patients received prophylaxis in 1 of 4 different treatment cohorts (dexamethasone [DEX] 4 mg; DEX 8 mg; montelukast 10 mg; methotrexate 25 mg) following Simon’s 2-stage design with an expansion stage. The primary endpoint is the incidence of IRRs at cycle (C)1 day (D)1.^3-5
  • Only the DEX 8 mg cohort met the success criteria for IRR incidence rate (stage 1, IRR in ≤3 of 6 patients; stage 2, IRR in ≤8 of 16 patients) and passed both stage 1 (IRR, 2 of 6 patients) and stage 2 (IRR, 6 of 16 patients) to proceed to the expansion stage.^4,5
  • On C1D1, 22.5% (9 of 40) of patients receiving DEX 8 mg prophylactic treatment reported IRRs (all grade 1-2), compared with 67.4% with standard IRR management (Table: Incidence of IRRs on C1D1). The most frequent IRR-related symptoms in the DEX 8 mg cohort were nausea (8%), dyspnea (5%), and hypotension (5%).⁵
  • By the end of C3, 10 of 41 patients (24.4%) in the DEX 8 mg cohort had experienced IRRs, 9 of whom had IRRs on C1D1 and 1 patient on C2D1 (all grade 1-2 in severity, except for 1 grade 3 IRR on C2D1).⁵
  • At the median follow-up of 4.2 months, investigator-assessed objective response rate (ORR) was 33% (95% confidence interval [CI], 19-49) for all responders and 28% (95% CI, 15-44) for confirmed responders.⁵
  • Prophylaxis-related adverse events (AEs) were reported in 3 patients in the DEX 8 mg cohort, with 1 patient each experiencing gastroesophageal reflux disease, muscle atrophy, and somnolence. These AEs were grade 1-2 in severity.⁵
  • The median duration of RYBREVANT infusion on C1D1 in the DEX 8 mg cohort was 4.4 hours (range, 3.9-7.5). Median time in treatment room, time in chair, and active healthcare provider (HCP) time were 5.9, 5.9, and 7.7 hours, respectively.⁵

PRODUCT LABELING

• RYBREVANT (amivantamab-vmjw) [Prescribing Information]. Horsham, PA: Janssen Biotech, Inc.; https://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/RYBREVANT-pi.pdf.
• LAZCLUZE (lazertinib) [Prescribing Information]. Horsham, PA: Janssen Biotech, Inc.; https://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/LAZCLUZE-pi.pdf.

clinical study

SKIPPirr Study

Study Design/Methods

• Ongoing, phase 2, global, open-label study evaluating the potential of DEX, montelukast, and methotrexate in preventing RYBREVANT-associated IRRs in patients with EGFR-mutated (Exon19del or Exon 21 L858R) advanced or metastatic NSCLC with disease progression on or after osimertinib and doublet platinum-based chemotherapy using Simon’s 2-stage design with an expansion stage if a cohort passed both stages.^3-5 
• Prior to the administration of RYBREVANT IV and lazertinib PO, patients received prophylaxis in 1 of 4 different treatment cohorts as follows: DEX 4 mg PO, DEX 8 mg PO, montelukast 10 mg PO, and subcutaneous (SC) methotrexate 25 mg.⁵ 
• All patients received RYBREVANT IV 1050 mg (1400 mg if ≥80 kg) once weekly for 4 weeks and then every 2 weeks thereafter, in combination with lazertinib 240 mg PO once daily. Initial RYBREVANT dose was administered as a split dose over 2 days on C1D1 (350 mg) and C1D2 (remainder of dose).⁵
• All patients also received standard premedication with antihistamines, antipyretics, and DEX 10 mg IV.⁵
• Dosing for the DEX 8 mg cohort was DEX 8 mg (two 4 mg tablets) PO twice daily at home 2 days and 1 day prior to the RYBREVANT infusion, and 1 dose of DEX 8 mg PO 1 hour before the RYBREVANT infusion on C1D1 in the clinic (with standard antihistamine, antipyretic, and DEX 10 mg IV). Adequate oral hydration was encouraged with prophylactic DEX PO.^5,6 
• The study design is shown in Figure: SKIPPirr Study Design.

Results

Patient Characteristics

• A total of 68 patients received prophylaxis across 4 different treatment cohorts: DEX 4 mg (n=6), DEX 8 mg (n=41), montelukast 10 mg (n=15), and methotrexate 25 mg (n=6).⁵ 
• The patient demographics and baseline characteristics are included in Table: Demographics and Baseline Characteristics.

Primary Endpoint

Incidence and Severity of IRRs on C1D1

• The DEX 4 mg and methotrexate cohorts did not pass stage 1, as IRRs were reported in 5 of 6 patients (83.3%) each.⁵
• The montelukast cohort passed stage 1 (IRR, 3 of 6 patients) but not stage 2 (IRR, 10 of 15 patients; 66.7%).^4,5
• The DEX 8 mg cohort passed both stage 1 (IRR, 2 of 6 patients) and stage 2 (IRR, 6 of 16 patients) to proceed to the expansion stage.^4,5
  • At the data cutoff date of June 24, 2024, an additional 24 patients were enrolled and treated in the expansion stage.⁵
    • On C1D1, 9 of 40 patients (22.5%) in the DEX 8 mg cohort reported IRRs (Table: Incidence of IRRs on C1D1).
      • All IRRs were grade 1-2 in severity.
    • The most frequent IRR-related symptoms were nausea (8%), dyspnea (5%), and hypotension (5%; Table: Incidence of IRR-Related Symptoms on C1D1).
      • All symptoms were grade 1-2 in severity.

Secondary Endpoints

Incidence and Severity of IRRs in Subsequent Cycles

• By the end of C3, 10 of 41 patients (24.4%) in the DEX 8 mg cohort had experienced IRRs.⁵
  • Nine of these patients had IRRs on C1D1 (with 1 patient also experiencing an IRR on C1D2); 1 patient had an IRR on C2D1.
  • All IRRs were grade 1-2, except for the 1 grade 3 IRR that occurred on C2D1.

Efficacy

• At the median follow-up of 4.2 months, the investigator-assessed ORR for all responders and confirmed responders in the DEX 8 mg cohort remained consistent with previous reports.⁵
• Efficacy outcomes are summarized in Table: Investigator-Assessed Efficacy Outcomes.

Safety

• Safety data are included in Table: Safety Profile.
  • In the DEX 8 mg cohort, the most common AEs related to EGFR inhibition (rash, 41%; paronychia, 39%) and MET inhibition (hypoalbuminemia, 41%) were similar to those observed across all cohorts and consistent with previous reports.⁵
• In the DEX 8 mg cohort, 3 patients experienced AEs potentially related to DEX prophylaxis, including gastroesophageal reflux disease, muscle atrophy, and somnolence (1 event each). These AEs were grade 1-2 in severity.⁵

Health Care Utilization

• In the DEX 8 mg cohort (n=38), the median duration of RYBREVANT infusion (including actual infusion time and interruption time) on C1D1 was 4.4 hours (range, 3.9-7.5).⁶
• By C1D15 and onward, the median duration of RYBREVANT infusion was approximately 2.3 hours for all cohorts.⁵
• Time and motion data on C1D1 are included in Table: Median Time and Motion Endpoints on C1D1.

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 24 January 2025.