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.²
• No data regarding blood-brain barrier (BBB) or central nervous system (CNS) penetration pharmacokinetics (PK) for RYBREVANT were identified in the published literature.

Combination with Lazertinib

• MARIPOSA (NCT04487080) is an ongoing, phase 3, randomized study evaluating the efficacy and safety of RYBREVANT and lazertinib combination therapy (open-label, n=429) vs osimertinib (double-blind, n=429) vs lazertinib (double-blind, n=216) as first-line treatment in patients with EGFR-mutated (Exon 19 deletion [Exon19del] or Exon 21 L858R substitution) locally advanced or metastatic NSCLC.^2-4
  • At baseline, the number of patients with a history of brain metastases in the RYBREVANT-lazertinib arm was 178 (41%) and in the osimertinib arm was 172 (40%). All patients underwent magnetic resonance imaging (MRI) of the head at baseline, followed by every 8±1 weeks for the first 30 months, and then every 12 or 24±1 weeks until disease progression in patients with or without a history of brain metastases, respectively.⁴
  • In a subgroup analysis for progression-free survival (PFS) by blinded independent central review (BICR) in patients with a history of brain metastases, median PFS by BICR was 18.3 months (95% confidence interval [CI], 16.6-23.7) for RYBREVANT-lazertinib and 13 months (95% CI, 12.2-16.4) for osimertinib (hazard ratio [HR], 0.69 [95% CI, 0.53-0.92]). In patients without a history of brain metastases, median PFS by BICR was 27.5 months (95% CI, 22.1-not estimable [NE]) for RYBREVANT-lazertinib and 19.9 months (95% CI, 16.6-22.9) for osimertinib (HR, 0.69 [95% CI, 0.53‑0.89]).⁴
  • Safety was not separately evaluated for patients with brain metastases. Serious AEs were reported in 49% of patients treated with RYBREVANT-lazertinib and 33% of patients treated with osimertinib. Venous thromboembolism (VTE) rates were increased with RYBREVANT-lazertinib compared with osimertinib. Treatment-related AEs (TRAEs) leading to discontinuation of all agents occurred in 10% of patients treated with RYBREVANT-lazertinib and in 3% of patients treated with osimertinib.⁴
• A phase 2 single-arm study (NCT04965090) is evaluating the efficacy and safety of RYBREVANT and lazertinib in patients with EGFR-mutated metastatic or recurrent NSCLC with progressive or new CNS metastases (brain metastases, n=20; leptomeninges, n=22) on previous treatment. Coprimary endpoints were systemic overall response rate (ORR) by Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 and CNS ORR by Response Assessment in Neuro-Oncology (RANO) criteria.^5,6
  • Efficacy was evaluated after a median treatment duration of 3.9 months (range, 0.3-18.6) for patients with brain metastases and 8.1 months (range, 0-21.7) for patients with leptomeninges.⁶
    • At baseline, all patients with EGFR Exon19del (n=17), Exon 21 L858R (n=17), or atypical (n=3) mutations had received prior osimertinib, and all patients with EGFR Exon20ins (n=5) had received prior chemotherapy.
    • The systemic ORR per RECIST was 30% (95% CI, 13-54) for patients with brain metastases and 33% (95% CI, 15-57) for patients with leptomeninges.
    • The intracranial ORR per RANO criteria was 40% (95% CI, 20-64) for patients with brain metastases.
    • Median PFS and overall survival (OS) were 8.3 months (95% CI, 3.3-12.2) and 14.4 months (95% CI, 8.0-NR) in patients with leptomeninges and 5.9 months (95% CI, 2.8-14.1) and 17.9 months (95% CI, 15.4-not reached [NR]) in patients with brain metastases, respectively.
    • Among patients with leptomeninges with a median treatment time of 8.3 months (95% CI, 3.3-8.9), 14 (82%) patients reported a decreased number of circulating tumor cells in their cerebrospinal fluid and improvement in neurological symptoms.
  • The most common (≥30% in overall population) TRAEs were rash (71%), infusion-related reactions (IRRs; 59%), paronychia (43%), fatigue (40%), edema (40%), mucositis (33%), and nausea (33%).⁶
    • The most common (≥5%) grade ≥3 TRAEs were IRRs (7%), thromboembolic events (5%), elevated aspartate transaminase/alanine transaminase (5%), and rash (5%).
    • Three (7%) patients discontinued treatment with RYBREVANT due to TRAEs.

Combination with Chemotherapy (+/- Lazertinib)

• PAPILLON (NCT04538664) is an ongoing, phase 3, randomized, open-label study designed to compare the efficacy and safety of RYBREVANT-chemotherapy (carboplatin and pemetrexed; n=153) vs chemotherapy alone (carboplatin and pemetrexed; n=155) in patients with untreated locally advanced or metastatic NSCLC and EGFR Exon 20 insertion (Exon20ins) mutations.^7,8
  • Eligible patients did not have untreated brain metastases. Patients with asymptomatic or previously treated stable brain metastases were eligible only if they had discontinued corticosteroid treatment for ≥2 weeks prior to randomization.
  • At baseline, the number of patients with a history of brain metastases in the RYBREVANT-chemotherapy arm was 35 (23%) and in the chemotherapy alone arm was 36 (23%).
  • Overall, at a median follow-up of 14.9 months, median PFS by BICR was 11.4 months for RYBREVANT-chemotherapy and 6.7 months for chemotherapy alone (HR, 0.4 [95% CI, 0.3‑0.53]; P<0.001).
  • In a subgroup analysis for PFS by BICR in patients with a history of brain metastases, the HR for disease progression or death was 0.63 (95% CI, 0.38-1.06) for RYBREVANT-chemotherapy vs chemotherapy alone. In patients without a history of brain metastases, the HR for disease progression or death was 0.33 (95% CI, 0.23-0.46) for RYBREVANT-chemotherapy vs chemotherapy alone.^8,9
  • The most common (≥15% in either arm) AEs for RYBREVANT‑chemotherapy were neutropenia (59%), paronychia (56%), and rash (54%), and for chemotherapy alone were anemia (55%), neutropenia (45%), and nausea (42%). Safety was not separately evaluated for patients with brain metastases.

• MARIPOSA-2 (NCT04988295) is an ongoing, phase 3, open-label, randomized study designed to assess the efficacy and safety of RYBREVANT-lazertinib-chemotherapy (pemetrexed and carboplatin; n=263) and RYBREVANT-chemotherapy (pemetrexed and carboplatin; n=131) vs chemotherapy alone (pemetrexed and carboplatin; n=263) in patients with EGFR-mutated (Exon19del or Exon 21 L858R substitution) locally advanced or metastatic NSCLC on or after osimertinib monotherapy.^10,11
  • Patients with brain metastases were eligible if their intracranial disease was clinically stable and asymptomatic with stable doses of steroids and could receive ≤10 mg prednisone or equivalent daily for intracranial disease. Eligible patients did not require prior definitive local treatment with radiation or surgery, and any such treatment must have been completed ≥14 days prior to randomization.
  • At baseline, the number of patients with a history of brain metastases in the RYBREVANT-lazertinib-chemotherapy arm was 120 (46%), in the RYBREVANT‑chemotherapy arm was 58 (44%), and in the chemotherapy alone arm was 120 (46%). The number of patients with a history of brain metastases and no prior brain radiation in the RYBREVANT-lazertinib-chemotherapy arm was 56 (47%), in the RYBREVANT-chemotherapy arm was 24 (41%), and in the chemotherapy alone arm was 61 (51%).¹¹
  • Overall, at a median follow-up of 8.7 months, median PFS by BICR was 8.3 months (95% CI, 6.8-9.1) for RYBREVANT-lazertinib-chemotherapy and 4.2 months (95% CI, 4-4.4) for chemotherapy alone (HR, 0.44; 95% CI, 0.35-0.56; P<0.001). Median PFS was 6.3 months (95% CI, 5.6-8.4) for RYBREVANT-chemotherapy and 4.2 months (95% CI, 4-4.4) for chemotherapy alone (HR, 0.48; 95% CI, 0.36-0.64; P<0.001).
  • In a subgroup analysis for PFS by BICR in patients with a history of brain metastases, median PFS by BICR was 6.9 months (95% CI, 5.6-11.1) for RYBREVANT-lazertinib-chemotherapy, 5.6 months (95% CI, 5.3-7) for RYBREVANT‑chemotherapy, and 4 months (95% CI, 3-4.3) for chemotherapy alone. The HR for disease progression or death was 0.48 (95% CI, 0.34-0.67) for RYBREVANT-lazertinib-chemotherapy vs chemotherapy alone and 0.52 (95% CI, 0.35-0.78) for RYBREVANT-chemotherapy vs chemotherapy alone. In patients without a history of brain metastasis, median PFS by BICR was 8.3 months (95% CI, 6.9-10.3) for RYBREVANT-lazertinib-chemotherapy, 8.3 months (95% CI, 5.6-11.3) for RYBREVANT-chemotherapy, and 4.2 months (95% CI, 4.1-5.4) for chemotherapy alone. The HR for disease progression or death was 0.42 (95% CI, 0.31-0.58) for RYBREVANT-lazertinib-chemotherapy vs chemotherapy alone and 0.48 (95% CI, 0.33-0.7) for RYBREVANT-chemotherapy vs chemotherapy alone.^11,12
  • In an analysis of intracranial PFS (icPFS) in the overall population, median icPFS by BICR was 12.8 months (95% CI, 11.1-14.3) for RYBREVANT-lazertinib-chemotherapy, 12.5 months (95% CI, 10.8-NE) for RYBREVANT-chemotherapy, and 8.3 months (95% CI, 7.3-11.3) for chemotherapy alone. The HR for disease progression or death was 0.58 [95% CI, 0.44-0.78] for RYBREVANT-lazertinib-chemotherapy vs chemotherapy alone and 0.55 (95% CI, 0.38-0.79) for RYBREVANT-chemotherapy vs chemotherapy alone.¹¹
    • The overall icPFS rates at 6 and 12 months were 79% and 54%, respectively, for RYBREVANT-lazertinib-chemotherapy, 78% and 50%, respectively, for RYBREVANT-chemotherapy, and 66% and 34%, respectively, for the chemotherapy alone.
    • In patients with a history of brain metastases and no prior brain radiotherapy, median icPFS was 11.1 months (95% CI, 7-13.5) for RYBREVANT-lazertinib-chemotherapy, NE (5.6 months-NE) for RYBREVANT-chemotherapy, and 6.3 months (95% CI, 3.5-8.5) for chemotherapy alone. The HR for disease progression or death was 0.44 (95% CI, 0.25-0.79) for RYBREVANT-lazertinib-chemotherapy vs chemotherapy alone and 0.36 (95% CI, 0.16-0.84) for RYBREVANT-chemotherapy vs chemotherapy alone.
  • Higher rates of grade ≥3 AEs were seen for RYBREVANT-lazertinib-chemotherapy (n=263) and RYBREVANT-chemotherapy (n=130) vs chemotherapy alone (n=243). The most common (≥10% in any arm) grade ≥3 AEs were neutropenia, thrombocytopenia, anemia, and leukopenia. TRAEs leading to death occurred in 4 (2%), 2 (2%), and 1 (0.4%) patient(s) in the RYBREVANT-lazertinib-chemotherapy, RYBREVANT-chemotherapy, and chemotherapy alone arms, respectively. Safety was not separately evaluated for patients with brain metastases.

Single Agent RYBREVANT

• CHRYSALIS (NCT02609776) is an ongoing, phase 1, open-label, multicenter, dose escalation and doses expansion study evaluating the safety, efficacy, and PK of RYBREVANT as monotherapy and in combination with other therapies in adult patients with advanced NSCLC harboring EGFR mutations who had disease progression during or after previous standard of care (SOC) treatment.^13,14
  • Patients with untreated or active brain metastases were excluded; however, patients whose brain metastases were previously treated and asymptomatic at screening were eligible.¹⁴
  • Results for patients with advanced NSCLC harboring Exon20ins mutations who received treatment with RYBREVANT at the recommended phase 2 dose (RP2D) from CHRYSALIS have been reported.¹⁴
    • The ORR by BICR for the efficacy population was 40% (95% CI, 29%-51%) and the ORR in a subgroup analysis of 18/81 (22%) patients with a history of brain metastases was 39% (95% CI, 17%64%).
    • AEs were mostly grade 1-2 (35% were grade ≥3). Treatment discontinuations occurred due to rash (n=2), IRRs (n=2), and paronychia (n=1). Safety was not separately evaluated for patients with brain metastases.

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.

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 08 July 2024.