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 DATA

MARIPOSA Study

Study Design/Methods

• Phase 3, ongoing, randomized study designed to assess the efficacy and safety of RYBREVANT plus lazertinib (open-label, n=429) vs osimertinib (double-blind, n=429) vs lazertinib (double-blind, n=216) as first-line treatment in 1074 patients with epidermal growth factor receptor (EGFR)mutated (Exon 19 deletion [Exon19del] or Exon 21 L858R substitution) locally advanced or metastatic non-small cell lung cancer (NSCLC).^2,8,9
  • RYBREVANT 1050 mg intravenous (IV; 1400 mg IV for body weight ≥80 kg) was administered every week for the first 4 weeks, with the initial dose as a split infusion on cycle 1 day 1 (C1D1) and D2, followed by every 2 weeks thereafter.
  • Lazertinib 240 mg was administered orally (PO) once daily.
  • Osimertinib 80 mg PO was administered once daily.

Results

• The median duration of treatment was 18.5 months for RYBREVANT plus lazertinib and 18 months for osimertinib.^2,8
• The incidence of interstitial lung disease (ILD) or pneumonitis reported in the MARIPOSA study is shown in the table below.

PAPILLON Study

Study Design/Methods

• Phase 3, ongoing, randomized, open-label study designed to compare the efficacy and safety of RYBREVANT plus 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.^10,11
  • RYBREVANT 1400 mg IV (1750 mg IV for body weight ≥80 kg) was administered every week for the first 4 weeks, with the initial dose as a split infusion on C1D1 and D2, followed by RYBREVANT 1750 mg IV (2100 mg IV for body weight ≥80 kg) every 3 weeks starting at week 7 (C3D1) until disease progression.
  • Pemetrexed 500 mg/m² IVwas administered every 3 weeks until disease progression.¹⁹
  • Carboplatin area under the curve (AUC) 5 IV was administered every 3 weeks for up to 4 cycles.

Results

• The median duration of treatment was 9.7 months (range, 0.1-26.9) for RYBREVANT plus chemotherapy and 6.7 months (range, 0-25.3) for chemotherapy alone.^10,11
• The incidence of ILD and pneumonitis reported in the PAPILLON study is shown in the table below.

MARIPOSA-2 Study

Study Design/Methods

• Phase 3, ongoing, randomized, open-label study designed to assess the efficacy and safety of RYBREVANT-lazertinib-chemotherapy (n=263) and RYBREVANT-chemotherapy (n=131) vs chemotherapy alone (n=263) in 657 patients with EGFR-mutated locally advanced or metastatic NSCLC on or after osimertinib monotherapy (as the most recent line of therapy).^13,14
  • RYBREVANT 1400 mg IV (1750 mg IV for body weight ≥80 kg) was administered every week for the first 4 weeks, with the initial dose as a split infusion on C1D1 and D2, followed by 1750 mg IV (2100 mg IV for body weight ≥80 kg) every 3 weeks starting at week 7 (C3D1) until disease progression.
  • Lazertinib 240 mg PO was administered once daily.
  • Chemotherapy was administered every 3 weeks at the beginning of each cycle, with carboplatin at AUC 5 IV for the first 4 cycles, and pemetrexed at 500 mg/m² IV until disease progression.
• In the RYBREVANT-lazertinib-chemotherapy arm, patients randomized before November 7, 2022 received lazertinib on C1D1. Due to an increase in hematologic and gastrointestinal toxicities in the arm, the regimen was modified to start lazertinib after carboplatin completion.¹³
  • An open-label, randomized, extension cohort will evaluate the efficacy and safety of the modified RYBREVANT-lazertinib-chemotherapy regimen vs RYBREVANT-chemotherapy.

Results

• At a median follow-up of 8.7 months, the median duration of treatment was 5.8 months for RYBREVANT-lazertinib-chemotherapy, 6.3 months for RYBREVANT-chemotherapy, and 3.7 months for chemotherapy alone.^13,14
• The incidence of ILD and pneumonitis reported in the MARIPOSA-2 study is shown in the table below.

CHRYSALIS Study

The results of the CHRYSALIS study are also included in the RYBREVANT product labeling. The incidence of adverse reactions described below may vary from that in the RYBREVANT product labeling due to the evaluation of different patient populations for safety analyses, contributing to differences in reported percentages. The summary below describes safety results from patients with metastatic or unresectable NSCLC and EGFR Exon20ins mutations with disease progression during or after platinum-based chemotherapy who received RYBREVANT at the recommended phase 2 dose (RP2D) and all patients treated at the RP2D.

Study Design/Methods

• Phase 1, ongoing, open-label, multicenter, dose-escalation and dose-expansion study evaluating the safety, efficacy, and pharmacokinetics 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.¹⁵
  • RYBREVANT monotherapy was administered at the RP2D: 1050 mg IV (1400 mg IV for body weight ≥80 kg) every week for C1, with the initial dose as a split infusion on C1D1 and D2, and every 2 weeks thereafter until disease progression or unacceptable toxicity.
  • A total of 114 patients with metastatic or unresectable NSCLC and EGFR Exon20ins mutations with disease progression during or after platinum-based chemotherapy were evaluated for safety, and 81 evaluable patients were assessed for efficacy.

Results

• The median follow-up for safety was 5.1 months (range, 0.2-29.3 months).¹⁵
• Five (4%) patients in the safety population (n=114) experienced ILD events:
  1 (0.9%) patient with ILD and 4 (3.5%) patients with pneumonitis.^15,16
• Each of the ILD (grouped term) treatment-emergent adverse events (TEAEs) in this population was grade 1/2 in severity, and none led to treatment discontinuation of RYBREVANT.¹⁶
• The treatment-related serious adverse events (AEs) of ILD and pneumonitis were reported in 1 patient each in the safety population¹⁵:
  • One patient, with a relevant medical history of radiation to C5-T6 spine and brain, tobacco use, and ongoing dyspnea and chest wall pain, developed grade 2 ILD (assessed as possibly related) on day 57, 15 days after the last dose of RYBREVANT (1050 mg). The patient did not receive any further treatment with RYBREVANT. Treatment included a prednisolone taper and trimethoprim/sulfamethoxazole on day 57 and the patient did not require hospitalization for the event. RYBREVANT treatment was discontinued due to progressive disease on day 98, approximately 6 weeks after the onset of the ILD, and the patient withdrew consent for the study at the same time. As of the last follow-up, the event had not resolved.¹⁶
  • One patient, with a history of tobacco use, exertional dyspnea and cough (both grade 1 and nonserious) and no history of radiation to the chest, experienced grade 1 pneumonitis (assessed as probably related and serious) on day 57, 14 days after the last dose of RYBREVANT (1400 mg). Treatment included prednisolone and co-trimoxazole (for Pneumocystis jiroveci coverage). RYBREVANT was discontinued at this time due to progressive disease, although the patient remained in the study in the follow-up period as of the clinical cutoff. The pneumonitis resolved on day 86.¹⁶
• In the safety population, the median time to onset of an ILD event from the first dose of RYBREVANT was 44 days (range, 42-57).¹⁶
• In a long-term analysis of 114 patients in CHRYSALIS cohort D with a median follow-up of 19.2 months, (data cutoff: September 12, 2022), any-grade ILD and pneumonitis were reported in 8 (7%) patients; no grade ≥3 ILD and pneumonitis were reported. Among all patients treated at the RP2D (n=474), any-grade ILD and pneumonitis were reported in 16 (3%) patients. Grade ≥3 ILD and pneumonitis were reported in 4 (1%) patients.¹⁷

monitoring and management of suspected pulmonary toxicity in the MARIPOSA AND MARIPOSA-2 STUDIES

The information provided in this section summarizes interventions investigators in the MARIPOSA²⁰ and MARIPOSA-2²¹ studies were instructed to perform to monitor and manage suspected pulmonary toxicity. These are not recommendations for individual patient care. Interventions should be based on patient presentation and the clinical judgment of the treating physician.

General Considerations for Monitoring

The etiology of any clinically significant change in respiratory status was investigated in accordance with local practice/guidelines to rule out early ILD/pneumonitis. Evaluations included^20,21:

• Detailed focused history reviewing respiratory status and exercise tolerance.
• Focused physical exam including full assessment of vital signs (with pulse oximetry).
• Unscheduled radiological assessment including chest x-ray or computed tomography (CT) scan (high-resolution CT is preferred).
• Infectious evaluation including blood and sputum cultures, atypical pneumonia panels, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) testing, if indicated.
• Hematology and other laboratory tests including serum albumin levels.
• Referral to a pulmonologist for evaluation including bronchoscopy with biopsy, cell counts, and cultures, as feasible.
• Evaluation of cardiac function, if indicated.

Management of Suspected Pulmonary Toxicity

• If new or worsening pulmonary symptoms (eg, dyspnea) or radiological abnormality suggestive of pulmonary AE is observed, including ILD/pneumonitis, RYBREVANT should be withheld, and appropriate treatment/management should be promptly initiated.²¹
• For symptomatic grade ≥2 pneumonitis, treatment with steroids should be initiated in addition to withholding RYBREVANT treatment.²¹
• Where other causes of respiratory symptoms are excluded, a diagnosis of ILD/pneumonitis should be considered and RYBREVANT treatment should be permanently discontinued.²¹
• RYBREVANT treatment should be discontinued upon confirmation of ILD/pneumonitis.²¹

monitoring and management of suspected pulmonary toxicity in the PAPILLON AND chrysalis studIES

The information provided in this section summarizes interventions investigators in the PAPILLON¹⁹ and CHRYSALIS²² studies were instructed to perform to monitor and manage suspected pulmonary toxicity. These are not recommendations for individual patient care. Interventions should be based on patient presentation and the clinical judgment of the treating physician.

General Considerations for Monitoring

The etiology of any clinically significant change in respiratory status or non-oncogenic change in pulmonary radiographic appearance (eg, ground glass opacities) were investigated in accordance with local practice/guidelines to rule out early ILD/pneumonitis. Evaluations included^19,22:

• Detailed focused history reviewing respiratory status and exercise tolerance.
• Focused physical exam including full assessment of vital signs (with pulse oximetry).
• Unscheduled radiological assessment including chest X-ray or CT scan, to rule out pneumonitis and to investigate other causes such as pneumonia, pulmonary embolus, or worsening pulmonary disease.

Management of Suspected Pulmonary Toxicity

• Documentation of ILD/pneumonitis of any grade should prompt withholding RYBREVANT treatment and contacting the treating physician.^19,22
• For symptomatic grade ≥2 pneumonitis, treatment with steroids should be initiated in addition to withholding RYBREVANT treatment.^19,22
• RYBREVANT treatment should be discontinued upon confirmation of ILD/pneumonitis.

Literature Search

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and DerwentDrug File (and/or other resources, including internal/external databases) was conducted on 01 July 2024. Data included in this response are limited to the RYBREVANT phase 3 studies and pivotal studies included in the product labeling.