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 tyrosine kinase inhibitor (TKI).²
• 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
  • Venous thromboembolism (VTE) occurred in 37% and 9% of patients, respectively, in the RYBREVANT plus lazertinib and osimertinib arms. At the time of the first VTE, few patients were receiving anticoagulation (RYBREVANT plus lazertinib, 1%; osimertinib, 0%; Table: MARIPOSA: Incidence of VTE, AE of Special Interest).⁴
  • Study participants receiving the combination of RYBREVANT and lazertinib in the MARIPOSA study were recommended to receive prophylactic-dose anticoagulation as per local guidelines during the first 4 months of combination therapy per protocol (amendment). Investigators were instructed to refer to the NCCN Guidelines for examples of prophylactic-dose anticoagulants in ambulatory cancer patients. The benefit-risk assessment for participants to tolerate prophylactic-dose anticoagulation was performed at the discretion of the treating investigator. If a VTE event was diagnosed, the participant was to be treated with treatment-dose anticoagulation as per local guidelines. Vitamin K antagonists were not recommended for VTE prophylaxis or treatment because of numerous drug interactions.⁵
• 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.^6,7
  • VTE occurred in 22%, 10%, and 5% of patients, respectively, in the RYBREVANT-lazertinib-chemotherapy, RYBREVANT-chemotherapy, and chemotherapy alone arms. At the time of the first VTE, few patients were receiving anticoagulation (RYBREVANT-lazertinib-chemotherapy, 2%; RYBREVANT-chemotherapy, 0%; chemotherapy alone, 1%; Table: MARIPOSA-2: Incidence of Treatment-Emergent VTE).
• An analysis evaluating the incidence rates of VTE among patients receiving RYBREVANT monotherapy, lazertinib monotherapy, and RYBREVANT plus lazertinib combination therapy to identify any elevated risk and to understand the potential predisposing risk factors using data from the open-label, singlearm cohort studies: CHRYSALIS (RYBREVANT monotherapy), LASER201 (lazertinib monotherapy), and CHRYSALIS-2 (RYBREVANT plus lazertinib) has been conducted. All patients included in the analysis received RYBREVANT at the recommended phase 2 dose (RP2D) as monotherapy or in combination.⁸
  • The incidence of any-grade VTE events was numerically higher in patients who received RYBREVANT plus lazertinib (20%) compared with those who received RYBREVANT (11%) or lazertinib monotherapy (11%). The incidence of grade ≥3 VTE and serious VTE events was comparable between the treatment arms, with no grade 5 events reported for RYBREVANT plus lazertinib; Table: VTE Safety Profile.
  • The majority (72%) of VTE events among patients who received RYBREVANT plus lazertinib occurred in the first 4 months of treatment. The most common VTE events by preferred term were pulmonary embolism (range, 6%-9%) and deep vein thrombosis (range, 2%-7%). No patients discontinued RYBREVANT plus lazertinib treatment due to VTE.
  • After excluding progressive disease (PD)-associated VTE, age ≥60 years, Eastern Cooperative Oncology Group performance status (ECOG PS) of 1 (vs 0), and response to therapy (partial response [PR] or better) were identified as significant risk factors for VTE while receiving RYBREVANT plus Lazertinib; Table: Identified Risk Factors For VTE.
• Please refer to RYBREVANT and LAZCLUZE product labeling for complete safety information, including dose modification guidelines for adverse reactions.
• Please refer to product labeling for carboplatin and/or pemetrexed for complete prescribing information.
• Please refer to national oncology supportive care guidelines for additional information.

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 EGFR-mutated (Exon19del or L858R) locally advanced or metastatic NSCLC.^2-4
  • 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.

Results⁴

• The median duration of treatment was 18.5 months for RYBREVANT plus lazertinib and 18 months for osimertinib.
• The incidence of VTE reported in the MARIPOSA study is shown in Table: MARIPOSA: Incidence of VTE, AE of Special Interest.
  • Most VTEs were grade 1-2. The incidence of grade 4-5 VTEs was low in both arms.
  • The most common VTE events were pulmonary embolism (17% [n=73] vs 5% [n=20]) and deep vein thrombosis (14% [n=61] vs 3% [n=11]) for RYBREVANT plus lazertinib vs osimertinib, respectively.⁹
• At the time of the first VTE, few patients were receiving anticoagulation (RYBREVANT plus lazertinib, 1%; osimertinib, 0%). The majority of the first VTE events in the RYBREVANT plus lazertinib arm occurred within the first 4 months.
• The rates of treatment discontinuations due to VTE were low and comparable between both arms.
• Study participants receiving the combination of RYBREVANT and lazertinib in the MARIPOSA study were recommended to receive prophylactic-dose anticoagulation as per local guidelines during the first 4 months of combination therapy per protocol (amendment). Investigators were instructed to refer to the NCCN Guidelines for examples of prophylactic-dose anticoagulants in ambulatory cancer patients. The benefit-risk assessment for participants to tolerate prophylactic-dose anticoagulation was performed at the discretion of the treating investigator. If a VTE event was diagnosed, the participant was to be treated with treatment-dose anticoagulation as per local guidelines. Vitamin K antagonists were not recommended for VTE prophylaxis or treatment because of numerous drug interactions.⁵
• Prophylactic-dose anticoagulation is recommended for the first 4 months of treatment in ongoing trials of RYBREVANT plus lazertinib.

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).^6,7
  • 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 area under the curve (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.⁷
  • An open-label, randomized, extension cohort will evaluate the efficacy and safety of the modified RYBREVANT-lazertinib-chemotherapy regimen vs RYBREVANT-chemotherapy.

Results⁷

• 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.
• The incidence of treatment-emergent VTE reported in the MARIPOSA-2 study is shown in Table: MARIPOSA-2: Incidence of Treatment-Emergent VTE.
  • At the time of the first VTE, few patients were receiving anticoagulation (RYBREVANT-lazertinib-chemotherapy, 2%; RYBREVANT-chemotherapy, 0%; chemotherapy alone, 1%).

Girard et al (2023)⁸ conducted an analysis that evaluated the incidence rates of VTE among patients receiving RYBREVANT monotherapy (n=560), lazertinib monotherapy (n=252), and RYBREVANT plus lazertinib combination therapy (n=408) to identify any elevated risk and to understand the potential predisposing risk factors using data from the open-label, singlearm cohort studies: CHRYSALIS (RYBREVANT monotherapy), LASER201 (lazertinib monotherapy), and CHRYSALIS-2 (RYBREVANT plus lazertinib). All patients included in the analysis received RYBREVANT at the RP2D as monotherapy or in combination.

Results

• The incidence of any-grade VTE events was numerically higher in patients who received RYBREVANT plus lazertinib (20%) compared with those who received RYBREVANT (11%) or lazertinib monotherapy (11%).
• The incidence of grade ≥3 VTE and serious VTE events was comparable between the treatment arms, with no grade 5 events reported for RYBREVANT plus lazertinib.
• The majority (72%) of VTE events among patients who received RYBREVANT plus lazertinib occurred in the first 4 months of treatment.
• The most common VTE events by preferred term were pulmonary embolism (range, 6%9%) and deep vein thrombosis (range, 2%-7%). No patients discontinued RYBREVANT plus lazertinib treatment due to VTE.
• An overview of VTE events is shown in Table: VTE Safety Profile.

Risk Analyses

• After excluding PD-associated VTE, age ≥60 years, ECOG PS of 1 (vs 0), and response to therapy (PR or better) were identified as significant risk factors for VTE while receiving RYBREVANT plus lazertinib.
• The identified risk factors are shown in Table: Identified Risk Factors For VTE.

Literature Search

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and DerwentDrug File (and/or other resources, including internal/external databases) was conducted on 08 July 2024.