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
• No prospective, randomized, head-to-head trials comparing the efficacy and safety of RYBREVANT with osimertinib have been published.
• 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 epidermal growth factor receptor (EGFR)-mutated (Exon 19 deletion [Exon19del] or Exon 21 L858R substitution) locally advanced or metastatic nonsmall cell lung cancer (NSCLC). Lazertinib is an investigational third-generation EGFR tyrosine kinase inhibitor (TKI). The primary endpoint (RYBREVANT plus lazertinib vs osimertinib) is progression-free survival (PFS), based on blinded independent central review (BICR).^2–4
  • At a median follow-up of 22 months, median PFS by BICR was 23.7 months (95% confidence interval [CI], 19.1-27.7) for RYBREVANT plus lazertinib and 16.6 months (95% CI, 14.8-18.5) for osimertinib (hazard ratio [HR], 0.70 [95% CI, 0.580.85]; P<0.001).⁴
  • EGFR- and MET-related adverse events (AEs) were increased with RYBREVANT plus lazertinib compared to osimertinib and were mostly grade 1-2 (Table: Summary of AEs). Venous thromboembolism (VTE) rates were also increased with RYBREVANT plus lazertinib compared to osimertinib and were mostly grade 1-2 (Table: AE of Special Interest: VTE).⁴
  • Treatment-related AEs leading to discontinuation of all agents occurred in 10% of patients treated with RYBREVANT plus lazertinib and in 3% with osimertinib.⁴
• A real-world study evaluating the effectiveness of RYBREVANT in comparison to real-world anticancer therapies, including osimertinib, has been published.⁵

ongoing clinical study

MARIPOSA Study

Study Design/Methods

• Phase 3, ongoing, randomized study designed to assess efficacy and safety of RYBREVANT plus lazertinib (open-label) vs osimertinib (doubleblind) vs lazertinib (double-blind) as first-line treatment in patients with EGFRmutated (Exon19del or L858R) locally advanced or metastatic NSCLC.^2–4
• The study design is shown in Figure: MARIPOSA Study Design.

Results⁴

Patient Characteristics

• A total of 1074 patients were randomized to receive RYBREVANT plus lazertinib (n=429), osimertinib (n=429), or lazertinib (n=216).
• The patient demographics and baseline characteristics are included in Table: Demographics and Baseline Disease Characteristics.

Efficacy

Primary Endpoint

• At a median follow-up of 22 months, median PFS by BICR was 23.7 months (95% CI, 19.127.7) for RYBREVANT plus lazertinib and 16.6 months (95% CI, 14.8-18.5) for osimertinib (HR, 0.70 [95% CI, 0.58-0.85]; P<0.001).
  • PFS rates at 12 and 24 months were 73% and 48%, respectively, for RYBREVANT plus lazertinib and 65% and 34%, respectively, for osimertinib.
• Median PFS was 18.5 months (95% CI, 14.8-20.1) for lazertinib monotherapy.
• At a median follow-up of 22 months, median extracranial PFS, defined as time from randomization to disease progression as detected by extracranial scans or death, by BICR was 27.5 months (95% CI, 22.1-NE) for RYBREVANT plus lazertinib and 18.5 months (95% CI, 16.5-20.3) for osimertinib (HR, 0.68 [95% CI, 0.56-0.83]; nominal P<0.001, endpoint was exploratory and not part of hierarchical hypothesis testing). This endpoint was not adjusted for multiple comparisons. Therefore, the Pvalue displayed is nominal, and statistical significance has not been established.
  • Extracranial PFS rates at 12 and 24 months were 77% and 53%, respectively, for RYBREVANT plus lazertinib and 67% and 38%, respectively, for osimertinib.
• For patients with a history of brain metastases, median PFS by BICR was 18.3 months (95% CI, 16.6-23.7) for RYBREVANT plus lazertinib and 13 months (95% CI, 12.2-16.4) for osimertinib (HR, 0.69 [95% CI, 0.53-0.92]). For patients without a history of brain metastases, median PFS by BICR was 27.5 months (95% CI, 22.1-NE) for RYBREVANT plus lazertinib and 19.9 months (95% CI, 16.6-22.9) for osimertinib (HR, 0.69 [95% CI, 0.530.89]).
• PFS across predefined clinically relevant subgroups was evaluated for RYBREVANT plus lazertinib vs osimertinib (Table: PFS Across Predefined Subgroups).

Secondary Endpoints

• The objective response rate (ORR) and best responses for RYBREVANT plus lazertinib vs osimertinib are included in Table: ORR and Best Response by BICR.
• Median duration of response (DOR) among confirmed responders by BICR was improved by 9 months for RYBREVANT plus lazertinib compared to osimertinib, 25.8 months (95% CI, 20.1-NE) and 16.8 months (95% CI, 14.8-18.5), respectively.

• At a median follow-up of 22 months, median PFS after first subsequent therapy (PFS2) estimates were not reliable (HR, 0.75 [95% CI, 0.58-0.98]; nominal P=0.03, endpoint was not part of hierarchical hypothesis testing). This endpoint was not adjusted for multiple comparisons. Therefore, the P-value displayed is nominal, and statistical significance has not been established.
  • In the RYBREVANT plus lazertinib arm, 98 patients started subsequent therapy, with 48 patients receiving EGFR TKI monotherapy and 32 patients receiving chemotherapy alone. In the osimertinib arm, 137 patients started subsequent therapy, with 37 patients receiving EGFR TKI monotherapy and 53 patients receiving chemotherapy alone.
• The interim overall survival (OS) reached 55% maturity. There were 214 deaths in the study at the time of the prespecified interim OS analysis (~390 projected deaths for the final OS analysis). Medians were not estimable (HR, 0.80 [95% CI, 0.61-1.05]; P=0.11).  

Safety

• Median duration of treatment was 18.5 months for RYBREVANT plus lazertinib and 18 months for osimertinib.
• Serious AEs and AEs leading to treatment interruptions, reductions, or discontinuations of any agent were higher with RYBREVANT plus lazertinib compared to osimertinib (Table: Safety Summary).
• Treatment-related AEs leading to discontinuation of all agents occurred in 10% of patients treated with RYBREVANT plus lazertinib and in 3% with osimertinib.

• EGFR- and MET-related AEs were increased with RYBREVANT plus lazertinib compared to osimertinib and were mostly grade 1-2 (Table: Summary of AEs).
• Grade ≥3 AEs in the RYBREVANT plus lazertinib arm were driven by EGFR- and MET-related AEs associated with RYBREVANT monotherapy.
  • Incidence of grade 4-5 AEs was low and comparable between both arms.
• Incidence of interstitial lung disease (ILD)/pneumonitis was low, at ~3% for both arms.

• VTE rates were higher with RYBREVANT plus lazertinib compared to osimertinib (Table: AE of Special Interest: VTE).
  • Most VTEs were grade 1-2. The incidence of grade 4-5 VTEs was low (<1%) and comparable between both arms.
  • Most common preferred terms were pulmonary embolism and deep vein thrombosis.
• At the time of first VTE, most patients were not on anticoagulants. Majority of first VTE events in the RYBREVANT plus lazertinib arm occurred within the first 4 months.
• Rates of treatment discontinuations due to VTE were low and comparable between both arms.
• Prophylactic dose anticoagulation is recommended for the first 4 months of treatment in ongoing trials of RYBREVANT plus lazertinib.

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 06 November 2023.