RYBREVANT, LAZCLUZE – MARIPOSA Study

RYBREVANT (amivantamab-vmjw) is a low fucose, fully human IgG1-based bispecific antibody with immune cell-directing activity that targets EGFR mutations and MET mutations and amplifications in NSCLC.¹
LAZCLUZE (lazertinib) is a third-generation EGFR TKI.²

Guidelines

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for NSCLC recommends amivantamab-vmjw (RYBREVANT) as a first-line therapy option in combination with lazertinib for EGFR Exon 19 deletion or Exon 21 L858R mutation discovered prior to first-line systemic therapy (NCCN Category 1, other recommended). If EGFR mutation is discovered during first-line systemic therapy, amivantamab-vmjw is recommended in combination with lazertinib (NCCN Category 2A).³
- Prophylactic anticoagulation is recommended for amivantamab-vmjw + lazertinib at the time of initiation to prevent venous thromboembolic events.
National Comprehensive Cancer Network® (NCCN®) Categories of Evidence are defined as³:
- Category 1 is based upon high-level evidence, and there is uniform NCCN consensus (≥85% support of the Panel) that the intervention is appropriate.
- Category 2A is based upon lower-level evidence, and there is uniform NCCN consensus (≥85% support of the Panel) that the intervention is appropriate.
NCCN Category of Preference of other recommended intervention is defined as other interventions that may be somewhat less efficacious, more toxic, or based on less mature data; or significantly less affordable for similar outcomes.³
Please refer to the NCCN Guidelines® for NSCLC at www.nccn.org for current and complete recommendations for the use of amivantamab-vmjw in NSCLC.³

MARIPOSA Study

MARIPOSA (NCT04487080) is an ongoing, phase 3, randomized, international 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 (Exon19del or Exon 21 L858R substitution) locally advanced or metastatic NSCLC. The primary endpoint is PFS, based on BICR.^2-5
- At a median follow-up of 22 months, median PFS by BICR for RYBREVANT plus lazertinib vs osimertinib was 23.7 months (95% CI, 19.1-27.7) vs 16.6 months (95% CI, 14.8 -18.5; HR, 0.70 [95% CI, 0.58-0.85]; P<0.001).⁵
  - For patients with a history of brain metastases, median PFS by BICR for RYBREVANT plus lazertinib vs osimertinib was 18.3 months (95% CI, 16.6-23.7) vs 13 months (95% CI, 12.2-16.4; HR, 0.69 [95% CI, 0.53-0.92]).^5,6
- Grade ≥3 AEs occurred in 75% of patients treated with RYBREVANT plus lazertinib and 43% of patients treated with osimertinib. VTE rates were increased with RYBREVANT plus lazertinib vs osimertinib. TRAEs leading to discontinuation of all agents occurred in 10% of patients treated with RYBREVANT plus lazertinib and in 3% of patients treated with osimertinib.⁵
- At a median long-term follow-up of 31.1 months, median OS for RYBREVANT plus lazertinib vs osimertinib was NE vs 37.3 months (95% CI, 32.5-NE; HR, 0.77 [95% CI, 0.61-0.96]; P=0.019^a).⁷
  - For patients with a history of brain metastases, median icPFS for RYBREVANT plus lazertinib vs osimertinib was 24.9 months (95% CI, 20.1-34.7) vs 22.2 months (95% CI, 18.4-26.1; HR, 0.82 [95% CI, 0.62-1.09];P=0.165^a).

Note: AE, adverse event; BICR, blinded independent central review; CI, confidence interval; EGFR, epidermal growth factor receptor; Exon19del, Exon 19 deletion; HR, hazard ratio; icPFS, intracranial PFS; IgG1, immunoglobulin G1; MET, mesenchymal-epithelial transition; NCCN, National Comprehensive Cancer Network; NE, not estimable; NSCLC, non-small cell lung cancer; OS, overall survival; PFS, progression-free survival; TKI, tyrosine kinase inhibitor; TRAE, treatment-related AE; VTE, venous thromboembolism.
^aThe endpoint was not part of formal statistical testing; the P-value displayed is nominal.

MARIPOSA Study

A secondary analysis in high-risk patients reported^6,8:
- For patients with high-risk disease (≥1 high-risk feature at baseline), median PFS by BICR for RYBREVANT plus lazertinib (n=280) vs osimertinib (n=288) was 20.3 months (95% CI, 18.2- 24.0) vs 15 months (95% CI, 13.0-16.8; HR, 0.72 [95% CI, 0.58-0.90]; P=0.004; P-values in these secondary analyses are nominal).
  - Baseline liver metastases: HR, 0.58 (95% CI, 0.37-0.91); P=0.017; TP53 co-mutations: HR, 0.65 (95% CI, 0.48-0.87); P=0.003; detectable baseline EGFR-mutated ctDNA: HR, 0.68 (95% CI, 0.53-0.86); P=0.002; without EGFR-mutated ctDNA clearance at C3D1: HR, 0.49 (95% CI, 0.27-0.87); P=0.015.
An Asian subgroup analysis reported⁹:
- At a median follow-up of 22.5 months, median PFS by BICR for RYBREVANT plus lazertinib vs osimertinib was 27.5 months (95% CI, 20.3-NE) vs 18.3 months (95% CI, 15.8-20.2; HR, 0.65 [95% CI, 0.50-0.83]; P<0.001^a).
- EGFR- and MET-related AEs were increased with RYBREVANT plus lazertinib vs osimertinib and were mostly grade 1-2. VTE rates were also increased with RYBREVANT plus lazertinib vs osimertinib and were mostly grade 1-2. There were no grade 4-5 VTEs.
A post-progression and safety analysis reported¹⁰:
- At a median follow-up of 22 months, in the RYBREVANT plus lazertinib vs osimertinib arm, 35% (147/421) vs 47% (203/428) of patients had PD, median TTD was 26.2 (95% CI, 22.1-NE) vs 23 months (95% CI, 20.3-25.3; HR, 0.88; 95% CI, 0.73-1.07; P=0.21^a), and median TTST was NE (95% CI, 26.8-NE) vs 24.1 months (95% CI, 22-29; HR, 0.82; 95% CI, 0.66-1; P=0.05^a).
- Key AEs occurred within the first 4 months of treatment. Late onset AEs were uncommon.
An exploratory analysis for RYBREVANT dose interruptions in the first 4 months of RYBREVANT exposure reported¹¹:
- At a median follow-up of 22 months, median PFS in patients with (n=188) vs without (n=190), RYBREVANT dose interruptions after the first 4 months of RYBREVANT exposure was 27 (95% CI, 20.3-NE) vs 25.7 months (95% CI, 22.2-NE). No significant association was found between dose interruptions and PFS after 4 months of RYBREVANT exposure (HR, 1.06; 95% CI, 0.73-1.44).
- Key AEs occurred most frequently during the first 4 months and declined over the next 4 months.
An exploratory analysis for lazertinib vs osimertinib reported¹²:
- At a median follow-up of 22 months, median PFS by BICR for lazertinib vs osimertinib was 18.5 months (95% CI, 14.8-20.1) vs 16.6 months (95% CI, 14.8-18.5; HR, 0.98 [95% CI, 0.79-1.22]).
- Most TEAEs were grade 1-2 in severity for lazertinib and osimertinib.
A ctDNA analysis for acquired resistance reported¹³:
- In the RYBREVANT plus lazertinib vs osimertinib arm, 4.4% vs 13.6% of patients had MET amplifications (P=0.017) and 0.9% vs 7.9% of patients had secondary EGFR resistance mutations (P=0.014).
A patient-relevant outcome analysis for TTSP and PROs reported¹⁴:
- At a median follow-up of 22 months, median TTSP for RYBREVANT plus lazertinib vs osimertinib was NE vs 29.3 months (95% CI, 25.3-NE; HR, 0.72 [95% CI, 0.57-0.91]; P=0.005).
- In the RYBREVANT plus lazertinib vs osimertinib arm, no meaningful changes from baseline were observed in patient-reported functioning; patient-reported total symptom scores and individual lung cancer-associated symptom scores were comparable.

Note: AE, adverse event; BICR, blinded independent central review; C, cycle; CI, confidence interval; ctDNA, circulating tumor DNA; D, day; EGFR, epidermal growth factor receptor; Exon19del, Exon 19 deletion; HR, hazard ratio; MET, mesenchymal- epithelial transition; NE, not estimable; NSCLC, non-small cell lung cancer; PD, progressive disease; PFS, progression-free survival; PRO, patient-reported outcome; TEAE, treatment-emergent AE; TTD, time to treatment discontinuation; TTSP, time to subsequent progression; TTST, time to subsequent therapy; VTE, venous thromboembolism.
^aThe endpoint was exploratory and 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.

MARIPOSA^2-5

MARIPOSA (NCT04487080) is an ongoing, phase 3, randomized study designed to evaluate 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 (Exon19del or Exon 21 L858R substitution) locally advanced or metastatic NSCLC.

N=1074

Key Eligibility Criteria^2-5

Age ≥18 years
Locally advanced or metastatic NSCLC
Treatment naïve for advanced disease
EGFR Exon19del or Exon 21 L858R substitution
ECOG PS 0 or 1

Study Design^2-5

Efficacy Results^5,7

At a median follow-up of 22 months, median PFS by BICR was 23.7 months (95% CI, 19.1-27.7) 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).⁵
- The 18-month PFS for RYBREVANT plus lazertinib vs osimertinib was 60% (95% CI, 55-64) vs 48% (95% CI, 43-53).
- The 24-month PFS for RYBREVANT plus lazertinib vs osimertinib was 48% (95% CI, 42-54) vs 34% (95% CI, 28-39).
Median PFS was 18.5 months (95% CI, 14.8-20.1) for Lazertinib monotherapy.⁵
At a median long-term follow-up of 31.1 months, median OS was NE for RYBREVANT plus lazertinib and 37.3 months (95% CI, 32.5-NE) for osimertinib (HR, 0.77; 95% CI, 0.61-0.96; P=0.019^d).⁷

Safety Results⁵

TRAEs leading to discontinuation of all agents occurred in 10% of patients treated with RYBREVANT plus lazertinib and 3% with osimertinib.
Grade ≥3 AEs were 75% vs 43% in the RYBREVANT plus lazertinib vs osimertinib arm.
VTE rates were higher with RYBREVANT plus lazertinib vs osimertinib.

Additional Analyses^6,8-14

Secondary analysis of high-risk patients^6,8: HR (95% CI) for median PFS: 0.72 (0.58-0.90; P=0.004) for RYBREVANT plus lazertinib vs osimertinib.
Subgroup analysis in Asian patients⁹: HR (95% CI) for median PFS: 0.65 (0.50-0.83; P<0.001^d) for RYBREVANT plus lazertinib vs osimertinib. Safety profile: comparable to the overall MARIPOSA study.
Post-progression and safety analysis¹⁰: HR (95% CI) for median TTD and TTST: 0.88 (0.73-1.07; P=0.21^d) and 0.82 (0.66-1; P=0.05^d) for RYBREVANT plus lazertinib vs osimertinib. Key AEs occurred within the first 4 months; late onset AEs were uncommon.
Exploratory analyses^11,12:
- Dose interruption: median PFS was 27.5 vs 25.7 months in patients with vs without RYBREVANT dose interruption after 4 months. The prevalence of key AEs was comparable in patients with and without RYBREVANT dose interruptions at all time points.¹¹
- Lazertinib vs osimertinib: median PFS was 18.5 vs 16.6 months. Most TEAEs were grade 1-2 in severity.¹²
ctDNA analysis for acquired resistance¹³: RYBREVANT plus lazertinib vs osimertinib: MET amplifications in 4.4% vs 13.6% (P=0.017); secondary EGFR resistance mutations in 0.9% vs 7.9% of patients (P=0.014), respectively.
Patient-relevant outcome analysis¹⁴: RYBREVANT plus lazertinib vs osimertinib: HR (95% CI) for median TTSP of 0.72 (0.57-0.91; P=0.005); no meaningful changes from baseline in patient-reported functioning; and comparable patient-reported total symptom scores and individual lung cancer-associated symptom scores.

Note: AE, adverse event; BICR, blinded independent central review; C, cycle; CI, confidence interval; D, day; ECOG PS, Eastern Cooperative Oncology Group performance status; EGFR, epidermal growth factor receptor; Exon19del, Exon 19 deletion; HR, hazard ratio; IV, intravenous; NE, not estimable; NSCLC, non-small cell lung cancer; OS, overall survival; PFS, progression-free survival; PO, orally; QD, once daily; Q2W, every 2 weeks; QW, once weekly; R, randomization; TEAE, treatment-emergent AE; TRAE, treatment-related AE; TTD, time to treatment discontinuation; TTSP, time to subsequent progression; TTST, time to subsequent therapy; VTE, venous thromboembolism.

^aIn patients <80 kg.
^bIn patients ≥80 kg.
^cThe first infusion was split over 2 days (350 mg on C1D1, and the remainder on C1D2).
^dThe endpoint was not part of formal statistical testing; the P-value displayed is nominal.

MARIPOSA (NCT04487080) is an ongoing, phase 3, randomized study designed to evaluate 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 (Exon19del or Exon 21 L858R substitution) locally advanced or metastatic NSCLC. ^2-5

Primary Endpoint

PFS by BICR per RECIST v1.1 in Arm A vs Arm B

Secondary Endpoints

Arm A vs Arm B

OS^e
Symptomatic PFS^f
PRO^h
ORR
icPFS
DOR
Safety
PFS2
TTSP^g

MARIPOSA (ClinicalTrials.gov Identifier: NCT04487080) enrollment period: November 2020 to May 2022; data cutoff: August 11, 2023.
^aIn patients <80 kg.
^bIn patients ≥80 kg.
^cThe first infusion was split over 2 days (350 mg on C1D1, and the remainder on C1D2).
^dSerial brain MRIs were required for all patients. Baseline brain MRI was required for all patients and performed ≤28 days prior to randomization; patients who could not have MRIs were allowed to have CT scans. Brain scan frequency was every 8 weeks for the first 30 months and then every 12 weeks thereafter for patients with a history of brain metastasis and every 24 weeks for patients with no history of brain metastasis. Extracranial tumor assessments were conducted every 8 weeks for the first 30 months and then every 12 weeks until disease progression is confirmed by BICR.
^eStatistical hypothesis testing included PFS and then OS.
^fThis secondary endpoint will be presented at a future congress.
^gAlso included death.
^hAssessed using EORTC-QLQ-C30 (threshold of 10-point difference for a clinically meaningful change) and NSCLC-SAQ.

A total of 1074 patients were randomized to receive RYBREVANT plus lazertinib (n=429), osimertinib (n=429), or lazertinib (n=216).⁵

Characteristic	RYBREVANT + Lazertinib (n=429)	Osimertinib (n=429)	Lazertinib (n=216)
Median age, years (range)	64 (25-88)	63 (28-88)	63 (31-87)
Female, n (%)	275 (64)	251 (59)	136 (63)
Race,^a n (%)
Asian	250 (58)	251 (59)	128 (59)
White	164 (38)	165 (38)	79 (37)
American Indian or Alaska Native	7 (2)	7 (2)	-
Black or African American	4 (1)	3 (1)	-
Native Hawaiian or Pacific Islander	1 (0.2)	1 (0.2)	-
Multiple	1 (0.2)	1 (0.2)
Unknown	2 (0.5)	1 (0.2)	-
ECOG PS 0, n (%)	141 (33)	149 (35)	76 (35)
ECOG PS 1, n (%)	288 (67)	280 (65)	140 (65)
History of smoking, n (%)	130 (30)	134 (31)	73 (34)
History of brain metastases, n (%)	178 (41)	172 (40)	86 (40)
EGFR mutation,^b n (%)
Exon19del	258 (60)	257 (60)	131 (61)
Exon 21 L858R	172 (40)	172 (40)	85 (39)
Adenocarcinoma subtype, n (%)	417 (97)	415 (97)	212 (98)
^aRace or ethnic group was reported by the patients. ^bOne patient in the RYBREVANT + lazertinib arm had both Exon19del and Exon 21 L858R.

Efficacy was evaluated at a median follow-up of 22 months (data cutoff: August 11, 2023).⁵
Median PFS by BICR was 23.7 months (95% CI, 19.1-27.7) 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).⁵
- The 12-month PFS for RYBREVANT plus lazertinib vs osimertinib was 73% (95% CI, 69-77) vs 65% (95% CI, 60-69).
- The 18-month PFS for RYBREVANT plus lazertinib vs osimertinib was 60% (95% CI, 55-64) vs 48% (95% CI, 43-53).
- The 24-month PFS for RYBREVANT plus lazertinib vs osimertinib was 48% (95% CI, 42-54) vs 34% (95% CI, 28-39).
Median PFS was 18.5 months (95% CI, 14.8-20.1) for lazertinib monotherapy.⁵
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 18.4 months (95% CI, 16.5-20.2) for osimertinib (HR, 0.68 [95% CI, 0.55-0.83].⁵
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, 0.53-0.89]).⁵

Median DOR by BICR among confirmed responders for RYBREVANT plus lazertinib vs osimertinib was 25.8 months (95% CI, 20.1-NE) vs 16.8 months (95% CI, 14.8-18.5).⁵
At a median follow-up of 22 months, median PFS2 estimates were not reliable (HR, 0.75 [95% CI, 0.58-0.98]; P=0.03).^5,a
- 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.
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 NE (HR, 0.80 [95% CI, 0.61-1.05]).⁵

ORR and Best Response by BICR⁵

BICR-Assessed Response^a	BICR-Assessed Response^a	RYBREVANT + Lazertinib (n=429)
ORR, % (95% CI)
All responders	86 (83-89)	85 (81-88)
All responders		Odds ratio: 1.15 (0.78-1.70)^b
Confirmed responders	80 (76-84)	76 (71-80)
Best responses,^c n (%)
CR^c	29 (7)	15 (4)
PR^c	334 (79)	335 (81)
SD	30 (7)	42 (10)
PD	7 (2)	11 (3)
NE/UNK	21 (5)	11 (3)
^aNumber of patients with measurable disease at baseline by BICR was 421 for RYBREVANT + lazertinib and 414 for osimertinib. ^bThe odds ratio is from a logistic regression model stratified by EGFR mutation type, Asian race, and history of brain metastasis; 95% CI widths have not been adjusted for multiplicity and cannot be used to infer definitive treatment effects. ^cIncludes all responders.

^aThe 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.

At a median long-term follow-up of 31.1 months (data cutoff: May 13, 2024), median OS for RYBREVANT plus lazertinib vs osimertinib was NE vs 37.3 months (95% CI, 32.5-NE; HR, 0.77 [95% CI, 0.61-0.96]; P=0.019^a).⁷
- The OS rates for RYBREVANT plus lazertinib vs osimertinib were 75% vs 70% at 24 months and 61% vs 53% at 36 months, respectively.

In patients with a history of brain metastases, median icPFS (defined as the time from randomization until the date of intracranial disease progression^b or death) by BICR for RYBREVANT plus lazertinib vs osimertinib was 24.9 months (95% CI, 20.1-34.7) vs 22.2 months (95% CI, 18.4-26.1; HR, 0.82 [95% CI, 0.62-1.09]; P=0.165^c).
- The icPFS rates for RYBREVANT plus lazertinib vs osimertinib were 51% vs 48% at 24 months and 38% vs 18% at 36 months, respectively.
In patients with a history of brain metastases at screening, median icDOR (defined as the time from the date of first documented intracranial CR or PR until the date of documented intracranial progression or death, whichever occurred first) by BICR for RYBREVANT plus lazertinib vs osimertinib was NE (95% CI,^d 21.4-NE) vs 24.4 months (95% CI,^d 22.1-31.2).
- The icDOR rates for RYBREVANT plus lazertinib vs osimertinib were 59% vs 52% at 24 months and 51% vs 0% at 36 months, respectively.
The icORR for RYBREVANT plus lazertinib vs osimertinib was 77% (95% CI, 70-83) vs 77% (95% CI, 71-83).

^aThe endpoint was not part of formal statistical testing; the P-value displayed is nominal. P-value was calculated from a log- rank test stratified by mutation type (Exon19del or Exon 21 L858R), race (Asian or Non-Asian), and history of brain metastasis (present or absent). HR was calculated from a stratified proportional hazards model.
^bProgression of brain metastasis or occurrence of new brain lesions.
^cThe endpoint was not part of formal statistical testing; the P-value displayed is nominal. P-value was calculated from a log- rank test stratified by mutation type (Exon19del or Exon 21 L858R) and race (Asian or Non-Asian). HR was calculated from a stratified proportional hazards model.
^d95% CI was estimated using the Kaplan-Meier method.

Median TTD (defined as the time from randomization to discontinuation of treatment for any reason, including disease progression, treatment toxicity, or death) for RYBREVANT plus lazertinib vs osimertinib was 26.3 months (95% CI, 22.3-30.4) vs 22.6 months (95% CI, 20.3- 24.5; HR, 0.80 [95% CI, 0.68-0.96]; P=0.014^a).
- At 24 and 36 months, respectively, 52% vs 46% and 40% vs 29% of patients in the RYBREVANT plus lazertinib vs osimertinib arm remained on treatment.
Median TTST (defined as the time from the date of randomization to the start date of the subsequent anticancer therapy following study treatment discontinuation or death, whichever occurs first) for RYBREVANT plus lazertinib vs osimertinib was 30 months (95% CI, 26.3-36) vs 24 months (95% CI, 22.5-26.2; HR, 0.77 [95% CI, 0.65-0.93]; P=0.005^a).
- At 24 and 36 months, respectively, 57% vs 50% and 45% vs 32% of patients in the RYBREVANT plus lazertinib vs osimertinib arm did not initiate the first subsequent therapy.
In the RYBREVANT plus lazertinib vs osimertinib arm, 72% vs 74% of patients had disease progression, discontinued treatment, and received subsequent therapies.

Median PFS2 (defined as the time from randomization until the date of the second objective disease progression after initiation of subsequent anticancer therapy, based on clinical progression as determined by the investigator or death, whichever occurred first) for RYBREVANT plus lazertinib vs osimertinib was NE (95% CI, 36-NE) vs 32.4 months (95% CI, 29.3-NE; HR, 0.73 [95% CI, 0.59-0.91]; P=0.004^a).
- The PFS2 rates for RYBREVANT plus lazertinib vs osimertinib were 73% vs 65% at 24 months and 57% vs 49% at 36 months, respectively.

Median duration of treatment was 18.5 months (range, 0.2-31.4) for RYBREVANT plus lazertinib and 18 months (range, 0.2-32.7) for osimertinib.⁵
Serious AEs and AEs leading to treatment interruptions, reductions, or discontinuations of any agent were higher with RYBREVANT plus lazertinib compared with osimertinib.⁵
- IRR (5%), rash (3%), and paronychia (3%) were the most common causes of treatment discontinuation in the RYBREVANT plus lazertinib group.
Treatment-related AEs leading to discontinuation of all agents occurred in 10% of patients treated with RYBREVANT plus lazertinib and in 3% with osimertinib.⁵

TEAE, n (%)	RYBREVANT + Lazertinib (n=421)	Osimertinib (n=428)
Any AE	421 (100)	425 (99)
Grade ≥3 AEs	316 (75)	183 (43)
Serious AEs	205 (49)	143 (33)
AEs leading to death	34 (8)	31 (7)
Any AE leading to:
Treatment interruptions of any agent	350 (83)	165 (39)
Treatment Reductions of any agent	249 (59)	23 (5)
Treatment discontinuations of any agent	147 (35)	58 (14)

Grade ≥3 AEs occurred in 75% of patients treated with RYBREVANT plus lazertinib and 43% of patients treated with osimertinib.⁵
Incidence of ILD/pneumonitis was low, at ~3%, with 1% being grade ≥3 for both arms.⁵
VTE rates were higher with RYBREVANT plus lazertinib compared with osimertinib.⁵
- Most common preferred terms were PE and DVT.
At the time of the 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.⁵
Rates of treatment discontinuations due to VTE were low and comparable between both arms.⁵
Study participants receiving the combination of RYBREVANT and lazertinib 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.¹⁶
Prophylactic dose anticoagulation is recommended for the first 4 months of treatment in ongoing trials of RYBREVANT plus lazertinib.⁵

In a secondary analysis of patients with high-risk disease biomarkers in the MARIPOSA study, patients with ctDNA, ctDNA nonclearance, TP53 co-mutations, and liver metastases at baseline who were randomized to receive RYBREVANT plus lazertinib (n=429) or osimertinib (n=429) were included.^6,8
- The presence of ctDNA and co-mutations was detected at baseline by NGS of blood using Guardant360 CDx.
- The presence and clearance of Exon19del and Exon 21 L858R ctDNA was evaluated at baseline and at C3D1 using Biodesix ddPCR.

Median PFS by BICR for patients with high-risk disease (≥1 high-risk feature at baseline; RYBREVANT plus lazertinib, n=280; osimertinib, n=288) was 20.3 months (95% CI, 18.2-24.0) for RYBREVANT plus lazertinib and 15 months (95% CI, 13.0-16.8) for osimertinib (HR, 0.72; 95% CI, 0.58-0.90; P=0.004). P-values for subgroup analyses are all nominal. ^6,8
At baseline, 540 patients had ctDNA detectable by NGS. Of them, 85% of patients had pathogenic ctDNA mutations and 56% vs 53% of patients had TP53 co-mutations in the RYBREVANT plus lazertinib vs osimertinib arms.^6,8

PFS Across Predefined High-Risk Disease Subgroups^6,8

Subgroup	Median PFS (95% CI), Months		HR (95% CI); P-Value^b
Subgroup		RYBREVANT + Lazertinib	HR (95% CI); P-Value^b	Osimertinib
Detectable baseline ctDNA by NGS	n=266 20.3 (18.2-23.9)	n=274 14.8 (12.9-16.6)	0.71 (0.57-0.89); P=0.003
TP53 co-mutation	n=149 18.2 (15.3-22.1)	n=144 12.9 (11.1-14.7)	0.65 (0.48-0.87); P=0.003
TP53 wild-type	n=117 22.1 (18.5-NE)	n=130 19.9 (14.8-23.9)	0.75 (0.52-1.07); P=0.114
Detectable baseline EGFR- mutant ctDNA by ddPCR^a	n=231 20.3 (16.6-24.0)	n=240 14.8 (12.9-16.5)	0.68 (0.53-0.86); P=0.002
Not cleared at C3D1	n=29 16.5 (9.3-18.4)	n=32 9.1 (5.5-11.1)	0.49 (0.27-0.87); P=0.015
Cleared at C3D1	n=163 24.0 (20.2-NE)	n=180 16.5 (14.9-19.9)	0.64 (0.48-0.87); P=0.004
Liver metastases at baseline
Present	n=64 18.2 (13.1-NE)	n=72 11.0 (7.4-12.8)	0.58 (0.37-0.91); P=0.017
Absent	n=365 24.0 (20.3-NE)	n=357 18.3 (16.5-20.1)	0.74 (0.60-0.91); P=0.004
^aOf the 231 patients in the RYBREVANT-lazertinib arm and 240 patients in the osimertinib arm, 192 and 212 patients, respectively, had matched samples at baseline and C3D1. ^bP-values for subgroup analyses are all nominal. The 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 a subgroup analysis of Asian patients in the MARIPOSA study, 501 Asian patients (defined by race) were randomized to receive RYBREVANT plus lazertinib (n=250) or osimertinib (n=251).⁹

Demographics and Baseline Disease Characteristics Among Asian Patients⁹

Characteristic	RYBREVANT + Lazertinib (n=250)	Osimertinib (n=251)
Median age, years (range)	63 (35-85)	63 (28-88)
Female, n (%)	152 (61)	143 (57)
Body Weight <80 kg, n (%)	236 (94)	238 (95)
ECOG PS 1, n (%)	181 (72)	167 (67)
History of smoking, n (%)	70 (28)	70 (28)
History of brain metastases, n (%)	110 (44)	108 (43)
EGFR mutation,^a n (%)
Exon19del	138 (55)	139 (55)
Exon 21 L858R	113 (45)	112 (45)
Adenocarcinoma histology, n (%)	244 (98)	239 (95)
Median time from metastatic disease diagnosis, months (range)	1.1 (0.2-24.1)	1.1 (0.1-9.1)
^aOne patient in the RYBREVANT + lazertinib arm had both Exon19del and Exon 21 L858R.

At a median follow-up of 22.5 months, median PFS by BICR was 27.5 months (95% CI, 20.3-NE) for RYBREVANT plus lazertinib and 18.3 months (95% CI, 15.8-20.2) for osimertinib (HR, 0.65; 95% CI, 0.50-0.83; P<0.001^a).
- PFS rates at 12 months were 76% and 66% for RYBREVANT plus lazertinib and osimertinib, respectively, and at 24 months were 53% and 36%, respectively.
Median PFS was 18.4 months (95% CI, 14.6-20.3) for lazertinib monotherapy.
PFS across predefined clinically relevant subgroups was evaluated for RYBREVANT plus lazertinib vs osimertinib.

Median DOR among confirmed responders by BICR was 26.1 months (95% CI, 20.1-NE) for RYBREVANT plus lazertinib and 17.5 months (95% CI, 14.8-20.4) for osimertinib.
At a median follow-up of 22.5 months, HR for PFS2 was 0.78 (95% CI, 0.54-1.11; P=0.17^a); the HR for interim OS was 0.84 (95% CI, 0.58-1.23; P=0.38^a).

Median duration of treatment was 19.8 months for RYBREVANT plus lazertinib and 18.7 months for osimertinib.⁹
Grade ≥3 AEs, serious AEs, and AEs leading to treatment interruptions, reductions, or discontinuations of any agent were higher with RYBREVANT plus lazertinib compared with osimertinib.⁹
TRAEs leading to discontinuation of all agents occurred in 9% of patients treated with RYBREVANT plus lazertinib.⁹

TEAEs, n (%)	RYBREVANT + Lazertinib (n=248)	Osimertinib (n=250)
Any AE	248 (100)	247 (99)
Grade ≥3 AEs	176 (71)	102 (41)
Serious AEs	117 (47)	80 (32)
AEs leading to death	17 (7)	12 (5)
Any AE leading to:
Treatment interruptions of any agent^a	208 (84)	98 (39)
Treatment reductions of any agent	145 (58)	14 (6)
Treatment discontinuations of any agent	73 (29)	30 (12)
^aExcludes IRRs.

EGFR- and MET-related AEs were increased with RYBREVANT plus lazertinib compared with osimertinib and were mostly grade 1-2.⁹
Grade ≥3 AEs in the RYBREVANT plus lazertinib arm were driven by grade 3 events.⁹
- Incidence of grade 4-5 AEs and AEs leading to death were low and comparable between both arms.
Incidence of ILD was low, 4% for RYBREVANT plus lazertinib vs 3% for osimertinib.⁹
VTE rates were higher with RYBREVANT plus lazertinib compared with osimertinib.⁹
- Most VTEs were grade 1-2. There were no grade 4-5 events.
At the time of first VTE, most patients (99%) were not on anticoagulants. Majority of first VTE events in the RYBREVANT plus lazertinib arm occurred within the first 4 months and were effectively managed with anticoagulants.⁹

An analysis assessed post-progression treatment outcomes and safety in patients from MARIPOSA receiving RYBREVANT plus lazertinib (open-label) vs osimertinib (double blind) as first-line treatment for EGFR-mutated (Exon19del or Exon 21 L858R) locally advanced or metastatic NSCLC.¹⁰

At a median follow-up of 22 months, 35% (147/421) of patients in the RYBREVANT plus lazertinib arm and 47% (203/428) of patients in the osimertinib arm had PD.
- Among patients with PD, 53% (78/147) in the RYBREVANT plus lazertinib arm and 51% (103/203) in the osimertinib arm continued treatment beyond progression for a median duration of 23.6 weeks (range, 16-34.9) and 15.9 weeks (range, 10.7-21.6), respectively.
Median TTD was 26.2 months (95% CI, 22.1-NE) for RYBREVANT plus lazertinib vs 23 months (95% CI, 20.3-25.3) for osimertinib (HR, 0.88; 95% CI, 0.73-1.07; P=0.21^a).
- At follow-up, 116 patients in the RYBREVANT plus lazertinib arm and 171 patients in the osimertinib arm discontinued study treatment, respectively.
- At 24 months, 53% and 47% of patients remained on treatment in the RYBREVANT plus lazertinib and osimertinib treatment arms, respectively.

Patient Disposition	Patient Disposition	RYBREVANT + Lazertinib (n=421)
Discontinued study treatment, n	116	171
Received subsequent therapy, n (%)	78 (67)	124 (73)
Died before receiving subsequent therapy, n (%)	25 (22)	34 (20)

Median TTST was NE (95% CI, 26.8-NE) for RYBREVANT plus lazertinib vs 24.1 months (22-29) for osimertinib (HR, 0.82; 95% CI, 0.66-1; P=0.05^a).

^aThe 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.

The most commonly prescribed first subsequent therapies¹⁰:
- After RYBREVANT plus lazertinib were doublet chemotherapy (36%) and third-generation TKIs (24%).
- After osimertinib were doublet chemotherapy (38%) and doublet chemotherapy plus IO/VEGFi (22%).

First Subsequent Therapies,^a %	First Subsequent Therapies,^a %	RYBREVANT + Lazertinib (n=78)
Doublet chemotherapy	36	38
Doublet chemotherapy + IO/VEGFi	12	22
Third-generation TKI	24	15
Other TKIs	14	8
TKI combination	9	8
^aSingle-agent chemotherapy percentages were not provided for both arms. Other therapies were reported as 7% for osimertinib and not provided for RYBREVANT plus lazertinib arm.

Median duration of exposure was 18.5 months for RYBREVANT plus lazertinib.¹⁰
Key AEs occurred within the first 4 months of treatment. Late onset AEs were uncommon.¹⁰
Some patients in the RYBREVANT plus lazertinib arm were prescribed antibiotics for rash management (21%) or were on anticoagulants (5%) at treatment initiation.¹⁰

Patients With Key AEs, %	Time to Onset
Patients With Key AEs, %	0-4 Months	5-8 Months	9-12 Months
Rash	55	2	1
Paronychia	50	12	3
Dermatitis acneiform	25	1	1
Stomatitis	25	2	0.5
VTE	23	6	3
Peripheral edema	21	6	3
Pruritus	17	3	1
Fatigue	12	2	1

An exploratory analysis evaluated the effect of RYBREVANT dose interruptions in the first 4 months of RYBREVANT exposure on the efficacy and safety of first-line RYBREVANT plus lazertinib in patients enrolled in the MARIPOSA study with EGFR-mutated advanced NSCLC.¹¹
- Of the 421 patients who received ≥1 dose of RYBREVANT, 206 (49%) had a dose interruption within the first 4 months of RYBREVANT exposure.

Median PFS, ORR, and DOR in patients with and without RYBREVANT dose interruptions in the first 4 months of RYBREVANT exposure are comparable between the groups.
- Evaluating treatment outcomes during RYBREVANT exposure could lead to bias since disease progression or death could occur before RYBREVANT dose interruption. To minimize this bias, outcomes were evaluated after the first 4 months of RYBREVANT exposure.
At a median follow-up of 22 months (data cutoff: August 11, 2023), median PFS and proportion of patients who achieved PFS at 24 months with vs without RYBREVANT dose interruptions after the first 4 months of RYBREVANT exposure are comparable between the groups.

A multivariate analysis was conducted using a Cox proportional hazards model (adjusted for age, ECOG PS, EGFR mutation type, Asian race, and history of brain metastases) in patients still at risk for progression after 4 months of RYBREVANT exposure. No significant association was found between dose interruptions and PFS after 4 months of RYBREVANT exposure (HR, 1.06; 95% CI, 0.73-1.44).

Key AEs reported were rash, paronychia, hypoalbuminemia, dermatitis acneiform, stomatitis, decreased appetite, peripheral edema, and diarrhea.
- The prevalence of key AEs was comparable between patients with and without RYBREVANT dose interruptions during the first 4 months of RYBREVANT exposure.
- The prevalence of key AEs was also comparable between patients with and without RYBREVANT dose interruptions at 5-8 months of RYBREVANT exposure.
Key AEs occurred most frequently during the first 4 months and declined over the next 4 months.
- Notably, rash decreased by ~50%, paronychia by ~30%, and diarrhea by ~70%.
No grade 4 or 5 AEs were reported.

A randomized, double-blind, exploratory analysis evaluated the efficacy and safety of single-agent lazertinib^a (n=216) vs osimertinib (n=429) in patients with EGFR-mutated locally advanced or metastatic NSCLC enrolled in the MARIPOSA study.¹²

At a median follow-up of 22 months, median PFS by BICR for lazertinib vs osimertinib was 18.5 months (95% CI, 14.8-20.1) vs 16.6 months (95% CI, 14.8-18.5; HR, 0.98 [95% CI, 0.79- 1.22]; P=0.86).
- The PFS rates for lazertinib vs osimertinib were 52% vs 48% at 18 months and 35% vs 34% at 24 months, respectively.
ORR among all responders for lazertinib vs osimertinib was 83% (95% CI, 77-88) vs 85% (95% CI, 81-88; P=0.57).
Median TTSP (defined as the time from randomization to the first onset of new/worsening of lung cancer symptoms requiring a change in therapy, clinical intervention, or death) for lazertinib vs osimertinib was NE vs 29.3 months (95% CI, 25.3-NE; HR, 0.85 [95% CI, 0.65-1.13]; P=0.27).
At the interim analysis, median OS for lazertinib vs osimertinib was NE (HR, 1.00 [95% CI, 0.73- 1.38]; P=1.00).

Most TEAEs were grade 1-2 in severity for lazertinib and osimertinib.
Serious AEs were reported in 35% of patients treated with lazertinib and 33% of patients treated with osimertinib.
AEs leading to death were reported in 6% of patients treated with lazertinib and 7% of patients treated with osimertinib.
The incidence of ILD and pneumonitis was 3% for both lazertinib and osimertinib.
Higher incidence rates of rash (45% vs 31%), muscle spasms (23% vs 7%), and paresthesia (15% vs 6%) were reported with lazertinib vs osimertinib.
Lower incidence rates of diarrhea (32% vs 44%), thrombocytopenia (9% vs 20%), and neutropenia (3% vs 13%) were reported with lazertinib vs osimertinib.
Treatment-related discontinuations occurred in 5% of patients treated with lazertinib and 3% of patients treated with osimertinib.

^aLazertinib monotherapy was administered to evaluate the contribution of the components in the combination treatment.

An early analysis from the MARIPOSA study evaluated the mechanisms of acquired resistance to first-line RYBREVANT plus lazertinib vs osimertinib in patients with EGFR-mutant locally advanced or metastatic NSCLC.¹³
- The analysis of detectable ctDNA was conducted at baseline and EOT (defined as at disease progression/treatment discontinuation or within 90 days of discontinuation) by NGS of paired blood samples using Guardant 360® companion diagnostics.

Patient Disposition	RYBREVANT + Lazertinib (n=429)	Osimertinib (n=429)
Treatment ongoing, n	214	177
Discontinued treatment, n	215	252
EOT^a samples, n	119	155
Matched baseline and EOT^a ctDNA data, n (%)	113 (53)	140 (56)
^aSamples taken within 90 days of discontinuation if EOT sample was unavailable; last EOT sample was collected in February 2024. Median follow-up, 32.6 months.

Incidence of Mutations, %	RYBREVANT + Lazertinib (n=113)	Osimertinib (n=140)
MET- and EGFR-dependent resistance
MET amplification^a	4.4	13.6
P-value	0.017
Secondary EGFR resistance mutations^b	0.9	7.9
P-value	0.014
MET- and EGFR-independent resistance
HER2 amplification	7.1	3.6
RAS/RAF^c	9.7	12.1
PI3K	8	8.6
Cell cycle^d	13.3	8.6
TP53/RB1 loss	0.9	2.9
^aMET amplifications are defined as >2.2 copy number alterations. Focal MET amplification incidence: RYBREVANT plus lazertinib vs osimertinib, 1.8% vs 9.3%. ^bC797S, L718X, G724X. ^cIncludes BRAF and KRAS. ^dIncludes CCNE1, CDKN2A, CDK4, CDK6, and CCND2.

Resistance mechanisms were unknown for 77 (68%) patients in the RYBREVANT plus lazertinib arm and 86 (61%) patients in the osimertinib arm.¹³
For patients with EGFR/MET-dependent and -independent resistance mechanisms in the RYBREVANT plus lazertinib vs osimertinib arm, the frequency of complex resistance (defined as ≥2 resistance pathway alterations detected by ctDNA) was 27.8% vs 42.6%.¹³

Incidence, %	RYBREVANT + Lazertinib (n=36)	Osimertinib (n=54)
EGFR driver mutations (Exon19del or Exon 21 L858R)
Baseline	78.8	82.9
EOT	53.1	72.1
Other mutations
EOT	85	88.6

An analysis evaluated the patient-relevant outcomes in patients from MARIPOSA receiving RYBREVANT plus lazertinib (n=429) vs osimertinib (n=429) as first-line treatment for EGFR- mutated (Exon19del or Exon 21 L858R) locally advanced or metastatic NSCLC.¹⁴

At a median follow-up of 22 months, median TTSP^a for RYBREVANT plus lazertinib vs osimertinib was NE vs 29.3 months (95% CI, 25.3-NE; HR, 0.72 [95% CI, 0.57-0.91]; P=0.005^b).
- The proportion of patients without symptomatic progression in the RYBREVANT plus lazertinib and osimertinib arms was 74% and 67% at 18 months and 67% and 59% at 24 months, respectively.

No meaningful changes from baseline were observed in the global health status and cognitive functioning subscales across the RYBREVANT plus lazertinib and osimertinib arms.

Patient-reported total symptom scores and individual lung cancer-associated symptom scores for dyspnea, pain, and cough were comparable across the RYBREVANT plus lazertinib and osimertinib arms.

^aMedian TTSP with 95% CI was calculated using the Kaplan-Meier method.
^bHR with 95% CI calculated using a stratified Cox regression model; nominal P-value calculated using a stratified log-rank test.
^cBased on EORTC-QLQ-C30.
^dBased on NSCLC-SAQ; outcomes were measured on D1 of the cycle.

ADC	Antibody-drug conjugate	EOT	End of treatment
AE	Adverse event	Exon19del	Exon 19 deletion
ALK	Anaplastic lymphoma kinase	HR	Hazard ratio
ALT	Alanine aminotransferase	icDOR	Intracranial DOR
AST	Aspartate aminotransferase	icORR	Intracranial ORR
BICR	Blinded independent central review	icPFS	Intracranial PFS
C	Cycle	IgG1	Immunoglobulin G1
c-MET	c-mesenchymal-epithelial transition factor	ILD	Interstitial lung disease
CI	Confidence interval	IO	Immuno-oncology
COVID-19	Coronavirus disease 2019	IQR	Interquartile range
CR	Complete response	IRR	Infusion-related reaction
ctDNA	Circulating tumor DNA	IV	Intravenous
D	Day	LLN	Lower limit of normal
ddPCR	Droplet digital polymerase chain reaction	LVEF	Left ventricular ejection fraction
DOR	Duration of response	MET	Mesenchymal-epithelial transition
DVT	Deep vein thrombosis	NCCN	National Comprehensive Cancer Network
ECOG PS	Eastern Cooperative Oncology Group performance status	NE	Not estimable
EGFR	Epidermal growth factor receptor	NE/UNK	Not evaluable/unknown
EORTC- QLQ-C30	European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire	NGS	Next-generation sequencing

NSCLC	Non-small cell lung cancer	Q2W	Every 2 weeks
NSCLC- SAQ	Non-Small Cell Lung Cancer Symptom Assessment Questionnaire	QW	Once weekly
ORR	Objective response rate	R	Randomization
OS	Overall survival	RECIST	Response Evaluation Criteria in Solid Tumors
PD	Progressive disease	SD	Stable disease
PE	Pulmonary embolism	TEAE	Treatment-emergent AE
PFS	Progression-free survival	TKI	Tyrosine kinase inhibitor
PFS2	PFS after first subsequent therapy	TTD	Time to treatment discontinuation
PO	Orally	TTSP	Time to subsequent progression
PR	Partial response	TTST	Time to subsequent therapy
PRO	Patient-reported outcome	VEGFi	Vascular endothelial growth factor inhibitor
QD	Once daily	VTE	Venous thromboembolism

A literature search of MEDLINE®, Embase®, BIOSIS Previews®, and Derwent Drug File (and/or other resources, including internal/external databases) was conducted on 10 September 2024.

Moores SL, Chiu ML, Bushey BS, et al. A novel bispecific antibody targeting EGFR and cMet is effective against EGFR inhibitor-resistant lung tumors. Cancer Res. 2016;76(13):3942-3953.
Cho BC, Felip E, Hayashi H, et al. MARIPOSA: phase 3 study of first-line amivantamab + lazertinib versus osimertinib in EGFR-mutant non-small cell lung cancer. Future Oncol. 2022;18(6):639-647.
Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer V.11.2024. ©National Comprehensive Cancer Network, Inc. 2024. All rights reserved. Accessed October 16, 2024. To view the most recent and complete version of the guideline, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.
Janssen Research & Development, LLC. A phase 3, randomized study of amivantamab and lazertinib combination therapy versus osimertinib versus lazertinib as first-line treatment in patients with EGFR-mutated locally advanced or metastatic non-small cell lung cancer. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [cited 2024 September 10]. Available from: https://clinicaltrials.gov/ct2/show/NCT04487080 NLM Identifier: NCT04487080.
Cho BC, Lu S, Felip E, et al. Amivantamab plus lazertinib in previously untreated EGFR-mutated advanced NSCLC. N Engl J Med. 2024;391:1486-1498.
Felip E, Cho BC, Gutiérrez V, et al. Amivantamab plus lazertinib vs osimertinib in first-line EGFR-mutant advanced non- small cell lung cancer (NSCLC) with biomarkers of high-risk disease: a secondary analysis from the phase 3 MARIPOSA study. Oral Presentation presented at: American Society of Clinical Oncology (ASCO) Annual Meeting; May 31-June 4, 2024; Chicago, IL.
Gadgeel SM, Cho BC, Lu S, et al. Amivantamab plus lazertinib vs osimertinib in first-line EGFR-mutant advanced NSCLC: longer follow-up of the MARIPOSA study. Oral Presentation presented at: International Association for the Study of Lung Cancer (IASLC) World Conference on Lung Cancer (WCLC); September 7-10, 2024; San Diego, CA.
Felip E, Cho BC, Gutiérrez V, et al. Amivantamab plus lazertinib versus osimertinib in first-line EGFR-mutant advanced non-small cell lung cancer with biomarkers of high-risk disease: a secondary analysis from MARIPOSA Ann Oncol. 2024; 35(9):805-816.
Lu S, Cho BC, Lee JS, et al. Amivantamab plus lazertinib vs osimertinib as first-line treatment among Asian patients with EGFR-mutated, advanced non-small cell lung cancer (NSCLC): MARIPOSA subgroup analysis. Oral Presentation presented at: European Society for Medical Oncology (ESMO) Asia Congress; December 1-3, 2023; Singapore.
Spira AI, Spigel D, Nguyen D, et al. Amivantamab plus lazertinib versus osimertinib in first-line EGFR-mutant advanced NSCLC: a post-progression and safety analysis of MARIPOSA. Oral Presentation presented at: North America Conference on Lung Cancer (NACLC); December 1-3, 2023; Chicago, IL.
Campelo M del RG, Cho BC, Girard N, et al. Effect of amivantamab dose interruptions on efficacy and safety of first-line amivantamab plus lazertinib in EGFR-mutant advanced NSCLC: exploratory analyses from the MARIPOSA study. Oral Presentation presented at: European Lung Cancer Congress (ELCC); March 20-23, 2024; Prague, Czech Republic.
Lee S-H, Cho BC, Hayashi H, et al. Lazertinib vs osimertinib in 1L EGFR-mutant advanced NSCLC: a randomized, double-blind, exploratory analysis from MARIPOSA. Oral Presentation presented at: International Association for the Study of Lung Cancer (IASLC) World Conference on Lung Cancer (WCLC); September 7-10, 2024; San Diego, CA.
Besse B, Lee S-H, Lu S, et al. Mechanisms of acquired resistance to first-line amivantamab plus lazertinib versus osimertinib in patients with EGFR-mutant advanced non-small cell lung cancer: an early analysis from the phase 3 MARIPOSA study. Oral Presentation presented at: European Society for Medical Oncology (ESMO) Congress; September 13-17, 2024; Barcelona, Spain.
Nguyen D, Besse B, Cho BC, et al. Amivantamab plus lazertinib vs osimertinib in first-line, EGFR-mutant advanced NSCLC: patient-relevant outcomes from MARIPOSA. Oral Presentation presented at: International Association for the Study of Lung Cancer (IASLC) World Conference on Lung Cancer (WCLC); September 7-10, 2024; San Diego, CA.
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		Events/N
Subgroup	HR (95% CI)	RYBREVANT + Lazertinib	Osimertinib
All randomized patients	0.7 (0.58-0.85)	192/429	252/429
Age
< 65 years	0.5 (0.39-0.65)	94/235	153/237
≥ 65 years	1.06 (0.8-1.41)	98/194	99/192
< 75 years	0.7 (0.57-0.85)	165/378	220/376
≥ 75 years	0.77 (0.46-1.3)	27/51	32/53
Sex
Female	0.7 (0.55-0.9)	112/275	140/251
Male	0.74 (0.55-0.98)	80/154	112/178
Race
Asian	0.67 (0.52-0.86)	105/250	144/251
Non-Asian	0.75 (0.56-0.99)	85/117	108/177
Body Weight
< 80 kg	0.7 (0.57-0.86)	161/376	209/368
≥ 80 kg	0.77 (0.48-1.22)	31/53	43/61
ECOG PS
0	0.79 (0.56-1.12)	56/141	76/149
1	0.66 (0.52-0.82)	136/288	176/280
Smoking history
Yes	0.78 (0.56-1.08)	67/130	79/134
No	0.67 (0.53-0.84)	125/299	173/295
History of brain metastases
Yes	0.69 (0.53-0.92)	94/178	111/172
No	0.69 (0.53-0.89)	98/251	141/257
EGFR mutation
Exon19del	0.65 (0.51-0.85)	101/257	142/257
Exon 21 L858R	0.78 (0.59-1.02)	90/171	110/172

CI, confidence interval; ECOG PS, Eastern Cooperative Oncology Group performance status; EGFR, epidermal growth factor receptor; Exon19del, Exon 19 deletion; HR, hazard ratio; PFS, progression-free survival.

First Subsequent Therapy,^a,b %	First Subsequent Therapy,^a,b %	RYBREVANT+ Lazertinib (n=111)
Any TKI	42	28
TKI combination	8	7
Other TKIs	7	5
Osimertinib/other third-generation TKIs	27	16
Any chemotherapy	54	68
Doublet chemotherapy + IO/VEGFi	12	20
Doublet chemotherapy^d	41	45

^aPercentages were not provided for single-agent chemotherapy, single-agent chemotherapy + IO/VEGFi, VEGFi alone therapy, or other therapy (including herbals, ADCs, ALK TKIs, C-MET TKIs, RYBREVANT, and investigational agents) for both treatment arms.
^bPercentages may not sum to 100 due to rounding.
^cTwo patients in the osimertinib arm received RYBREVANT as a subsequent treatment (monotherapy, n=1; combination with lazertinib, n=1).
^dIncludes 1 patient who received herbal + doublet chemotherapy.
ADC, antibody-drug conjugate; ALK, anaplastic lymphoma kinase; c-MET, c-mesenchymal-epithelial transition factor; IO, immuno-oncology; TKI, tyrosine kinase inhibitor; VEGFi, vascular endothelial growth factor inhibitor.

Most Common (≥15% in Either Group) AEs, n (%)	RYBREVANT + Lazertinib (n=421)		Osimertinib (n=428)
Most Common (≥15% in Either Group) AEs, n (%)		All Grades	Grade ≥3	All Grades	Grade ≥3
Paronychia	288 (68)	46 (11)	121 (28)	2 (0.5)
IRR	265 (63)	27 (6)	0	0
Rash	260 (62)	65 (15)	131 (31)	3 (1)
Hypoalbuminemia	204 (48)	22 (5)	26 (6)	0
Increased ALT	152 (36)	21 (5)	57 (13)	8 (2)
Peripheral edema	150 (36)	8 (2)	24 (6)	0
Constipation	123 (29)	0	55 (13)	0
Diarrhea	123 (29)	9 (2)	190 (44)	3 (1)
Dermatitis acneiform	122 (29)	35 (8)	55 (13)	0
Stomatitis	122 (29)	5 (1)	90 (21)	1 (0.2)
Increased AST	121 (29)	14 (3)	58 (14)	5 (1)
COVID-19	111 (26)	8 (2)	103 (24)	9 (2)
Decreased appetite	103 (24)	4 (1)	76 (18)	6 (1)
Pruritus	99 (24)	2 (0.5)	73 (17)	1 (0.2)
Anemia	96 (23)	16 (4)	91 (21)	7 (2)
Nausea	90 (21)	5 (1)	58 (14)	1 (0.2)
Hypocalcemia	88 (21)	9 (2)	35 (8)	0
Asthenia	78 (19)	12 (3)	46 (11)	4 (1)
PE	73 (17)	35 (8)	20 (5)	10 (2)
Fatigue	70 (17)	6 (1)	42 (10)	4 (1)
Muscle spasms	70 (17)	2 (0.5)	32 (7)	0
Dry skin	67 (16)	1 (0.2)	60 (14)	1 (0.2)
Thrombocytopenia	66 (16)	1 (0.2)	84 (20)	5 (1)
Cough	65 (15)	0	88 (21)	0
Pain in extremity	64 (15)	1 (0.2)	22 (5)	0
Dyspnea	51 (12)	6 (1)	68 (16)	17 (4)
Leukopenia	26 (6)	1 (0.2)	66 (15)	0

^aThe safety population included all the patients who had undergone randomization and received ≥1 dose of any trial treatment.

AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; COVID-19, coronavirus disease 2019; IRR, infusion-related reaction; PE, pulmonary embolism.

	RYBREVANT + Lazertinib (n=421)	Osimertinib (n=428)
Any VTE,^a n (%)	157 (37)	39 (9)
Grade 1	5 (1)	0
Grade 2	105 (25)	24 (6)
Grade 3	43 (10)	12 (3)
Grade 4	2 (0.5)	1 (0.2)
Grade 5	2 (0.5)	2 (0.5)
Anticoagulant use, n (%)
At baseline	21 (5)	23 (5)
Concomitant use	199 (47)	81 (19)
First bleeding event while on anticoagulants	34 (8)	14 (3)
Recurrent VTE event while on anticoagulants	8 (2)	0
Median (range) onset to first VTE, days	84 (6-777)	194 (10-675)
Within first 4 months, n (%)	97/157 (62)	13/39 (33)
Any VTE leading to death, n (%)	2 (0.5)	2 (0.5)
Any VTE leading to any discontinuation of any agent, n (%)	12 (3)	2 (0.5)

^aVTE grouping includes the following preferred terms: PE, DVT, venous thrombosis limb, thrombosis, venous thrombosis, superficial vein thrombosis, thrombophlebitis, embolism, embolism venous, jugular vein thrombosis, pulmonary infarction, axillary vein thrombosis, portal vein thrombosis, post thrombotic syndrome, sigmoid sinus thrombosis, superior sagittal sinus thrombosis, vena cava thrombosis, pelvic venous thrombosis, and pulmonary thrombosis.
AE, adverse event; VTE, venous thromboembolism.

		Events/N
Subgroup	HR (95% CI)	RYBREVANT + Lazertinib (n=250)	Osimertinib (n=251)
All randomized patients	0.65 (0.5-0.83)	105/250	144/251
Age
<65 years	0.5 (0.36-0.7)	54/143	88/140
≥65 years	0.95 (0.65-1.39)	51/107	56/111
<75 years	0.65 (0.5-0.85)	92/224	131/227
≥75 years	0.79 (0.36-1.73)	13/26	13/24
Sex
Female	0.63 (0.45-0.88)	58/152	81/143
Male	0.72 (0.49-1.05)	47/98	63/108
Body Weight
<80 kg	0.67 (0.51-0.86)	96/236	133/238
≥80 kg	0.65 (0.27-1.58)	9/14	11/13
ECOG PS
0	0.73 (0.44-1.2)	25/69	41/84
1	0.62 (0.46-0.83)	80/181	103/167
History of smoking
Yes	0.69 (0.43-1.1)	33/70	39/70
No	0.65 (0.48-0.88)	72/180	105/181
History of brain metastases
Yes	0.72 (0.51-1.02)	61/110	70/108
No	0.57 (0.39-0.83)	44/140	74/143
EGFR mutation
Exon19del	0.61 (0.42-0.88)	48/137	73/139
Exon 21 L858R	0.71 (0.5-1)	56/112	71/112

CI, confidence interval; ECOG PS, Eastern Cooperative Oncology Group performance status; EGFR, epidermal growth factor receptor; HR, hazard ratio; PFS, progression-free survival.

BICR-Assessed Response	BICR-Assessed Response	RYBREVANT + Lazertinib (n=250)
ORR,^a % (95% CI)	88 (84-92)	85 (80-90)
Best response,^a n (%)
CR	19 (8)	10 (4)
PR	200 (81)	202 (81)
SD	15 (6)	25 (10)
PD	3 (1)	4 (2)
NE	11 (4)	7 (3)
Ongoing responses,^b n (%)	132 (64)	93 (49)

^aNumber of patients with measurable disease at baseline by BICR was 248 for both groups, including confirmed responders.
^bAmong confirmed responders.
BICR, blinded independent central review; CI, confidence interval; CR, complete response; NE, not estimable; ORR, objective response rate; PD, progressive disease; PR, partial response; SD, stable disease.

Most Common TEAEs (≥25%) by Preferred Term, n (%)	RYBREVANT + Lazertinib (n=248)		Osimertinib (n=250)
Most Common TEAEs (≥25%) by Preferred Term, n (%)		All Grades	Grade ≥3	All Grades	Grade ≥3
EGFR-related
Paronychia	182 (73)	21 (8)	79 (32)	2 (1)
Rash	158 (64)	41 (17)	82 (33)	2 (1)
Diarrhea	65 (26)	4 (2)	105 (42)	1 (0.4)
Dermatitis acneiform	73 (29)	21 (8)	36 (14)	0
Stomatitis	84 (34)	3 (1)	79 (32)	1 (0.4)
MET-related
Hypoalbuminemia	140 (56)	17 (7)	19 (8)	0
Peripheral edema	83 (33)	3 (1)	10 (4)	0
Other
IRR	150 (60)	7 (3)	0	0
ALT increased	89 (36)	10 (4)	40 (16)	4 (2)
Constipation	85 (34)	0	34 (14)	0
AST increased	77 (31)	8 (3)	43 (17)	3 (1)
COVID-19	66 (27)	4 (2)	62 (25)	5 (2)
Decreased appetite	70 (28)	4 (2)	44 (18)	2 (1)
VTE^a	77 (31)	22 (9)	14 (6)	5 (2)

^aGrouping includes the following preferred terms: PE, DVT, embolism, venous thrombosis limb, venous thrombosis, embolism venous, jugular vein thrombosis, pelvic venous thrombosis, portal vein thrombosis, pulmonary infarction, pulmonary thrombosis, superficial vein thrombosis, superior sagittal sinus thrombosis, thrombophlebitis, and thrombosis.

Abbreviations: AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; COVID-19, coronavirus disease 2019; DVT, deep vein thrombosis; EGFR, epidermal growth factor receptor; IRR, infusion-related reaction; MET, mesenchymal-epithelial transition; TEAE, treatment-emergent AE.

Patients with (n=188) and without (n=190) dose interruption^a in the first 4 months of RYBREVANT exposure were included in the analysis.
Patients who discontinued the study, had disease progression, or died in the first 4 months of RYBREVANT exposure (n=43; 10%) were excluded from the analysis.
Median time to first interruption was 43 days (IQR, 16-72).
Median duration of interruption in patients who resumed RYBREVANT (94%) was 22 days (IQR, 14-41).

Characteristic	Dose Interruption in the First 4 Months (n=188)	No Dose Interruption in the First 4 Months (n=190)
Median age, years (range)	63 (35-86)	62 (24-88)
Female, n (%)	120 (64)	120 (63)
Race, n (%)
Asian	108 (57)	114 (60)
Non-Asian	78 (41)	76 (40)
Unknown	2 (1)	0
ECOG PS 1, n (%)	122 (65)	127 (67)
History of smoking, n (%)	61 (32)	54 (28)
History of brain metastases, n (%)	80 (43)	71 (37)
EGFR mutation, n (%)
Exon19del	101 (54)	124 (65)
Exon 21 L858R	87 (46)	66 (35)

^aDose interruption was defined as missed doses that were not compensated for. This group of patients also included patients who had a dose reduction or discontinued treatment.

ECOG PS, Eastern Cooperative Oncology Group performance status; EGFR, epidermal growth factor receptor; Exon19del, Exon 19 deletion; IQR, interquartile range.

Outcome, Median (95% CI)	Dose Interruption (n=206)	No Dose Interruption (n=215)	All Randomized Patients (n=429)
PFS, months	23.9 (18.5-NE)	23.7 (18.4-NE)	23.7 (19.1-27.7)
ORR, %	87 (81-91)	89 (84-93)	86 (83-89)
DOR in confirmed responders, months	25.8 (16.7-NE)	26.1 (20.1-NE)	25.8 (20.1-NE)

CI, confidence interval; DOR, duration of response; NE, not estimable; ORR, objective response rate; PFS, progression-free survival.

Outcome	Dose Interruption (n=188)	No Dose Interruption (n=190)
Median PFS, months (95% CI)	27.5 (20.3-NE)	25.7 (22.2-NE)
Patients who achieved PFS at 24 months, %	52	52

CI, confidence interval; NE, not estimable; PFS, progression-free survival.

Prespecified Subgroup	Lazertinib vs Osimertinib HR (95% CI)
Asian race	1.02 (0.77-1.35)
EGFR mutation
Exon19del	1.03 (0.78-1.37)
Exon 21 L858R	0.91 (0.65-1.28)
High-risk Subgroup	Median PFS (95% CI), Months		HR (95% CI); P-Value
High-risk Subgroup		Lazertinib (n=216)	HR (95% CI); P-Value	Osimertinib (n=429)
History of brain metastases
Yes	n=86 16.4 (12.9-19.4)	n=172 13 (12.2-16.4)	0.90 (0.65-1.25); P=0.54
No	n=130	n=257	1.01 (0.75-1.35)
Detectable ctDNA at baseline
Present^a	n=115 18.4 (14.6-20.2)	n=274 14.8 (12.9-16.6)	0.88 (0.66-1.17); P=0.38
Absent	n=31	n=42	1.32 (0.99-1.75)
TP53 mutation status at baseline
TP53 co-mutations^a	n=62 14.6 (11.0-19.4)	n=144 12.9 (11.1-14.7)	0.85 (0.58-1.23); P=0.38
TP53 wild type	n=84	n=172	0.95 (0.71-1.26)

^aPathogenic alterations were detected with the Guardant Health G360^® panel.

CI, confidence interval; ctDNA, circulating tumor DNA; EGFR, epidermal growth factor receptor; Exon19del, Exon 19 deletion; HR, hazard ratio; PFS, progression-free survival.

BICR-Assessed Response^a	BICR-Assessed Response^a	Lazertinib (n=216)
ORR, % (95% CI)
All responders	83 (77-88)	85 (81-88)
Confirmed responders	75 (68-80)	76 (71-80)
Best response,^b n (%)
CR	9 (4)	15 (4)
PR	168 (79)	335 (81)
SD	23 (11)	42 (10)
PD	9 (4)	11 (3)
NE	5 (2)	11 (3)
Median DOR,^c months (95% CI)	16.6 (14.8-20.2)	16.8 (14.8-18.5)
Ongoing responses, n/n (%)	77/160 (48)	151/314 (48)

^aNumber of patients with measurable disease at baseline by BICR was 214 for lazertinib and 414 for osimertinib.
^bIncludes all responders.
^cAmong confirmed responders.

BICR, blinded independent central review; CI, confidence interval; CR, complete response; DOR, duration of response; NE, not evaluable; ORR, objective response rate; PD, progressive disease; PR, partial response; SD, stable disease.

Most Common TEAEs (≥20%) by Preferred Term, n (%)	Lazertinib (n=213)		Osimertinib (n=428)
Most Common TEAEs (≥20%) by Preferred Term, n (%)		Grade 1-2	Grade ≥3	Grade 1-2	Grade ≥3
EGFR inhibition-related
Diarrhea	64 (30)	4 (2)	187 (44)	3 (1)
Rash	91 (43)	4 (2)	128 (30)	3 (1)
Paronychia	59 (28)	2 (1)	119 (28)	2 (0.5)
Stomatitis	37 (17)	1 (0.5)	89 (21)	1 (0.2)
Dermatitis acneiform	45 (21)	0	55 (13)	0
Other
COVID-19	39 (18)	3 (1)	94 (22)	9 (2)
Cough	36 (17)	1 (0.5)	88 (21)	0
Anemia	40 (19)	3 (1)	84 (20)	7 (2)
Thrombocytopenia	19 (9)	1 (0.5)	79 (18)	5 (1)
AST increased	42 (20)	3 (1)	53 (12)	5 (1)
ALT increased	44 (21)	6 (3)	49 (11)	8 (2)
Muscle spasms	49 (23)	1 (0.5)	32 (7)	0

ALT, alanine aminotransferase; AST, aspartate aminotransferase; COVID-19, coronavirus disease 2019; EGFR, epidermal growth factor receptor; TEAE, treatment-emergent AE.

Patients, %	Lazertinib	Osimertinib	P-value
LVEF^a	1	4	0.056
QT interval prolongation^b
>450 msec	9	17	0.005
>500 msec	0	0.7	-

^aPatients with LVEF <LLN and >10% absolute decrease from baseline.
^bPatients with maximum postbaseline values.

LLN, lower limit of normal; LVEF, left ventricular ejection fraction.

RYBREVANT® (amivantamab-vmjw)

Medical Information

RYBREVANT, LAZCLUZE – MARIPOSA Study

Guidelines

MARIPOSA Study

MARIPOSA Study

MARIPOSA^2-5

Key Eligibility Criteria^2-5

Study Design^2-5

Efficacy Results^5,7

Safety Results⁵

Additional Analyses^6,8-14

Primary Endpoint

Secondary Endpoints

ORR and Best Response by BICR⁵

PFS Across Predefined High-Risk Disease Subgroups^6,8

Demographics and Baseline Disease Characteristics Among Asian Patients⁹

Medical inquiries

RYBREVANT® (amivantamab-vmjw)

Medical Information

RYBREVANT, LAZCLUZE – MARIPOSA Study

Guidelines

MARIPOSA Study

MARIPOSA Study

MARIPOSA2-5

Key Eligibility Criteria2-5

Study Design2-5

Efficacy Results5,7

Safety Results5

Additional Analyses6,8-14

MARIPOSA Study Design2-5,14

Primary Endpoint

Secondary Endpoints

Demographics and Baseline Disease Characteristics5,15

PFS By BICR Across Predefined Subgroups: RYBREVANT Plus Lazertinib vs Osimertinib

ORR and Best Response by BICR5

Intracranial Outcomes7

Post-Progression Outcomes7

First Subsequent Therapies

Safety Summary5

Summary of AEs

AEs of Special Interest: VTE

PFS Across Predefined High-Risk Disease Subgroups6,8

Demographics and Baseline Disease Characteristics Among Asian Patients9

Primary Endpoint9

Secondary Endpoints9

PFS Across Predefined Subgroups Among Asian Patients

ORR and Best Response by BICR Among Asian Patients

Safety Summary Among Asian Patients9

Summary of AEs Among Asian Patients

Post-Progression Treatment Outcomes10

Patient Disposition10

First Subsequent Therapies10

Summary of AEs for RYBREVANT Plus Lazertinib10

Patient Characteristics

Efficacy11

Efficacy in Patients With and Without Dose Interruptions in the First 4 Months of RYBREVANT Exposures

Efficacy in Patients With and Without Dose Interruptions After the First 4 Months of RYBREVANT Exposures

Safety11

Efficacy12

PFS Across Subgroups

ORR, Best Response, and DOR by BICR

Safety12

Summary of TEAEs

Cardiac Safety Profile of Lazertinib vs Osimertinib

Patient Disposition13

Acquired Resistance Mechanisms13

Incidence of Mutations at Baseline and EOT13

TTSP14

Patient-Reported Functioning14,c

Patient-Reported Symptom Scores14,d

Medical inquiries

MARIPOSA^2-5

Key Eligibility Criteria^2-5

Study Design^2-5

Efficacy Results^5,7

Safety Results⁵

Additional Analyses^6,8-14

MARIPOSA Study Design^2-5,14

Demographics and Baseline Disease Characteristics^5,15

PFS By BICR Across Predefined Subgroups:
RYBREVANT Plus Lazertinib vs Osimertinib

ORR and Best Response by BICR⁵

Intracranial Outcomes⁷

Post-Progression Outcomes⁷

Safety Summary⁵

PFS Across Predefined High-Risk Disease Subgroups^6,8

Demographics and Baseline Disease Characteristics Among Asian Patients⁹

Primary Endpoint⁹

Secondary Endpoints⁹

Safety Summary Among Asian Patients⁹

Post-Progression Treatment Outcomes¹⁰

Patient Disposition¹⁰

First Subsequent Therapies¹⁰

Summary of AEs for RYBREVANT Plus Lazertinib¹⁰

Efficacy¹¹

Safety¹¹

Efficacy¹²

Safety¹²

Patient Disposition¹³

Acquired Resistance Mechanisms¹³

Incidence of Mutations at Baseline and EOT¹³

TTSP¹⁴

Patient-Reported Functioning^14,c

Patient-Reported Symptom Scores^14,d