This information is intended for US healthcare professionals to access current scientific information about J&J Innovative Medicine products. It is prepared by Medical Information and is not intended for promotional purposes, nor to provide medical advice.
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 LAZCLUZE combination therapy (open-label, n=429) vs osimertinib (double-blind, n=429) vs LAZCLUZE (double-blind, n=216) as first-line treatment in patients with EGFR-mutated (Exon19del or Exon 21 L858R) locally advanced or metastatic NSCLC. The primary endpoint is PFS, based on BICR.2,4,5
At the primary analysis (median follow-up of 22 months)5,6:
Median PFS by BICR for RYBREVANT plus LAZCLUZE 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 LAZCLUZE 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% vs 43% of patients in the RYBREVANT plus LAZCLUZE vs osimertinib arm. VTE rates were increased with RYBREVANT plus LAZCLUZE vs osimertinib. TRAEs leading to discontinuation of all agents occurred in 10% vs 3% of patients in the RYBREVANT plus LAZCLUZE vs osimertinib arm.5
At the long-term follow-up analysis (median follow-up of 31.1 months)7:
Median OS for RYBREVANT plus LAZCLUZE vs osimertinib was NE vs 37.3 months (95% CI, 32.5-NE; HR, 0.77 [95% CI, 0.61-0.96]; P=0.019a).
For patients with a history of brain metastases, median icPFS for RYBREVANT plus LAZCLUZE 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=0.165a).
At the final OS analysis (median follow-up of 37.8 months)8:
Median OS was NE (95% CI, 42.9-NE) for RYBREVANT plus LAZCLUZE and 36.7 months (95% CI, 33.4-41) for osimertinib (HR, 0.75 [95% CI, 0.61-0.92]; P=0.005).b
For patients with a history of brain metastases, median icPFS for RYBREVANT plus LAZCLUZE vs osimertinib was 25.4 months (95% CI, 20.1-29.5) vs 22.2 months (95% CI, 18.4-26.9; HR, 0.79 [95% CI, 0.61-1.02]).c
Grade ≥3 AEs occurred in 80% vs 52% of patients in the RYBREVANT plus LAZCLUZE vs osimertinib arm. No new safety signals were observed, with the first onset of key AEs occurring in the first 4 months.
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. bThe exact significance level for the OS analysis was determined using the O’Brien-Fleming alpha spending function, as applied through the Lan-DeMets method. P-value was calculated at a 2-sided significance level of 0.0484. cAssessed by BICR and estimated using the Kaplan-Meier method. The 95% CI for HR has not been adjusted for multiplicity and should not be used to infer definitive treatment effects.
MARIPOSA study
A secondary analysis in high-risk patients reported6,9:
For patients with high-risk disease (≥1 high-risk feature at baseline), median
PFS by BICR for
RYBREVANT plus LAZCLUZE (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).
At a median follow-up of 22.5 months, median PFS by BICR for RYBREVANT plus
LAZCLUZE 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<0.001a).
EGFR- and MET-related AEs were increased with RYBREVANT plus LAZCLUZE vs
osimertinib
and were mostly grade 1-2. VTE rates were also increased with RYBREVANT plus
LAZCLUZE vs
osimertinib and were mostly grade 1-2. There were no grade 4-5 VTEs.
A postprogression and safety analysis reported11:
At a median follow-up of 22 months, in the RYBREVANT plus LAZCLUZE 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=0.21a), 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=0.05a).
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 reported12:
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 months (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 LAZCLUZE vs osimertinib reported13:
At a median follow-up of 22 months, median PFS by BICR for LAZCLUZE 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 LAZCLUZE and osimertinib.
A ctDNA analysis for acquired resistance reported14:
In the RYBREVANT plus LAZCLUZE (n=148) vs osimertinib (n=198) arm, 3.4% vs 13.1% of patients had MET amplifications (P=0.002) and 1.4% vs 7.6% of patients had secondary EGFR resistance mutations (P=0.01).
A patient-relevant outcome analysis for TTSP and PROs reported15:
At a median follow-up of 22 months, median TTSP for RYBREVANT plus LAZCLUZE
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 LAZCLUZE 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.
MARIPOSA2,4,5
MARIPOSA (NCT04487080) is an
ongoing, phase 3, randomized study
designed to evaluate the efficacy
and safety of RYBREVANT and
LAZCLUZE combination therapy (open-label, n=429) vs osimertinib (double-blind, n=429) vs LAZCLUZE (double-blind, n=216) as first-line treatment
in patients with EGFR-mutated (Exon19del or
Exon 21 L858R) locally
advanced or metastatic NSCLC.
N=1074
Key eligibility criteria2,4,5
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 design2,4,5
Efficacy results5,7,8
At the primary analysis (median follow-up, 22 months),
median PFS by BICR was
23.7 months (95% CI, 19.1-27.7)
for RYBREVANT plus LAZCLUZE 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 LAZCLUZE vs
osimertinib was 60% (95% CI,
55-64) vs 48% (95% CI, 43-53).
The 24-month PFS for
RYBREVANT plus LAZCLUZE 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 LAZCLUZE monotherapy.5
At the long-term follow-up analysis (median follow-up of 31.1 months): median OS was NE for RYBREVANT plus LAZCLUZE and 37.3 months (95% CI, 32.5-NE) for osimertinib (HR, 0.77; 95% CI, 0.61-0.96; P=0.019d).7
At the final OS analysis (median follow-up of 37.8 months): median OS was NE (95% CI, 42.9-NE) for RYBREVANT plus LAZCLUZE and 36.7 months (95% CI, 33.4-41) for osimertinib (HR, 0.75; 95% CI, 0.61-0.92; P=0.005).8,e
Safety results5,8
At the primary analysis5:
Grade ≥3 AEs occurred in 75% vs 43% of patients in the RYBREVANT plus LAZCLUZE vs osimertinib arm.
TRAEs leading to discontinuation of all agents occurred in 10% vs 3% of patients in the RYBREVANT plus LAZCLUZE vs osimertinib arm.
VTE rates were higher with RYBREVANT plus LAZCLUZE vs osimertinib.
At the final OS analysis8:
Grade ≥3 AEs occurred in 80% vs 52% of patients in the RYBREVANT plus LAZCLUZE vs osimertinib arm.
No new safety signals were observed.
The first onset of key AEs occurred in the first 4 months.
Additional analyses6,9-15
Secondary analysis of high-risk patients6,9: HR (95% CI) for
median PFS: 0.72 (0.58-0.90; P=0.004) for RYBREVANT
plus LAZCLUZE vs osimertinib.
Subgroup analysis in Asian patients10: HR (95% CI) for
median PFS: 0.65 (0.50-0.83; P<0.001d) for RYBREVANT
plus LAZCLUZE vs osimertinib. Safety profile: comparable to
the overall MARIPOSA study.
Postprogression and safety analysis11: HR (95% CI) for
median TTD and TTST: 0.88 (0.73-1.07; P=0.21d) and 0.82
(0.66-1; P=0.05d) for RYBREVANT plus LAZCLUZE vs
osimertinib. Key AEs occurred within the first 4 months;
late onset AEs were uncommon.
Exploratory analyses12,13:
Patients with vs without RYBREVANT dose interruption: median PFS: 27.5 vs 25.7 months after 4 months. The prevalence of key AEs was comparable at all timepoints.12
LAZCLUZE vs osimertinib: median PFS: 18.5 vs 16.6 months. Most TEAEs were grade 1-2.13
ctDNA analysis for acquired resistance14: MET amplifications, 3.4% vs 13.1% (P=0.002); secondary EGFR resistance mutations, 1.4% vs 7.6% (P=0.01) for RYBREVANT plus LAZCLUZE (n=148) vs osimertinib (n=198).
Patient-relevant outcome analysis15: HR (95% CI) for median TTSP: 0.72 (0.57-0.91; P=0.005) for RYBREVANT plus LAZCLUZE vs osimertinib. No meaningful changes from baseline were observed in patient-reported functioning.
Note: AE, adverse event; BICR, blinded independent central review; C, cycle; CI,
confidence interval; ctDNA, circulating tumor DNA; 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; Q2W, every 2 weeks; QD, once daily; Q2W, every 2
weeks; QW, once a week;
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. eThe exact significance level for the OS analysis was determined using the O’Brien-Fleming alpha spending function, as applied through the Lan-DeMets method. P-value was calculated at a 2-sided significance level of 0.0484.
MARIPOSA (NCT04487080) is an ongoing, phase 3, randomized study designed to evaluate the
efficacy
and safety of RYBREVANT and LAZCLUZE combination therapy (open-label, n=429) vs osimertinib
(double-blind, n=429) vs LAZCLUZE (double-blind, n=216) as first-line treatment in patients
with EGFR-mutated (Exon19del or Exon 21 L858R) locally advanced or metastatic NSCLC.2,4,5
MARIPOSA study design2,4,5,15
Primary endpoint
PFS by BICR per RECIST v1.1 in arm A vs arm B
Secondary endpoints
Arm A vs arm B
OSe
PFS2
Safety
ORR
Symptomatic PFSf
TTSPg
DOR
icPFS
PROh
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 LAZCLUZE (n=429),
osimertinib (n=429), or LAZCLUZE (n=216).5
Demographics and baseline disease characteristics5,16
Characteristic
RYBREVANT
+ LAZCLUZE
(n=429)
Osimertinib
(n=429)
LAZCLUZE
(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 + LAZCLUZE 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 LAZCLUZE 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 LAZCLUZE vs osimertinib was 73% (95% CI,
69-77) vs
65% (95% CI, 60-69).
The 18-month PFS for RYBREVANT plus LAZCLUZE vs osimertinib was 60% (95% CI,
55-64) vs
48% (95% CI, 43-53).
The 24-month PFS for RYBREVANT plus LAZCLUZE 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 LAZCLUZE
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
LAZCLUZE 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 LAZCLUZE 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 LAZCLUZE 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
LAZCLUZE 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 LAZCLUZE 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 responsea
RYBREVANT + LAZCLUZE (n=429)
Osimertinib
(n=429)
ORR, % (95% CI)
All responders
86 (83-89)
85 (81-88)
OR, 1.15 (0.78-1.70)b
Confirmed responders
80 (76-84)
76 (71-80)
Best responses,c n (%)
CRc
29 (7)
15 (4)
PRc
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 + LAZCLUZE and 414
for osimertinib. bThe OR 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 LAZCLUZE vs osimertinib was NE vs 37.3 months (95% CI, 32.5-NE;
HR, 0.77
[95% CI, 0.61-0.96];
P=0.019a).7
The OS rates for RYBREVANT plus LAZCLUZE vs osimertinib were 75% vs 70%
at 24 months
and 61% vs 53% at 36 months, respectively.
Intracranial outcomes7
In patients with a history of brain metastases, median icPFS (defined as the
time from
randomization until the date of intracranial disease progressionb or
death) by BICR for RYBREVANT
plus LAZCLUZE 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=0.165c).
The icPFS rates for RYBREVANT plus LAZCLUZE 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
LAZCLUZE 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 LAZCLUZE vs osimertinib were 59% vs
52% at 24 months
and 51% vs 0% at 36 months, respectively.
The icORR for RYBREVANT plus LAZCLUZE 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.
Postprogression
outcomes7
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
LAZCLUZE 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=0.014a).
At 24 and 36 months, respectively, 52% vs 46% and 40% vs 29% of patients in
the
RYBREVANT plus LAZCLUZE 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 LAZCLUZE 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=0.005a).
At 24 and 36 months, respectively, 57% vs 50% and 45% vs 32% of patients in
the
RYBREVANT plus LAZCLUZE vs osimertinib arm did not initiate the first
subsequent
therapy.
In the RYBREVANT plus LAZCLUZE 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 LAZCLUZE 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=0.004a).
The PFS2 rates for RYBREVANT plus LAZCLUZE vs osimertinib were 73% vs 65% at
24 months
and 57% vs 49% at 36 months, respectively.
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.
Efficacy was evaluated at a median follow-up of 37.8 months (range, 0-48.1; data cutoff: December 04, 2024).8
Median OSa was NE (95% CI, 42.9-NE) for RYBREVANT plus LAZCLUZE and 36.7 months (95% CI, 33.4-41) for osimertinib (HR, 0.75 [95% CI, 0.61-0.92]; P=0.005).8,b,c
The 12-month OS rate for RYBREVANT plus LAZCLUZE vs osimertinib was 90% (95% CI, 86-92) vs 88% (95% CI, 84-91).
The 24-month OS rate for RYBREVANT plus LAZCLUZE vs osimertinib was 75% (95% CI, 71-79) vs 70% (95% CI, 65-74).
The 36-month OS rate for RYBREVANT plus LAZCLUZE vs osimertinib was 60% (95% CI, 55-64) vs 51% (95% CI, 46-55).
At the data cutoff, 161 patients (38%) in the RYBREVANT plus LAZCLUZE arm and 118 patients (28%) in the osimertinib arm remained on treatment.8
Based on an exponential distribution assumption, median OS with RYBREVANT plus LAZCLUZE is projected to be 48.9 months (calculated by dividing median OS of 36.7 months with osimertinib by an HR of 0.75), indicating a survival benefit of 12.2 months over osimertinib.17
aThe exact significance level for the OS analysis was determined using the O’Brien-Fleming alpha spending function, as applied through the Lan-DeMets method. bP-value was subsequently evaluated at a 2-sided significance level of 0.0484 using a log-rank test stratified by EGFR mutation type, Asian race, and history of brain metastases.8,17 cMedian OS and corresponding 95% CIs were estimated using the Kaplan-Meier method.17
Postprogression outcomes8
Median TTSP for RYBREVANT plus LAZCLUZE vs osimertinib was 43.6 months (95% CI, 36-NE) vs 29.3
months (95% CI, 26.4-33.4; HR, 0.69 [95% CI, 0.57-0.83]).a
The TTSP rate for RYBREVANT plus LAZCLUZE vs osimertinib was 66% vs 58% at 24 months, 55% vs 42% at 36
months, and 51% vs 35% at 42 months.18
Median TTD for RYBREVANT plus LAZCLUZE vs osimertinib was 27 months (95% CI, 22.3-30.6) vs 22.6 months (95% CI,
20.3-24.5; HR, 0.79 [95% CI, 0.67-0.93]).a
In the RYBREVANT plus LAZCLUZE vs osimertinib arm, 41% (n=175) vs 60% (n=258) of patients had disease
progression and discontinued treatment, among whom 74% and 76%, respectively, received subsequent anticancer
therapy.
In both arms, chemotherapy-based regimens were the most common subsequent therapy.
Median TTST for RYBREVANT plus LAZCLUZE vs osimertinib was 30.3 months (95% CI, 26.6-34.4) vs 24 months (95% CI, 22.2-26.2; HR, 0.76 [95% CI, 0.64-0.9]).a
Median PFS2 for RYBREVANT plus LAZCLUZE vs osimertinib was 42.9 months (95% CI, 37.6-NE) vs 32.8 months (95% CI, 29.7-37; HR, 0.74 [95% CI, 0.61-0.9]).a
Intracranial outcomes8,b
In patients with a history of brain metastases, median icPFS for RYBREVANT plus LAZCLUZE (n=178) vs osimertinib (n=173) was 25.4 months (95% CI, 20.1-29.5) vs 22.2 months (95% CI, 18.4-26.9; HR, 0.79 [95% CI, 0.61-1.02]).a,c
The 12-month icPFS rate for RYBREVANT plus LAZCLUZE vs osimertinib was 72% (95% CI, 64-78) vs 75% (95% CI, 68-81).
The 24-month icPFS rate for RYBREVANT plus LAZCLUZE vs osimertinib was 51% (95% CI, 44-59) vs 48% (95% CI, 40-56).
The 36-month icPFS rate for RYBREVANT plus LAZCLUZE vs osimertinib was 36% (95% CI, 28-43) vs 18% (95% CI, 12-25).
In patients with baseline brain lesions, the icORR for RYBREVANT plus LAZCLUZE (n=180) vs osimertinib (n=186) was 78% (95% CI, 71-84) vs 77% (95% CI, 71-83; OR, 1.01 [95% CI, 0.61-1.65]).a,d
Confirmed intracranial response for RYBREVANT plus LAZCLUZE vs osimertinib was observed in 69% (95% CI, 62-76) vs 70% (95% CI, 63-76) of patients.
Among confirmed responders, median icDOR for RYBREVANT plus LAZCLUZE (n=125) vs osimertinib (n=130) was 35.7 months (95% CI, 25.8-NE) vs 29.6 months (95% CI, 23.9-34.1).c
aThe 95% CI for HR has not been adjusted for multiplicity and should not be used to infer definitive treatment effects. bAssessed by BICR. cEstimated using the Kaplan-Meier method. dThe OR was calculated from a logistic-regression model stratified by EGFR mutation type and Asian race.
Median duration of treatment was 18.5 months (range, 0.2-31.4) for RYBREVANT
plus LAZCLUZE
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 LAZCLUZE compared with osimertinib.5
IRR (5%), rash (3%), and paronychia (3%) were the most common causes of
treatment discontinuation in the RYBREVANT plus LAZCLUZE group.
TRAEs leading to discontinuation of all agents occurred in 10% of patients
treated
with RYBREVANT plus LAZCLUZE and in 3% with osimertinib.5
Safety summary5
TEAEs, n (%)
RYBREVANT + LAZCLUZE
(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 LAZCLUZE
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 LAZCLUZE 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 LAZCLUZE arm occurred within the first 4
months.5
Rates of treatment discontinuations due to VTE were low and comparable between
both
arms.5
Patients receiving the combination of RYBREVANT and LAZCLUZE 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 patients to tolerate prophylactic-dose anticoagulation was
performed at the discretion of the treating investigator. If a VTE event was
diagnosed, the patient 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.19
Prophylactic dose anticoagulation is recommended for the first 4 months of
treatment in ongoing trials of RYBREVANT plus LAZCLUZE.5
Median duration of treatment was 27 months (range, 0.2-47.2) for RYBREVANT plus
LAZCLUZE and 22.4 months (range, 0.2-48.5) for osimertinib.8
Most AEs were related to EGFR and MET inhibition.8
Safety summary8,17,a
n (%)
RYBREVANT + LAZCLUZE (n=421)
Osimertinib (n=428)
Any AE
421 (100)
426 (100)
Grade ≥3 AEs
337 (80)
224 (52)
Serious AEs
233 (55)
177 (41)
AEs leading to death
37 (9)
34 (8)
AEs leading to death within 6 months of randomization
29 (7)
19 (4)
TRAEs
5 (1)b
1 (<1)
AEs unrelated to treatment
19 (5)
14 (3)
PD
5 (1)
4 (1)
aThe safety population included all the patients who had
undergone randomization and received ≥1 dose of any trial
treatment. bTRAEs leading to death within 6 months
of randomization to the RYBREVANT + LAZCLUZE arm included bone
marrow failure, hypersensitivity pneumonitis, pneumonitis, and
sudden death.
No new safety signals were observed with longer follow-up.8
The first onset of key AEs was reported in the first 4 months.8
In 21% of patients, antibiotics were prescribed for rash at study
initiation.18
VTEa occurred in 40% of patients in the RYBREVANT plus LAZCLUZE arm and
11% of patients in the osimertinib arm.8
VTEs can be managed with prophylactic anticoagulation for the first 4 months
of treatment and per local guidelines.
At baseline, 5% of patients received anticoagulation.8
aVTE, a grouped term including PE, DVT, limb venous thrombosis, venous
thrombosis, thrombosis, superficial vein thrombosis, thrombophlebitis, embolism, venous
embolism, jugular vein thrombosis, sigmoid sinus thrombosis, axillary vein thrombosis,
pulmonary infarction, vena cava thrombosis, central venous catheterization, portal vein
thrombosis, post thrombotic syndrome, pulmonary thrombosis, superior sagittal sinus
thrombosis, transverse sinus thrombosis, pelvic venous thrombosis, and superior vena
cava syndrome.
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 LAZCLUZE (n=429) or osimertinib
(n=429) were
included.6,9
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 LAZCLUZE, n=280; osimertinib, n=288) was 20.3 months (95% CI,
18.2-24.0)
for RYBREVANT plus LAZCLUZE 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.6,9
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
LAZCLUZE vs osimertinib arms.6,9
PFS across predefined high-risk disease subgroups6,9
Subgroup
Median PFS (95% CI),
Months
HR (95% CI);
P-Valueb
RYBREVANT +
LAZCLUZE
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 ddPCRa
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 plus LAZCLUZE 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 LAZCLUZE (n=250) or osimertinib
(n=251).10
Demographics and baseline disease characteristics among asian patients10
Characteristic
RYBREVANT + LAZCLUZE
(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 + LAZCLUZE arm had both
Exon19del and Exon 21 L858R.
Primary
endpoint10
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 LAZCLUZE and 18.3 months (95% CI, 15.8-20.2) for
osimertinib (HR, 0.65;
95% CI, 0.50-0.83;
P<0.001a).
PFS rates at 12 months were 76% and 66% for RYBREVANT plus LAZCLUZE 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 LAZCLUZE
monotherapy.
PFS across predefined clinically relevant subgroups was evaluated
for RYBREVANT plus LAZCLUZE vs
osimertinib.
Secondary
endpoints10
Median DOR among confirmed responders by BICR was 26.1 months (95% CI, 20.1-NE)
for
RYBREVANT plus LAZCLUZE 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=0.17a); the
HR for interim OS was 0.84 (95% CI, 0.58-1.23; P=0.38a).
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.
Median duration of treatment was 19.8 months for RYBREVANT plus LAZCLUZE and
18.7 months for osimertinib.10
Grade ≥3 AEs, serious AEs, and AEs leading to treatment
interruptions, reductions, or
discontinuations of any agent were higher with RYBREVANT plus LAZCLUZE
compared with
osimertinib.10
TRAEs leading to discontinuation of all agents occurred in 9% of patients
treated with RYBREVANT plus LAZCLUZE.10
Safety summary among asian patients10
TEAEs, n (%)
RYBREVANT +
LAZCLUZE
(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 agenta
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
LAZCLUZE compared with
osimertinib and were mostly grade 1-2.10
Grade ≥3 AEs in the RYBREVANT plus LAZCLUZE arm were driven by grade 3
events.10
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 LAZCLUZE vs 3% for
osimertinib.10
VTE rates were higher with RYBREVANT plus LAZCLUZE compared
with osimertinib.10
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 LAZCLUZE arm occurred within the first 4
months and were
effectively managed with anticoagulants.10
An analysis assessed postprogression treatment outcomes and safety in patients
from MARIPOSA receiving RYBREVANT plus LAZCLUZE (open-label) vs osimertinib (double-blind)
as first-line
treatment for EGFR-mutated (Exon19del or Exon 21 L858R) locally advanced or
metastatic
NSCLC.11
Postprogression treatment outcomes11
At a median follow-up of 22 months, 35% (147/421) of patients in the RYBREVANT
plus LAZCLUZE
arm and 47% (203/428) of patients in the osimertinib arm had PD.
Among patients with PD, 53% (78/147) in the RYBREVANT plus LAZCLUZE 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 LAZCLUZE vs 23
months
(95% CI, 20.3-25.3) for osimertinib (HR, 0.88; [95% CI, 0.73-1.07]; P=0.21a).
At follow-up, 116 patients in the RYBREVANT plus LAZCLUZE 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
LAZCLUZE and osimertinib treatment arms, respectively.
Patient disposition11
Patient disposition
Patient disposition
RYBREVANT +
LAZCLUZE
(n=421)
Osimertinib
(n=428)
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 LAZCLUZE vs 24.1
months (95% CI, 22-29) for osimertinib (HR, 0.82 [95% CI, 0.66-1]; P=0.05a).
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 therapies11:
After RYBREVANT plus LAZCLUZE were doublet chemotherapy (36%) and
third-generation TKIs
(24%).
After osimertinib were doublet chemotherapy (38%) and doublet chemotherapy
plus IO/VEGFi (22%).
First subsequent therapies11
First subsequent therapies,a %
First subsequent therapies,a %
RYBREVANT +
LAZCLUZE
(n=78)
Osimertinib
(n=124)
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 LAZCLUZE arm.
Median duration of exposure was 18.5 months for RYBREVANT plus
LAZCLUZE.11
Key AEs occurred within the first 4 months of treatment. Late onset AEs were
uncommon.11
Some patients in the RYBREVANT plus LAZCLUZE arm were prescribed antibiotics
for rash
management (21%) or were on anticoagulants (5%) at treatment
initiation.11
Summary of AEs for RYBREVANT plus LAZCLUZE11
Patients with key AEs, %
Time to onset
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
LAZCLUZE in
patients enrolled in the MARIPOSA study with EGFR-mutated advanced
NSCLC.12
Of the 421 patients who received ≥1 dose of RYBREVANT, 206 (49%) had a
dose interruption
within the first 4 months of RYBREVANT exposure.
Efficacy12
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).
Safety12
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 LAZCLUZEa (n=216) vs osimertinib (n=429) in patients with EGFR-mutated
locally
advanced or metastatic NSCLC enrolled in the MARIPOSA study.13
Efficacy13
At a median follow-up of 22 months, median PFS by BICR for LAZCLUZE 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 LAZCLUZE vs osimertinib were 52% vs 48% at 18 months and
35% vs 34%
at 24 months, respectively.
ORR among all responders for LAZCLUZE 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 LAZCLUZE 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 LAZCLUZE vs osimertinib was NE (HR, 1.00 [95% CI, 0.73-1.38]; P=1.00).
Safety13
Most TEAEs were grade 1-2 in severity for LAZCLUZE and osimertinib.
Serious AEs were reported in 35% of patients treated with LAZCLUZE and 33% of
patients treated with osimertinib.
AEs leading to death were reported in 6% of patients treated with LAZCLUZE and
7% of patients treated with osimertinib.
The incidence of ILD and pneumonitis was 3% for both LAZCLUZE and osimertinib.
Higher incidence rates of rash (45% vs 31%), muscle spasms (23% vs 7%), and
paresthesia (15% vs 6%) were reported with LAZCLUZE vs osimertinib.
Lower incidence rates of diarrhea (32% vs 44%), thrombocytopenia (9% vs 20%), and
neutropenia (3% vs 13%) were reported with LAZCLUZE vs osimertinib.
Treatment-related discontinuations occurred in 5% of patients treated with
LAZCLUZE and 3% of patients treated with osimertinib.
aLAZCLUZE monotherapy was administered to evaluate the contribution of
the components in the combination treatment.
An early analysis (median follow-up of 32.6 months) from the MARIPOSA study evaluated the mechanisms of acquired resistance to first-line RYBREVANT plus LAZCLUZE vs osimertinib in patients with EGFR-mutant locally advanced or metastatic NSCLC.20
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.
An updated analysis (median follow-up of 39.3 months) evaluated the mechanisms of acquired resistance to first-line RYBREVANT plus LAZCLUZE vs osimertinib.14
Patient disposition14
Patient disposition, n
RYBREVANT +
LAZCLUZE
(n=429)
Osimertinib
(n=429)
Treatment ongoing
159
113
Discontinued treatment
270
316
With baseline ctDNA data
187
218
EOTa samples
158
214
Matched baseline and EOTa ctDNA data
148
198
aSamples taken within 90 days of discontinuation if EOT sample was unavailable; last EOT sample was collected in December 2024. Among the matched baseline and EOT subset, median follow-up was 39.3 months.
Acquired resistance mechanisms by pathway14
Incidence of mutations, %
RYBREVANT + LAZCLUZE
(n=148)
Osimertinib
(n=198)
MET- and EGFR-dependent resistance
MET amplificationa
3.4
13.1
P-value
0.002
Secondary EGFR resistance
mutationsb
1.4
7.6
P-value
0.01
MET- and EGFR-independent resistance
HER2 amplification
8.8
4.5
PI3K
8.1
9.1
RAS/RAFc
10.1
11.6
Other RTK
2
4.5
Cell cycled
12.8
9.6
TP53/RB1 loss
1.4
2.5
aMET amplifications are defined as >2.2 copy number alterations.20 bC797S, L718X, and G724X. cIncludes BRAF, KRAS, NRAS, PTPN11, and RAF1. dIncludes CCNE1, CDK4, CDKN2A, CCND2,
CDK6, and CCND1.
No clear resistance mechanisms (unknown) were reported for 68% of patients in the RYBREVANT plus LAZCLUZE arm and 59% of patients in the osimertinib arm.14
No acquired MET amplifications were reported in 98% (99/101) of patients receiving RYBREVANT for ≥6 months.14
No acquired EGFR C797S mutations were reported in patients (0/101) receiving RYBREVANT for ≥1 months.14
The incidence of acquired MET amplifications with RYBREVANT plus LAZCLUZE vs osimertinib in association with timing of treatment discontinuation was as follows14:
Discontinuation within 6 months: 4% (1/27) vs 23% (5/22)
Discontinuation within 9 months: 5% (2/37) vs 21% (9/44)
Discontinuation within 12 months: 4% (2/54) vs 19% (12/64)
No MET amplifications were reported at baseline. Acquired EGFR mutations occurred after 12 months, with incidence in the RYBREVANT plus LAZCLUZE arm remaining <2% at all timepoints.14
The incidence of ≥2 pathogenic alterations at EOT was 54.7% with RYBREVANT plus LAZCLUZE and 67.2% with osimertinib (P=0.02).14
The index of overall mutational heterogeneitya (EGFR/MET dependent and independent) at EOT was reported for RYBREVANT plus LAZCLUZE vs osimertinib (P=0.0073).14
aIndex of mutational heterogeneity was calculated using the Shannon Index integrating the total number of somatic variants and their respective allele frequencies using all somatic variants.
An analysis evaluated the patient-relevant outcomes in patients from MARIPOSA
receiving
RYBREVANT plus LAZCLUZE (n=429) vs osimertinib (n=429) as first-line treatment for
EGFR-
mutated (Exon19del or Exon 21 L858R) locally advanced or metastatic
NSCLC.15
TTSP15
At a median follow-up of 22 months, median TTSPa for RYBREVANT plus LAZCLUZE vs
osimertinib was NE vs 29.3 months (95% CI, 25.3-NE; HR, 0.72 [95% CI, 0.57-0.91];
P=0.005b).
The proportion of patients without symptomatic progression in the RYBREVANT
plus LAZCLUZE
and osimertinib arms was 74% and 67% at 18 months and 67% and 59% at 24 months,
respectively.
Patient-reported
functioning15,c
No meaningful changes from baseline were observed in the global health status and
cognitive
functioning subscales across the RYBREVANT plus LAZCLUZE and osimertinib arms.
Patient-reported
symptom scores15,d
Patient-reported total symptom scores and individual lung cancer-associated symptom
scores for dyspnea, pain, and cough were comparable across the RYBREVANT plus
LAZCLUZE
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
QW
Once a week
NSCLC-
SAQ
Non-Small Cell Lung Cancer
Symptom Assessment
Questionnaire
R
Randomization
ORR
Objective response rate
RECIST
Response Evaluation Criteria
in Solid Tumors
OR
Odds ratio
RTK
Receptor tyrosine kinase
OS
Overall survival
SD
Stable disease
PD
Progressive disease
TEAE
Treatment-emergent AE
PE
Pulmonary embolism
TKI
Tyrosine kinase inhibitor
PFS
Progression-free survival
TRAE
Treatment-related AE
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
Q2W
Every 2 weeks
A literature search of MEDLINE®, Embase®, BIOSIS Previews®, and Derwent Drug File (and/or
other resources, including internal/external databases) was conducted on 01 September 2025.
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.
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 2025 September 01]. 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(16):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.
Yang JCH, Lu S, Hayashi H, et al. Overall survival with amivantamab-lazertinib in EGFR-mutant advanced NSCLC. N Engl J Med.
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.
Hayashi H, Besse B, Lee SH, at al. Mechanisms of acquired resistance to first-line amivantamab plus lazertinib vs osimertinib: updated analysis from MARIPOSA. Poster presented at: International Association for the Study of Lung Cancer (IASLC) World Conference on Lung Cancer (WCLC); September 6-9, 2025; 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.
Cho BC, Felip E, Spira AI, et al. Amivantamab plus lazertinib vs osimertinib as first-line treatment in EGFR-mutated, advanced NSCLC: primary results from MARIPOSA, a phase 3, global, randomized controlled trial. Oral Presentation presented at: European Society for Medical Oncology (ESMO) Congress; October 20-24, 2023; Madrid, Spain.
Yang JCH, Lu S, Hayashi H, et al. Supplementary Appendix for: Overall survival with amivantamab-lazertinib in EGFR-mutant advanced NSCLC. N Engl J Med.
Yang JCH, Kim YJ, Lee SH, et al. Amivantamab plus lazertinib vs osimertinib in first-line EGFR-mutant advanced NSCLC: final overall survival from the phase 3 MARIPOSA study. Oral Presentation presented at: European Lung Cancer Congress (ELCC); March 26-29, 2025; Paris, France.
Cho BC, Lu S, Felip E, et al. Clinical Protocol for: Amivantamab plus lazertinib in previously untreated EGFR-mutated advanced NSCLC. N Engl J Med. 2024;391(16):1486-1498.
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.
PFS by BICR across predefined
subgroups: RYBREVANT plus LAZCLUZE vs
Osimertinib5
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
LAZCLUZE, n=1). dIncludes 1 patient who received herbal + doublet chemotherapy.
Patients with (n=188) and without (n=190) dose interruptiona 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).
Demographics and baseline disease characteristics12
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.
aNumber of patients with measurable disease at baseline by BICR was 214 for
LAZCLUZE and 414 for osimertinib. bIncludes all responders. cAmong confirmed responders.
Cardiac safety profile of LAZCLUZE vs Osimertinib13
Patients, %
LAZCLUZE
Osimertinib
P-value
LVEFa
1
4
0.056
QT interval prolongationb
>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.
OS in predefined subgroups8,a
Subgroup
HR (95% CI)
N
RYBREVANT +
LAZCLUZE
Osimertinib
All randomized patients
0.75 (0.61-0.92)
429
429
Age
< 65 years
0.53 (0.4-0.7)
235
237
≥ 65 years
1.11 (0.84-1.48)
194
192
< 75 years
0.75 (0.6-0.93)
378
376
≥ 75 years
0.79 (0.47-1.33)
51
53
Sex
Female
0.73 (0.56-0.95)
275
251
Male
0.81 (0.6-1.09)
154
178
Race
Asian
0.75 (0.58-0.98)
250
251
non-Asian
0.74 (0.54-1)
177
177
Body weight
< 80 kg
0.78 (0.63-0.97)
376
368
≥ 80 kg
0.62 (0.36-1.07)
53
61
ECOG PS
0
0.88 (0.61-1.28)
141
149
1
0.7 (0.55-0.89)
288
280
History of smoking
Yes
0.78 (0.55-1.1)
130
134
No
0.74 (0.58-0.95)
299
295
History of brain metastases
Yes
0.67 (0.5-0.9)
178
173
No
0.82 (0.62-1.08)
251
256
EGFR mutation
Exon19del
0.66 (0.5-0.86)
257
257
Exon 21 L858R
0.9 (0.67-1.21)
171
172
aHRs and 95% CIs for the subgroups were obtained from an unstratified proportional-hazards model. The 95% CIs for HRs have not been adjusted for multiplicity and should not be used to infer definitive treatment effects.
aPercentages may not sum to 100 due to rounding. bIncluded 1 patient who was rechallenged with osimertinib + afatinib as a subsequent therapy. cPercentages were not provided for single-agent chemotherapy and single-agent chemotherapy + IO/VEGFi therapy. dIncluded 3 patients who received triplet chemotherapy + IO/VEGFi. eIncluded 1 patient who received quadruplet chemotherapy. fIncluded IO alone, herbals, ADCs, ALK TKIs, c-MET TKIs, RYBREVANT (1 patient received RYBREVANT + chemotherapy after RYBREVANT + LAZCLUZE; after osimertinib, 1 patient received RYBREVANT + chemotherapy, 1 patient received RYBREVANT + LAZCLUZE, and 1 patient received RYBREVANT monotherapy), and investigational agents.
