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 subsequent therapy option, if not previously given, in combination with carboplatin and pemetrexed for EGFR Exon 19 deletion or Exon 21 L858R mutation positive advanced, or metastatic nonsquamous disease after progression on osimertinib in patients with multiple systemic lesions who are symptomatic (NCCN Category 1, preferred).3
NCCN Category of Evidence of Category 1 is defined as based upon high-level evidence, and there is uniform NCCN consensus (≥85% support of the Panel) that the intervention is appropriate.3
NCCN Category of Preference of Preferred intervention is defined as interventions that are based on superior efficacy, safety, and evidence; and, when appropriate, affordability.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-2 Study
MARIPOSA-2 (NCT04988295) is an ongoing, phase 3, open-label, randomized study designed to
assess the efficacy and safety of RYBREVANT-lazertinib-chemotherapy (pemetrexed and
carboplatin; n=263) and RYBREVANT-chemotherapy (pemetrexed and carboplatin; n=131) vs
chemotherapy alone (pemetrexed and carboplatin; n=263) in patients with EGFR-mutated
(Exon19del or Exon 21 L858R substitution) locally advanced or metastatic NSCLC on or after
osimertinib monotherapy. The dual primary endpoint is PFS, based on BICR, comparing
RYBREVANT-lazertinib-chemotherapy to chemotherapy alone and RYBREVANT-chemotherapy to
chemotherapy alone.4,5
At a median follow-up of 8.7 months, median PFS by BICR was 8.3 months (95% CI,
6.8-9.1) for RYBREVANT-lazertinib-chemotherapy and 4.2 months (95% CI, 4-4.4) for
chemotherapy alone (HR, 0.44; 95% CI, 0.35-0.56; P<0.001); 6.3 months (95%
CI, 5.6-8.4) for RYBREVANT-chemotherapy and 4.2 months (95% CI, 4-4.4) for chemotherapy
alone (HR, 0.48; 95% CI, 0.36-0.64; P<0.001).5
Higher rates of grade ≥3 AEs were observed in the RYBREVANT-lazertinib-chemotherapy (n=263) and RYBREVANT-chemotherapy (n=130) arms vs chemotherapy alone (n=243) arm.5
At a median long-term follow-up of 18.1 months, median OS at the second interim analysis
was 17.7 months (95% CI, 16-22.4) for RYBREVANT-chemotherapy and 15.3 months
(95% CI, 13.7-16.8) for chemotherapy alone (HR, 0.73; 95% CI, 0.54-0.99; P=0.039b).6
An Asian subgroup analysis reported7:
At a median follow-up of 9.5 months, median PFS by BICR was 6.8 months (95% CI,
5.5-11.1) for RYBREVANT-chemotherapy and 4.2 months (95% CI, 4.1-5.4) for chemotherapy
alone (HR, 0.54; 95% CI, 0.37-0.81; nominal P=0.002a).
EGFR- and MET-related AEs were higher with RYBREVANT-chemotherapy vs chemotherapy
alone. AEs of special interest included rash (40% vs 3%), VTE (<7% for both arms),
and ILD (2% vs 0%).
A post-progression analysis reported8:
At a median follow-up of 8.7 months, median TTD was 11 months vs 4.5 months (HR, 0.37; 95% CI, 0.28-0.50; nominal P<0.0001a), median TTST was 12.1 months vs 6.6 months (HR, 0.42; 95% CI, 0.30-0.59; nominal P<0.0001a), and median PFS2 was 13.9 months vs 11.3 months (HR, 0.60; 95% CI, 0.40-0.92; nominal P=0.017a) for the RYBREVANT-chemotherapy vs chemotherapy alone arms, respectively.
Hematologic AEs were most frequent and severe during C1 and decreased over time.
Note: AE, adverse event; BICR, blinded independent central review; C, cycle; CI, confidence
interval; EGFR, epidermal growth factor receptor; Exon19del, Exon 19 deletion; HR, hazard ratio;
IgG1, immunoglobulin G1; ILD, interstitial lung disease; MET, mesenchymal-epithelial transition;
NCCN, National Comprehensive Cancer Network; NSCLC, non-small cell lung cancer; OS, overall survival; PFS, progression-free survival; TKI, tyrosine kinase inhibitor; TTD, time to treatment discontinuation; 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. bP-Value is from a log-rank test stratified by osimertinib line of therapy (first-line vs second-line), history of brain metastases
(yes vs no), and Asian race (yes vs no). OS was evaluated at a 2-sided alpha of 0.0142.
MARIPOSA-24,5
MARIPOSA-2 (NCT04988295) is an ongoing, phase 3, randomized, open-label study designed to
assess the efficacy and safety of RYBREVANT-lazertinib-chemotherapy (pemetrexed and
carboplatin) and RYBREVANT-chemotherapy (pemetrexed and carboplatin) vs chemotherapy alone
(pemetrexed and carboplatin) in patients with EGFR-mutated locally advanced or
metastatic
NSCLC on or after osimertinib monotherapy (as the most recent line of therapy)
N=657
Key Eligibility Criteria4,5,9
Age ≥18 years
Locally advanced or metastatic NSCLC
Documented EGFR Exon19del or Exon 21 L858R
Progressed on or after osimertinib monotherapy (as most recent line)
Stable brain metastases; radiation or definitive treatment was not
required (untreated)
ECOG PS 0 or 1
Study Design4,5,9
Efficacy Results5,6
At a median follow-up of 8.7 months, median PFS by BICR was as follows5:
8.3 months (95% CI, 6.8-9.1)
for RYBREVANT-lazertinib-chemotherapy and 4.2 months (95% CI, 4-4.4) for
chemotherapy alone (HR, 0.44; 95% CI, 0.35-0.56; P<0.001)
6.3 months (95% CI, 5.6-8.4) for RYBREVANT-chemotherapy and 4.2 months (95%
CI, 4-4.4) for chemotherapy alone (HR, 0.48; 95% CI, 0.36-0.64;
P<0.001)
PFS rates at 6 and 12 months, respectively, were 59% and 37% for
the RYBREVANT-lazertinib-chemotherapy arm, 51% and 22% for the
RYBREVANT-chemotherapy arm, and 30% and 13% for the chemotherapy alone arm.5
At a median long-term follow-up of 18.1 months, median OS was 17.7 months (95% CI, 16-22.4) for RYBREVANT-chemotherapy and 15.3 months (95% CI, 13.7-16.8) for chemotherapy alone (HR, 0.73; 95% CI, 0.54-0.99;
P=0.039b).6
Safety Results5
Higher rates of grade ≥3 AEs were observed in the RYBREVANT-lazertinib-chemotherapy
(n=263) and RYBREVANT-chemotherapy (n=130) arms vs chemotherapy alone (n=243) arm.
The most common grade ≥3 AEs (≥10% in any arm) included neutropenia,
thrombocytopenia, anemia, and leukopenia.
Serious TEAEs occurred in 52%, 32%, and 20% of patients, respectively, in the
RYBREVANT-lazertinib-chemotherapy, RYBREVANT-chemotherapy, and chemotherapy alone
arms.
The most common serious TEAEs (≥5% in any arm) included thrombocytopenia,
neutropenia, and febrile neutropenia.
Additional Analyses7,8
Subgroup analysis in Asian patients7:
At a median follow-up of 9.5 months, median PFS by BICR was 6.8 months (95%
CI, 5.5-11.1) for RYBREVANT-chemotherapy and 4.2 months (95% CI, 4.1-5.4) for
chemotherapy alone (HR, 0.54; 95% CI, 0.37-0.81; nominal
P=0.002a).
EGFR- and MET-related AEs were higher with RYBREVANT-chemotherapy compared with
chemotherapy alone.
Post-progression analysis8:
At a median follow-up of 8.7 months,
for the RYBREVANT-chemotherapy vs chemotherapy alone arms, median TTD was 11
months (95% CI, 7.9-12.7) vs 4.5 months (95% CI, 4.2-5.2), median TTST was
12.1 months (95% CI, 11-14.9) vs 6.6 months (95% CI, 6.2-8.1), and median PFS2
was 13.9 months (95% CI, 11.4-NE) vs 11.3 months (95% CI, 9.1-13.8).
Hematologic AEs were most frequent and severe during C1 and decreased over
time.
Note: AE, adverse event; BICR, blinded independent central review; C, cycle; CI, confidence
interval; ECOG PS, Eastern Cooperative Oncology Group performance status; EGFR, epidermal growth
factor receptor; Exon19del, Exon 19 deletion; HR, hazard ratio; IV,
intravenous; MET, mesenchymal-epithelial transition; NSCLC, non-small cell lung cancer; OS, overall survival; PFS,
progression-free survival; PO, orally; Q3W, every 3 weeks; QD, daily; R, randomization; TEAE,
treatment-emergent AE; TTD, time to treatment discontinuation; TTST, time to subsequent therapy.
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. bP-value is from a log-rank test stratified by osimertinib line of therapy (first-line vs second-line), history of brain metastases (yes vs no), and Asian race (yes vs no). OS was evaluated at a 2-sided alpha of 0.0142.
MARIPOSA-2 (NCT04988295) is an ongoing, phase 3, open-label, randomized study designed to
assess the efficacy and safety of RYBREVANT-lazertinib-chemotherapy and RYBREVANT-chemotherapy
vs chemotherapy alone in patients with EGFR-mutated locally advanced or metastatic
NSCLC on or after osimertinib monotherapy (as the most recent line of therapy).4,5
In the RYBREVANT-lazertinib-chemotherapy arm, patients randomized before November 7, 2022,
received lazertinib on the first day of C1. Due to an increase in hematologic and
gastrointestinal toxicities in the arm, the regimen was modified to start lazertinib after
carboplatin completion.5
An open-label, randomized, extension cohort study will evaluate the efficacy and safety
of the modified RYBREVANT-lazertinib-chemotherapy vs RYBREVANT-chemotherapy regimen.
MARIPOSA-2 Study Design4,5,9
Stratification
Osimertinib line of therapy (1st vs 2nd)
Asian race (yes vs no)
History of brain metastases (yes vs no)
Dual Primary Endpointsg
PFS by BICRf for amivantamab-lazertinib-chemotherapy vs
chemotherapy
PFS by BICRf for amivantamab-chemotherapy vs chemotherapy
Secondary Endpointsg
ORR
OS
PFS2
TTSP
Symptomatic PFS
DOR
icPFS
TTST
TTD
Safety
aBrain MRI was performed at baseline, 6 (+1) weeks, 12 (±1) weeks, and then every
12
(±1) weeks until intracranial disease progression was confirmed by BICR.
bIn patients ≥80 kg.
cThe first amivantamab infusion was split over 2 days, with 350 mg on C1D1 and the
remainder on C1D2.
dAfter completion of carboplatin chemotherapy. All patients randomized before
November 7, 2022, were initiated on lazertinib on the first day of C1.
eChemotherapy was administered at the beginning of every cycle and consisted of
carboplatin AUC 5 IV for the first 4 cycles + pemetrexed 500 mg/m 2 IV until
disease
progression.
fPer RECIST v1.1.
gGraphical testing strategy was used to control for type 1 errors. PFS, ORR, and
then
OS were included in the hierarchical testing. P-values are nominal for all other secondary and
exploratory endpoints.
A total of 657 patients were randomized to receive RYBREVANT-lazertinib-chemotherapy
(n=263), RYBREVANT-chemotherapy (n=131), or chemotherapy alone (n=263).5
A total of 636 (97%) patients received treatment (RYBREVANT-lazertinib-chemotherapy
[n=263], RYBREVANT-chemotherapy [n=130], or chemotherapy alone [n=243]).
At a median follow-up of 8.7 months, median duration of the study treatment was 5.8 months
for the RYBREVANT-lazertinib-chemotherapy arm (n=263), 6.3 months for the
RYBREVANT-chemotherapy arm (n=130), and 3.7 months for the chemotherapy alone arm (n=243).5,9
Patients in the RYBREVANT-lazertinib-chemotherapy arm received a median of 4 cycles
(range, 1-4) of carboplatin and 7 cycles (range, 1-25) of pemetrexed.9
Patients in the RYBREVANT-chemotherapy arm received a median of 4 cycles (range,
1-4) of carboplatin and 9 cycles (range, 1-22) of pemetrexed.9
Patients in the chemotherapy alone arm received a median of 4 cycles (range, 1-5) of
carboplatin and 6 cycles (range, 1-23) of pemetrexed.9
Baseline characteristics were balanced between the study arms.5
Demographics and Baseline Disease Characteristics5
Characteristic
RYBREVANT-
Lazertinib-
Chemotherapy
(n=263)
RYBREVANT-
Chemotherapy
(n=131)
Chemotherapy
(n=263)
Age, median (range), years
61 (23-83)
62 (36-84)
62 (31-85)
<65 years, n (%)
163 (62)
79 (60)
166 (63)
≥65 years, n (%)
100 (38)
52 (40)
97 (37)
Female/male, n(%)
168 (64)/95 (36)
81 (62)/50 (38)
157 (60)/106 (40)
Race, n (%)
Asian
125 (47.5)
63 (48)
127 (48)
White
129 (49)
60 (46)
123 (47)
Othera
9 (3)
8 (6)
13 (5)
Region of enrolment, n (%)
North America
21 (8)
13 (10)
22 (8)
South America
15 (6)
6 (5)
19 (7)
Europeb
96 (37)
45 (34)
96 (37)
Asiac
131 (50)
67 (51)
126 (48)
aOther includes American Indian or Alaska Native, Black or African
American,
multiple, unknown, and not reported.
bRussia counted as part of Europe.
cTurkey counted as part of Asia.
All patients randomized to the RYBREVANT-lazertinib-chemotherapy arm were evaluated
regardless of the dosing regimen received (n=263).5
A total of 166 patients received lazertinib concurrently and 97 received
lazertinib after carboplatin completion, with a median follow-up of 11.5 and 5.4
months, respectively.
At a median follow-up of 8.7 months (data cutoff: July 10, 2023), PFS was significantly longer in
the
RYBREVANT-containing arms vs chemotherapy alone arm.5
Median PFS based on investigator assessment was 8.3 months (95% CI,
7.1-9.9) for RYBREVANT-lazertinib-chemotherapy, 8.2 months (95% CI, 6.8-10.9) for
RYBREVANT-chemotherapy, and 4.2 months (95% CI, 4-4.5) for chemotherapy
alone.5
PFS rates at 6 and 12 months, respectively, were 59% and 37% for the
RYBREVANT-lazertinib-chemotherapy arm, 51% and 22% for the RYBREVANT-chemotherapy arm,
and 30% and 13% for the chemotherapy alone arm.5
PFS by BICR5
RYBREVANT-Lazertinib-
Chemotherapy
(n=263)
Chemotherapy
(n=263)
PFS, median (95% CI), months
8.3 (6.8-9.1)
4.2 (4-4.4)
HR (95% CI)
0.44 (0.35-0.56); P<0.001
RYBREVANT-Chemotherapy
(n=131)
Chemotherapy
(n=263)
PFS, median (95% CI), months
6.3 (5.6-8.4)
4.2 (4-4.4)
HR (95% CI)
0.48 (0.36-0.64); P<0.001
Note: The efficacy analysis set included all randomized patients.
ORR by BICR was 63% (95% CI, 57-69) for the
RYBREVANT-lazertinib-chemotherapy arm
and 36% (95% CI, 30-42) for the chemotherapy alone arm (OR, 2.97; 95% CI, 2.08-4.24;
P<0.001). ORR by BICR was 64% (95% CI, 55-72) for the RYBREVANT-chemotherapy
arm
and
36% (95% CI, 30-42) for the chemotherapy alone arm (OR, 3.1; 95% CI, 2-4.8;
P<0.001).5
Median DOR was numerically longer for both the RYBREVANT-containing
arms.5
Median icPFS by BICR was evaluated in the overall population and in a
subgroup of patients with
a history of brain metastases and no prior brain radiotherapy.5
The icPFS rates at 6 and 12 months, respectively, were 79% and 54% for
the RYBREVANT-lazertinib-chemotherapy arm, 78% and 50% for the RYBREVANT-chemotherapy
arm, and 66% and 34% for the chemotherapy alone arm.5
At the time of the prespecified first interim OS analysis,the HR for death
was
0.77 (95% CI,0.49-1.21) for the RYBREVANT-lazertinib-chemotherapy vs chemotherapy
alone
arm and 0.96 (95% CI, 0.67-1.35) for the RYBREVANT-chemotherapy vs chemotherapy alone
arm.5
At a median long-term follow-up of 18.1 months (data cutoff: April 26, 2024), median OS at the second interim analysisa was 17.7 months (95% CI, 16-22.4) for RYBREVANT-chemotherapy and 15.3 months (95% CI, 13.7-16.8) for chemotherapy alone (HR, 0.73; 95% CI, 0.54-0.99; P=0.039b).6,c
The OS rates in the RYBREVANT-chemotherapy and chemotherapy alone arms, respectively, were 70% and 63% at 12 months and 50% and 40% at 18 months.
Median TTSP (defined as the time from randomization to the onset of new symptoms or worsening of lung cancer symptoms requiring a change in anticancer therapy and/or clinical intervention or death, whichever occurred first) was 16 months (95% CI, 12.7-19.4) for RYBREVANT-chemotherapy and 11.8 months (95% CI, 8.9-13.6) for chemotherapy alone (HR, 0.73; 95% CI, 0.55-0.96; P=0.026b).
The proportion of patients without symptomatic progression in the RYBREVANT-chemotherapy and chemotherapy alone arms, respectively, was 60% and 49% at 12 months and 43% and 34% at 18 months.
Median TTD (defined as the time from randomization to discontinuation of all study treatments for any reason, including disease progression, treatment toxicity, or death) was 10.4 months (95% CI, 7.9-11.6) for RYBREVANT-chemotherapy and 4.5 months (95% CI, 4.2-5) for chemotherapy alone (HR, 0.42; 95% CI, 0.33-0.53; P<0.0001b).
The proportion of patients who continued treatment in the RYBREVANT-chemotherapy and chemotherapy alone arms, respectively, was 40% and 11% at 12 months and 22% and 4% at 18 months.
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 occurred first) was 12.2 months (95% CI, 10.7-14.3) for RYBREVANT-chemotherapy and 6.6 months (95% CI, 6.1-7.4) for chemotherapy alone (HR, 0.51; 95% CI, 0.39-0.65; P<0.0001b).
The proportion of patients who did not initiate a first subsequent therapy in the RYBREVANT-chemotherapy and chemotherapy alone arms, respectively, was 51% and 24% at 12 months and 31% and 12% at 18 months.
The proportion of patients with disease progression in the RYBREVANT-chemotherapy and chemotherapy alone arms, respectively, was 68% (n=88/130) and 83% (n=202/243).
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 investigator assessment [after that used for PFS] or death, whichever occured first) was 16 months (95% CI, 13.9-17.6) for RYBREVANT-chemotherapy and 11.6 months (95% CI, 10.1-13) for chemotherapy alone (HR, 0.64; 95% CI, 0.48-0.85; P=0.002b).
The PFS2 rates in the RYBREVANT-chemotherapy and chemotherapy alone arms, respectively, were 64% and 48% at 12 months and 39% and 27% at 18 months.
aThe second interim analysis of OS was prespecified when ~75% of the planned OS events were observed. OS was evaluated at a 2-sided alpha of 0.0142 sided alpha of 0.0142 based on the O’Brien-Fleming alpha spending approach, as implemented by the Lan-DeMets method.
bP-value is from a log-rank test stratified by osimertinib line of therapy (first-line vs second-line), history of brain metastases, (yes vs no), and Asian race (yes vs no).
cThe OS benefit of RYBREVANT-chemotherapy vs chemotherapy alone was consistent across predefined subgroups.
Higher rates of grade ≥3 AEs were observed in the RYBREVANT-containing arms vs chemotherapy alone arm.5
The most common grade ≥3 AEs (≥10% in any arm) included neutropenia, thrombocytopenia, anemia, and leukopenia.
In the RYBREVANT-lazertinib-chemotherapy, RYBREVANT-chemotherapy, and
chemotherapy alone arms, the rates of febrile neutropenia were 8%, 2%, and 2%,
respectively,
and the rates of grade 3 or 4 bleeding were 3%, 1%, and 0%, respectively.5
Serious TEAEs occurred in 52%, 32%, and 20% of patients, respectively, in the
RYBREVANT-lazertinib-chemotherapy, RYBREVANT-chemotherapy, and chemotherapy alone arms.5
The most common serious TEAEs (≥5% in any arm) included thrombocytopenia,
neutropenia,
and febrile neutropenia.
Infusion-related reactions occurred in 56% and 58% of patients,
respectively,
in the RYBREVANT-lazertinib-chemotherapy and RYBREVANT-chemotherapy arms.5
VTE occurred in 22%, 10%, and 5% of patients, respectively, in the
RYBREVANT-lazertinib-chemotherapy, RYBREVANT-chemotherapy, and chemotherapy alone arms. At
the time of the first VTE, a few patients were receiving anticoagulation
(RYBREVANT-lazertinib-chemotherapy, 2%; RYBREVANT-chemotherapy, 0%; chemotherapy alone,
1%).5
The most common reasons for dose interruptions, reductions, and
discontinuations due to AEs were hematologic toxicities.5
Discontinuation of all study agents due to treatment-related AEs was
reported
in 25 (10%), 11 (8%), and 6 (2%) patients, respectively, in the
RYBREVANT-lazertinib-chemotherapy, RYBREVANT-chemotherapy, and chemotherapy alone
arms.5
Death within 30 days of the last dose occurred in 10%, 5%, and 3% of
patients, respectively, in the RYBREVANT-lazertinib-chemotherapy, RYBREVANT-chemotherapy,
and chemotherapy alone arms.5
There were 4 (2%), 2 (2%), and 1 (0.4%) treatment-related AEs leading to
death, respectively, in the RYBREVANT-lazertinib-chemotherapy, RYBREVANT-chemotherapy, and
chemotherapy alone arms.5
Summary of AEs5
TEAE, n (%)
RYBREVANT-
Lazertinib-
Chemotherapy
(n=263)
RYBREVANT-
Chemotherapy
(n=130)
Chemotherapy
(n=243)
Any AEs
263 (100)
130 (100)
227 (93)
Grade ≥3 AEs
242 (92)
94 (72)
117 (48)
Serious AEs
137 (52)
42 (32)
49 (20)
AEs leading to death
14 (5)
3 (2)
3 (1)
Any AE leading to treatment
Interruptions of any agent
202 (77)
84 (65)
81 (33)
Reductions of any agent
171 (65)
53 (41)
37 (15)
Discontinuations of any agent
90 (34)
24 (18)
9 (4)
Note: The safety population included all randomized patients who received ≥1 dose of
any
study treatment.
In a subgroup analysis of Asian patients in the MARIPOSA-2 study, 315 Asian
patients (defined by race) were randomized to receive
RYBREVANT-lazertinib-chemotherapy (n=125), RYBREVANT-chemotherapy (n=63), or
chemotherapy alone (n=127).7
This analysis focuses on evaluating the efficacy and safety of
RYBREVANT-chemotherapy vs chemotherapy alone among Asian patients.
Demographics and Baseline Disease Characteristics Among Asian Patients7
Characteristic
RYBREVANT-Chemotherapy
(n=63)
Chemotherapy
(n=127)
Age, median (range), years
61 (36-84)
61 (31-85)
Sex, female, n (%)
42 (67)
74 (58)
Weight <80 kg, n (%)
62 (98)
120 (94)
ECOG PS 1, n (%)
39 (62)
85 (66)
History of smoking, n (%)
14 (22)
33 (26)
History of brain metastasis, n (%)
27 (43)
58 (46)
Osimertinib line of therapy, n (%)
First line
40 (63)
77 (61)
Second line
23 (37)
50 (39)
EGFR mutation type, n (%)
Exon19del
42 (67)
90 (71)
Exon 21 L858R
21 (33)
37 (29)
Adenocarcinoma histology, n (%)
63 (100)
127 (100)
Time from metastatic diagnosis, median (range), months
25.7 (0.2-69.1)
22.5 (0.1-99.1)
Note: Percentages may not sum up to 100 due to rounding.
Primary
Endpoint7
At a median follow-up of 9.5 months, median PFS by BICR was 6.8 months (95%
CI,
5.5-11.1) for RYBREVANT-chemotherapy and 4.2 months (95% CI, 4.1-5.4) for
chemotherapy alone (HR, 0.54; 95% CI, 0.37-0.81; nominal
P=0.002a).
PFS rates for RYBREVANT-chemotherapy and chemotherapy alone,
respectively,
were 53% and 30% at 6 months and 21% and 16% at 12 months.
Median PFS based on investigator assessment was 10.3 months for
RYBREVANT-chemotherapy and 4.2 months for chemotherapy alone (HR, 0.39; 95%
CI,
0.26-0.59; nominal P<0.0001a).
PFS across predefined clinically relevant subgroups was
assessed
for RYBREVANT-chemotherapy vs chemotherapy alone.
Secondary
Endpoints7
At a median follow-up of 9.5 months, median icPFS by BICR was 12.5 months (95%
CI, 10.8-13.9) for RYBREVANT-chemotherapy and 8.5 months (95% CI, 7.5-13.8)
for
chemotherapy alone (HR, 0.58; 95% CI, 0.34-1.00; nominal
P=0.049a).
icPFS rates for RYBREVANT-chemotherapy and chemotherapy alone,
respectively, were 84% and 69% at 6 months and 53% and 43% at 12 months.
At a median follow-up of 9.5 months, median icPFS by BICR (in patients with a
history of brain metastases and without a prior brain radiotherapy) was NE
(95%
CI, 5.3-NE) for RYBREVANT-chemotherapy and 4.3 months (95% CI, 1.5-9.8) for
chemotherapy alone (HR, 0.33; 95% CI, 0.11-1.03; nominal
P=0.041a).
icPFS rates for RYBREVANT-chemotherapy and chemotherapy alone,
respectively, were 75% and 49% at 6 months and NE and 16% at 12 months.
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.
Median duration of treatment was 7.4 months (range, 0.1-14.7) for
RYBREVANT-chemotherapy and 4 months (range, 0-15.9) for chemotherapy
alone.7
Patients in the RYBREVANT-chemotherapy arm received a median of 4 cycles
(range, 1-4) of carboplatin and 10 cycles (range, 1-22) of pemetrexed,
whereas those in the chemotherapy alone arm received a median of 4 cycles
(range, 1-5) of carboplatin and 6 cycles (range, 1-23) of pemetrexed.
RYBREVANT-chemotherapy had higher rates of dose modifications
compared with chemotherapy alone. TEAEs leading to RYBREVANT discontinuation
occurred in 11% of patients.7
AEs of special interest included incidences of rash (40% for
RYBREVANT-chemotherapy vs 3% for chemotherapy alone), VTE (<7% for both arms),
and ILD (2% for RYBREVANT-chemotherapy vs 0% for chemotherapy alone).7
EGFR- and MET-related AEs were higher with
RYBREVANT-chemotherapy compared with chemotherapy alone.7
Summary of AEs Among Asian Patients7
TEAE, n (%)
RYBREVANT-Chemotherapy
(n=62)
Chemotherapy
(n=116)
Any AEs
62 (100)
108 (93)
Grade ≥3 AEs
49 (79)
53 (46)
Serious AEs
25 (40)
20 (17)
AEs leading to death
3 (5)
0
Any AE leading to treatment
Interruptions of any agent
37 (60)
40 (34)
Reductions of any agent
28 (45)
13 (11)
Discontinuations of any agent
14 (23)
1 (1)
Note: The safety population included all randomized patients who received
≥1 dose of any
study treatment.
TTD8
At a median follow-up of 8.7 months, median TTD was 11.0 months (95% CI,
7.9-12.7) for RYBREVANT-chemotherapy and 4.5 months (95% CI, 4.2-5.2) for
chemotherapy alone (HR, 0.37; 95% CI, 0.28-0.5; nominal
P<0.0001a).
The proportion of patients without a discontinuation event for
RYBREVANT-chemotherapy and chemotherapy alone, respectively, was 68% and
35% at 6 months and 38% and 12% at 12 months.
The proportion of patients who had PD in the
RYBREVANT-chemotherapy arm and chemotherapy alone arm, respectively, was
42% (n/N=55/130) and 71% (n/N=173/243).
Treatment beyond disease progression was reported in 35% (n/N=19/55) of
patients in the RYBREVANT-chemotherapy arm and 16% (28/173) of patients in
the chemotherapy alone arm for a median duration post-progression of 18.3
weeks (95% CI, 9-NE) and 9 weeks (95% CI, 6-16.4), respectively.
TTST8
At a median follow-up of 8.7 months, median TTST was 12.1 months (95% CI,
11-14.9) for RYBREVANT-chemotherapy and 6.6 months (95% CI, 6.2-8.1) for
chemotherapy alone (HR, 0.42; 95% CI, 0.3-0.59; nominal
P<0.0001a).
The proportion of patients without a subsequent therapy event for
RYBREVANT-chemotherapy and chemotherapy alone, respectively, was 81% and
59% at 6 months and 51% and 26% at 12 months.
The number of patients who received subsequent therapy in the
RYBREVANT-chemotherapy arm and chemotherapy alone arm, respectively, was
26 and 101 patients.
Among patients treated with RYBREVANT-chemotherapy and chemotherapy
alone, respectively, the most common subsequent therapies included
chemotherapy (27% and 33%), chemotherapy plus IO/VEGFi (19% and 18%),
TKI alone (23% and 18%), TKI combination (15% and 17%), IO alone (4%
and 7%), and other therapies (12% and 8%).
PFS28
At a median follow-up of 8.7 months, median PFS2 was 13.9 months (95% CI,
11.4-NE) for RYBREVANT-chemotherapy and 11.3 months (95% CI, 9.1-13.8) for
chemotherapy alone (HR, 0.6; 95% CI, 0.4-0.92; nominal
P=0.017a).
PFS2 rates for RYBREVANT-chemotherapy and chemotherapy alone,
respectively, were 88% and 83% at 6 months and 59% and 47% at 12 months.
aThis 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.
The incidence and severity of hematologic AEs were highest during C1 and
decreased over subsequent cycles.8
AEs in the Post-Progression Analysis8
AE, (%)
RYB- Chemo
Chemo
RYB- Chemo
Chemo
RYB- Chemo
Chemo
RYB- Chemo
Chemo
Grade 1
Grade 2
Grade 3
Grade 4
C1
Neutropenia
0.8
4.5
8.5
10.7
25.4
12.3
10.8
2.9
Thrombocytopenia
13.8
11.1
10.8
6.2
8.5
4.1
6.2
1.6
Anemia
6.9
7.4
6.2
7.8
3.1
3.3
0
0
Leukopenia
0.8
3.7
6.9
11.5
15.4
5.8
1.5
0
C2-4
Neutropenia
0.8
4.1
11.5
11.9
12.3
6.6
3.8
2.1
Thrombocytopenia
3.8
3.7
3.1
4.5
0.8
1.6
2.3
1.6
Anemia
6.9
8.2
5.4
10.3
10
5.8
0
0
Leukopenia
1.5
4.1
5.4
7.8
1.5
2.5
0
0.4
C≥5
Neutropenia
3.4
2
10.9
4.4
5
6.4
0.8
1.5
Thrombocytopenia
5
4.9
1.7
2.9
0.8
1.5
0
0.5
Anemia
8.4
5.9
6.7
5.4
0
1.5
0
0
Leukopenia
2.5
1.5
5.9
2
5
4.4
0
0.5
Note: The event experienced by the patient with the worst toxicity in
each period is reported. AEs were coded using MedDRA version 25.0. In
the study, labs were measured weekly in C1 for both arms.
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, open-label, randomized study of
amivantamab and lazertinib in combination with platinum-based chemotherapy compared
with platinum-based chemotherapy in patients with EGFR-mutated locally advanced or
metastatic non-small cell lung cancer after osimertinib failure. In:
ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US).
2000- [cited 2024 September 11]. Available from: https://clinicaltrials.gov/ct2/show/NCT04988295
NLM Identifier: NCT04988295.
Passaro A, Wang J, Wang Y, et al. Amivantamab plus chemotherapy with and without
lazertinib in EGFR-mutant advanced NSCLC after disease progression on osimertinib:
primary results from the phase 3 MARIPOSA-2 study. Ann Oncol.
2024;35(1):77-90.
Popat S, Reckamp KL, Califano R, et al. Amivantamab plus chemotherapy vs chemotherapy in EGFR-mutated, advanced
non-small cell lung cancer after disease progression on osimertinib. Oral Presentation presented at: European Society for
Medical Oncology (ESMO) Congress; September 13-17, 2024; Barcelona, Spain.
Shih JY, Wang J, Wang Y, et al. Amivantamab plus chemotherapy vs chemotherapy
among Asian patients with EGFR-mutant advanced NSCLC after progression on
osimertinib: a MARIPOSA-2 subgroup analysis. Oral Presentation presented at:
European Society for Medical Oncology (ESMO) Asia Congress; December 1-3, 2023;
Singapore.
Gentzler RD, Spira AI, Melosky B, et al. Amivantamab plus chemotherapy vs
chemotherapy in EGFR-mutant advanced NSCLC after progression on osimertinib: a
post-progression analysis of MARIPOSA-2. Oral Presentation presented at: European
Lung Cancer Congress (ELCC); March 20-23, 2024; Prague, Czech Republic.
Passaro A, Wang J, Wang Y, et al. Supplement to: Amivantamab plus chemotherapy with
and without lazertinib in EGFR-mutant advanced NSCLC after disease progression on
osimertinib: primary results from the phase 3 MARIPOSA-2 study. Ann Oncol.
2024;35(1):77-90.
A literature search of MEDLINE®, Embase®, BIOSIS Previews®, and Derwent Drug File
(and/or other resources, including internal/external databases) was conducted on 11 September 2024.
AE
Adverse event
MedDRA
Medical Dictionary for Regulatory Activities
ALK
Anaplastic lymphoma kinase
MET
Mesenchymal-epithelial transition
ALT
Alanine aminotransferase
MRI
Magnetic resonance imaging
AST
Aspartate aminotransferase
NCCN
National Comprehensive Cancer Network
AUC
Area under the curve
NE
Not estimable
BICR
Blinded independent central review
NE/UNK
Not evaluable/unknown
C
Cycle
NSCLC
Non-small cell lung cancer
CI
Confidence interval
OR
Odds ratio
Chemo
Chemotherapy
ORR
Objective response rate
COVID-19
Coronavirus disease 2019
OS
Overall survival
CR
Complete response
PD
Progressive disease
D
Day
PFS
Progression-free survival
DOR
Duration of response
PFS2
PFS after first subsequent therapy
ECOG PS
Eastern Cooperative Oncology Group performance status
Additional Demographics and Baseline Disease Characteristics5
Characteristic
RYBREVANT-
Lazertinib-
Chemotherapy
(n=263)
RYBREVANT - Chemotherapy (n=131)
Chemotherapy
(n=263)
Body weight, median (range), kg
64 (35-118)
63 (38.5-112)
63 (37-118)
<80 kg, n (%)
226 (86)
113 (86)
226 (86)
≥80 kg, n (%)
37 (14)
18 (14)
37 (14)
ECOG PS 0/1, n (%)
92 (35)/171 (65)
55 (42)/76 (58)
101 (38)/162 (62)
Smoking history, n (%)
No
175 (66.5)
90 (69)
168 (64)
Yes
87 (33)
41 (31)
95 (36)
Unknown
1 (0.4)
0
0
Time from metastatic diagnosis, median (range), months
21.5 (0.9-115.3)
23.0 (0.2-115.3)
21.0 (0.1-99.1)
Histologic type, n (%)
Adenocarcinoma
260 (99)
130 (99)
260 (99)
Othera
3 (1)
1 (1)
3 (1)
History of brain metastases, n (%)
120 (46)
58 (44)
120 (46)
No prior brain radiation
56 of 120 (47)
24 of 58 (41)
61 of 120 (51)
Osimertinib line of therapy,b n (%)
First
185 (70)
97 (74)
181 (69)
Second
77 (29)
34 (26)
82 (31)
EGFR mutation type, n (%)
Exon19del
165 (63)
89 (68)
183 (70)
Exon 21 L858R
98 (37)
42 (32)
79 (30)
aOther includes large cell carcinoma, squamous cell carcinoma, and other.
bOne patient in the RYBREVANT-lazertinib-chemotherapy arm received
osimertinib later than second-line and is not included in the table.
Note: The efficacy analysis set included all randomized patients.
aThe number of patients with measurable disease at baseline by BICR was
260
for chemotherapy, 130 for RYBREVANT-chemotherapy, and 259 for
RYBREVANT-lazertinib-chemotherapy.
bIncludes all responders.
BICR, blinded independent central review; CI, confidence interval; CR,
complete response; DOR, duration of response; NE, not estimable; NE/UNK, not
evaluable/unknown; ORR, objective response rate; PD, progressive disease;
PR, partial response; SD, stable disease.
icPFS by BICR5
RYBREVANT-Lazertinib-
Chemotherapy
(n=263)
Chemotherapy
(n=263)
icPFS, median (95% CI), months
12.8 (11.1-14.3)
8.3 (7.3-11.3)
HR (95% CI)
0.58 (0.44-0.78)
Patients with a history of brain metastases and no prior brain radiotherapy, n
56
61
icPFS, median (95% CI), months
11.1 (7-13.5)
6.3 (3.5-8.5)
HR (95% CI)
0.44 (0.25-0.79)
RYBREVANT-Chemotherapy
(n=131)
Chemotherapy
(n=263)
icPFS, median (95% CI), months
12.5 (10.8-NE)
8.3 (7.3-11.3)
HR (95% CI)
0.55 (0.38-0.79)
Patients with a history of brain metastases and no prior brain radiotherapy, n
24
61
icPFS, median (95% CI), months
NE (5.6-NE)
6.3 (3.5-8.5)
HR (95% CI)
0.36 (0.16-0.84)
Note: The efficacy analysis set included all randomized patients.
BICR, blinded independent central review; CI, confidence interval;
icPFS,
intracranial progression-free survival; HR, hazard ratio; NE, not estimable.
Most Common AEs (≥15% of Patients in Any Treatment Arm)5
AEs (≥ 15% of Patients in Any Treatment Arm) by Preferred Term, n (%)
RYBREVANT-
Lazertinib-
Chemotherapy
(n=263)
RYBREVANT-
Chemotherapy
(n=130)
Chemotherapy
(n=243)
All Grades
Grade ≥3
All Grades
Grade ≥3
All Grades
Grade ≥3
Neutropenia
181 (69)
144 (55)
74 (57)
59 (45)
101 (42)
52 (21)
Thrombocytopenia
158 (60)
96 (37)
57 (44)
19 (15)
72 (30)
22 (9)
Infusion-related reaction
148 (56)
9 (3)
76 (58)
7 (5)
1 (0.4)
0
Anemia
141 (54)
48 (18)
51 (39)
15 (12)
97 (40)
23 (9)
Paronychia
133 (51)
11 (4)
48 (37)
3 (2)
1 (0.4)
0
Nausea
131 (50)
16 (6)
58 (45)
1 (1)
90 (37)
2 (1)
Rash
126 (48)
17 (6)
56 (43)
8 (6)
12 (5)
0
Stomatitis
120 (46)
24 (9)
41 (32)
1 (1)
21 (9)
0
Leukopenia
106 (40)
71 (27)
37 (28)
26 (20)
68 (28)
23 (9)
Hypoalbuminemia
104 (40)
12 (5)
29 (22)
3 (2)
21 (9)
1 (0.4)
Constipation
96 (37)
3 (1)
50 (38)
1 (1)
72 (30)
0
Decreased appetite
85 (32)
7 (3)
40 (31)
0
51 (21)
3 (1)
Peripheral edema
85 (32)
1 (0.4)
42 (32)
2 (2)
15 (6)
0
Vomiting
76 (29)
10 (4)
32 (25)
1 (1)
42 (17)
1 (0.4)
Fatigue
69 (26)
15 (6)
36 (28)
4 (3)
47 (19)
4 (2)
Diarrhea
68 (26)
10 (4)
18 (14)
1 (1)
16 (7)
1 (0.4)
Asthenia
67 (25)
14 (5)
34 (26)
1 (1)
40 (16)
5 (2)
Dermatitis acneiform
62 (24)
17 (6)
26 (20)
5 (4)
7 (3)
0
ALT increased
55 (21)
14 (5)
26 (20)
7 (5)
67 (28)
10 (4)
Hypokalemia
55 (21)
16 (6)
24 (18)
6 (5)
15 (6)
6 (2)
COVID-19
44 (17)
0
27 (21)
2 (2)
25 (10)
0
Hypocalcemia
44 (17)
3 (1)
16 (12)
1 (1)
9 (4)
0
AST increased
43 (16)
7 (3)
19 (15)
1 (1)
57 (23)
0
Hyponatremia
42 (16)
10 (4)
13 (10)
5 (4)
16 (7)
2 (1)
Pruritus
30 (11)
0
20 (15)
0
17 (7)
0
Note: The safety population included all randomized patients who received ≥1 dose of
any study treatment.
Note: The safety population included all randomized patients who received ≥1 dose of
any study treatment.
aGrouping included the following preferred terms: rash, dermatitis
acneiform, rash maculopapular, erythema, acne, rash pruritic, rash erythematous, rash
macular, drug eruption, folliculitis, dermatitis, skin lesion, rash pustular,
papule,
rash follicular, exfoliative rash, pustule, rash papular, and skin exfoliation.
bGrouping included the following preferred terms: pulmonary embolism,
deep
vein thrombosis, embolism, renal vein thrombosis, venous thrombosis limb, embolism
venous, jugular vein thrombosis, superficial vein thrombosis, thrombophlebitis, and
thrombosis.
cGrouping included the following preferred terms: pneumonitis and
ILD.
ORR, Best Response and DOR by BICR Among Asian Patients7
BICR-Assessed Responsea
RYBREVANT- Chemotherapy
(n=63)
Chemotherapy
(n=127)
ORR, %
66
32
OR, 4; nominal
P<0.0001b
Best response, n (%)
CR
0
1 (1)
PR
41 (66)
40 (31)
SD
9 (15)
50 (39)
PD
7 (11)
22 (17)
NE
5 (8)
14 (11)
Median DOR,c months (95% CI)
6.9 (4.3-NE)
7.2 (4.1-NE)
aNumber of Asian patients with measurable disease at baseline by BICR
was
62 for RYBREVANT-chemotherapy and 127 for chemotherapy alone. Response data are
presented based on the number of patients with measurable disease at baseline.
bNominal P-value; the 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.
cAmong confirmed responders.
aPercentages may not sum to 100 due to rounding. bThree patients received RYBREVANT as the first subsequent therapy (monotherapy, n=2; combination with carboplatin/pemetrexed, n=1). cThe other category included VEGFi alone, bispecific monoclonal antibodies, antibody-drug conjugate-based regimens, ALK TKIs, herbal, and other investigational agents.
