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
PAPILLON study
PAPILLON (NCT04538664) is an ongoing, phase 3, randomized, open-label
study designed to compare the efficacy and safety of RYBREVANT plus chemotherapy
(carboplatin and pemetrexed; n=153) vs chemotherapy alone (carboplatin and pemetrexed;
n=155) in patients with untreated locally advanced or metastatic NSCLC and EGFR
Exon20ins mutations. The primary endpoint is PFS, based on BICR.2-4
At the primary analysis (median follow-up of 14.9 months)4:
Median PFS by BICR was 11.4 months (95% CI, 9.8-13.7) for RYBREVANT plus chemotherapy and 6.7 months (95% CI, 5.6-7.3) for chemotherapy alone (HR, 0.4 [95% CI, 0.3-0.53]; P<0.001).
The most common (≥15% in either group) AEs for RYBREVANT plus chemotherapy were neutropenia (59%), paronychia (56%), and rash (54%), and for chemotherapy alone were anemia (55%), neutropenia (45%), and nausea (42%).
The majority of patients in the study experienced ≥1 AE.
At the final OS analysis (median follow-up of 48.6 months)5:
Median OS was 34.3 months (95% CI, 27-40.8) for RYBREVANT plus chemotherapy and 27.9 months (95% CI, 24-32.4) for chemotherapy alone (HR, 0.87 [95% CI, 0.66-1.14]; P=0.307).
Median OS was 34.3 months (95% CI, 27-40.8) for RYBREVANT plus chemotherapy and crossover-adjusted OS was 22.1 months (95% CI, 16.4-27.6) for IPCW-adjusted chemotherapy alone (97/128 patients; HR, 0.57 [95% CI, 0.39-0.82]; nominal Pa=0.003).
No new safety signals were identified.
An Asian subgroup analysis reported6:
At a median follow-up of 16.6 months, median PFS by BICR was 11.5 months (95% CI, 9.8-13.7) for RYBREVANT plus chemotherapy and 5.6 months (95% CI, 4.9-7) for chemotherapy alone (HR, 0.34 [95% CI, 0.23-0.49]; nominal P<0.0001a).
EGFR- and MET-related AEs were higher with RYBREVANT plus chemotherapy compared with chemotherapy alone and were mostly grade 1-2.
A post-progression analysis reported overall TTD, overall TTST, results from the crossover group of patients receiving optional 2L RYBREVANT alone, and overall sites of first progression.7,8
At a median follow-up of 14.9 months in the overall population, the median TTD and TTST were 13.2 months (95% CI, 11.8-15.2) and 17.7 months (95% CI, 13.7-NE) for RYBREVANT plus chemotherapy and 7.5 months (95% CI, 7-8.4) and 9.9 months (95% CI, 8.6-11.1) for chemotherapy alone (TTD HR, 0.38 [95% CI, 0.28-0.51]; TTST HR, 0.35 [95% CI, 0.25-0.49]; nominal P<0.0001a for both). PFS2 for RYBREVANT plus chemotherapy vs chemotherapy alone, respectively, were 67% vs 46% at 18 months and 57% vs 35% at 24 months.7,8
At a median follow-up of 9.8 months in the crossover group (n=65) that received RYBREVANT Q3W alone, the median PFS was 6.8 months (95% CI, 4.4-9.6) and median OS was 17.7 months (95% CI, 12.1-NE).8
No new safety signals were reported.7
An exploratory analysis evaluated PFS among patients from PAPILLON across high-risk
biomarker subgroups.9
The risk of progression or death was reduced by >60% in the RYBREVANT plus
chemotherapy arm compared with the chemotherapy alone arm in both the NGS ctDNA
analyzable population (HR, 0.35; P<0.0001) and the site of insertion
population (HR, 0.39; P<0.0001).
PRO analysis reported10:
At a median follow-up of 14.9 months, in the RYBREVANT plus chemotherapy
vs chemotherapy alone arm, 54% vs 43% and 36% vs 13% of patients reported improved
or stable global health status at 6 and 12 months postbaseline, respectively.
The median TTSP was NE (95% CI, 18.6 months-NE) vs 20.1 months (95%
CI, 13.1-NE) for the RYBREVANT plus chemotherapy vs chemotherapy alone arm (HR,
0.67; 95% CI, 0.46-0.98; nominal P=0.04a).
Note: AE, adverse event; BICR, blinded independent central review; CI, confidence interval; ctDNA, circulating tumor DNA; DNA, deoxyribonucleic acid; EGFR, epidermal growth factor receptor; Exon20ins, Exon 20 insertion; HR, hazard ratio; IgG1, immunoglobulin G1; IPCW, inverse probability of censoring weighting; MET, mesenchymal-epithelial transition; NE, not evaluable; NGS, next-generation sequencing; NSCLC, non-small cell lung cancer; OS, overall survival; PFS, progression-free survival; PFS2, progression-free survival 2; PRO, patient-reported outcome; Q3W, every 3 weeks; TTD, time to treatment discontinuation; TTSP, time to symptomatic progression; 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.
PAPILLON study2-4
PAPILLON (NCT04538664) is an ongoing, phase 3,
randomized, open-label study designed to compare the efficacy and safety of RYBREVANT plus
chemo (carboplatin and pemetrexed) vs chemo alone (carboplatin and pemetrexed) in patients
with untreated locally advanced or metastatic NSCLC and EGFR Exon20ins mutations
N=308
Key inclusion criteria2-4
Age ≥18 years
Treatment-naïve, locally advanced or metastatic NSCLC with a
documented EGFR Exon20ins mutation
Measurable disease
ECOG PS ≤1
Adequate organ and bone marrow function
Study design2-4
Efficacy results4,5
At the primary analysis (median follow-up, 14.9 months)4:
Outcome
RYB +
chemo
(n=153)
Chemo
(n=155)
PFS (BICR), median
(95% CI), months
11.4
(9.8-13.7)
6.7
(5.6-7.3)
HR, 0.4 (95% CI,
0.3-0.53); P<0.001
PFS (investigator
assessed), median
(95% CI), months
12.9
(11.4-16.7)
6.9
(6.2-8.3)
HR, 0.38 (95% CI,
0.29-0.51)
PFS rates by BICR for RYBREVANT plus chemo and chemo alone, respectively, were 48% and 13% at 12 months and 31% and 3% at 18 months.4
At the final OS analysis (median follow-up of 48.6 months)5:
Median OS was 34.3 months (95% CI, 27-40.8) for RYBREVANT plus chemotherapy and 27.9 months (95% CI, 24-32.41) for chemotherapy alone (HR, 0.87; 95% CI, 0.66-1.14; P=0.307).
24- month OS rate: 66% vs 58%
36- month OS rate: 47% vs 38%
Safety results4,5
At the primary analysis4:
The majority of patients in the study experienced ≥1 AE.
The most common (≥15% in either group) AEs for RYBREVANT plus chemo were neutropenia (59%), paronychia (56%), and rash (54%), and for chemo alone were anemia (55%), neutropenia (45%), and nausea (42%).
The most common grade ≥3 AEs were neutropenia (33%), leukopenia (11%), and rash (11%) for RYBREVANT plus chemo and neutropenia (23%), anemia (12%), and thrombocytopenia (10%) for chemo alone.
Serious AEs were reported in 37% of patients in the RYBREVANT plus chemo arm and 31% in the chemo alone arm.
At the final OS analysis5:
No new safety signals were identified.
Additional analyses6-10
Asian subgroup analysis6,a
Outcome
RYB + chemo (n=97)
Chemo (n=89)
Median PFS by BICR (95% CI), months
11.5 (9.8-13.7)
5.6 (4.9-7)
HR, 0.34 (95% CI, 0.23-0.49) nominal
P<0.0001b
aMedian follow-up of 16.6 months
Post-progression analysis8,c
Outcome
RYB + chemo (n=153)
Chemo (n=155)
Overall median TTD (95% CI), months
13.2 (11.8-15.2)
7.5 (7-8.4)
Overall median TTST (95% CI), months
17.7 (13.7-NE)
9.9 (8.6-11.1)
cMedian follow-up of 14.9 months
Exploratory analysis of PFS in high-risk biomarker subgroups reported >60% reduction in risk of progression or death with RYBREVANT plus chemo vs chemo alone in NGS ctDNA analyzable population (HR, 0.35; P<0.0001) and site-of-insertion population (HR, 0.39; P<0.0001).9
PRO analysis: At a median follow-up of 14.9 months, more patients receiving RYBREVANT plus chemo vs chemo alone achieved improved or stable global health status (54% vs 43% at 6 months; 36% vs 13% at 12 months), with median TTSP NE vs 20.1 months.10
Note: AE, adverse event; AUC, area under the concentration-time curve; BICR, blinded independent central review; C, cycle; chemo, chemotherapy; CI, confidence interval; ctDNA, circulating tumor DNA; D, day; DNA, deoxyribonucleic acid; ECOG PS, Eastern Cooperative Oncology Group performance status; EGFR, epidermal growth factor receptor; Exon20ins, Exon 20 insertion; HR, hazard ratio; IV, intravenous; MET, mesenchymal-epithelial transition; NE, not evaluable; NGS, next-generation sequencing; NSCLC, non-small cell lung cancer; OS, overall survival; PFS, progression-free survival; QW, once weekly; R, randomization; RYB, RYBREVANT; TTD, time to treatment discontinuation; TTST, time to subsequent therapy. bThe 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.
PAPILLON (NCT04538664) is an ongoing phase 3, randomized, open-label study designed to
compare the efficacy and safety of RYBREVANT plus chemotherapy vs chemotherapy alone in
patients with untreated locally advanced or metastatic NSCLC with EGFR Exon20ins
mutations.2-4
PAPILLON study design2-4
Primary endpointf
PFS by BICRb
Secondary endpointsf
ORR
DOR
Protocol-specified final OSg
Safety
PFS2
Symptomatic PFS
TTST
aBrief monotherapy with common EGFR TKIs was allowed if lack of response was
document but removed as stratification factor since only 4 patients had prior EGFR TKI. bPer RECIST v1.1. cPatients with brain metastases were eligible if they received definitive
treatment and were asymptomatic, clinically stable, and off corticosteroid treatment for ≥2
weeks prior to randomization. dIn patients ≥80 kg. eCrossover was only allowed after BICR confirmation of disease progression;
amivantamab monotherapy on Q3W dosing per main study. fA hierarchical testing strategy was used for primary and secondary endpoints to
control for type 1 error. PFS, ORR, and then OS were included in hierarchical testing. P-values are nominal for all other secondary endpoints. gEstimated to provide ~ 56% power to detect a statistically significant difference in OS, with statistical power further attenuated due to crossover. Key statistical assumption: 300 patients with 200 events needed for 90% power to detect an HR of 0.625 (estimated PFS of 8 vs 5 months). PFS, ORR, and then OS were included in hierarchical testing.
A total of 308 patients were enrolled, of whom 153 patients were randomized to receive
RYBREVANT in combination with chemotherapy and 155 patients to chemotherapy alone.4
Baseline characteristics were balanced between the study arms.4
EGFR Exon20ins status was determined by local testing using tissue (92%) and/or
plasma (8%) samples.4
At a median follow-up of 14.9 months, the median treatment duration was 9.7 months (range,
0.1-26.9) for RYBREVANT plus chemotherapy and 6.7 months (range, 0-25.3) for chemotherapy
alone.4
Demographics and baseline disease characteristics4
Characteristic
RYBREVANT +
chemotherapy (n=153)
Chemotherapy (n=155)
Median age, years (range)
61 (27-86)
62 (30-92)
<65 years, n (%)
97 (63)
92 (59)
≥65 to <75 years, n (%)
44 (29)
48 (31)
≥75 years, n (%)
12 (8)
15 (10)
Female/male, n (%)
85 (56)/68 (44)
93 (60)/62 (40)
Race,a n (%)
Asian
97 (64)
89 (59)
White
49 (32)
60 (39)
Black or African American
2 (1)
0
American Indian or Alaska Native
1 (1)
2 (1)
Multipleb
1 (1)
0
Unknown
1 (1)
1 (1)
Region of enrollment, n (%)
North America
14 (9)
13 (8)
South America
6 (4)
5 (3)
Europec
35 (23)
36 (23)
Asiad
96 (63)
97 (63)
Oceania
2 (1)
4 (3)
Median body weight, kg (range)
61.8 (39-127)
66.5 (37-112)
<80 kg, n (%)
132 (86)
128 (83)
≥80 kg, n (%)
21 (14)
27 (17)
aIn some regions, reporting of race was not required (RYBREVANT +
chemotherapy: n=151; chemotherapy alone: n=152) bMultiple includes 1 patient who selected Black or African American and
White. cRussia counted as part of Europe. dTurkey counted as part of Asia.
At a median follow-up of 14.9 months, median PFS by BICR was 11.4 months (95% CI,
9.8-13.7) for RYBREVANT plus chemotherapy and 6.7 months (95% CI, 5.6-7.3) for
chemotherapy alone (HR, 0.4 [95% CI, 0.3-0.53]; P<0.001).4
Median PFS based on investigator assessment was 12.9 months (95% CI, 11.4-16.7)
for RYBREVANT plus chemotherapy arm and 6.9 months (95% CI, 6.2-8.3) for
chemotherapy alone (HR, 0.38 [95% CI, 0.29-0.51]).
PFS rates by BICR for RYBREVANT plus chemotherapy and chemotherapy alone,
respectively, were 48% and 13% at 12 months and 31% and 3% at 18 months.4
PFS across predefined clinically relevant subgroups was evaluated for RYBREVANT plus
chemotherapy and chemotherapy alone.4
PFS across predefined subgroups by BICR4
Subgroup
HR (95% CI)
Events/N
RYBREVANT
+ chemotherapy
Chemotherapy
All randomized patients
0.4 (0.3-0.53)
84/153
132/155
Age
<65 years
0.37 (0.26-0.53)
56/97
77/92
≥65 years
0.44 (0.27-0.7)
28/56
55/63
Sex
Female
0.31 (0.21-0.46)
41/85
81/93
Male
0.51 (0.34-0.78)
43/68
51/62
Race
Asian
0.36 (0.25-0.52)
55/97
77/89
Non-Asian
0.41 (0.26-0.67)
27/53
51/62
Body weight
<80 kg
0.41 (0.31-0.56)
74/132
108/128
≥80 kg
0.26 (0.12-0.57)
10/21
24/27
ECOG PS
0
0.35 (0.22-0.55)
31/59
51/58
1
0.42 (0.29-0.61)
53/94
81/97
Smoking history
Yes
0.45 (0.29-0.68)
37/65
57/64
No
0.37 (0.25-0.53)
47/88
75/91
History of brain metastasis
Yes
0.63 (0.38-1.06)
28/36
34/38
No
0.33 (0.23-0.46)
56/117
98/117
An improvement in ORR by BICR was observed for RYBREVANT plus chemotherapy compared
with chemotherapy alone.4,11
Mean percent decrease in tumor size was 53% for RYBREVANT plus chemotherapy and 34%
for chemotherapy alone.4
Median DOR by BICR was longer for RYBREVANT plus chemotherapy compared with
chemotherapy alone, 9.7 months (95% CI, 8.2-13.5) and 4.4 months (4.1-5.6),
respectively.11
As of the data cutoff, responses were ongoing in 49% of patients treated with
RYBREVANT plus chemotherapy compared with 17% of patients treated with chemotherapy
alone.
Investigator-assessed ORR was 66% (95% CI, 58-74) for RYBREVANT plus chemotherapy and
43% (95% CI, 35-51) for chemotherapy alone.11
Median DOR by investigator assessment was 13.5 months (95% CI, 10.1-19.2) for
RYBREVANT plus chemotherapy and 6.8 months (95% CI, 5.45-7.75) for chemotherapy
alone.11
Median PFS2 was NE (95% CI, 22.8-NE) for RYBREVANT plus chemotherapy and 17.2 months
(95% CI, 14.0-21.5) for chemotherapy alone (HR, 0.49 [95% CI, 0.32-0.76]); 95% CI widths
have not been adjusted for multiplicity and cannot be used to infer definitive treatment
effects.11
In the RYBREVANT plus chemotherapy arm, 43 patients started subsequent systemic
therapy, with 13 patients receiving chemotherapy alone. In the chemotherapy alone
arm, 94 patients started subsequent systemic therapy, with 71 patients receiving
RYBREVANT monotherapy.
The interim OS reached 33% maturity. There were 70 deaths in the study at the time of
the prespecified interim OS analysis (~210 projected for the final OS analysis). The
median OS was NE (95% CI, NE-NE) for RYBREVANT plus chemotherapy and 24.4 months (95%
CI, 22.1-NE) for chemotherapy alone arm (HR, 0.67 [95% CI, 0.42-1.09];
P=0.11).4
Of the 107 patients with disease progression in the chemotherapy arm, 71 patients (65
patients as part of the crossover arm plus an additional 6 patients off-protocol)
received second-line RYBREVANT monotherapy.4
Efficacy was evaluated at a median follow-up of 48.6 months (range, 0.3-59.4; data cutoff: March 20, 2026).5
Median OS was 34.3 months (95% CI, 27-40.8) for RYBREVANT plus chemotherapy and 27.9 months (95% CI, 24-32.4) for chemotherapy alone (HR, 0.87 [95% CI, 0.66-1.14]; P=0.307).5
The 24-month OS rate for RYBREVANT plus chemotherapy vs chemotherapy alone was 66% vs 58%.
The 36-month OS rate for RYBREVANT plus chemotherapy vs chemotherapy alone was 47% vs 38%.
Of 128 chemotherapy-randomized patients who discontinued treatment due to BICR-confirmed disease progression, 97 patients (76%; 87 as part of the crossover cohort and 10 off-protocol) crossed over to receive 2L RYBREVANT monotherapy.5
Crossover-adjusted final OS5
Subgroup
RYBREVANT + chemotherapy
IPCW-adjusted chemotherapya
HR (95% CI)
Median OS (95% CI), months
34.3 (27-40.8)
22.1 (16.4-27.6)
0.57 (0.39-0.82); nominal Pb=0.003
aTwo additional recommended models demonstrated improvement in the OS benefit consistent with IPCW: TSE: HR, 0.54 (95% CI, 0.35-0.77) and RPSFT: HR, 0.71 (95% CI, 0.37-1.36). bThe 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.
A total of 83/153 patients from the RYBREVANT plus chemotherapy arm and 129/155 patients from the chemotherapy alone arm received a subsequent therapy.5
Median PFS2 (PFS from randomization to second progression event) was 28.3 months (95% CI, 21.8-36.2) for RYBREVANT plus chemotherapy and 17.5 months (95% CI, 15.2-21) for chemotherapy alone (HR, 0.59 [95% CI, 0.45-0.77; nominal Pb<0.0001]).5
The 24-month PFS2 rate for RYBREVANT plus chemotherapy vs chemotherapy alone was 56% vs 36%.
The 36-month PFS2 rate for RYBREVANT plus chemotherapy vs chemotherapy alone was 42% vs 19%.
TTD was 14.1 months for RYBREVANT plus chemotherapy and 7.6 months for chemotherapy alone (HR, 0.36 [95% CI, 0.28-0.46; P<0.0001]).5
TTST was 16.9 months for RYBREVANT plus chemotherapy and 9.9 months for chemotherapy alone (HR, 0.37 [95% CI, 0.29-0.48; P<0.0001]).5
bThe 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 9.7 months (range, 0.1-26.9) for RYBREVANT plus
chemotherapy and 6.7 months (range, 0-25.3) for chemotherapy alone.4
Patients in the RYBREVANT plus chemotherapy arm received a median of 4 cycles (range,
1-4) of carboplatin and 13 cycles (range, 1-34) of pemetrexed. Patients in the
chemotherapy alone arm received a median of 4 cycles (range, 1-5) of carboplatin and 10
cycles (range, 1-37) of pemetrexed.11
The majority of patients in the study experienced at least ≥1 AE.4
The most common (≥15% in either group) AEs for RYBREVANT plus chemotherapy were neutropenia
(59%), paronychia (56%), and rash (54%), and for chemotherapy alone were anemia (55%),
neutropenia (45%), and nausea (42%).4
The rate of febrile neutropenia was 3% for RYBREVANT plus chemotherapy and 2% for
chemotherapy alone.
The incidence of IRRs was 42% for RYBREVANT plus chemotherapy and 1% for chemotherapy alone.4
The most common grade ≥3 AEs were neutropenia (33%), leukopenia (11%), and rash/dermatitis
acneiform (11%/4%) for RYBREVANT plus chemotherapy and neutropenia (23%), anemia (12%), and
thrombocytopenia (10%) for chemotherapy alone.4
Serious AEs were reported in 37% of patients in the RYBREVANT plus chemotherapy arm and 31%
in the chemotherapy alone arm.4
AEs leading to dose interruptions, reductions, and discontinuations of any study agent,
respectively, occurred in 104 (69%), 73 (48%), and 36 (24%) patients in the RYBREVANT plus
chemotherapy arm and 56 (36%), 35 (23%), and 16 (10%) patients in the chemotherapy alone
arm.4
Deaths occurred for 28 (18%) and 42 (27%) patients, with 20 and 30 deaths due to PD, in the
RYBREVANT plus chemotherapy and chemotherapy alone arms, respectively.4
The safety profile was consistent with prior reports, and no new safety signals were identified.5
PAPILLON study was conducted prior to evaluation of prophylactic strategies for AEs and subcutaneous RYBREVANT.5
Median duration of treatment was 13.4 months for RYBREVANT plus chemotherapy and 6.9 months for chemotherapy alone.5
A total of 151 patients were included in the RYBREVANT plus chemotherapy arm as part of the safety population, as 2 patients withdrew consent after randomization and did not receive study drugs.
In a subgroup analysis of Asian patients in the PAPILLON study, 186 Asian patients (defined by race) were randomized to receive RYBREVANT plus chemotherapy (n=97) or chemotherapy alone (n=89).6
Demographics and baseline disease characteristics among Asian patients6
Characteristic
RYBREVANT + chemotherapy (n=97)
Chemotherapy (n=89)
Median age, years (range)
57 (32-86)
62 (31-80)
<65 years, n (%)
65 (67)
54 (61)
≥65 years, n (%)
32 (33)
35 (39)
Female, n (%)
54 (56)
52 (58)
ECOG PS 1, n (%)
69 (71)
67 (75)
History of smoking, n (%)
32 (33)
32 (36)
History of brain metastasis,a n (%)
20 (21)
22 (25)
Prior EGFR TKI use,b n (%)
0
2 (2)
Adenocarcinoma histology, n (%)
96 (99)
89 (100)
Data cutoff date: May 3, 2023. aPatients with treated brain metastases were eligible if asymptomatic, clinically stable, and have been off corticosteroid treatment for ≥2 weeks prior to randomization. bTransient monotherapy with common EGFR TKIs was allowed if a lack of response was documented.
Primary endpoint6
At a median follow-up of 16.6 months, median PFS by BICR was 11.5 months (95% CI, 9.8-13.7) for RYBREVANT plus chemotherapy and 5.6 months (95% CI, 4.9-7) for chemotherapy alone (HR, 0.34 [95% CI, 0.23-0.49]; nominal P<0.0001a).
Median PFS based on investigator assessment was 14.1 months for RYBREVANT plus chemotherapy and 6.7 months for chemotherapy alone (HR, 0.31 [95% CI, 0.21-0.45]; nominal P<0.0001a).
PFS rates by BICR for RYBREVANT plus chemotherapy and chemotherapy alone, respectively, were 49% and 12% at 12 months and 31% and 3% at 24 months.
At data cutoff date of May 3, 2023, 49% of patients in the RYBREVANT plus chemotherapy arm and 11% in the chemotherapy alone arm remained on treatment.
Secondary endpoints6
Median PFS2 was NE for RYBREVANT plus chemotherapy and 18.8 months for chemotherapy alone (HR, 0.46 [95% CI, 0.26-0.83]; nominal P=0.008a).
PFS2 rates for RYBREVANT plus chemotherapy and chemotherapy alone, respectively, were 71% and 52% at 18 months and NE and 41% at 24 months.
Median interim OS was NE for RYBREVANT plus chemotherapy and 24.4 (95% CI, 22.1-NE) months for chemotherapy alone (HR, 0.65 [95% CI, 0.34-1.24]; nominal P=0.189a).
Interim OS rates for RYBREVANT plus chemotherapy and chemotherapy alone, respectively, were 79% and 76% at 18 months and 76% and 62% at 24 months.
Median TTD was 14.4 months (95% CI, 12.5-18.4) for RYBREVANT plus chemotherapy and 7.1 months (95% CI, 5.98-8.34) for chemotherapy alone (HR, 0.3 [95% CI, 0.2-0.43]; nominal P<0.0001a).
Median TTST was 22.9 months (95% CI, 15.9-NE) for RYBREVANT plus chemotherapy and 8.9 months (95% CI, 7.5-10.2) for chemotherapy alone (HR, 0.21 [95% CI, 0.13-0.33]; nominal P<0.0001a).
Of the 67 patients with disease progression in the chemotherapy alone arm, 49 patients (47 patients as part of the crossover arm plus an additional 2 patients off protocol) received 2L RYBREVANT monotherapy.
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 10.5 months for RYBREVANT plus chemotherapy and 6.3 months for chemotherapy alone.6
The median number of cycles received by each patient was 15 and 9 for RYBREVANT plus chemotherapy and chemotherapy alone, respectively.
In the RYBREVANT plus chemotherapy arm, 68 (70%) patients had ≥1 RYBREVANT dose interruption due to TEAEs, of which 46 (47%) were considered related to RYBREVANT.6
The most common related TEAEs leading to RYBREVANT dose interruption were IRR (n=24), rash (n=5), dermatitis acneiform (n=4), and paronychia (n=4).
RYBREVANT dose reductions due to TEAEs occurred in 33 (34%) patients, of which all were considered related to RYBREVANT.6
The most common related TEAEs leading to RYBREVANT dose reductions were rash (n=8) and paronychia (n=7).
Dose interruptions of carboplatin and pemetrexed due to TEAEs were reported in 21 (22%) and 55 (57%) patients, respectively, in the RYBREVANT plus chemotherapy arm and 14 (16%) and 29 (33%) patients, respectively, in the chemotherapy alone arm.6
Dose reductions in carboplatin and pemetrexed were reported in 17 (18%) and 24 (25%) patients, respectively, in the RYBREVANT plus chemotherapy arm and 9 (10%) and 15 (17%) patients, respectively, in the chemotherapy alone arm.6
Almost all TEAEs leading to dose reductions in the chemotherapy alone arm were considered treatment related.
The most common related TEAE leading to dose reduction in either carboplatin or pemetrexed was neutropenia in both arms.
In the RYBREVANT plus chemotherapy arm, discontinuations due to RYBREVANT-related TEAEs were reported in 8 (8%) patients (skin and subcutaneous tissue disorders, n=4 [dermatitis acneiform, n=2]; pneumonitis, n=2; skin infection, n=1; IRR, n=1). Discontinuations due to ≥1 chemotherapy-related TEAE were reported in 9 (9%) patients.6
EGFR- and MET-related AEs were higher with RYBREVANT plus chemotherapy compared with chemotherapy alone and were mostly grade 1-2.6
A post-progression analysis reported overall TTD, overall TTST, overall sites of first progression, and results from the crossover group of patients receiving optional 2L RYBREVANT monotherapy per protocol.7,8
PFS2 rates for RYBREVANT plus chemotherapy and chemotherapy alone, respectively, were 67% and 46% at 18 months and 57% and 35% at 24 months.7
TTD7,8
TTD was defined as the time from randomization to discontinuation of all study treatments for any reason.8
At a median follow-up of 14.9 months, median TTD was 13.2 months (95% CI, 11.8-15.2) for RYBREVANT plus chemotherapy and 7.5 months (95% CI, 7-8.4) for chemotherapy alone (HR, 0.38; 95% CI, 0.28-0.51; nominal P<0.0001a).8
The proportion of patients without a discontinuation event for RYBREVANT plus chemotherapy and chemotherapy alone, respectively, was 58% and 21% at 12 months and 35% and 5% at 18 months.
The proportion of patients who discontinued treatment in the RYBREVANT plus chemotherapy arm and chemotherapy alone arm, respectively, was 54% (n/N=83/153) and 85% (n/N=131/155).8
Progressive disease led to treatment discontinuation among 33% of patients treated with RYBREVANT plus chemotherapy and 69% of patients treated with chemotherapy alone.7
Treatment for >28 days beyond disease progression was reported in 11 patients in the RYBREVANT plus chemotherapy arm for a median duration of 40.4 weeks (95% CI, 8.7-NE).7
TTST8
TTST was defined as the time from randomization to the start of the first subsequent anticancer therapy after study treatment discontinuation or death, whichever occurred first.
At a median follow-up of 14.9 months, median TTST was 17.7 months (95% CI, 13.7-NE) for RYBREVANT plus chemotherapy and 9.9 months (95% CI, 8.6-11.1) for chemotherapy alone (HR, 0.35; 95% CI, 0.25-0.49; nominal P<0.0001a).
The proportion of patients without a subsequent therapy event for RYBREVANT plus chemotherapy and chemotherapy alone, respectively, was 68% and 36% at 12 months and 49% and 14% at 18 months.
The proportion of patients who received subsequent therapy in the RYBREVANT plus chemotherapy arm and chemotherapy alone arm, respectively, was 28% (n/N=43/153) and 61% (n/N=94/155).
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.
Sites of first progression7
Among 45 patients who progressed on RYBREVANT plus chemotherapy and 83 patients
who progressed on chemotherapy alone, there were 55 and 106 sites of progression,
respectively.
Among patients treated with RYBREVANT plus chemotherapy and chemotherapy
alone, respectively, these sites were located in the lymph node (3.3% and
5.2%), soft tissue/muscle (0% and 0.6%), bone (11.1% and 12.3%), abdominal
viscera (5.2% and 18.7%), brain (5.2% and 9%), and lung/pleura (11.1% and
22.6%).
Efficacy8,12
The optional crossover group included 65/155 (42%) patients who received 2L RYBREVANT Q3W alone after progression on chemotherapy.8
Patients were exposed to RYBREVANT for a median duration of 4.9 months (range 0-18.2).12
At a median follow-up of 9.8 months, median PFS was 6.8 months (95% CI, 4.4-9.6).
PFS rates were 52% at 6 months and 25% at 12 months.
At a median follow-up of 9.8 months, median OS was 17.7 months (95% CI, 12.1-NE).
The 12-month OS was 70%.
At a median follow-up of 9.8 months, the median TTD was 9.7 months (95% CI, 6.7-11) and the median TTST was 9.7 months (95% CI, 7.7-12.1).
2L RYBREVANT monotherapy was discontinued by 30/65 (46%) patients.12
Safety7,12
The safety profile of RYBREVANT Q3W alone was consistent with that of RYBREVANT Q2W alone from CHRYSALIS in patients with EGFR Exon20ins advanced NSCLC.7
The deaths of 17 patients were reported.12
An exploratory analysis evaluated PFS for the RYBREVANT plus chemotherapy arm
and chemotherapy alone arm among patients from PAPILLON across high-risk biomarker
subgroups.9
RYBREVANT plus chemotherapy exhibited a reduced risk of progression or death by
>60% compared with chemotherapy alone in both the NGS ctDNA analyzable population
(HR, 0.35; P<0.0001) and the site of insertion population (HR, 0.39;
P<0.0001).9
Patient disposition for biomarker analysis9
Disposition, n
ITT population (N=308)
Patients with analyzable plasma ctDNA NGSa samples
206
Pathogenic alterations detected at baseline
178
TP53 co-mutation
104
Matched analyzable samples at baseline and C3D1
154
Detectable Exon20ins at baseline and matched samples at C3D1
117
Patients with site of insertion datab
238
Site of Exon20insc
Near loop
197
Far loop
30
Helical
11
aUsing Guardant360® CDx, and excluding patients
enrolled in China sites who were not analyzable for ctDNA (n=87) and those
who did not pass QC (n=15). bUsing Guardant360® CDx (plasma;
global/excluding China sites) or AmoyDx LC10 NGS panel (tissue; China
sites). cExon20ins sites were further grouped into helical
(E762-M766), near-loop (A767-P772), and far-loop (H773-C775) regions.
Among patients with detectable Exon20ins ctDNA at baseline, the PFS was 11.1
months for RYBREVANT plus chemotherapy compared with 5.8 months for chemotherapy
alone (HR, 0.38; 95% CI, 0.26-0.55; P<0.0001). At baseline, 86%
patients receiving RYBREVANT plus chemotherapy and 87% of patients receiving
chemotherapy alone had detectable levels of Exon20ins ctDNA. After 6 weeks of
treatment (C3D1), 31% of patients receiving RYBREVANT plus chemotherapy and 55% of
patients receiving chemotherapy alone had detectable levels of Exon20ins
ctDNA.9
PFS outcomes across biomarkers of high-risk
disease9
Subgroup
HR (95% CI)a,b; P-Value
Median PFS,b,c (95% CI),
months
Patients who are progression-free at 12
months (%)
RYBREVANT + chemotherapy
Chemotherapy
RYBREVANT +
chemotherapy
Chemotherapy
Detectable Exon20ins ctDNA and ctDNA clearance analyzable
population
Cleared Exon20ins ctDNA after 6 weeks of treatment
0.26 (0.13-0.5); P<0.0001
12.2 (9.4-15.5)
6.8 (5.6-8.9)
52
8
Not cleared Exon20ins ctDNA after 6 weeks of treatment
0.55 (0.27-1.13); P=0.098
9.8 (5.7-15.1)
4.8 (4.2-5.8)
37
13
Presence of TP53 co-mutations
TP53 co-mutations
0.29 (0.17-0.47); P<0.0001
11.1 (8.3-12.5)
5.6 (4.4-5.8)
43
0
Wild-type TP53
0.45 (0.25-0.82); P=0.008
11.3 (7.8-NE)
8.5 (5.8-9.8)
44
24
Site of Exon20ins population
Near-loop region
0.4 (0.28-0.58); P<0.0001
11.3 (9.7-13)
5.8 (5.6-7.2)
46
12
Far-loop region
0.19 (0.06-0.69); P=0.005
9.4 (2.6-NE)
4.1 (1.5-5.7)
42
11
Helical region
0.55 (0.1-3.1); P=0.49
11.1 (4.4-NE)
9.1 (5.4-NE)
40
25
aHR is calculated using a stratified proportional hazards model.
P-value is calculated using a log-rank test stratified by ECOG PS
(0 or 1) and history of brain metastases (yes or no). bValues at a median follow-up of 14.9 months. cAssessed by BICR.
Post hoc analyses evaluated patient-relevant outcomes in patients from PAPILLON receiving RYBREVANT plus chemotherapy vs chemotherapy alone for EGFR-mutated NSCLC.10
PRO instruments used included PROMIS PF8c and EORTC QLQ-C30.10
PROs for all treatment arms were collected at baseline up to 24 hours before C1D1, C3D1, on the first day of subsequent odd-numbered cycles (C5D1, C7D1, etc), at the end-of-treatment visit, and every 12 weeks for 1 year after progression.
Baseline compliance for all PROs exceeded 97% in both treatment arms and remained above 80% for all PROs through C31.
EORTC QLQ-C30 global health status at 6 and 12 months postbaseline10
Patient response, %
6 monthsa,b
12 monthsb,c
RYBREVANT + chemotherapy
Chemotherapy
RYBREVANT + chemotherapy
Chemotherapy
Improved or stable
54
43
36
13
Worsened
23
18
11
4
Missing
11
11
14
10
Discontinued/death
12
28
38
73
Note: Percentages exclude patients with insufficient follow-up. Role functioning
is measured by limitation in pursuing work or other daily activities. aNominal
P=0.064. bThe endpoint was exploratory and not part of hierarchical hypothesis testing.
This endpoint was not adjusted for multiple comparisons. Therefore, the P-values displayed are nominal,
and statistical significance has not been established. cNominal P<0.0001.
TTSP10
At a median follow-up of 14.9 months (range, 0.3-27), the median TTSPa was NE (95% CI,b 18.6 months-NE) vs 20.1 months (95% CI,b 13.1-NE) for the RYBREVANT plus chemotherapy vs chemotherapy alone arm (HR, 0.67; 95% CI, 0.46-0.98; nominal P=0.04c).
At 12 months, 77% vs 60% of patients in the RYBREVANT plus chemotherapy vs chemotherapy alone arm showed no symptomatic progression or death. At median follow-up, 71% vs 59% showed no symptomatic progression, respectively.
At the primary analysis, 92% of patients who experienced symptomatic progression also had radiographic disease progression at some point during the study.
aTTSP was defined as the time from randomization to the onset of new symptom(s) or symptomatic worsening, that is related to lung cancer and required either a change in anticancer treatment and/or clinical intervention to manage symptom(s), or the time from randomization to death from any cause, whichever occurred first. bMedian TTSP of the ITT population with 95% CIs calculated using the Kaplan-Meier method. cHR with 95% CI calculated using a stratified Cox regression model; P-value calculated using a stratified log-rank test. 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.
2L
Second-line
ORR
Objective response rate
AE
Adverse event
OS
Overall survival
AUC
Area under the concentration-time curve
PD
Progressive disease
BICR
Blinded independent central review
PFS
Progression-free survival
C
Cycle
PFS2
PFS after first subsequent therapy
Chemo
Chemotherapy
PRO
Patient-related outcome
CI
Confidence interval
PROMIS PF8c
Patient-Reported Outcomes Measurement Information System - Physical Function Short Form 8c
ctDNA
Circulating tumor DNA
QC
Quality check
D
Day
Q2W
Every 2 weeks
DNA
Deoxyribonucleic acid
Q3W
Every 3 weeks
DOR
Duration of response
QW
Once weekly
ECOG PS
Eastern Cooperative Oncology Group performance status
R
Randomization
EGFR
Epidermal growth factor receptor
RECIST
Response Evaluation Criteria in Solid Tumors
EORTC QLQ-C30
European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire Core 30
RPSFT
Rank preserving structural failure time
Exon20ins
Exon 20 insertion
RYB
RYBREVANT
HR
Hazard ratio
TEAE
Treatment-emergent adverse event
IPCW
Inverse probability of censoring weighting
TKI
Tyrosine kinase inhibitor
IRR
Infusion-related reaction
TP53
Tumor protein P53
ITT
Intention-to-treat
TSE
Two-stage estimation
IV
Intravenous
TTD
Time to treatment discontinuation
MET
Mesenchymal-epithelial transition
TTSP
Time to symptomatic progression
NE
Not evaluable
TTST
Time to subsequent therapy
NGS
Next-generation sequencing
VEGFi
Vascular endothelial growth factor inhibitor
NSCLC
Non-small cell lung cancer
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 2026.
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.
Agrawal T, Artis E, Xie J, et al. PAPILLON: a randomized phase 3 study of
amivantamab plus chemotherapy vs chemotherapy alone in EGFR exon 20ins NSCLC. Poster
presented at: International Association for the Study of Lung Cancer (IASLC) World
Conference on Lung Cancer Singapore (WCLC); January 28-31, 2021; Worldwide Virtual
Event.
Janssen Research & Development, LLC. A randomized, open-label phase 3 study of
combination amivantamab and carboplatin-pemetrexed therapy, compared with
carboplatin-pemetrexed, in patients with EGFR exon 20ins mutated locally advanced or
metastatic non-small cell lung cancer. In: ClinicalTrials.gov [Internet]. Bethesda
(MD): National Library of Medicine (US). 2000- [cited 2026 September 11]. Available
from: https://www.clinicaltrials.gov/ct2/show/NCT04538664 NLM
Identifier: NCT04538664.
Zhou C, Tang KJ, Cho BC, et al. Amivantamab plus chemotherapy in NSCLC with EGFR
exon 20 insertions. N Engl J Med. 2023;389(22):2039-2051.
Kim C, Tang KJ, Cho BC, et al. First-line amivantamab-chemotherapy vs chemotherapy in NSCLC with EGFR Exon 20 insertions:
overall survival from PAPILLON. Oral Presentation presented at: International Association for the Study of Lung Cancer (IASLC) World
Conference on Lung Cancer (WCLC); September 12-15, 2026; Seoul, Republic of Korea.
Zhou C, Tang KJ, Liu B, et al. Amivantamab plus chemotherapy versus chemotherapy for first-line treatment of participants with EGFR exon 20 insertion-mutated advanced non-small cell lung cancer: PAPILLON Asia subgroup analysis. Lung Cancer. 2026;213:109302.
Felip E, Shu C, Aguilar A, et al. Amivantamab plus chemotherapy vs chemotherapy as first-line treatment in EGFR exon 20 insertionmutated advanced NSCLC: analysis of post-progression endpoints from PAPILLON. Oral Presentation presented at: European Lung Cancer Congress (ELCC); March 20-23, 2024; Prague, Czech Republic.
Sanborn RE, Zhou C, Tang KJ, et al. Amivantamab-chemotherapy in non-small cell lung cancer with EGFR exon 20 insertions: impact of treatment crossover and other endpoints from the phase III PAPILLON study. Target Oncol. 2025;20(6):979-989.
Goldman J, Cho BC, Cheng S, et al. PAPILLON: TP53 co-mutations, sites of insertion, and ctDNA clearance among patients with EGFR Ex20ins-mutated advanced NSCLC. 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.
Paz-Ares L, Veillon R, Majem M, et al. Patient-reported outcomes and time to symptomatic progression from PAPILLON: amivantamab plus chemotherapy vs chemotherapy as first-line treatment of EGFR exon 20 insertion-mutated advanced NSCLC. Lung Cancer. 2026;213:108788.
Zhou C, Tang KJ, Cho BC, et al. Supplement to: Amivantamab plus chemotherapy in NSCLC with EGFR exon 20 Insertions. N Engl J Med. 2023;389(22):2039-2051.
Sanborn RE, Zhou C, Tang KJ, et al. Supplement to: Amivantamab-chemotherapy in non-small cell lung cancer with EGFR exon 20 insertions: impact of treatment crossover and other endpoints from the phase III PAPILLON study. Target Oncol. 2025;20(6):979-989.
Paz-Ares L, Veillon R, Majem M, et al. Supplement to: Patient-reported outcomes and time to symptomatic progression from PAPILLON: amivantamab plus chemotherapy vs chemotherapy as first-line treatment of EGFR exon 20 insertion-mutated advanced NSCLC. Lung Cancer. 2026;213:108788.
Additional demographics and
baseline disease characteristics4
Characteristic
RYBREVANT +
Chemotherapy (n=153)
Chemotherapy (n=155)
ECOG PS 0/1, n (%)
54 (35)/99 (65)
55 (35)/100 (65)
Smoking history: yes/no, n (%)
65 (42)/88 (58)
64 (41)/91 (59)
Median time from initial diagnosis, months (range)
1.8 (0.5-80.8)
1.8 (0.6-95.9)
Median time from metastatic diagnosis, months (range)
1.5 (0.2-40)
1.6 (0.3-30.7)
Histologic type, n (%)
151 (99)/2 (1)
153 (99)/2 (1)
Adenocarcinoma
151 (99)
153 (99)
Large cell carcinoma
0
1 (1)
Squamous cell carcinoma
0
0
Other
2 (1)
1 (1)
History of brain metastases, n (%)
35 (23)
36 (23)
ECOG PS, Eastern Cooperative Oncology Group performance status.
Final OS in predefined groups5
Subgroup
RYBREVANT +
Chemotherapy
Chemotherapy
HR (95% CI)
All randomized patients
153
155
0.87 (0.66-1.14)
Age category
<65 years
97
92
0.87 (0.61-1.24)
≥65 years
56
63
0.82 (0.53-1.26)
<75 years
141
140
0.81 (0.61-1.08)
≥75 years
12
15
1.33 (0.55-3.25)
Sex
Female
85
93
0.58 (0.4-0.84)
Male
68
62
1.33 (0.88-2.01)
Race
Asian
97
89
0.9 (0.63-1.28)
Non-Asian
53
62
0.74 (0.47-1.17)
Body weight
<80 kg
132
128
0.8 (0.59-1.07)
≥80 kg
21
27
1.06 (0.52-2.16)
History of brain metastases
No
117
117
0.82 (0.6-1.13)
Yes
36
38
0.97 (0.57-1.62)
ECOG PS
0
59
58
0.77 (0.49-1.22)
1
94
97
0.9 (0.64-1.26)
History of smoking
No
88
91
0.63 (0.44-0.91)
Yes
65
64
1.22 (0.81-1.85)
Note: Subgroup analyses were not part of the hypothesis testing of the trial and should not be used to infer definitive treatment effects.
CI, confidence interval; ECOG PS, The Eastern Cooperative Oncology Group performance status; HR, hazard ratio; OS, overall survival.
Summary of subsequent therapy5
Subsequent therapy
RYBREVANT +
Chemotherapy (n=153)
Chemotherapy (n=155)
Did not receive subsequent therapy (non-PD), %
18
8
Did not receive subsequent therapy (PD), %
16
8
Ongoing therapy, %
12
0
Received a first subsequent therapy, n (%)
83 (54)
129 (83)
RYBREVANT, n
2
97
Other EGFR-targeted or TKI- based regimens,a n
31
15
Chemotherapy or ICI regimens, n
39
13
Otherb, n
11
4
aEGFR-targeted or TKI-based regimens included afatinib, firmonertinib, mobocertinib, ORIC 114, osimertinib, sunvozertinib, zipalertinib, and EGFR TKI combination regimens. TKI in combination with chemotherapy, immunotherapy, or VEGF inhibitor therapies were only counted in the TKI-based regimen category. bOther therapy included antineoplastic agents, bevacizumab, cantharidin, investigational agents, other protein kinase inhibitors, and SKB 264.
Time to worsening of symptomsa was prolonged with RYBREVANT plus chemotherapy vs chemotherapy alone.
Time to deterioration by EORTC QLQ-C30 symptom scales5
Symptom scale
Median (95% CI), months
HR (95% CI)
P-value
RYBREVANT +
chemotherapy (n=153)
Chemotherapy (n=155)
Fatigue
2.8 (1.6-4.2)
2.9 (1.9-3.9)
0.85 (0.66-1.09)
-
Nausea and vomiting
6.9 (3.9-10.8)
4.3 (3-7.3)
0.75 (0.58-0.98)
<0.05
Pain
9.5 (6.2-11.8)
6 (4.4-7.8)
0.73 (0.56-0.96)
<0.05
Dyspnea
12.4 (7.2-15)
7.8 (5.6-9.3)
0.68 (0.51-0.9)
<0.05
Insomnia
13.8 (10.3-18.7)
8.5 (7.3-10.7)
0.69 (0.52-0.93)
<0.05
Appetite loss
5.9 (2.9-13)
6.3 (4.6-8.6)
0.92 (0.71-1.21)
-
Constipation
3.8 (2.9-8.5)
7.5 (4.6-9.2)
0.95 (0.73-1.25)
-
Diarrhea
16.9 (13.9-21.5)
11.7 (7.8-13.1)
0.72 (0.54-0.96)
<0.05
TTSPb was prolonged with RYBREVANT plus chemotherapy vs chemotherapy alone (28.8 vs 22.4 months; HR, 0.77 [95% CI, 0.59-1.01; P=0.055).5
aTime to worsening in EORTC QLQ-C30 symptom scales was defined as the time from randomization until the first clinically meaningful worsening in the symptom (an increase of ≥10 points) or death. bTTSP was defined as the time from randomization to the onset of new or worsening symptoms that was considered by the investigator to be related to lung cancer and required either a change in anticancer treatment and/or clinical intervention to manage symptoms, whichever occurred first.
EORTC QLQ-C30, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30; CI, confidence interval; HR, hazard ratio; TTSP, time to symptomatic progression.
Patient disposition5
Disposition, n (%)
Randomized (N=308)
RYBREVANT +
Chemotherapy (n=153)
Chemotherapy (n=155)
Did not receive study drugsa
2
-
Received treatment
151
155
Discontinued treatment
133 (88)
155 (100)
Disease progression
94 (62)
128 (83)
AE
17 (11)
17 (11)
Withdrawal by patient
19 (13)
7 (5)
Otherb
3 (2)
3 (2)
Crossed over to RYBREVANT monotherapy after treatment discontinuedc
-
87 (as part of the study) 10 (off-protocol)
Treatment ongoingd
18 (12)
0
aBoth patients withdrew consent after randomization. bOther includes: noncompliance, other, and physician’s decision (n≤2 for all). c97/128 (76%) patients crossed over to 2L RYBREVANT after discontinuing chemotherapy due to progressive disease. dData cutoff date: March 20, 2026.
2L, second-line; AE, adverse event.
Baseline characteristics of patients whose disease progressed12
Characteristic, n (%)
Progressed on chemotherapy; did not cross over to 2L RYBREVANT (n=61)
Progressed on chemotherapy; crossed over to 2L RYBREVANT (n=65)
All disease progressions on chemotherapy (n=126)
Progressed on RYBREVANT + chemotherapy (n=75)
Sex
Female
41 (67)
37 (57)
78 (62)
37 (49)
Male
20 (33)
28 (43)
48 (38)
38 (51)
Race
Asian
28 (46)
47 (72)
75 (60)
52 (69)
Non-Asian
29 (48)
18 (28)
47 (37)
21 (28)
Unknown
4 (7)
0
4 (3)
2 (3)
History of brain metastases
13 (21)
19 (29)
32 (25)
26 (35)
History of liver metastases
14 (23)
13 (20)
27 (21)
8 (11)
History of tobacco use
24 (39)
29 (45)
53 (42)
31 (41)
Prior major surgery
9 (15)
9 (14)
18 (14)
7 (9)
Best overall response (BICR)
CR
1 (2)
0
1 (1)
2 (3)
PR
30 (49)
27 (42)
57 (45)
53 (71)
SD
24 (39)
26 (40)
50 (40)
16 (21)
PD
5 (8)
11 (17)
16 (13)
4 (5)
NE
1 (2)
1 (2)
2 (2)
0
Respondera
31 (51)
27 (42)
58 (46)
55 (73)
Nonresponderb
30 (49)
38 (58)
68 (54)
20 (27)
aComplete or partial response. bStable, progressive, or NE.
Censor at time of crossover and reweight using stabilized weights
58
0.52 (0.28-0.94)
<0.031
TSE
Weibull regression model without recensoring
65
0.55 (0.31-0.92)
<0.032c
RPSFT
Treatment grouping without recensoring
70
0.6 (0.32-1.12)
<0.0001
aMedian follow-up: 14.9 months. bThe endpoint was exploratory and not part of hierarchical hypothesis testing. This endpoint was not adjusted for multiple comparisons. Therefore, the P-values displayed are nominal, and statistical significance has not been established. cP-value calculated by assuming log (HR) is normally distributed.
CI, confidence interval; HR, hazard ratio; IPCW, inverse probability of censoring weighting; ITT, intention-to-treat; OS, overall survival; RPSFT, rank-preserving structural failure time; TSE, two-stage estimation.
ORR and best response by
BICR4,11
BICR-assessed responsea
RYBREVANT +
chemotherapy (n=153)
Chemotherapy (n=155)
ORR, % (95% CI)
73 (65-80)
47 (39-56)
Risk ratio, 1.5 (95% CI, 1.32-1.68);
P<0.001
Best response, n (%)
CR
6 (4)
1 (1)
PR
105 (69)
71 (47)
SD
29 (19)
62 (41)
PD
4 (3)
16 (11)
NE/Unknown
8 (5)
2 (1)
Median time to response, weeks (range)
6.7 (5.1-72.5)
11.4 (5.1-60.2)
Note: The efficacy analysis set included all randomized patients. aNo. of patients with measurable disease at baseline by BICR was 152 in
both arms; response data presented among all responders.
aFor the RYBREVANT plus chemotherapy arm, includes patients who
discontinued RYBREVANT, carboplatin, and pemetrexed at any time and patients who
discontinued RYBREVANT and pemetrexed after completion of carboplatin; for the
chemotherapy arm, includes patients who discontinued carboplatin and pemetrexed at
any time and patients who discontinued pemetrexed after completion of carboplatin.
AE, adverse event.
PFS by BICR among Asian patients across predefined subgroups6
ORR, best response, and DOR by
BICR among Asian patients6
BICR-assessed responsea
RYBREVANT +
chemotherapyb (n=97)
Chemotherapy (n=89)
Best response, n (%)
CR
5 (5)
1 (1)
PR
62 (65)
44 (50)
SD
22 (23)
35 (40)
PD
3 (3)
7 (8)
NE/unknown
4 (4)
1 (1)
ORR,c n (%)
67 (70) (95% CI, 60-79)
45 (51) (95% CI, 40-62)
OR, 2.2 (95% CI, 1.2-3.9); P=0.012d
Median DOR,e months (95% CI)
10.1 (8.5-15.2)
5.5 (4.3-7.1)
aThe number of patients with measurable disease at baseline by BICR was 96 in the RYBREVANT + chemotherapy arm and 88 in the chemotherapy alone arm; response data were presented among all responders with postbaseline tumor assessment. bAll patients treated with RYBREVANT + chemotherapy achieved a reduction in tumor size. cORR was the percentage of patients achieving either CR or PR per RECIST v1.1. dNominal 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. eAmong the confirmed responders (RYBREVANT + chemotherapy, n=61; chemotherapy alone, n=32).
aOne patient in the RYBREVANT + chemotherapy arm withdrew from the study prior to receiving any study treatment, leaving 96 patients in the safety analysis. bWithin 30 days of last study treatment dose. None of the deaths was considered related to RYBREVANT. cThe most common TEAEs leading to discontinuation of any agent in the RYBREVANT + chemotherapy arm were dermatological TEAEs (n=5) and infections and infestations (n=4).
Most common first subsequent systemic therapy classes7,8
Patients, %
RYBREVANT + chemotherapy (n=43)
Chemotherapy
(n=94)
Chemotherapy + IO/VEGFi
21
7
Chemotherapya
30
2
RYBREVANT (per protocol)
0
69
RYBREVANT (off protocol)
2
6
EGFR TKIs
21
7
EGFR TKIs combination
5
4
Otherb
21
3
aIn the RYBREVANT + chemotherapy and chemotherapy alone arms, 23% and 1% of patients received single-agent chemotherapy, respectively, and 7% and 1% of patients received doublet chemotherapy, respectively. bIncluded IO alone and investigational agents.
Most common (≥15%) AEs by
preferred term among Asian patients6
Most common (≥15%) AEs by
preferred term, n (%)
RYBREVANT + chemotherapy (n=96)a
Chemotherapy (n=89)
All grades
Grade ≥3
All grades
Grade ≥3
Associated with EGFR inhibition
Paronychia
63 (66)
7 (7)
0
0
Rashb
52 (54)
12 (13)
7 (8)
0
Stomatitis
30 (31)
2 (2)
4 (4)
0
Dermatitis acneiform
28 (29)
5 (5)
1 (1)
0
Associated with MET inhibition
Hypoalbuminemia
46 (48)
4 (4)
11 (12)
0
Edema peripheral
23 (24)
1 (1)
7 (8)
0
Other
Neutropeniac
58 (60)
34 (35)
43 (48)
20 (22)
Anemia
52 (54)
10 (10)
48 (54)
9 (10)
Leukopenia
49 (51)
15 (16)
37 (42)
4 (4)
Thrombocytopenia
38 (40)
11 (11)
26 (29)
8 (9)
Constipation
37 (39)
0
27 (30)
1 (1)
Aspartate aminotransferase increased
35 (36)
1 (1)
38 (43)
1 (1)
Alanine aminotransferase increased
32 (33)
3 (3)
39 (44)
2 (2)
IRRd
32 (33)
2 (2)
0
0
Decreased appetite
32 (33)
2 (2)
29 (33)
1 (1)
COVID-19
26 (27.1)
2 (2)
12 (13.5)
1 (1)
Nausea
24 (25)
1 (1)
34 (38)
0
Hypokalemia
22 (23)
10 (10)
3 (3)
0
Vomiting
20 (21)
1 (1)
11 (12)
0
Diarrhea
18 (19)
2 (2)
6 (7)
0
Malaise
16 (17)
0
12 (14)
0
Weight decreased
16 (17)
1 (1)
11 (12)
0
Gamma-glutamyl transferase increased
15 (16)
4 (4)
21 (24)
6 (7)
Hemorrhoids
14 (15)
2 (2)
0
0
aOne patient in the RYBREVANT + chemotherapy arm withdrew from the study prior to receiving any study treatment, leaving 96 patients in the safety analysis. bAll cases of grade 3 rash were either resolving or had resolved by the cut-off date of May 3, 2023. Most cases of rash required no change to the treatment regimen. Only 1 patient discontinued treatment with RYBREVANT due to treatment-related rash, with onset on day 316. cIn the RYBREVANT + chemotherapy arm, 10 patients had dose interruptions due to neutropenia and 3 patients had febrile neutropenia, none of which required dose modifications. dMost IRRs occurred during the first infusion and were mild-to-moderate in severity. Grade ≥3 IRRs were reported in 2 patients, 1 during infusion with RYBREVANT and 1 with carboplatin. The drug was withdrawn in both cases.
aBaseline PRO scores were reported for patients with a non-missing value for the specific PRO at the
specified time point. EORTC QLQ-C30: RYBREVANT + chemotherapy, n=148; chemotherapy, n=151. PROMIS PF8c:
RYBREVANT + chemotherapy, n=149; chemotherapy, n=151. bAt C3D1. cNominal
P-values; the endpoint was exploratory and not part of hierarchical hypothesis testing. This endpoint was not
adjusted for multiple comparisons. Therefore, the P-values displayed are nominal, and statistical significance
has not been established.
dEORTC QLQ-C30 is a 30-item validated PRO instrument measuring QoL in cancer. It includes 5
functional scales (cognitive, physical, role, social, and emotional), 3 symptom scales (nausea and vomiting,
pain, and fatigue), 1 global scale, 5 single-item symptom measures (dyspnea, insomnia, appetite loss,
constipation, and diarrhea), and 1 financial difficulties item. All scores range from 0 to 100 per the EORTC
QLQ-C30 scoring manual, v3.0. A higher score indicates better QoL on the functional and global health scales,
whereas a higher score indicates greater symptomatology on the symptoms scales. eMinor
variations were observed in LSMEANS change from baseline for both arms throughout the treatment cycles. LSMEANS
difference between arms remained small and non-significant across subsequent cycles. fPROMIS
PF8c is an 8-item instrument that assesses activities of daily living, mobility, and the global impact of
physical functioning over the past 7 days, with higher scores indicating better physical ability. A T-score
metric is calculated, with possible scores ranging from 15 to 61. This tool is designed for use in patients with
solid tumors or hematologic malignancies undergoing anticancer therapy and with an ECOG status of 0 to 3.
C, cycle; CI, confidence interval; D, day; ECOG, Eastern Cooperative Oncology Group; EORTC QLQ-C30, European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire Core 30; LSMEANS, least-squares means; PRO, patient-reported outcome;PROMI S PF8c, Patient-Reported Outcomes Measurement Information System - Physical Function Short Form 8c; QoL, quality of life.
