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
Guidelines
NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for NSCLC recommends amivantamab-vmjw (RYBREVANT) as a first-line therapy option in combination with carboplatin and pemetrexed for EGFR Exon 20 insertion mutation positive advanced, or metastatic nonsquamous disease (NCCN Category 1, preferred).2
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.
2
NCCN Category of Preference of Preferred intervention is defined as interventions that are based on superior efficacy, safety, and evidence; and, when appropriate, affordability.2
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.2
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. 3-5
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, 0.40 [95% CI, 0.30-0.53]; P<0.001).5
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%).5
The majority of patients in the study experienced ≥1 AE.5
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 second-line RYBREVANT alone, and overall sites of first progression.7
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.
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).
No new safety signals were reported.
An exploratory analysis evaluated PFS among patients from PAPILLON across high-risk biomarker subgroups.8
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).
Note: AE, adverse event; BICR, blinded independent central review; C, cycle; CI, confidence interval; ctDNA, circulating tumor DNA; D, day; DNA, deoxyribonucleic acid; EGFR, epidermal growth factor receptor; Exon20ins, Exon 20 insertion; HR, hazard ratio; IRR, infusion-related reaction; IV, intravenous; MET, mesenchymal-epithelial transition; NCCN, National Comprehensive Cancer Network; NE, not evaluable; NGS, next-generation sequencing; NSCLC, non-small cell lung cancer; PK, pharmacokinetics; PD, progressive disease; OS, overall survival; PFS, progression-free survival; QW, every week; Q2W, every 2 weeks; Q3W, every 3 weeks; RP2D, recommended phase 2 dose; SOC, standard of care; TTD, time to treatment discontinuation; TLS, tumor lysis syndrome; 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 Study3-5
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 Criteria3-5
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 Design3-5
Efficacy Results5
At a median follow-up of 14.9 months
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.
Safety Results5
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.
Additional Analyses6-8
Outcome
RYB + Chemo
Chemo
Subgroup analysis in Asian patients at a median follow-up of 16.6 months6,a
PFS (BICR), median (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<0.0001a
a186 Asian patients were randomized to receive RYBREVANT plus chemo (n=97) or chemo alone (n=89). EGFR- and MET-related AEs were higher with RYBREVANT plus chemo compared with chemo alone and were mostly grade 1-2.
Post-progression analysis at a median follow-up of 14.9 months7,b
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)
b308 patients were randomized to receive RYBREVANT plus chemo (n=153) or chemo alone (n=155). No new safety signals were reported.
Exploratory analysis of PFS across high-risk biomarker subgroups8:
The risk of progression or death was reduced by >60% in the RYBREVANT plus chemo arm compared with the chemo 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).
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. 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 (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.3-5
PAPILLON Study Design3-5
Primary Endpointf
PFS by BICRb
Secondary Endpointsf
ORR
DOR
OS
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.
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.5
Baseline characteristics were balanced between the study arms.5
EGFR Exon20ins status was determined by local testing using tissue (92%) and/or plasma (8%) samples.5
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.5
Demographics and Baseline Disease Characteristics5
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).5
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.5
PFS across predefined clinically relevant subgroups was evaluated for RYBREVANT plus chemotherapy and chemotherapy alone.5
PFS Across Predefined Subgroups by BICR5
Subgroup
HR (95% CI)
Events/N
RYBREVANT
+ Chemotherapy
Chemotherapy
All randomized patients
0.4 (0.30-0.53)
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>
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.5,9
Mean percent decrease in tumor size was 53% for RYBREVANT plus chemotherapy and 34% for chemotherapy alone.5
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.9
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.9
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.9
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.9
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).5
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.5
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.5
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.9
The majority of patients in the study experienced at least ≥1 AE.5
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%).5
The rate of febrile neutropenia was 3% for RYBREVANT plus chemotherapy and 2% for chemotherapy alone.
The incidence of infusion-related reactions was 42% for RYBREVANT plus chemotherapy and 1% for chemotherapy alone.5
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.5
Serious AEs were reported in 37% of patients in the RYBREVANT plus chemotherapy arm and 31% in the chemotherapy alone arm.5
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.5
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.5
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)
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, n (%)
20 (21)
22 (25)
Prior EGFR TKI use,a n (%)
0
2 (2)
Adenocarcinoma histology, n (%)
96 (99)
89 (100)
aTransient 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 18 months.
At data cutoff, 49% of patients in the RYBREVANT plus chemotherapy arm and 11% in the chemotherapy alone arm remained on treatment.
Secondary Endpoints6
PFS2 and interim OS among Asian patients were consistent with results from the overall PAPILLON study population.
Median PFS2 was NE (95% CI, 18.6-NE) for RYBREVANT plus chemotherapy and 18.8 months (95% CI, 14.2-NE) 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 (95% CI, NE-NE) for RYBREVANT plus chemotherapy and 24.4 months (95% CI, 22.1-NE) 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.
Of the 67 patients with disease progression in the chemotherapy alone arm, 49 Asian patients (47 patients as part of the crossover arm plus an additional 2 patients off protocol) received second-line 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
Patients in the RYBREVANT plus chemotherapy arm received a median of 14.5 cycles of pemetrexed, whereas those in the chemotherapy alone arm received a median of 9 cycles of pemetrexed.
The pneumonitis rate was 2% in the RYBREVANT plus chemotherapy arm.6
The discontinuation rate of RYBREVANT due to TEAEs was low (8%).6
AEs Among Asian Patients6
TEAEs, n (%)
RYBREVANT + Chemotherapy (n=96)
Chemotherapy
(n=89)
Any AE
96 (100)
88 (99)
Grade ≥3 AEs
72 (75)
47 (53)
Serious AEs
33 (34)
24 (27)
AEs leading to death
3 (3)
1 (1)
AEs leading to discontinuation of any agent
19 (20)
5 (6)
AEs leading to discontinuation of all agent
7 (7)
6 (7)
Note: Data were obtained from the safety population, which included all randomized patients who received ≥1 dose of the study treatment
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, results from the crossover group of patients receiving optional second-line RYBREVANT alone, and overall sites of first progression.7
PFS2 rates for RYBREVANT plus chemotherapy and chemotherapy alone, respectively, were 67% and 46% at 18 months and 57% and 35% at 24 months.
TTD7
TTD was defined as the time from randomization to discontinuation of all study treatments for any reason.
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).
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 24 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).
Progressive disease led to treatment discontinuation among 33% of patients treated with RYBREVANT plus chemotherapy and 69% of patients treated with chemotherapy alone.
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).
TTST7
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 24 months.
The number of patients who received subsequent therapy in the RYBREVANT plus chemotherapy arm and chemotherapy alone arm, respectively, was 43 and 94 patients.
Among patients treated with RYBREVANT plus chemotherapy and chemotherapy alone, respectively, the most common subsequent therapies included chemotherapy (30% and 2%), chemotherapy plus IO/VEGFi (21% and 7%), EGFR TKI (21% and 7%), EGFR TKI combination (5% and 4%), RYBREVANT (2% and 76%), and other therapies (21% and 3%).
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%).
Efficacy7
The optional crossover group included 65 patients who received second-line RYBREVANT Q3W alone after progression on chemotherapy.
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, 6.7-11.0) and the median TTST was 9.7 months (95% CI, 7.7-12.1).
Safety7
The safety profile of RYBREVANT Q3W alone was consistent with that of RYBREVANT Q2W alone from CHRYSALIS in patients with EGFR Exon20ins advanced NSCLC.
The deaths of 17 patients were reported.
An exploratory analysis evaluated PFS for the RYBREVANT plus chemotherapy arm and chemotherapy alone arm among patients from PAPILLON across high-risk biomarker subgroups.8
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).8
Patient Disposition for Biomarker Analysis8
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.8
PFS Outcomes Across Biomarkers of High-risk Disease8
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 ctDNAand 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.
AE
Adverse event
NGS
Next-generation sequencing
AUC
Area under the concentration-time curve
NSCLC
Non-small cell lung cancer
BICR
Blinded independent central review
OR
Odds ratio
C
Cycle
ORR
Objective response rate
Chemo
Chemotherapy
OS
Overall survival
CI
Confidence interval
PD
Progressive disease
COVID-19
Coronavirus disease 2019
PFS
Progression-free survival
CR
Complete response
PFS2
PFS after first subsequent therapy
ctDNA
Circulating tumor DNA
PR
Partial response
D
Day
QC
Quality check
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
Exon20ins
Exon 20 insertion
RYB
RYBREVANT
HR
Hazard ratio
SD
Stable disease
IgG1
Immunoglobulin G1
TEAE
Treatment-emergent adverse event
IO
Immuno-oncology
TKI
Tyrosine kinase inhibitor
ITT
Intention-to-treat
TP53
Tumor protein P53
IV
Intravenous
TTD
Time to treatment discontinuation
MET
Mesenchymal-epithelial transition
TTST
Time to subsequent therapy
NCCN
National Comprehensive Cancer Network
VEGFi
Vascular endothelial growth factor inhibitor
NE
Not evaluable
A literature search of MEDLINE®, Embase®, BIOSIS Previews®, and Derwent Drug File (and/or other resources, including internal/external databases) was conducted on 03 September 2024.
Moores SL, Chiu ML, Bushey BS, et al. A novel bispecific antibody targeting EGFR and cMet is effective against EGFR inhibitor–resistant lung tumors. Cancer Res. 2016;76(13):3942-3953.
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 2024 September 03]. 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.
Zhou C, Tang KJ, Liu B, et al. Amivantamab plus chemotherapy vs chemotherapy as a first-line treatment among Asian patients with EGFR exon 20 insertion-mutated advanced non-small cell lung cancer (NSCLC): PAPILLON subgroup analysis. Oral Presentation presented at: European Society for Medical Oncology (ESMO) Asia Congress; December 1-3, 2023; Singapore.
Felip E, Shu C, Aguilar A, et al. Amivantamab plus chemotherapy vs chemotherapy as first-line treatment in EGFR exon 20 insertion-mutated 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.
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.
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.
Additional Demographics and Baseline Disease Characteristics5
Characteristic
RYBREVANT +
Chemotherapy (n=153)
Chemotherapy (n=155)
ECOG PS 0/1, n (%)
(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.
ORR and Best Response by BICR5,9
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.
ORR, Best Response, and DOR by BICR Among
Asian Patients6
BICR-Assessed Responsea
RYBREVANT +
Chemotherapy (n=97)
Chemotherapy (n=89)
ORR, % (95% CI)
70 (60-79)
51 (40-62)
OR, 2.2 (95% CI, 1.2-3.9); nominal P=0.012b
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)
Median DOR,c months (95% CI)
10.1 (8.5-15.2)
5.5 (4.3-7.1)
Note: ORR, best response, and DOR observed in Asian patients were consistent with those in the overall PAPILLON study population (ORR, 73% vs 47% [OR, 3.0; P<0.0001]; DOR (months), 10.1 vs 5.6). aThe number of patients with measurable disease at baseline by BICR was 96 in the RYBREVANT plus chemotherapy arm and 88 in the chemotherapy alone arm; response data were presented among all responders with postbaseline tumor assessment. 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 the confirmed responders (RYBREVANT plus chemotherapy, n=61; chemotherapy alone, n=32).
