[Slide 1]
EGFR single cell atlas of different cell states
National Cancer
Centre Segapore
Segmests
Dominant malignant programs (DMP)
Normal ad acent
Treatment naive
1.0
Proliferative
TKI on-treatment
TKI resistance
(3,543 s.n)
Proportion (x 100%)
0.8
Neuroendocrine/ EMT-like
(21,636 s.n)
0.6
Inflammatory
(16,147 s.n)
Developmental stem-like
Normal adjacent ussue
Primary
Post-TKI
0.4
(17,025 s.n)
Treatment have
Post-TKI on
resistance
(N=9)
resistance
(N*9)
treatment (N=12)
Differentiated epithelial
(N=3)
(N=12)
Short term (<6 weeks)
0.2
(14,887 s.n)
Long term TXI
Baseline epithelial
No secondary mutation
P mths)
(13,387 s.n)
0.0
NAT TN OT TKIR
Unassigned
H
Normal adjection
Treatment have
TKI on treatment
TKI resistance
Treatment group
(114 s.n)
EGRA
TPS2
18.000
I I
10.000
Developmental
sociey
stem-like
100
Differentiated
Proliferative
75-
Proportion €
epithelial
Neur
50
Baseline epi.
Daniel Tan
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TN008 AN
TN004 AN
TN006 AN
TN007 AN
TN001 AN
TN002 AN
TN005 AN TN005_AN
TN003 AN
TN009 AN
TN008
TN004
TN006
TN007
TN001
TN002
TN005
TN003
TN009
0003
0002
D001
P003
P002
P006
POOB
P012
P005
P013
P001
P009
P011
1000
E001
R006
R003
R001
R010
R009
R007
R005
*R008
R012
R004
R002
*R011
Transitional
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Mally
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Broad cell yes,
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---
[Slide 2]
EGFR TKI resistance
National Cancer
Center Separe
Signature
Tumor burden (response)
Primary
Secondary
Secondary/ Tertiary
Resistance
Resistance
Resistance
1G/2G TKI
1/2G > 3G; 3G > 4G
PFS
Off target
resistance
On target
resistance
Osimertinib
BIOMARKER AGNOSTIC
resistance
T790M+
TROPION Lung05 and 01
OPTI-TROP
HERTHENA 01
Selective pressure/ evolutionary bottleneck
IZA-BREN
HARMONI
Time (PFS)
Biomarker VS
Daniel Tan
Agnostic approaches
Association 10 the Study of Lung Cancer
1/2G EGFR TKI
3G EGFR TKI
Chemo
2026 TASLC International Symposium on
Treatment Advances in Lung Cancer
3G EGFR TKI
Chemo
Jan.10 11 2026
Combination 3G EGFR TKI
National aisan-University Cancer Center
International Conference Center
---
[Slide 3]
Factors influencing efficacy:toxicity ratio of ADCs
National Cancer
Centre Singapore
Signath
Antibody selectivity
Binding and internalisation
Antigen expression VS dependency
Sensitivity to payload
Immunogenic cell death
On-target on-tumor
(typically <1%)
Distribution
Clearance
ADC metabolism
Off-target (including
Payload in circulation
on-target off-tumor)
1,000
(typically >99%)
Concentration (nmol/L)
100
10
ADC PK
1
Payload PK
Daniel Tan
0.1
0
7
14
21
Time after dose (days)
Linker stability
Albumin-bound
Free circulating payload
the Study Cancer
2026 TASLC International Symposium on
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---
[Slide 4]
Role of 4G EGFR TKI
Duration of treatment
National Cancer
Tumor assessment
Comm Shiport
Della-
Della 1700M
Seguion
40
LBSAR
Date
20
Best changes
in target lesions (%)
Dulla
0
Date
Del18-7700M-
20
Della-
40
80mg
LASAR
160mg
30mg
160mg
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240mg
L147 пки-
240mg
320mg
Delli
320mg
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ongoing
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LASER
17808
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LASER-
CMS -
CIDNA baseline
:
12
24
36
48
Treatment (weeks)
Tumer
(not)
mg (n+5)
240 mg (7)
320 mg (n+2)
Total (n=21)
Partial response PALN OR (PA),
1(17)
1 (29)
(29)
0 (0)
4(19)
Subie disease (10) N(%)
(50)
$ (80)
$ (71)
(100)
15 (71)
Progressive docase (POLN (S)
2 (33)
0.00
0 (0)
0.00
2 (10)
Disease Control Rate (DCR), %
ST
100
100
100
90
Overall Response Rate (DAR), %
17
20
29
0
19
Median Duration of Trustment, Weeks (range)
13 O-NO
14-11-ND
15 (6-NE)
11 (I-NO
14 (3-ND)
evaluable patients at eat and tumor assessed with cycle of treatment Disease control rate CR+PR=SD NO Not
estimable
Data - of CAT N 205
Myung M MO,PNO
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ESMD
ctDNA clearance
Patient ID
Dose level
EGFR mutants
Prior TKIs
Best changes in
Brain lesion
Best
Daniel Tan
(C797S)
Target lesions (%)
response
response
Dacomitinib
1
40 mg
L858R/C797S/R776H
Osimertinib
100%
-51.4
Response
PR
2
160 mg
Del19/C797S
Osimertinib
100%
-45.3
Response
PR
Taiwan
Association
for
the
Study
of
Cancer
3
Lazertinib
240 mg
Del19/C797S
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Response
PR
Treatment Advances in Lung Cancer
4
80 mg
Del19/C797S
Osimertinib
90%
31.2
Non-response
PD
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National
Cancer
Center
International Conference
[Slide 1]
MARIPOSA-2
Intracranial Progression-free Survival by BICR Among Patients
With a History of Brain Metastases and No Prior Brain Radiotherapy
Amivantamab-Chemotherapy
Amivantamab-Lazertinib-
100
vs Chemotherapy
Chemotherapy vs Chemotherapy
1001
Median icPFS: NE VS 6.3 months
Median icPFS: 11.1 vs 6.3 months
HR, 0.36
HR, 0.44
80
76%
(95% CI, 0.16-0.84)
(95% CI, 0.25-0.79)
Patients who are progression-free (%)
IIIIIIII.
P=0.013ᵇ
P=0.005ᵇ
60
70%
53%
Amivantamab-Chemotherapy
52%
40%
40
Amivantamab-Lazertinib-Chemotherapy
20
Chemotherapy
26%
0
0
3
6
9
12
15
Months
No. at risk
Amivantamab-Chemotherapy
24
20
13
8
1
0
Amivantamab-Lazertinib-Chemotherapy
56
42
22
10
5
0
Chemotherapy
61
32
17
7
1
0
MADRID
congress
2023
ESMO
Amivantamab-lazertinib-chemotherapy arm includes all patients regardless of the dosing regimen received. Nominal P-value; endpoint not part of hierarchical hypothesis testing.
BICR, blinded independent central review; CI, confidence interval; HR, hazard ratio; icPFS, intracranial progression-free survival; NE, not estimable.
Copies of TVS presentation obtained through OR code are for personal 250 only
and may not be reproduced without written permission of the authors
---
[Slide 2]
CheckMate 816 (NIVO + chemo vs chemo): 3-y results by tumor PD-L1 expression
Efficacy outcomes in patients with tumor PD-L1 < 1%
pCR
EFS
os
NIVO + chemo
Chemo
NIVO + chemo
Chemo
50
(n 78)
(n 77)
(n 78)
(n 77)
Median EFS, mo
26.4
20.8
Median os, mo
NR
NR
(95% CI)
(14.8-NR)
(13.9-42.1)
(95% CI)
(48.6-NR)
(31.2-NR)
HR (95% CI)
0.87 (0.57-1.35)
HR (95% CI)
0.81 (0.48-1.36)
40
100
100
89%
Difference
80
87%
79%
80
30
72%
71%f
pCR rate (%)
14.1%a
70%
60
66%
52%
60
NIVO + chemo
20
16.7%b
EFS (%)
42%d
os (%)
60%g
Chemo
NIVO chemo
40
43%
40
39%e
Chemo
10
20
20
2.6%c
0
0
0
NIVO + chemo
Chemo
0
6
12
18
24
30
36
42
48
54
0
6
12
18
24
30
36
42
48
54
60
n/N
13/78
2/77
Months from randomization
Months from randomization
No. at risk
NIVO chemo
78
57
46
37
33
30
18
8
4
0
78
71
66
62
60
54
46
26
8
2
0
Chemo
77
59
45
36
28
26
18
8
3
0
77
72
66
59
51
45
37
22
11
3
0
Median TTDM (95% CI) was 48.6 mo (36.6-NR) VS 27.4 mo (21.4-NR) for NIVO + chemo vs chemo (HR, 0.72; 95% CI, 0.45-1.15); 3-year TTDM rates were 63%h vs 46%¹
Baseline characteristics were generally similar between tumor PD-L1 subgroups and treatment arms, although a higher proportion of patients
with tumor PD L1 < 1% had ECOG PS 1 (both arms)
Minimum/median follow-up: 32.9/41.4 months.
MPR rates were 29.5% (95% CI, 19.7-40.9) with NIVO chemo and 14.3% (95% CI, 7.4-24.1) with chemo (difference, 15.2%; 95% CI, 2.1-27.7). Unweighted differences in pCR and MPR rates between treatment arms were
calculated using the Newcombe method. **95% Cl: 4.8-24.0; 9.2-26.8; 0.3-9.1; 30-54; *28-51; '59-80; 48-71; 51-74; 34-57.
---
[Slide 3]
Depth of response by Investigator Assessment
Waterfall plot for change in target lesions
100
BEST RESPONSE
SD
80
PR
60
Best % change in sum of target lesions dimension from baseline
40
20
0
-20
-40
-60
8
-100
MADRID
ESMO
congress
2023
Claudia Proto, MD
Content of this presentation is copyright and responsibility of the author. Permission is required for re-use.
MARIPOSA-2 is a Phase 3, randomized, open-label trial (NCT04988295) that established Rybrevant (amivantamab) plus chemotherapy as the first and only targeted regimen to significantly improve progression-free survival compared to chemotherapy alone in patients with EGFR-mutated advanced NSCLC after progression on osimertinib. The trial enrolled 657 patients across three arms and demonstrated that amivantamab combined with carboplatin and pemetrexed reduced the risk of disease progression or death by 52%, with consistent benefit across all prespecified subgroups including patients with brain metastases.
FDA APPROVED Rybrevant (amivantamab-vmjw) — In combination with carboplatin and pemetrexed for the treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations, whose disease has progressed on or after treatment with an EGFR tyrosine kinase inhibitor
On September 19, 2024, the FDA approved amivantamab-vmjw (Rybrevant) with carboplatin and pemetrexed for adult patients with EGFR-mutated advanced NSCLC progressing on or after an EGFR TKI. This was the third new indication for Rybrevant in 2024, following the exon 20 insertion + chemo approval (March 2024) and the frontline amivantamab + lazertinib approval (August 2024). Approved under Project Orbis. NCCN Category 1 recommendation for patients progressing on osimertinib who are symptomatic with multiple lesions.
Phase 3, randomized (1:2:2), open-label, multicenter trial evaluating two amivantamab-containing regimens versus chemotherapy alone in patients with locally advanced or metastatic EGFR-mutant (exon 19 deletion or L858R) NSCLC progressing on or after osimertinib. Dual primary endpoints compared PFS by BICR (RECIST v1.1) for each experimental arm versus chemotherapy.
Population
Adults with locally advanced or metastatic NSCLC harboring EGFR exon 19 deletions or L858R substitution mutations whose disease progressed on or after treatment with osimertinib. All participants underwent serial brain imaging to assess intracranial endpoints, as approximately 30% of patients had a history of brain metastases.
Interventions
Arm 1: Amivantamab + carboplatin + pemetrexed (amivantamab + CP). Arm 2: Amivantamab + lazertinib + carboplatin + pemetrexed. Arm 3: Carboplatin + pemetrexed alone (control). Amivantamab is a bispecific antibody targeting EGFR and MET with immune cell-directing activity; lazertinib is an oral third-generation EGFR TKI.
Primary Endpoints
Dual primary endpoint: PFS by BICR for each amivantamab arm vs. chemotherapy. Key secondary endpoints: overall survival (OS), objective response rate (ORR), duration of response (DOR), time to subsequent therapy, PFS after first subsequent therapy (PFS2), and intracranial PFS.
Progression-Free Survival (PFS)
Amivantamab + chemotherapy demonstrated a median PFS of 6.3 months (95% CI: 5.6-8.4) vs. 4.2 months (95% CI: 4.0-4.4) for chemotherapy alone (HR 0.48; 95% CI: 0.36-0.64; P<0.0001), representing a 52% reduction in the risk of disease progression or death. The triplet arm (amivantamab + lazertinib + chemo) showed median PFS of 8.3 months vs. 4.2 months (HR 0.44; 95% CI: 0.35-0.56; P<0.001), a 56% risk reduction. PFS benefit was consistent across all prespecified subgroups.
At the prespecified second interim analysis with 85% of deaths needed for the final analysis, amivantamab + chemotherapy showed a favorable trend toward improved overall survival (stratified OS HR 0.73; 95% CI: 0.54-0.99), but this did not reach statistical significance. Time to symptomatic progression was significantly improved: median 16.0 months (95% CI: 12.7-19.4) vs. 11.8 months (95% CI: 8.9-13.6) for chemotherapy (HR 0.73; 95% CI: 0.55-0.96; P=0.026). OS follow-up is ongoing.
The most common adverse events (>=20%) with amivantamab + chemo were rash, infusion-related reactions, fatigue, nail toxicity, nausea, constipation, edema, stomatitis, decreased appetite, musculoskeletal pain, vomiting, and COVID-19 infection. Serious AEs occurred in 32% with amivantamab + chemo vs. 20% with chemo alone. The triplet (+ lazertinib) had higher serious AE rate of 52% and increased hematologic toxicity. VTE rates were higher in amivantamab arms but mostly Grade 1-2, with no Grade 5 events and discontinuation due to VTE in ≤1%. ILD/pneumonitis incidence was ≤3% across amivantamab arms. Treatment-related death rates were low and comparable across all arms.
MARIPOSA-2 established amivantamab + chemotherapy as the new standard of care for EGFR-mutated NSCLC after progression on osimertinib, addressing a critical unmet need where platinum-based chemotherapy was previously the only option. The amivantamab doublet (without lazertinib) received FDA approval based on a favorable benefit-risk profile, as the triplet added toxicity without clearly superior efficacy. Key clinical debates include the role of the triplet versus doublet, competition with ivonescimab + chemo (HARMONi-A), optimal management of VTE risk, and whether intracranial PFS improvements translate to meaningful CNS disease control.
