new age ADC S in lung cancer

1. DR. R. RAJKUMAR D.M.
CONSULTANT MEDICAL ONCOLOGIST
VELAMMAL MEDICAL COLLEGE HOSPITALS

2. INTRODUCTION
HER2
HER3
TROP2
C MET
FUTURE

3. INTRODUCTION
20XX 3

4. NSCLC as
one
disease
Squamous
34%
Other
11%
Adenoca
55%
NON-SMALL-CELL LUNG CANCER: NOT
ONE DISEASE, BUT MANY!
Then Histology-Based Subtyping Now
Adenocarcinoma
KRAS
25%
ALK
7%
EGFR
Sensitizing
17%
No Known
Oncogenic Driver
Detected
31%
EGFR Other 4%
MET 3%
> 1 Mutation 3%
HER2 2%
ROS1 2%
BRAF 2%
RET 2%
NTRK < 1%
PIK3CA 1%
MEK1 < 1%

5. CAN WE FURTHER CLASSIFY NSCLC BY
PROTEIN TARGETS?
.
Histology-Based Subtyping
All NSCLC
PD-L1+
Protein Subtyping
Adenocarcinoma
KRAS
25%
ALK
7%
EGFR
Sensitizing
17%
No Known
Oncogenic Driver
Detected
31%
EGFR Other 4%
MET 3%
> 1 Mutation 3%
HER2 2%
ROS1 2%
BRAF 2%
RET 2%
NTRK < 1%
PIK3CA 1%
MEK1 < 1%
+
??
AND
MET+
TROP-2+
??
??
??
??
PTK7+
CEA-CAM+
HER2+
??
??
??
??
??

6. ANTIBODY-DRUG CONJUGATES IN NSCLC:
LIKE IT OR NOT, THEY’RE COMING FOR YOU
 Immunotherapy
 Chemotherapy
 Targeted therapy
 Antibody-drug conjugates

7. ANTIBODY DRUG CONJUGATES (ADC): TRUE
TARGETED THERAPY
 ADC represent targeted
delivery system, potentially
shifting efficacy: toxicity ratio
of attached drug
‒ 3 drug-related components
‒ 3 patient-related variables
Trastuzumab
(HER2-targeted mAb)
Cytotoxic agent:
DM1
Thioether linker
.
Example: Trastuzumab deruxtecan (T-DXd)

8. KEY COMPONENTS

9. DRUG-RELATED COMPONENTS OF ANTIBODY
DRUG CONJUGATES
 Payload:
‒ DAR (drug antibody ratio): mean ratio of cytotoxic drug/Ab
‒ Topo I inhibitors, MMAE derivatives (microtubule interference), other cytotoxics,
other active moieties
 Antibody Epitope: associated ‘extras’
‒ Signaling interference via ligand blocking, dimerization interference, internalization,
and degradation
‒ ADCC
 Linker: primarily influences circulating free-drug vs release in cells
.

10. PATIENT-RELATED VARIABLES RELEVANT TO
ANTIBODY DRUG CONJUGATES
 Epitope expression level in tumor vs other tissues[1]
 Prior/current therapy influencing resistance/uptake[2]
 Biology of cancer influences:
‒ Impact of any signaling interference (ie, addicted or not to epitope-related
pathway)
‒ Stability of epitope expression (eg, due to addiction, surface half-life, etc)
‒ Sensitivity of cancer cell to payload[3]
.

11. MILESTONES IN THE DEVELOPMENT
OF ADC

13. ADC IN LUNG CANCER
 HER2/ERBB2
‒ Trastuzumab emtansine (T-DM1)*
‒ Trastuzumab deruxtecan (T-DXd)*
 HER3
‒ Patritumab deruxtecan
 Trop-2
‒ Datopotamab deruxtecan (DS-1062a)
‒ Sacituzumab govitecan (IMMU-132)*
 c-MET
‒ Telisotuzumab vedotin (Teliso-V, ABBV-
399)
 CEACAM5 - SAR408701
 Axl - Enapotamab Vedotin (EnaV)
‒ PTK7 - Cofetuzumab pelidotin (ABBV-
647, PF-06647020)
‒ NaPi2b – lifastuzumab vedotin
‒ Nectin-4 – enfortumab vedotin* (no
data in NSCLC available)
*FDA approved in other cancer types (breast, gastric/GEJ, urothelial)

15. ADO-TRASTUZUMAB EMTANSINE (T-DM1) FOR
PATIENTS WITH HER2 AMPLIFIED OR MUTANT
LUNG CANCERS
 Phase II basket trial to evaluate
HER2-targeted antibody-drug
conjugate, ado-trastuzumab
emtansine, in patients with HER2-
mutant lung cancers (N = 18)[1,2]
‒ Patients with MET positive
resistance to prior treatments
‒ ≤ 4 prior lines of therapy; 50% of
patients had prior HER2 directed
therapy (TKI or mAb)
1. Li. JCO. 2018;36:2532. 2. NCT02675829.
Trastuzumab
(HER2-targeted
mAb)
Cytotoxic agent:
DM1
Thioether linker

16. ADO-TRASTUZUMAB-EMTANSINE (T-DM1) IN
HER2-MUTANT LUNG CANCERS
 Primary endpoint:
ORR per RECIST v1.1
‒ ORR: 44% (95% CI:
22-69)
‒ Median PFS: 5 mos
(95% CI: 3-9)
1. Li. JCO. 2018;36:2532.
-100
-75
-50
-25
0
25
50
75
100
Patients
-30%
Best
Response
per
RECIST
v1.1
(%)
Confirmed partial response
Stable disease
Progressive disease

17. ADO-TRASTUZUMAB-EMTANSINE (T-DM1) IN NSCLC:
PATIENT HER2 BIOMARKER ASSESSMENT
 IHC expression or protein analysis did not predict response; 2 patients with HER2
amplification had PR/SD
NGS Result
FISH,
(HER2/CEP17
ratio)
IHC
Result
Mass
Spectometry
(amol/µg)
PR
(Yes or No)
Exon 20 p.A775_G776insYVMA 1.1 (2.7/2.5) 0 NA y
Exon 20 p.A775_G776insYVMA 1.8 (8.1/4.5) 2+ 642 N
Exon 20 p.A775_G776insYVMA NA NA NA N
Exon 20 p.A775_G776insYVMA 1.4 (4.5/3.3) 1+ 586 Y
Exon 20 p.A775_G776insYVMA 1.9 (5.6/2.9) 1+ 548 Y
Exon 20 p.G778_P780dup 1.6 (7.6/4.8) 1+ 0 N
Exon 20 p.G778_P780dup 1.8 (4.6/2.5) 2+ 507 Y
Exon 20 p.G778_P780dup 1.4 (5.8/4.2) 2+ NA N
Exon 20 p.G778-779 insCPG 1.6 (4.3/2.7) 0 NA N
NGS Result
FISH,
(HER2/CEP17
ratio)
IHC
Result
Mass
Spectometry
(amol/µg)
PR
(Yes or No)
Exon 20
p.G776_V777.VCV
NA NA NA Y
Exon 20
p.G776delinsVC
1.6 (5.7/3.6) 0 205 Y
Exon 19 p.L755P 1.5 (3.2/2.1) 2+ 434 N
Exon 19 p.L755P NA 0 NA N
Exon 17 p.V659E 1.2 (2.4/2.0) 2+ NA N
Exon 17 p.V659E 1.1 (2.3/2.0) 2+ 688 Y
Exon 8 p.S310F,
amplification fold
change 2.8
4.1 (8.4/2.5) 2+ 1495 Y
Exon 8 p.S310F 1.8 (3.2/1.8) 0 0 N
Exon 8 p.S335C 2.4 (4.8/2.0) 2+ 902 N

18. Trastuzumab Deruxtecan (T-DXd)
NSCLC
Deruxtecan
Humanized anti-HER2 mAb, same
amino acid sequence as trastuzumab
Tetrapeptide-based
cleavable linker
Membrane-permeable payload:
Topoisomerase I inhibitor,
an exatecan derivative
18

19. HER2-TARGETED ADC: TRASTUZUMAB
DERUXTECAN (T-DXD)
 High drug:antibody
ratio: ~ 8
 Stable linker-payload
 Tumor-selectable
cleavable linker
 High potency,
membrane-permeable
payload with short
systemic half-life
 Bystander killing effect
.
Humanized anti-HER2 IgG1 mAb
with same AA sequence as
trastuzumab
Tetrapeptide-based cleavable linker
Cysteine residue
Drug/linker
Topoisomerase I inhibitor (DXd) payload
(exatecan derivative)
HO
O
F
NH
O
O
O
N
N
OH
OH
H
N
O
O
O
O
O
O
O
O
O
O
O
O
H
N
N
H
N
H
N
H
N
N
N
F
H
N
Cys

29. H
N
PATRITUMAB DERUXTECAN (U3-1402):
NOVEL HER3-TARGETED ANTIBODY–DRUG
CONJUGATE
.
Patritumab (HER3 antibody)
Conjugation chemistry
Linked to cysteine residues of the antibody
Cysteine residue
Drug linker
Payload (DXd)
Exatecan derivative
N
H
N
Drug linker
O
O
O
Intracellular enzyme
N
H
O
O
H
N
O
O
N
H O F
O
O
OH
O
O
O
HO
NH
OH
H
N
F

35. Sacituzumab Govitecan (IMMU-132): Trop-2–Targeted
Antibody–Drug Conjugate
Bystander effect: In acidic tumor microenvironment, SN-38
is released from anti–Trop-2 antibody, diffuses into
neighboring Trop-2–negative cells
Slide credit: clinicaloptions.com
Khoury. ASCO 2019. Abstr e14651. Bardia. JCO. 2017;35:2141.
Humanized RS7 Antibody
 Targets Trop-2, an antigen expressed in many
epithelial cancers, including mTNBC (88%)
 Antibody type: h-IgG1
SN-38 Payload
 Targets 136-fold more
than parent compound
irinotecan
 Unique chemistry
improves solubility,
selectively delivers
SN-38 to tumor
Irinotecan (Topoisomerase Inhibitor)
Linker for SN-38
 High drug-to-
antibody ratio (7.6:1)
 pH-sensitive linker
for rapid release of
payload at or inside
tumor
O
O
O
O
O
O
O
O
O
O O
O
O
HO
N
N
H
N
H
N N
N
N
H
Lys-N CH2O
(1)
S Anti-Trop-2 IgG
SN-38
[ ]7
N
O
O
OH
O
N
N
O
(1)
O
N
N
(2)
Irinotecan
SN-38

36. Targeting Trop-2: Sacituzumab Govitecan in Previously Treated
Metastatic NSCLC
 Single-arm, multicenter trial of (N = 47)
‒ Median no. prior therapies: 3 (range: 2–7)
 Sacituzumab govitecan dosing: 8 or
10 mg/kg i.v. on Days 1 and 8 of 21-
day cycles
 ORR: 19%
 Median DoR: 6 months
 Median PFS: 5.2 months
 Median OS: 9.5 months
 > 90% of tumor specimens were
highly positive for Trop-2, but
expression did not predict response
Heist. JCO. 2017;35:2790. Slide credit: clinicaloptions.com
Best
Change
in
Target
Lesions
from
BL
(%)
0
20
40
-20
-40
-60
-80
PR
SD
Progression
Squamous cell histology
8 mg/kg starting dose
Prior checkpoint inhibitor Tx
Early CT assessment after 2 doses

38. H
N
Datopotamab Deruxtecan (DS-1062; Dato-DXd):
TROP2 Antibody–Drug Conjugate
Heist. WCLC 2019. Abstract 3854.
Datopotamab (TROP2 antibody)
Conjugation chemistry
Linked to cysteine residues of the antibody
Cysteine residue
Drug linker
Payload (DXd)
Exatecan derivative
N
H
N
Drug linker
O
O
O
Intracellular enzyme
N
H
O
O
H
N
O
O
N
H O F
O
O
OH
O
O
O
HO
NH
OH
H
N
F

39.  Median PFS, mos (95 % CI):
‒ 4 mg/kg: 4.3 mos (2.0-NE); 6 mg/kg: 8.2 mos
(1.5-11.8); 8 mg/kg: 5.4 mos (4.1-7.1)
TROPION-PanTumor01 Phase I Trial: Updated Results
with Datopotamab Deruxtecan in Advanced NSCLC
Change in Sum of Diameters for Target Lesions (BICR)
Overall
Response
(BICR)
Dato-DXd Dose
4
mg/kg
6
m/kg
8
mg/kg
Evaluable
pts, n
40 39 80
Confirmed
CR/PR, n
7 6 19
CR/PR*, n 2 2 1
ORR, n (%) 9 (23) 8 (21) 20 (25)
DCR, n (%)
29
(73)
26 (67) 64 (80)
PD, n (%) 6 (15) 8 (21) 7 (9)
*CR/PR too early for confirmation.
Best Change in Sum of Diameters
80
60
40
50
0
-20
-40
-60
-80
-100
Dato-DXd dose
4 mg/kg
6 mg/kg
8 mg/kg
Best
percent
change
in
SoD
from
baseline,
%
6 12 18 24 30 36 42 48 54 60 84
-100
-80
-60
-40
-20
0
20
40
60
80
100
Best
percent
change
in
SoD,
%
4 mg/kg
Weeks
6 12 18 24 30 36 42 48 54 60 72
-100
-80
-60
-40
-20
0
20
40
60
80
100
6 mg/kg
Weeks
6 12 18 24 30 36 42 48 54 60 66
-100
-80
-60
-40
-20
0
20
40
60
80
100
8 mg/kg
Weeks

41. Targeting c-MET: Telisotuzumab Vedotin (ABBV-399) in
Advanced Solid Tumors
 First-in-human phase I dose
escalation/expansion study (N = 48)
 All patients required to be c-MET
positive (Met CONFIRM H score ≥ 150;
60% positive rate)
 Median PFS: 5.7 months
Response, n (%)
All Patients*
(N = 48)
c-MET-Pos*
NSCLC (n = 16)
CR 0 0
PR 3 (6.3) 3 (18.8)
SD 22 (45.8) 6 (37.5)
DCR (PR + SD) 25 (52.1) 9 (56.3)
PD 20 (41.7) 5 (31.1)
*Patients treated at all dose levels.
.
Membrane c-Met H score
Best response
PR: Nonsquamous/squamous NSCLC
SD: Nonsquamous/squamous NSCLC
PD: Nonsquamous/squamous NSCLC
† § ¶
-60
-50
-40
-30
-20
-10
0
10
20
30
40
50
#
0
50
100
150
200
250
300
Membrane
c-Met
H-Score
Change
in
Target
Lesions
From
Baseline
(%)

42. Targeting c-MET: Telisotuzumab Vedotin (ABBV-399) in c-MET+
Advanced Squamous Cell Lung Cancer
 Lung-MAP S1400K: Single-arm phase II study (N = 23)
‒ Enrollment required positive H score ≥ 150 by SP44 assay
 ORR: 9% in checkpoint
inhibitor naive
 mOS: 5.6 months
 mPFS: 2.4 months
Waqar. Clin Lung Cancer. 2020; [Epub].
ICI Naive
ICI Refractory
Inadequate Assessment
Symptomatic Deterioration
New Lesions
Unequivocal Progression
IA
SD
NL
UP
Best
Percentage
Change
from
Baseline
100
80
60
40
20
0
-20
-40
-60
-80
-100
IA SD SDIA/NLNL NL NL NL
NL
UP

43. 1.3 3.7
Telisotuzumab Vedotin (ABBV-399) + Erlotinib in c-
MET+ EGFR-Mutant NSCLC
 Open-label phase Ib study
‒ Current analysis in subgroup with EGFR mutation (del19 or L858R), H-score ≥ 150 or
MET amplification ≥ 2 (n = 29)
Camidge. WCLC 2019. Abstr MA14.03.
 ORR: 33% - (with erlotinib)
 mPFS: 5.9 months
Best
Percent
Change
from
Baseline
Subjects (N=29)
-47.9
-47.1
-44.7
-40.5
25
0
-25
-50
-75
-100
-60.9
-62.2
-62.5
-64.7
-76.3
-100
-36.9
-34.4
-20
-15.2
-14.0
-12.5
-11.6
-5.3
-4.2
-3
-2.1
0
0
3.1
4.3
5.7
9.9
18.2
37.6
1.3 2.3 5.4 1.4 3.0 8.3 2.8 6.8 1.6 3.7 4.3 5.6 1.3 5.3 1.4 11 5.3 4.0 2.7 6.711.38.2 2.7 7.412.310.26.9
PD SD SD SD SD PD SD SD SD SD SD SD SD SD SD SD PD PR PD PD PR PR PR PR PR PR PR PR CR
230180185150150280255300195240150290180185270190190250 275288300295290 - 250170 215250275

44. FUTURE

45. TAKE HOME POINTS
 A variety of ADCs against different epitopes with different linkers are being
developed
 Some require prescreening for gene mutations or protein expression, while
others are currently “unselected”
 Adverse events commonly include nausea/vomiting, cytopenias, and
neuropathy depending on payload, and variable pneumonitis/ILD variable
 These agents combine the advantages of both targeted therapy plus cytotoxic
chemotherapy

46. The way to get
started is to quit talking
and begin doing.
Walt Disney
Presentation title 20XX 46

47. THANK YOU!
DR. R. RAJKUMAR D.M.
Phone
9677722024
Email
drraj12319@gmail.com