Nutrition - Esmo

1. ESMO Annual Meeting, 9–13 September 2022, Paris, France
T-cell Engagers:
Changing the Treatment
Paradigm in Solid
Tumors
Martin Reck, MD, PhD
Lung Clinic Grosshansdorf
Grosshansdorf, Germany

2. Disclosures
• Honoraria for lectures and consultancy from Amgen, AstraZeneca, Beigene, Boehringer
Ingelheim, Daiichi-Sankyo, Lilly, Mirati, Merck, MSD, Novartis, Pfizer, Roche, Sanofi, Samsung
Bioepis
• Compensated membership in study steering committees for Amgen, AstraZeneca, Beigene,
Daiichi-Sankyo, Mirati, Merck, MSD, Novartis, Pfizer, Roche, Sanofi
• Compensated membership in data safety monitoring committees for Daiichi-Sankyo, Sanofi

3. Immuno-oncology:
Current Landscape
and Next Frontier

4. The Field of Immunotherapy Has Created New Options for the Treatment
of Cancer
• Immuno-oncology therapies may activate the patient’s own immune system to engage with cancer cells1
• Recent advances in immunotherapeutic approaches include2,3:
CAR = chimeric antigen receptor; CTLA-4 = cytotoxic T-lymphocyte-associated protein 4; PD-1 = programmed cell death protein 1; PD-L1 = programmed death-ligand 1; TCE = T-cell engager.
1. Viardot A, et al. Ann Hematol. 2020;99(10):2215–2229; 2. Ellerman D. Methods. 2019;154:102–117; 3. Huehls AM, et al. Immunol Cell Biol. 2015;93(3):290–296.
Immune modulators, e.g. anti-CTLA-4 and anti-PD-(L)1
CAR-T cells
Cancer vaccines
Bispecific antibodies, e.g. TCEs
Oncolytic viruses

5. In Recent Years, ICIs Have Emerged As Front-line Treatment for a Range
of Different Cancer Types
• A number of different ICIs have been approved as first- and later-line options in a wide range of cancer
types, including metastatic melanoma, non–small cell lung cancer, renal cell carcinoma and
bladder/urothelial cancer14
CTLA-4 = cytotoxic T-lymphocyte-associated protein 4, ICI = immune checkpoint inhibitor; PD-1 = programmed cell death protein 1; PD-L1 = programmed cell death-ligand 1.
1. Park Y-J, et al. Exp Mol Med. 2018;50(8):1-13; 2. Alsaab HO, et al. Front Pharmacol. 2017;23;8:561; 3. Korman AJ, et al. Adv Immunol. 2006;90:297339; 4. ClinicalTrials.gov.
https://clinicaltrials.gov/ct2/results?cond=checkpoint+inhibitor&recrs=a&recrs=f&recrs=d&age_v=&gndr=&type=&rslt=&phase=2&Search=Apply. Accessed August 2, 2022.
2022: 21 recruiting/active
Phase 3 studies of ICIs
ongoing

6. ICIs Are Rapidly Expanding Treatment Options for Cancers Such As
NSCLC1-8
aSingle-agent pembrolizumab also approved for ≥1% PD-L1 but not broadly recommended by experts; guideline-recommended for PD-L1 1-49% if poor PS or contraindications to combining w/CT; bNeoadjuvant
has not yet been approved in the EU
CT = chemotherapy; ICI = Immmune checkpoint inhibitor; NSCLC, non-small cell lung cancer; RT = radiotherapy.
1. NCCN. Clinical practice guidelines in oncology: NSCLC. v.3.2022. nccn.org; 2. Planchard D, et al. Ann Oncol. 2019;30(5):863-70; 3. Xiong A, et al. Frontiers Oncol. 2021:4883; 4. Mamdami H, et al. Frontiers
Immunol. 2022;13; 5. Remon J, et al. Ann Oncol. 2021;32(12):1637-42; 6. Pas-Ares L et al. The Lancet 2021;22:198-211; 7. Pas-Ares L et al. ESMO 2022 Virtual Plenary Abstract VP3-2022
https://doi.org/10.1016/j.annonc.2022.02.224; 8. Forde PM et al. N Engl J Med 2022; 386:1973-1985.
ICI Monotherapy
(Atezolizumab,
Cemiplimab, or
Pembrolizumab)
PD-L1
1%-49%a
PD-L1 ≥50% PD-L1 <1%
ICI + Chemotherapy
ICI Combo Therapy
(Nivolumab/Ipilimumab) + 2 cycles chemo
Stage IV (NSCLC without
actionable mutation)
• For first-line treatment, options include:1-5
‒ ICI monotherapy +/- chemotherapy
‒ Double ICI +/- chemotherapy
‒ Double ICI + short chemotherapy (2 cycles)6
Stage III
(unresectable)
After RT and CT
ICI Monotherapy
in PD-L1 ≥ 1%
(Durvalumab)
• Immunotherapy options are also available in other NSCLC
settings:
‒ In unresectable Stage III NSCLC after CT/RT
‒ As adjuvant in resected NSCLC with high PD-L1 expression7
‒ As neoadjuvant in combination with CT in resectable NSCLC8
Stage IB - IIIA
(resectable)
Complete
resection
Adjuvant
Chemotherapy
Adjuvant
Atezolizumab
(PD-L1 ≥50%)
CT +
Neoadjuvant
ICI8,b

7. Despite Broad Activity of Anti-PD-L1/PD-1 in Cancer, Only a Subset of
Patients Benefit
• Response rates to ICIs typically range
from 10% to 30% depending on the tumor
type1-3
• While lymphoma typically has the highest
response rate, sarcoma and ovarian
cancer have the lowest
ICI = immune checkpoint inhibitor; PD-1 = programmed cell death protein 1; PD-L1 = programmed cell death ligand 1.
1. Zhao B, et al. Ther Adv Med Oncol. 2020;12:122; 2. Sun JY, et al. Biomark Res. 2020;8:35; 3. Zhang T, et al. Oncotarget. 2016;7(45):7306873079.
Breast cancer
(12%)
Melanoma
(30%)
Renal cancer
(23%)
Lung cancer
(20%)
Urothelial
cancer (20%)
Sarcoma (8%)
Ovarian cancer
(9%)
Colorectal
cancer (3%)
Glioblastoma
(11%)
Head and neck
cancer (15%)
Liver cancer
(19%)
Gastric cancer
(11%)
Lymphoma
(62%)
Anti-PD-L1/PD-1 response rates among various
tumor types1

8. TCEs: Targeted Therapies That Induce the Elimination of Poorly
Immunogenic Tumors
• Most tumor cells have a loss or depletion of MHC, which hampers the effect of activated T-cells1
• TCEs directly activate T-cells without relying on the TCR/MHC interaction and redirect them to target
tumor-associated antigens on cancer cells, leading to apoptosis1,2
CAR = chimeric antigen receptor; CTLA-4 = cytotoxic T-lymphocyte-associated protein 4; MHC = major histocompatibility complex; PD-1 = programmed cell death protein 1; PD-L1 = programmed death-ligand 1;
TCE = T-cell engager; TCR = T-cell receptor.
1. Shin HG, et al. Int J Mol Sci. 2022;23(10):5686; 2. Owen DH, et al. J Hematol Oncol. 2019;12(1):61.
Immune modulators, e.g. anti-CTLA-4 and anti-PD-(L)1
CAR-T cells
Cancer vaccines
Bispecific antibodies, e.g. TCEs
Oncolytic viruses

9. T-cell Engagers as an
Immunotherapeutic
Strategy

10. TCEs Bridge the Gap Between a T Cell and a Cancer Cell
• TCEs are bispecific antibodies with two antigen-binding domains1,2
• One binds to a tumor-associated antigen on a cancer cell, while the other binds to a TCR (usually via the
CD3 co-receptor)1,2
• The structure and specificity of a TCE are designed to create a physical link between a T cell and a
cancer cell,3 bypassing the normal requirements for TCR activation1,2
• TCEs may elicit a polyclonal T-cell response that is not affected by cancer cell escape mechanisms,2
potentially eliminating cancer cells that are “invisible” to the immune system by promoting an
inflammatory/“hot” TME4
CD3 = cluster of differentiation 3; mAb = monoclonal antibody; TCE = T-cell engager; TCR = T-cell receptor.
1. Vafa O, Trinklein N. Front Oncol. 2020;10:446; 2. Ellerman D. Methods. 2019;154:102–117; 3. Huehls AM, et al. Immunol Cell Biol. 2015;93(3):290–296; 4. Abbott RC, et al. Int J Mol Sci 2020;21(2):515.
mAb for tumor-
associated antigen
mAb for CD3
co-receptor
TCE

11. The TCE Landscape is Expanding: Treatment of Solid Tumors is a
Specific Unmet Therapeutic Need
ALL = acute lymphoblastic leukemia; BCMA = B-cell maturation antigen; CD = cluster of differentiation; CRC = colorectal cancer; DLL3 = delta-like ligand 3; GPRC5D = G-protein coupled receptor family C group
5 member D; HLA = human leukocyte antigen; MF = mycosis fungoides; NET = Neuroendocrine tumor; SCLC = small cell lung carcinoma; TCE = T-cell engager.
1. Blincyto®. Prescribing information, 2021; 2.Kimmtrak®. Prescribing information, 2022; 3. Hipp S, et al. Clin Cancer Res. 2020;26:5258–5268; 4. NCT04429087.
https://clinicaltrials.gov/ct2/show/NCT04429087. Accessed July 2022; 5. Giffin M, et al. Clin Cancer Res 2021;27:1526–1537; 6. NCT03319940. https://clinicaltrials.gov/ct2/show/NCT03319940. Accessed August
2, 2022; 7. Ramalingam S, et al. ASCO 2022. Abstract TPS8603; 8. NCT05060016. https://clinicaltrials.gov/ct2/show/NCT05060016. Accessed August 2, 2022; 9. Johnson ML, et al. J Clin Oncol.
2022;40(16_suppl):85668566; 10. NCT04471727. https://clinicaltrials.gov/ct2/show/NCT04471727. Accessed August 2, 2022; 11. Hipp S, et al. AACR 2021. Abstract 56; 12. NCT04752215.
https://clinicaltrials.gov/ct2/show/NCT04752215. Accessed August 2, 2022; 13. Shin, HG, et al. Int J Mol Sci. 2022;23:5686; 14. NCT04101331. https://clinicaltrials.gov/ct2/show/NCT04101331. Accessed August
2, 2022; 15. NCT04634552. https://clinicaltrials.gov/ct2/show/NCT04634552. Accessed August 2, 2022; 16. NCT05083169. https://clinicaltrials.gov/ct2/show/NCT05083169. Accessed August 2, 2022.
Blinatumomab Tebentafusp
Tebentafusp is indicated
for the treatment of HLA-
A*02:01-positive adult
patients with
unresectable/metastatic
uveal melanoma2
Blinatumomab is
indicated for treatment of
CD19-positive,
relapsed/refractory
B-precursor ALL1
Currently Approved for Use Ongoing Clinical Trials
TCE Company Target Indication Phase
BI 7645323,4 Boehringer
Ingelheim
DLL3/CD3
SCLC, DLL3 expressing
neuroendocrine neoplasms
Phase I
AMG 7575-8 Amgen DLL3/CD3 Relapsed/refractory SCLC Phase I/2
HPN 3289.10 Harpoon
Therapeutics
DLL3/CD3
Advanced SCLC, DLL3
expressing neuroendocrine
neoplasms
Phase I/2
BI 76504911,12 Boehringer
Ingelheim
B7-H6/CD3
CRC and other B7-H6
expressing solid tumors
Phase I
AFM1313,14 Affimed CD16/CD30
Peripheral T-cell
lymphoma or transformed
MF
Phase 2
JNJ-
6440756413,15
Johnson &
Johnson
CD3/GPRC5D
Relapsed/refractory
multiple myeloma
Phase 2
JNJ-
6400795713,16
Johnson &
Johnson
CD3/BCMA
Relapsed/refractory
multiple myeloma Phase 3
This table is not a comprehensive list.

12. DLL3: An Emerging Target in SCLC and NEC
• DLL3 is an inhibitory Notch ligand that is expressed on
the cell surface of tumors with an endocrine origin,
including SCLC, GBM and NEC1-6
• In SCLC, DLL3 is expressed on the cell surface in >80%
of SCLC tumors1,2
• DLL3 expression was increased in high-grade SCLC
tumors and associated with higher rates of mitosis,
necrosis, and pleural infiltration6
DLL3 = delta-like ligand 3; GBM = glioblastoma multiforme; NEC = neuroendocrine carcinoma; SCLC, = small cell lung carcinoma.
1. Saunders LR, et al. Sci Transl Med. 2015;7:302ra136; 2. Rudin CM, et al. Lancet Oncol. 2017;18:4251; 3. Tanaka K, et al. Lung Cancer. 2018;115:116120; 4. National Center for Biotechnology Information.
DLL3 delta like canonical Notch ligand 3 [ Homo sapiens (human) ]. https://www.ncbi.nlm.nih.gov/gene/10683. Accessed August 2, 2022; 5. Owen DH, et al. J Hematol Oncol. 2019;12:61; 6. Ali G, et al. Front
Oncol. 2021;11:729765.
High levels of DLL3 expression are found in
neuroendocrine tumors of the lung6
DLL3 Staining in Lung Neuroendocrine tumors
DLL3-negative
DLL3-positive large cell NEC DLL3-positive SCLC
Image reproduced with permission from Ali G, et al. Front Oncol. 2021;11:729765.

13. SCLC Accounts for Approximately 15% of Lung Cancers
*Estimate based on diagnosis of 2.1 million new lung cancers globally in 2018,1 with SCLC accounting for 15% of these.2
NSCLC = non–small cell lung cancer; SCLC = small cell lung cancer.
1. International Agency for Research on Cancer (IARC). Estimated number of new cases of cancer in 2018. https://gco.iarc.fr/today/home. Accessed August 2, 2002; 2. National Comprehensive Cancer Network.
NCCN Guidelines: Small Cell Lung Cancer, Version 3. 2020. https://www.nccn.org/professionals/physician_gls/pdf/sclc.pdf. Accessed August 2, 2022; 3. Früh M, et al. Ann Oncol. 2013;24(suppl. 6):vi99–105; 4.
Bernhardt EB, Jalal SI. Cancer Treat Res. 2016;170:301–22; 5. Byers LA, Rudin CM. Cancer. 2015;121(5):664–672.
SCLC is characterized by the presence of
early, widespread metastases, with
60%–70% of patients having extensive-
stage disease at the time of diagnosis4,5
SCLC originates from neuroendocrine-cell
precursors and is characterized by rapid
growth3
SCLC 15%
NSCLC 85%
An estimated
300,000 cases of
SCLC are diagnosed
globally each year1,2,*

14. The Burden of SCLC is High Because of Early Metastases, Treatment
Resistance, and Mortality Rate
Mortality Rate
Less than 7% of patients with SCLC (all stages) will
survive for ≥5 years2
Treatment Resistance
The high response rate of SCLC to frontline
chemotherapy (60%–70%) contrasts with its
resistance to subsequent therapies after
recurrence2
5-year relative survival for SCLC by stage
at diagnosis 2010–20161
27%
16%
3%
0%
5%
10%
15%
20%
25%
30%
Localized Regional Distant
Relative
survival
(%)
Stage at diagnosis
SCLC = small cell lung cancer.
1. Howlader N, et al. (eds). SEER Cancer Statistics Review, 1975–2017 (Accessed June 2020); 2. Byers LA, Rudin CM. Cancer 2015;121(5):664–672.

15. SCLC Is Highly Sensitive to Frontline Chemotherapy Initially, with
Resistance Developing in Metastatic Disease
2021 ESMO Guidelines1
• Standard of care for
patients with metastatic
SCLC is platinum-based
chemotherapy ±
immunotherapy2
• SCLC has a high
response rate (60%–
70%) to frontline
chemotherapy3
• Addition of anti–PD-1
antibodies has improved
outcomes, but nearly all
patients relapse, and
prognosis is poor2
SCLC = small cell lung cancer.
1. Dingemans A-M C, et al. Ann Oncol. 2021;32(7):839–853; 2. Regzedmaa O, et al. Onco Targets Ther. 2019;12:4605–4620; 3. Byers LA, Rudin CM. Cancer. 2015;121(5):664–672.
.
Image reproduced with permission from Dingemans A-M C, et al. Ann Oncol. 2021;32(7):839–853.

16. Despite Improvements with ICIs, Additional Efficacious Approaches Are
Needed
• Median survival with platinum chemotherapy (standard of care for more than 2 decades) is
approximately 10 months in patients with extensive stage SCLC1
• With addition of ICIs, median overall survival increases only by 2-3 months1,2
IMpower 1331 Atezolizumab
+ CP/ET
(n=201)
Placebo
+CP/ET
(n=202)
Median OS,
mo (95% CI)
12.3
(10.8 – 15.8)
10.3
(9.3 – 11.3)
HR (95%
CI)
0.76 (0.6 – 0.95)
P = 0.0154
Durvalumab
+ EP
EP
Median OS,
mo (95% CI)
12.9
(11.3 – 14.7)
10.5
(9.3 – 11.2)
HR (95%
CI)
0.71 (0.6 – 0.86)
P = 0.0003
CASPIAN2
CI = confidence interval; CP = carboplatin; EP = etoposide + either cisplatin or carboplatin; ET = etoposide; HR = hazard ratio; OS = overall survival.
1. Liu S et al. J Clin Oncol 2020; 39(6):619; 2. Paz-Ares L et al. ESMO Open. 2022;7(2):100408.
Figure reproduced with permission from Liu S et al. J Clin Oncol 2020; 39(6):619.
Figure reproduced with permission from Paz-Ares L et al. ESMO Open. 2022;7(2):100408.

17. Neuroendocrine Neoplasms Comprise of ≈2% of All Malignancies1,2
• Neuroendocrine neoplasms (NENs) are rare
and heterogeneous tumors that are classified
as well-differentiated neuroendocrine
tumors (NETs) or poorly differentiated
neuroendocrine carcinomas (NECs)3,4
• 10-20% of NENs are NECs that are
characterized by rapid disease
progression5
• The increased incidence of NENs may be
associated with the rise in detection of
early-stage disease6
1. Oronsky B, et al. Neoplasia 2017;19(12):991–1002; 2. Pavel M, et al. Ann Oncol 2020;31(7):844–60; 3. Fraenkel M, et al. Endocr Relat Cancer 2014;21(3):R153–63; 4. Ito T, et al. J Gastroenterol
2010;45(2):234–243; 5. Das S, Dasari A. Curr Oncol Rep. 2021;23:43; 6. Dasari A, et al. JAMA Oncol 2017;3(10):1335–1342.
Incidence of GEP-NENs per 100,000 people per year3,4
3–4 2–3 1–2 <1 Data not available

18. GEP-NENs Are Classified As Well-differentiated NETs or Poorly
Differentiated NECs
*The Ki-67 index is a measure of tumor cell proliferation and is defined as the percentage of nuclei positive for Ki-67 using the MIB1 antibody in areas of highest labeling.4
**In mixed neuroendocrine–non-neuroendocrine neoplasms, grading is performed separately for the NEN component and the non-neuroendocrine component; the NEN component can be either NET or NEC.
GEP = gastroenteropancreatic; NEC = neuroendocrine carcinoma; NEN = neuroendocrine neoplasm; NET = neuroendocrine tumor; WHO = World Health Organization.
1. Pavel M, et al. Ann Oncol. 2020;31(7):844–860; 2. Garcia-Carbonero R, et al. Neuroendocrinology. 2016;103(2):186–194; 3. European Neuroendocrine Tumor Society Guidelines.
https://www.enets.org/guidelines.html (Accessed: August 2022); 4. Rindi G, et al. Nat Rev Endocrinol. 2020;16(10):590–607.
Morphology** Grade
Mitotic
count
(2 mm2)
Ki-67 index
(%)*
Well-differentiated NETs G1 <2 <3
Well-differentiated NETs G2 2–20 3–20
Well-differentiated NETs G3 >20 >20
Poorly differentiated NECs
• Small-cell
• Large-cell
G3 >20 >20
WHO 2019 classification for GEP-NENs1
GEP-NENs are graded according to
the Ki-67 proliferation index* and
mitotic count1–3
Well-differentiated NETs and
poorly-differentiated NECs are
biologically and genetically distinct1
Clinical history, histomorphology and
genetics can help to distinguish
NETs from NECs1
Consensus guidelines for the diagnosis, classification and treatment of neuroendocrine
tumors are also provided by the European Neuroendocrine Tumor Society (ENETS)3

19. Effective Treatment Options Are Limited for Those with High-grade,
Progressive Disease
• Therapeutic decision-making
is based on proliferative
activity, somatostatin
receptor expression, tumor
growth rate and extent of
the disease1
• Conventional therapeutic
options are surgery, SSAs,
chemotherapy, molecular
targeted agents, and PRRT1,2
• Therapy selection in
advanced disease is limited
due to the absence of
predictive markers and
paucity of clinical trials1,2
5-FU = 5-fluorouracil; CAP = capecitabine; CAPTEM = capecitabine and temozolomide; ChT = chemotherapy; EVE = everolimus; FOLFIRI = 5-fluorouracil/leucovorin/irinotecan; FOLFOX = 5-
fluorouracil/leucovorin/oxaliplatin; GEP-NEN = gastroenteropancreatic neuroendocrine neoplasm; IFN-a = interferon alpha; NEC = neuroendocrine carcinoma; NET = neuroendocrine tumor; Pan-NET =
pancreatic neuroendocrine tumor; PRRT = peptide receptor radionuclide therapy; RECIST = response evaluation criteria in solid tumors; SI = small intestinal; SI-NET = small intestinal neuroendocrine tumor;
SSA = somatostatin analogue; SSTR = somatostatin receptor; STZ = streptozotocin; SUN = sunitinib; TEM = temozolomide.
1. Pavel M, et al. Ann Oncol. 2020;31(7):844–860; 2. Tsoli M, et al. Ther Adv Encorinol Metab. 2019;10:1–18.
NET G2
NET G1
stable
disease or
slow growth
SSTR-
negative
NET G3 Ki-67
<50%
STZ/5-FU
CAPTEM
EVE
SUN
PRRT
SSAf
STZ/5-FU
CAPTEM
EVE
SUN
PRRT
STZ/5-FU
CAPTEM
EVE
SUN
CAPTEM
STZ/5-FU
EVE SUN
PRRT
Cisplatin or
carboplatin +
etoposide
FOLFIRI
FOLFOX
CAPTEM
GEP-NENs
Pan-NETs NEC G3
NET G1/G2
SSTR-
positive Ki-
67 <10% or
slow growtha
SSA
PRRTc
EVE
SSTR-
negative
Loco-
regional
therapye
EVE
IFN⍺
NET G2 Ki-67
>10%-15% or
rapid growthd
EVE
PRINT
FOLFOX
TEM+/-
CAP
Watch-and-
wait
SI-NETs
Ki67 <10%
+/-
Locoregional
therapye
Image adapted with permission from Pavel M, et al. Ann Oncol. 2020;31(7):844–860.

20. The DLL3/CD3 TCE Tarlatamab is Currently Being Investigated as a
Therapeutic Option for R/R SCLC
• Tarlatamab is designed to bind DLL3 on target cancer cell and CD3 on T-cells, inducing T-cell
dependent killing of tumor cells1,2
3L = third line; CD = cluster of differentiation; DCR = disease control rate; DLL3 = delta-like ligand 3; mDOR = median duration of response; PR = partial response; R/R = relapsed/refractory; RECIST = response
evaluation criteria in solid tumors; SCLC = small cell lung carcinoma; SD = stable disease.
1. Ramalingam S et al. ASCO 2022. Oral presentation; 2. Owonikoko T et al. ASCO 2021. Abstract 8510. Oral Presentation; 3. NCT05060016. https://clinicaltrials.gov/ct2/show/NCT05060016. Accessed August
2, 2022.
Modified RECIST 1.1 Response, n (%)
Patients
(N=64)
PR, confirmed 13 (20)
PR, unconfirmed 1 (2)
SD 17 (27)
DCR, % 30 (47)
• A confirmed partial response was noted in 20%
of patients with a mDOR of 8.7 months2
• 7/13 patients are still on treatment with ongoing
response
Phase I interim results showed that antitumor efficacy was observed across different dose ranges
in patients with R/R SCLC1,2
• Based on these results, a Phase II study
(DeLLphi-301) is currently enrolling patients to
evaluate the efficacy, safety, and tolerability of
tarlatamab as ≥3L treatment for SCLC3
Image reproduced with permission from Owonikoko T et al. ASCO 2021. Abstract 8510. Oral Presentation.

21. The DLL3/CD3 TCE BI 764532 Directs Cytolytic T Cells to DLL3-
Expressing Tumor Cells
• BI 764532 is a novel, half-life–extended,
IgG-like TCE that induces the formation
of a cytolytic synapse by binding
concomitantly to DLL3 on tumor cells
and to CD3 on T cells, thereby
selectively targeting DLL3-positive
neoplasms
• In preclinical studies, BI 764532:
• Induced cytotoxicity of DLL3-positive
cells
• Potently inhibited tumor growth
• Modulated the inflammatory
environment in the tumor tissue by
redirecting CD4-positive and CD8-
positive T-cell cytotoxicity toward DLL3-
positive SCLC cells, without affecting
DLL3-negative target cells
This is an investigational compound and has not been approved. Its safety and efficacy have not been established yet.
CD = cluster of differentiation; DLL3 = delta-like ligand 3; IgG = immunoglobulin G; SCLC = small cell lung cancer; TCE = T-cell engager.
Hipp S, et al. Clin Cancer Res. 2020;26(19):5258–5268.
.
Active T-cell
Inactive T-cell
Tumor cell
DLL3/CD3
bispecific
antibody
CD3
DLL3
CD3 Cytolytic
synapse
Cytolytic
granules
DLL3
DLL3/CD3 bispecific
antibody

22. DLL3/CD3 T-Cell Engager: Phase 1a Study Objectives
• To determine the maximum
tolerated dose and
recommended dosing
regimen for further
development of
BI 764532 based on dose
limiting toxicities for patients
with DLL3-positive tumors1,2
• To evaluate safety,
tolerability,
pharmacokinetics, and
preliminary efficacy1,2
This is an investigational compound and has not been approved. Its safety and efficacy have not been established yet.
CD3 = cluster of differentiation 3; DLL3 = delta-like ligand 3; SCLC = small cell lung carcinoma.
1. Wermke M, et al. ASCO 2021. Presentation TPS8588; 2. NCT04429087. https://clinicaltrials.gov/ct2/show/NCT04429087. Accessed August 2, 2022.
As of July 2022, patients are being recruited in early dose escalation
cohorts in the United States, Japan, Spain, and Germany2

23. First-in-human, open-label, dose-escalation trial (NCT04429087) of BI 764532 administered i.v.
in patients with DLL3-positive tumors (SCLC, NEC)1,2
Fixed single i.v. dose once every 3 weeks Fixed single i.v. dose once every 3 weeks
DLL3/CD3 T-Cell Engager: Phase 1a Study Design
• DLL3 status to be assessed with the Ventana DLL3 (SP347) assay at the Roche CDx CAP/CLIA laboratory
• Up to 3 dosing regimens assessed
• Patients are treated until disease worsening or a maximum duration of 36 months
• Dose escalation is guided by a Bayesian Logistic Regression Model with overdose control fitted to binary toxicity
outcomes
This is an investigational compound and has not been approved. Its safety and efficacy have not been established yet.
CD = cluster of differentiation; DLL3 = delta-like ligand 3; i.v., intravenous; NEC = neuroendocrine carcinoma; SCLC = small cell lung cancer.
1. Wermke M, et al. ASCO 2021. Presentation TPS8588; 2. NCT04429087. https://clinicaltrials.gov/ct2/show/NCT04429087. Accessed August 2, 2022.

24. The B7-H6/CD3 TCE is a Novel T-cell Redirecting Agent
• BI 765049 simultaneously binds to both the
CD3 subunit of the T-cell receptor complex
as well as to B7-H6 on tumor cells,
resulting in lysis of B7-H6–positive target
cells, activation and proliferation of T
cells, and secretion of cytokines2
• Preclinical studies done on colorectal
cancer models have shown2:
• Selective lysis of B7-H6–positive
colorectal cancer cell lines
• Infiltration and activation of T cells in the
tumor tissue resulting in tumor cell death
and conversion of a non-inflamed (“cold”)
tumor into an inflamed (“hot”) tumor
This is an investigational compound and has not been approved. Its safety and efficacy have not been established yet.
CD = cluster of differentiation; TCE = T-cell engager.
1. Falchook G, et al. ASCO 2022. Poster TPS3175; 2. Hipp S. AACR 2021; Oral Presentation 56.
Mechanism of action of BI 7650491

25. B7-H6/CD3 TCE: Phase 1 Study Design and Objectives
• The primary objective is to determine the MTD of BI 765049 ± ezabenlimab based on the number of
patients with DLTs during the MTD evaluation period
• Secondary objectives are to evaluate safety, tolerability, PK, PD, and preliminary efficacy
This is an investigational compound and has not been approved. Its safety and efficacy have not been established yet.
CD = cluster of differentiation; DLT = dose limiting toxicity; MTD = maximum tolerated dose; PD = pharmacodynamics; PK = pharmacokinetics; TCE = T-cell engager.
Falchook G, et al. ASCO 2022. Poster TPS3175.
NCT04752215 is a first-in-human, open-label, dose-escalation trial of BI 765049 ± ezabenlimab in patients with
advanced colorectal cancer or other B7-H6–positive tumors

26. Summary
• T-cell engagers can be powerful tools to turn up the heat in non-immunoreactive tumors,
making them visible and vulnerable to the immune system: by directing the immune system in the
right way, the tumor can be unveiled and become visible again  the immune system becomes
the drug1-3
• T-cell engagers are bispecific antibodies that may elicit a polyclonal T-cell response that is not
affected by cancer cell escape mechanisms, potentially eliminating cancer cells that are “invisible” to
the immune system by promoting an inflammatory/“hot” TME3-5
• Several T-cell engagers are being investigated for the treatment of both solid tumors and
hematological malignancies, including BI 764532 in patients with DLL3-expressing SCLC and
neuroendocrine neoplasms6 and BI 765049 with or without a PD-1 inhibitor in patients with
CRC or advanced B7-H6–expressing solid tumors7,8
BI 764532 and BI 765049 are investigational compounds and have not been approved. Their safety and efficacy have not been established yet.
1. Shin, HG, et al. Int J Mol Sci. 2022;23:5686; 2. Ochoa de Olza M, et al. Lancet. 2020;21:e419-e430; 3. Abbott RC, et al. Int J Mol Sci 2020;21(2):515; 4. Ellerman D. Methods 2019;154:102–117; 5. Huehls
AM, et al. Immunol Cell Biol 2015;93(3):290–296; 6. NCT04429087. https://clinicaltrials.gov/ct2/show/NCT04429087. Accessed August 2, 2022; 7. NCT04752215.
https://clinicaltrials.gov/ct2/show/study/NCT04752215. Accessed August 2, 2022; 8. Falchook GS, et al. SITC 2021. Poster 480.

27. To learn more about the T-cell engager mechanism of action
and watch an educational animation, please visit the DLL3 or
B7-H6 pages at Boehringer Ingelheim’s InOncology.com

28. These presentations will be available on-
demand on the ESMO website through
September 20 and then will be available on
the Boehringer Ingelheim Congress Hub
Oncology