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
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
Immuno-oncology:
Current Landscape
and Next Frontier
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:

Immune modulators, e.g. anti-CTLA-4 and anti-PD-(L)1

Oncolytic viruses

CAR-T cells

Cancer vaccines

Bispecific antibodies, e.g. TCEs

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.
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

2022: 21 recruiting/active
Phase 3 studies of ICIs
ongoing

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.
ICIs Are Rapidly Expanding Treatment Options for Cancers Such As
NSCLC1-8
• For first-line treatment, options include:1-5 • Immunotherapy options are also available in other NSCLC
‒ ICI monotherapy +/- chemotherapy settings:
‒ Double ICI +/- chemotherapy ‒ In unresectable Stage III NSCLC after CT/RT
‒ Double ICI + short chemotherapy (2 cycles)6 ‒ As adjuvant in resected NSCLC with high PD-L1 expression 7
‒ As neoadjuvant in combination with CT in resectable NSCLC 8
Stage IV (NSCLC without Stage III Stage IB - IIIA
actionable mutation) (resectable)
(unresectable)

PD-L1 Complete CT +
PD-L1 ≥50% PD-L1 <1% After RT and CT
1%-49%a resection Neoadjuvant
ICI8,b
ICI + Chemotherapy Adjuvant
ICI Monotherapy Chemotherapy
in PD-L1 ≥ 1%
ICI Combo Therapy Adjuvant
(Nivolumab/Ipilimumab) + 2 cycles chemo
(Durvalumab)
Atezolizumab
(PD-L1 ≥50%)
ICI Monotherapy
(Atezolizumab,
Cemiplimab, or
Pembrolizumab)

a
Single-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.
Despite Broad Activity of Anti-PD-L1/PD-1 in Cancer, Only a Subset of
Patients Benefit

Anti-PD-L1/PD-1 response rates among various

tumor types1
Glioblastoma Head and neck • Response rates to ICIs typically range from
(11%) cancer (15%)
10% to 30% depending on the tumor type1-
3
Melanoma Lung cancer
(20%)
• While lymphoma typically has the highest
(30%)
response rate, sarcoma and ovarian
cancer have the lowest
Breast cancer Gastric cancer
(12%) (11%)

Liver cancer Sarcoma (8%)

(19%)

Urothelial Renal cancer

cancer (20%) (23%)

Ovarian cancer Colorectal

(9%) cancer (3%)
Lymphoma
(62%)

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.
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

Immune modulators, e.g. anti-CTLA-4 and anti-PD-(L)1

Oncolytic viruses

CAR-T cells

Cancer vaccines

Bispecific antibodies, e.g. TCEs

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.
T-cell Engagers as an
Immunotherapeutic
Strategy
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

mAb for CD3 mAb for tumor-

co-receptor associated antigen

TCE

• 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.
The TCE Landscape is Expanding: Treatment of Solid Tumors is a
Specific Unmet Therapeutic Need

Currently Approved for Use Ongoing Clinical Trials

TCE Company Target Indication Phase

Blinatumomab Tebentafusp Boehringer
SCLC, DLL3 expressing
BI 7645323,4 DLL3/CD3 neuroendocrine Phase I
Ingelheim
neoplasms
AMG 7575-8 Amgen DLL3/CD3 Relapsed/refractory SCLC Phase I/2
Advanced SCLC, DLL3
Harpoon expressing
HPN 328 9.10
DLL3/CD3 Phase I/2
Therapeutics neuroendocrine
neoplasms

Blinatumomab is Tebentafusp is indicated BI 76504911,12

Boehringer
B7-H6/CD3
CRC and other B7-H6
Phase I
Ingelheim expressing solid tumors
indicated for treatment of for the treatment of HLA-
Peripheral T-cell
CD19-positive, A*02:01-positive adult AFM1313,14 Affimed CD16/CD30 lymphoma or transformed Phase 2
relapsed/refractory patients with MF

B-precursor ALL1 unresectable/metastatic JNJ-

6440756413,15
Johnson &
Johnson
CD3/GPRC5D
Relapsed/refractory
multiple myeloma
Phase 2
uveal melanoma2
Relapsed/refractory
JNJ- Johnson &
CD3/BCMA multiple myeloma Phase 3
6400795713,16 Johnson

This table is not a comprehensive list.

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.
DLL3: An Emerging Target in SCLC and NEC

• DLL3 is an inhibitory Notch ligand that is expressed on DLL3 Staining in Lung Neuroendocrine tumors
the cell surface of tumors with an endocrine origin, DLL3-negative
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-positive large cell NEC DLL3-positive SCLC

Image reproduced with permission from Ali G, et al. Front Oncol. 2021;11:729765.

High levels of DLL3 expression are found in

neuroendocrine tumors of the lung6

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.
SCLC Accounts for Approximately 15% of Lung Cancers

An estimated
300,000 cases of SCLC SCLC originates from neuroendocrine-cell
SCLC are diagnosed 15%
precursors and is characterized by rapid
globally each year1,2,*
growth3

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
NSCLC
85%

*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.
The Burden of SCLC is High Because of Early Metastases, Treatment
Resistance, and Mortality Rate

5-year relative survival for SCLC by stage

at diagnosis 2010–20161 Treatment Resistance
30%
27%
The high response rate of SCLC to frontline
25% chemotherapy (60%–70%) contrasts with its
resistance to subsequent therapies after
recurrence2
Relative survival (%)

20%
16%
15%

10%
Mortality Rate

5%
3% Less than 7% of patients with SCLC (all stages) will
survive for ≥5 years2
0%
Localized Regional Distant

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.
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

Image reproduced with permission from Dingemans A-M C, et al. Ann Oncol. 2021;32(7):839–853.

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.
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 SCLC 1
• With addition of ICIs, median overall survival increases only by 2-3 months 1,2
Atezolizumab Placebo Durvalumab + EP
IMpower 1331 + CP/ET +CP/ET EP
(n=201) (n=202) CASPIAN 2

Median OS, 12.3 10.3 Median OS, 12.9 10.5

mo (95% CI) (10.8 – 15.8) (9.3 – 11.3) mo (95% CI) (11.3 – 14.7) (9.3 – 11.2)

HR (95% 0.76 (0.6 – 0.95) HR (95% 0.71 (0.6 – 0.86)

CI) P = 0.0154 CI) P = 0.0003

Figure reproduced with permission from 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.

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.
Neuroendocrine Neoplasms Comprise of ≈2% of All Malignancies 1,2

• 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

Incidence of GEP-NENs per 100,000 people per year 3,4

3–4 2–3 1–2 <1 Data not available

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.
GEP-NENs Are Classified As Well-differentiated NETs or Poorly
Differentiated NECs

WHO 2019 classification for GEP-NENs1

Well-differentiated NETs and Mitotic
poorly-differentiated NECs are Ki-67 index
Morphology** Grade count
(%)*
biologically and genetically distinct 1 (2 mm2)

Well-differentiated NETs G1 <2 <3

Clinical history, histomorphology and Well-differentiated NETs G2 2–20 3–20

genetics can help to distinguish
NETs from NECs1 Well-differentiated NETs G3 >20 >20

Poorly differentiated NECs

• Small-cell G3 >20 >20
GEP-NENs are graded according to
• Large-cell
the Ki-67 proliferation index* and
mitotic count1–3 Consensus guidelines for the diagnosis, classification and treatment of neuroendocrine
tumors are also provided by the European Neuroendocrine Tumor Society (ENETS) 3

*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.
Effective Treatment Options Are Limited for Those with High-grade,
Progressive Disease

GEP-NENs
• Therapeutic decision-making
is based on proliferative
activity, somatostatin
SI-NETs Pan-NETs NEC G3
receptor expression, tumor
growth rate and extent of
the disease1
NET G1/G2
NET G1
SSTR- NET G2 Ki-67 Cisplatin or
SSTR- stable NET G3 Ki-67 SSTR-
positive Ki- >10%-15% or NET G2 carboplatin +
negative disease or <50% negative
67 <10% or rapid growthd etoposide
slow growth
slow growtha

Ki67 <10%
• Conventional therapeutic
Watch-and-
options are surgery, SSAs,
Loco- SSAf STZ/5-FU
wait SSA
+/-
EVE
regional
STZ/5-FU
STZ/5-FU
CAPTEM
CAPTEM
STZ/5-FU
CAPTEM
EVE
FOLFIRI
FOLFOX chemotherapy, molecular
therapye
Locoregional
therapye
PRINT

FOLFOX
CAPTEM
EVE
EVE
SUN EVE SUN
SUN
CAPTEM
targeted agents, and PRRT1,2
EVE SUN
PRRTc
TEM+/-
CAP
PRRT PRRT • Therapy selection in
IFN⍺ PRRT
EVE advanced disease is limited
due to the absence of
Image adapted with permission from Pavel M, et al. Ann Oncol. 2020;31(7):844–860. 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.
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
Phase I interim results showed that antitumor efficacy was observed across different dose ranges
in patients with R/R SCLC1,2

Patients
Modified RECIST 1.1 Response, n (%)
(N=64)

PR, confirmed 13 (20)

PR, unconfirmed 1 (2)

SD 17 (27)

DCR, % 30 (47)
Image reproduced with permission from Owonikoko T et al. ASCO 2021. Abstract 8510. Oral Presentation.

• A confirmed partial response was noted in 20% • Based on these results, a Phase II study
of patients with a mDOR of 8.7 months2 (DeLLphi-301) is currently enrolling patients to
• 7/13 patients are still on treatment with ongoing evaluate the efficacy, safety, and tolerability of
response tarlatamab as ≥3L treatment for SCLC3

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.
The DLL3/CD3 TCE BI 764532 Directs Cytolytic T Cells to DLL3-
Expressing Tumor Cells

• BI 764532 is a novel, half-life–extended,

Inactive T-cell
IgG-like TCE that induces the formation
Active T-cell
of a cytolytic synapse by binding
concomitantly to DLL3 on tumor cells
and to CD3 on T cells, thereby
CD3 CD3 Cytolytic selectively targeting DLL3-positive
synapse
DLL3/CD3 neoplasms
bispecific DLL3/CD3 bispecific
antibody antibody • In preclinical studies, BI 764532:
Cytolytic
granules • Induced cytotoxicity of DLL3-positive
cells
DLL3 DLL3
• Potently inhibited tumor growth
• Modulated the inflammatory
environment in the tumor tissue by
redirecting CD4-positive and CD8-
Tumor cell 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.
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

As of July 2022, patients are being recruited in early dose escalation

cohorts in the United States, Japan, Spain, and Germany2

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.
DLL3/CD3 T-Cell Engager: Phase 1a Study Design

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 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.
The B7-H6/CD3 TCE is a Novel T-cell Redirecting Agent

• BI 765049 simultaneously binds to both the

Mechanism of action of BI 7650491 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.
B7-H6/CD3 TCE: Phase 1 Study Design and Objectives

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

• 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.
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.
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
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