Pieris Pharmaceuticals : European Society for Medical Oncology (ESMO) Virtual Congress 2020 - Presentation

A Phase 1 Dose Escalation Study of PRS-343, a HER2/4-1BB Bispecific Molecule, in Patients with HER2-positive Malignancies

Authors: Sarina Piha-Paul1, Johanna Bendell2, Anthony Tolcher3, Sara Hurvitz4,

Anuradha Krishnamurthy5, Anthony El-Khoueiry6, Amita Patnaik7, Rachna

Shroff8, Anne Noonan9, Paula Pohlmann10, Noah Hahn11, Marc Matrana12,

Markus Zettl13, Kayti Aviano13, Lynn Mar13, Patrick Jolicoeur13, Shane Olwill13,

Ingmar Bruns13, Geoffrey Ku14

1The University of Texas MD Anderson Cancer Center, Texas, USA	8University of Arizona Cancer Center, Arizona, USA
2Sarah Cannon Research Institute/Tennessee Oncology, LLC, Tennessee,	9The Ohio State University, Department of Internal Medicine,
USA	Division of Medical Oncology, Ohio, USA
3NEXT Oncology, Texas, USA	10Georgetown University Lombardi Comprehensive Cancer Center,
4University of California Los Angeles Jonsson Comprehensive	Washington DC, USA
Cancer Center, California, USA	11Sydney Kimmel Cancer Center at Johns Hopkins, Maryland, USA
5University of Pittsburgh Medical Center, Pennsylvania, USA	12Ochsner Cancer Institute, Louisiana, USA
6 Keck School of Medicine of USC, Norris Comprehensive	13Pieris Pharmaceuticals, Inc., Massachusetts, USA
Cancer Center, California, USA	14Memorial Sloan Kettering Cancer Center, New York, USA
7START San Antonio, Texas, USA

Disclosure Information

GEOFFREY KU

Reports relationships with the following:

2

Arog Pharmaceuticals - Research Support

AstraZeneca - Research Support, Consulting

Bristol-MyerSquibb - Research Support, Consulting

Daiichi Sankyo - Research Support

Eli Lilly - Consulting

Merck - Research Support, Consulting

Pieris Pharmaceuticals - Research Support, Consulting

Zymeworks - Research Support

PRS-343, a HER2 4-1BB Bispecific, Drives 4-1BB Agonism in the Tumor Microenvironment in HER2 Positive Solid Tumors

HER2-targeting moiety of the drug localizes to the tumor microenvironment and facilitates 4-1BBcross-linking

4-1BBcross-linking ameliorates T-cell exhaustion and is critical for T-cell expansion

CLINICALLY-RELEVANT BIOMARKERS

4-1BB Pathway

Activation

HER2

targeting			HER2
Antibody	PD-L1
	PRS-343	Atezolizumab		PRS-343
4-1BB			Co-Stimulation
targeting	PD-1
Anticalin®	Blockade of		4-1BB
Proteins	Checkpoint
		Inhibition

Soluble 4-1BB

T-cell Proliferation

CD8+ and CD8+/Ki67+

3

Study Design: Monotherapy and Combination with Atezolizumab

Primary Objectives

• Characterize safety profile of PRS-343and in combination with fixed dose of atezolizumab
• Identify MTD and/or RP2D of PRS-343 alone and in combination with atezolizumab

Secondary Objectives

• Assess potential immunogenicity and PD effects
• Characterize PK profile
• Investigate dosing schedule
• Investigate efficacy

	Dose Levels
Monotherapy	Dose Levels in	Dose
Combination with
Dose Levels	(mg/kg)
1200mg Atezolizumab
1		0.0005
2		0.0015
3		0.005
4		0.015
5	1	0.05
6	2	0.15
7	3	0.5
8	4	1
9	5	2.5
10	6	5

ACTIVE SCHEDULES

Schedule 1: Q3W dosing on day 1; 21-day cycle

Schedule 2 (b): Q2W dosing on days 1, 15; 28-day cycle

Schedule 3 (c): Q1W dosing on days 1, 8, 15; 21-day cycle

In combination with atezolizumab: Q3W dosing on day 1; 21-daycycle

11	7	8
11 (b)		8
11 (c)		8
12 (b)		12
13 (b)		18
Obinutuzumab		8
+ 11(b)
Data cut-off:27-Jul-20

4

Key Enrollment Criteria: Monotherapy and Combination with Atezolizumab

Inclusion Criteria

• Diagnosis of HER2+ advanced/metastatic solid tumor malignancy that has progressed on standard therapy or for which no standard therapy is available
• HER2+ solid tumors documented by ASCO, CAP or institutional guidelines (monotherapy); HER2+ status documented by clinical pathology report (combination)
• Patients with breast, gastric and GEJ cancer must have received at least one prior HER2-targeted therapy for advanced / metastatic disease
• Measurable disease per RECIST v1.1
• ECOG 0 or 1 (monotherapy); ECOG 0-2 (combination)
• Adequate liver, renal, cardiac and bone marrow function

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Exclusion Criteria

• Ejection fraction below the lower limit of normal with trastuzumab and/or pertuzumab
• Systemic steroid therapy or any other form of immunosuppressive therapy within seven days prior to registration
• Known, symptomatic, unstable or progressing CNS primary malignancies
• Radiation therapy within 21 days prior to registration (limited field radiation to non- visceral structures is allowed, e.g., limb bone metastasis)

Baseline Characteristics Monotherapy and Combination with Atezolizumab

All Subjects (n = 74, 41)

Characteristic	Monotherapy; n (%)	In Combination with
Atezolizumab; n (%)
Age, Median (range)	63 (24-92)	59	(26-87)
Gender
F	44 (59%)	23 (56%)
M	30 (41%)	18 (44%)
ECOG PS
0	19 (26%)	12 (29%)
1	55 (74%)	18 (44%)
Prior Therapy Lines
1	9 (12%)	5	(12%)
2	10 (14%)	7	(17%)
3	15 (21%)	6	(15%)
4	11 (15%)	6	(15%)
5+	28 (38%)	17 (41%)
Median no. of anti-HER2
Treatments
Breast	7		3-4
Gastric	3		1

Data cut-off:27-Jul-20

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Primary Cancer Type	Monotherapy; n (%)	In Combination with
Atezolizumab; n (%)
Gastroesophageal	27	(36%)	7 (17%)
Breast	16	(22%)	12	(29%)
Colorectal	10	(14%)	5 (12%)
Gynecological	9 (12%)	4 (10%)
Biliary Tract	7	(9%)	6 (15%)
Non-Small Cell Lung		-	4 (10%)
Bladder	2	(3%)	1	(2%)
Pancreatic	1	(1%)	1	(2%)
Other - Cancer	1	(1%)	1	(2%)
of Unknown Origin
Other - Salivary Duct	1	(1%)		-

Monotherapy

A Phase 1, Open-label, Dose Escalation Study of PRS-343 in Patients with HER2-Positive Advanced or Metastatic Solid Tumors

Treatment-Related Adverse Events for Monotherapy

All Subjects

Occurred in > 1 Patient			Monotherapy
n = 145 (%)		% Grade 3
Infusion Related Reaction	27	(19%)		3 (2%)
Fatigue	11 (8%)		1 (1%)
Nausea	11 (8%)
Vomiting	8	(6%)
Chills	8	(6%)
Abdominal pain
Anemia	2	(1%)		1 (1%)
Anorexia
Arthalgia	2	(1%)
Asthenia	2	(1%)
Cough	2	(1%)
Decreased appetite	2	(1%)
Diarrhea	6	(4%)
Dizziness	2	(1%)
Dry mouth
Dyspnoea	3	(2%)
Fever
Flushing	5	(3%)		2 (1%)
Lightheadness
Lymphocyte count decreased
Neutrophil count decreased
Non-cardiac chest pain	4	(3%)
Paraesthesia	3	(2%)		1 (1%)
Peripheral sensory neuropathy
Pruritis	3	(3%)
Rash	2	(1%)
				Data cut-off:27-Jul-20
One TRAE above Grade 3: Grade 4 Infusion Related Reaction in cohort 10 (5mg/kg PRS-343, Q3W).

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Summary of Responses at Active

Dose Range of PRS-343 in Monotherapy

Based on clinical data, serum concentration of > 20 µg/ml defines active dose range (beginning at Cohort 9)

Cohort	13b	12b	11c	Obi	11b	11	10	9
									Total
Best Response	18 mg/kg,	12 mg/kg,	8 mg/kg,	8 mg/Kg,	8 mg/kg,	8 mg/kg,	5 mg/kg,	2.5 mg/kg,
Q2W	Q2W	QW	Q2W	Q2W	Q3W	Q3W	Q3W
Evaluable Patients	3	2	4	2	7	4	6	5	33
CR	1	-	-		-	-	-	-	1
PR	-	-	-		3	-	-	-	3
SD	-	-	1	1	3	3	3	2	13
ORR	33%	0%	0%	0%	43%	0%	0%	0%	12%
DCR	33%	0%	25%	50%	86%	75%	50%	40%	52%

Data cut-off:27-Jul-20

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Increase in CD8+ T Cells and Circulating Soluble 4-1BB Support 4-1BB Engagement by PRS-343

Tumor	Tcells	area
inductionCD8+	/mm
		tumor
		2
	Fold

6

5

4

3

2

1

0

Biopsy

Pre-dose

*

• Unpaired 2 tailed t- test
  P<0,05

PRS-343

(Cycle 1 Day 1)

SD≥C6

PR

CR

PD

Biopsy

PRS-343Post-dose

(Cycle 2 Day 1)

(Cycle 2 Days 2-8)

			10/25 patients			21/43 patients
		30000	evaluated			evaluated
Serum	[pg/ml]s41BB
20000
		10000
		6000
		4000
		2000
		0
		C1	C3	C4	C1	C3	C4

Time (Cycles)

Non-Active Dose	Active Dose
Cohorts 1-8	Cohorts 9-13b

Non-Active Dose	Active Dose
Cohorts 1-8	Cohorts 9-13b

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Gastric Cancer Patient (107-012) with PR

Patient Profile, Treatment History and Treatment Outcome

Patient Profile

• Cohort 11b | 8 mg/kg every two weeks
• 80-yearold woman; initial diagnosis in June 2017
• Stage IV gastric adenocarcinoma
• Metastases to liver, lymph node and adrenal glands
• HER2 IHC 3+; PD-L1 positive (CPS=3)
• NGS: ERBB2 amplification, TP53 mutation, alteration of CDK12 and SF3B1

Lesions	Lesion Site	Baseline
Target 1	Liver	14

Oncology Treatment History	Duration
Trastuzumab, Pembrolizumab	July 2017 - June 2018
+ Capecitabine/oxaliplatin
Nivolumab with IDO1 inhibitor	Aug 2018 - Jan 2019
(investigational drug)

	Lesion Size (mm)
C2 Post-treatment	C3 Post-treatment	C4 Post-treatment	C6 Post-treatment
12	10	9	8

	Target 2	Liver	20	16	10	8	9
	Target 3	Pancreas	19	16	14	14	14
% Change from Baseline		-17%	-36%	-42%	-42%
Non-target 1	Lung	Present	Present	Present	Present	Present
Non-target 2	Stomach	Present	Present	Present	Present	Absent
Non-target 3	Stomach	Present	Present	Present	Present	Absent
11		Data cut: 24-Jan-2020

CD8+ T Cell Numbers in the Tumor and Circulating

s4-1BB Increase Post-Treatment in responding Gastric Cancer Patient (107-012)

Baseline	Post-treatment
	C4

Tumor	T cells (n/mm2)
	CD8 +

250

200

150

100

50

0

CD8 fold change: 5.7

CD8 pre [n/mm2]: 38

CD8 +Ki67+ T cells (n/mm2)

Pre Post

CD8Ki67 fold change: 5.8

CD8 pre [n/mm2]: 16

100

90

80

70

60

50

40

30

20

10

0

Pre Post

		Fold Change to Predose	3
Serum	s41BB	2
1
0
			2	4	8	15	Pre C2
			Baseline

Timepoint (days)

	2000	1.9 x
			increase
[pg/ml]	1500
1000
s41BB
500
		0
		predoseC1 day	2	d8
		C1
	C1

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Rectal Cancer Patient (103-021) with CR

Patient Profile, Treatment History and RECIST

Monotherapy: Rectal Cancer Patient with Confirmed CR

Oncology Treatment History	Duration
Capecitabine + XRT	Apr-May 2017

• Cohort 13b | 18 mg/kg Q2W
• 59-year-oldmale; initial diagnosis March 2017
• Stage 4 rectal adenocarcinoma cancer; metastasized to heart and lung

• FoundationOne Her2 amplification; in-house testing IHC 3+
• MSS, TMB low (2 mt/Mb)

Neoadjuvant Folfox	May-Sep 2017
Resection	Dec 2017
Folfiri/Avastin	Mar-Jul 2018
5FU/Avastin maintenance	Aug 2018-May 2019
Irinotecan/Avastin	May-Nov 2019
SBRT	Nov 2019

Lesions	Lesion Site		Lesion Size (mm)
Baseline	C2 Post-treatment	C4 Post-treatment	C6 Post-treatment
Target 1	Lung	22	13	0	0
% Change			-41%	-100%	-100%
from Baseline
Non-target 1	-	Present	Present	Absent	Absent

Data cut-off:27-Jul-20

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CD8+ T Cell Numbers in the Tumor and Circulating

s4-1BB Increase Post-Treatment in CR Rectal

Cancer Patient (103-021)

Baseline	Post-treatment	Post-treatment
	C2	C6

CD8 fold change: 2.3 CD8 pre [n/mm2]: 238

Tumor	(n/mmcellsT 2)	700
600
		500
		400
		300
	+	200
	CD8	100
		0

Pre Post

Serum

	a s e l i n e	6
					l ]
B	o B	4				g / m
B	t					p
s 4 1	a n g e	2				1 B B [
	C h				s 4
	F o l d	0
		B a s e l i n e 2	3	4	8	1 5 P r e C 2
			T i m e p o i n t ( d a y s )

6 0 0 0

8 . 2

x

i n c r e a s e

4 0 0 0

2 0 0 0

0

B L Q

e

2

e

s

y

s

d

o

a

d

o

d

e

1

e

r

C

r

1

p

2

p

C

C

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Combination Therapy with Atezolizumab

A Phase 1B, Open-label, Dose Escalation Study of PRS-343 in Combination With Atezolizumab in Patients with Specific HER2-Positive Advanced or Metastatic Solid Tumors

PRS-343 + Atezolizumab Duration of Exposure

Ovarian 102-122

Bladder 111-111 BCA 102-120 NSCLC 113-104 Ovarian 112-106 Lung 107-104 Gallbladder 107-103 CUP 102-115 Rectal 113-102 BCA 108-105

Gastric Cancer 102-123 Rectal 102-121 GEJ 112-107 BCA 102-116 NSCLC 111-110 GEJ 102-114

Esophageal 114-101 Rectal 112-101 BCA 108-101 BCA 112-102 NSCLC 107-109 GYN 111-112 GYN 108-106

Pancreatic 113-101 CHOL 108-102 CRC 111-107 BCA 102-113 *BCA 102-112 Rectal 102-111 GEJ 102-109

Gallbladder 107-107 Cholangiocarcinoma 107-105 BCA 102-105 BCA 111-106

Gallbladder 102-104

C2D21

C6D21

C10D21

C14D21

C18D21

C22D21

C24D21

X

Cohort 7 (8mg/kg)

Cohort 6 (5mg/kg)

Cohort 5 (2.5mg/kg)

Cohort 4 (1mg/kg)

Partial Response Stable Disease

Disease Progression

Death

On Treatment Discontinued (AE)

Discontinued (Clinical Progression)

Discontinued (Patient and/or Physician decision)

Discontinued (Disease Progression)

• Scan and EOT on same day; RECIST response is presented

DAYS ON TREATMENT | Data Cut: 18-AUG-2020

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Treatment-Related Adverse Events for

Combination with Atezolizumab

All Subjects

Occurred in > 1 Patient		Combination with Atezolizumab
n = 148 (%)		% Grade 3
Infusion Related Reaction	38	(26%)		3 (2%)
Fatigue	12 (8%)
Nausea	8	(5%)
Vomiting	38	(26%)
Chills
Abdominal pain	2	(1%)
Anemia	4	(3%)		2 (1%)
Anorexia	2	(1%)
Arthalgia	2	(1%)
Asthenia
Cough
Decreased appetite
Diarrhea	5	(3%)		1 (1%)
Dizziness
Dry mouth	3	(2%)
Dyspnoea
Fever	3	(2%)
Flushing
Lightheadness	2	(1%)
Lymphocyte count decreased	3	(2%)		1 (1%)
Neutrophil count decreased	3	(2%)		1 (1%)
Non-cardiac chest pain
Paraesthesia
Peripheral sensory neuropathy	2	(1%)
Pruritis	4	(3%)
Rash
Two TRAEs above Grade 3: Grade 4 AST increase, Grade 3 transaminitis, and eventually Grade 5 hepatic failure in cohort 7 (8mg/kg + 1200mg	Data cut-off:27-Jul-20
atezolizumab); Grade 4 hemolytic anemia (unrelated to PRS-343, related to atezolizumab) in cohort 7.

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Soluble 4-1BB Increases in Active Dose Cohorts & Clinical

Benefit is Associated with Tumoral Immune Cell Activation

4-1BB target engagement

Soluble 4-1BB in serum

CD8+ T cell Numbers		CD8+ T cell Proliferation

Tumor-localized activity

IHC on tumor tissue

Patients with prolonged clinical benefit show a trend of increased CD8+ T cell numbers, proliferation and elevated cytolytic function in tumor biopsies

Substantial increase of s4-1BB is observed in active dose cohorts (4-7), suggesting PRS-343-mediated target engagement

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Breast Cancer Patient (108-101) with PR

Patient Profile, Treatment History and RECIST

PRS-343+Atezolizumab: Breast Cancer Patient with PR

Oncology Treatment History	Duration
Trastuzumab/Docetaxel/

• Cohort 6 | 5 mg/kg Q3W + 1200mg atezolizumab
• 52-year-oldmale; Initial diagnosis July 2011
• Stage 2 Invasive Ductal Breast Cancer

• FISH HER2/CEP17 ratio 2.4, HER2 copy number 4.8 In-house testing IHC2+, FISH+
• PD-L1low in pre-treatment and high in post treatment biopsy

Tamoxifen/Carboplatin	Sep 2011-Jul 2013
Trastuzumab/Pertuzumab/Vinorelbine	Aug 2013-Jan 2016
T-DM1/Fulvestrant	Nov 2017-Mar 2018
Capecitabine/Lapatinib	Mar 2018
Palbociclib/Arimidex	Apr-May 2019

					Lesion Size (mm)
Lesions	Lesion Site
Baseline	C2 Post-	C4 Post-		C6 Post-	C8 Post-	C12 Post-	C16 Post-
		treatment	treatment		treatment	treatment	treatment	treatment
Target 1	right pulmonary	16	18	15	13	13	6	5
ligament lymph node
% Change			+12.5%	-6%	-19%	-19%	-63%	-69%
from Baseline
Non-target1-4	-	Present	Present	Present		Present	Present	Present	Present

Data cut-off:27-Jul-20

19

Tumoral and Circulating s4-1BB Increase Post- Treatment in PR Breast Cancer Patient (108-101)

CD8+ T cell Numbers

/	1200
cellsTCD8Abs.+ mmtumor2	1000		Pre	Post
	800
	600
	400
	200
	0

Abs. CD8+Ki67+

CD8+ T cell Proliferation	Soluble 4-1BB

/cellsTtumor mm2	150		1BB-s4 [pg/ml]	4000
Post	C1	C3	C4
Pre
	100			3000
				2000
	50			1000
	0			0

CD8+ T cell numbers, proliferation, cytolytic molecules and s4-1BB increase post-treatment, demonstrating 4-1BB arm activity of PRS-343

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Conclusions

Acceptable safety profile in all doses and schedules tested in monotherapy as well as in combination with atezolizumab

Demonstrated durable anti-tumoractivity in heavily pre-treated patient population across multiple tumor types, including those usually not responsive to immune therapy; novel and non-redundant MoA among HER2-targeting therapies

Showed a clear increase in CD8+ T cell numbers and proliferative index in the tumor microenvironment of responders, soluble 4-1BB increase demonstrates activity of the 4-1BB arm of the molecule

2L HER2+ gastric/gastroesophageal cancer trial in combination with Paclitaxel and Ramucirumab in preparation

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Acknowledgements

Patients, their families and caregivers

Investigators, as well as their site personnel

Monotherapy		Combination with Atezolizumab

Study 0416 (NCT03330561 A Phase 1, Open-label, Dose Escalation Study of PRS-343 in Patients with HER2-Positive Advanced or Metastatic Solid Tumors) sponsored by Pieris

• The University of Texas MD Anderson	• University of Pittsburgh Medical Center -
Cancer Center - S. Piha-Paul, B. Bruggman	A. Krishnamurthy, B. Foster, A. Blasko
• Sarah Cannon Research Institute, LLC -	• University of Arizona Cancer Center -
J. Bendell, J. Costin	R. Shroff, D. Pennington
• NEXT Oncology - A. Tolcher, K. Dotson	• Georgetown University Hospital -
• University of California Los Angeles Jonsson	P. Pohlmann, S. Wagner
• Sydney Kimmel Cancer Center at Johns
Comprehensive Cancer Center - S. Hurvitz,
M. Rocha, R. Rubin	Hopkins - N. Hahn, E. Lee
• South Texas Accelerated Research	• Memorial Sloan Kettering Cancer Center -
Therapeutics - A. Patnaik, K. Rivas	G. Ku, T. Shrivastav, P. Collins

Study 0818 (NCT03650348, A Phase 1B, Open-label, Dose Escalation Study of PRS-343 in Combination With Atezolizumab in Patients with Specific HER2-Positive Advanced or Metastatic Solid Tumors) sponsored by Pieris, atezolizumab kindly supplied by F. Hoffmann-La Roche Ltd

• The University of Texas MD Anderson		School of Medicine of USC, Norris
Cancer Center - S. Piha-Paul,		Comprehensive Cancer Center - A.
B. Bruggman		El-Khoueiry
• NEXT Oncology - A. Tolcher,	•	The Ohio State University, Department
K. Dotson		of Internal Medicine - A. Noonan
• University of California Los Angeles	•	Ochsner Cancer Institute -
Jonsson Comprehensive Cancer		M. Matrana, S. Jerdonek
Center - J. Bendell, J. Costin	• Memorial Sloan Kettering Cancer
• University of Southern California, Keck
	Center - G. Ku, T. Shrivastav

Pieris associates: Corinna Schlosser, Aizea Morales Kastresana

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