ASCO-SITC Clinical Immuno-Oncology Symposium SEMA4D-related Oral Presentation: CLASSICAL-Lung Combination Trial of Pepinemab with Avelumab

CLASSICAL-Lung Combination trial of Pepinemab with Avelumab

Michael R. Shafique, MD - H. Lee Moffitt Cancer Center, Tampa, FL

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Disclosures

Institutional Research Funding

		COMPANY	RECIPIENT	COMMENTS
		Merck Serono	H. Lee Moffitt Cancer Center	Site Principal Investigator
		Vaccinex	H. Lee Moffitt Cancer Center	Site Principal Investigator
		Nektar	H. Lee Moffitt Cancer Center	Site Principal Investigator
		PsiOxus Therapeutics	H. Lee Moffitt Cancer Center	Site Principal Investigator
		Amphivena	H. Lee Moffitt Cancer Center	Site Principal Investigator
Travel
		Janssen	Michael R. Shafique

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Pepinemab

Proposed Mechanism of Action

• Semaphorin 4D signals through Plexin B1 and Plexin B2 receptors to regulate cellular cytoskeleton and its function in cell migration and differentiation
• Anti-SEMA4Dshifts the balance of immune infiltration and myeloid suppression to promote anti-tumor T cell activity1,2
• • Promotes infiltration of potent APC
  • Reverses recruitment and function of MDSC, M2 TAM and Treg
  •  Facilitates infiltration and activity of CD8+ T cells
• Pepinemab (VX15/2503), a humanized IgG4 with hinge modification, binds to SEMA4D and blocks its signaling activity

1. Evans EE et al. Cancer Immunol Research 2015
2. Clavijo et al. Cancer Immunol Research 2019

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Anti-SEMA4D shifts balance of chemokines and suppressor cells to enhance infiltration and activity of tumoral T cells

1. • Dendritic cells (DC) express
2. high affinity receptor PLXNB1 and CD11c+ (red stain).
3. • Binding to SEMA4D at tumor edge restricts penetration of
4. PLXNB1+ DC into Colon26 tumor.
5. • Shift in balance of immune cells and factors within TME

Colon26 Tumors

Control

IgG

SEMA4D CD11c F4/80

αSema4D

Mab67

The Sema4D	Inflammatory	Increase in Pro-
gradient is	DC's migrate	inflammatory
neutralized	into tumor	APC

(vessel)

CD8+ CTL

Increase in CD8+ T cell infiltration and activity

Evans EE et al. Cancer Immunol Research 2015;3(6): 689-701

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http://www.ncbi.nlm.nih.gov/pubmed/25614511

Anti-SEMA4D Antibody Enhances Activity of Immune Checkpoint Antibodies in Preclinical Syngeneic Models

anti-CTLA-4 Combination: MOC1 HNSCC	anti-LAG3 Combination: Colon26

anti-PD-L1 Combination: Colon26	Anti-TGFβ: MC38

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Phase 1b/2 CLASSICAL- Lung Study Design

Combination Trial of Pepinemab with Avelumab in NSCLC

Phase 1b

Dose Escalation	5 mg/kg	10 mg/kg	20 mg/kg
IO Naïve	(n=3)	(n=6)	(n=3)

(n=12)

Phase 2

Dose Expansion	IO Failure	IO Naive
10 mg/kg	10 mg/kg
(n=50)
	(n=32)	(n= 18)

Study Objectives

pepinemab

+

10 mg/kg avelumab

Q2W

• The primary objective is safety, tolerability, and identification of the RP2D for dose expansion.
• Secondary objectives include evaluation of efficacy, immunogenicity, and PK/PD, and an exploratory objective is to identify candidate biomarkers of activity

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Demographics

		(IO Failure)	(IO	Naïve)		(All)
Subjects Enrolled n=		32		30		62
Age (years)
	Median		67		62		66
	Range		51-85	30-83		30-85
	18 to <65	12	38%	16	53%	28	45%
	65 and over	20	63%	14	47%	34	55%
Sex
	Men	23	72%	14	47%	37	60%
	Women	9	28%	16	53%	25	40%
Race
	Asian	1	3%	0	0%	1	2%
	Black or African American	3	9%	0	0%	3	5%
	Native Hawaiian or Other P.I.	0	0%	1	3%	1	2%
	White	28	88%	29	97%	57	92%
Ethnicity
	Non-Hispanic or Latino	30	94%	30	100%	60	97%
	Hispanic or Latino	2	6%	0	0%	2	3%
ECOG performance status
0	5	16%	10	33%	15	24%
1	27	84%	20	67%	47	76%
Disease Stage at Screening
	IIIA	1	3%	0	0%	1	2%
	IV	31	97%	30	100%	61	98%
Histology
	Adenocarcinoma	20	63%	19	63%	39	63%
	Squamous Cell	12	38%	11	37%	23	37%
PD-L1 (Dako 73-10 pharmDx) Status
	No PD-L1 expression	11	38%	8	36%	19	37%
	1-49%PDL-1 expression	12	41%	10	45%	22	43%
	50-79%PDL-1 expression	6	21%	3	14%	9	18%
	≥80% PDL-1 expression	0	0%	1	5%	1	2%
	Cancelled*		3		8		11

*Not included in % calculation

5 subjects still on study:

2 ION / 3 IOF

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Safety Summary

CLASSICAL-Lung

• The combination therapy of pepinemab plus avelumab is well tolerated at all dose levels; no concerning safety signals identified to date.
• One DLT, a grade 3 pulmonary embolism, occurred in the 10mg/kg pepinemab + 10mg/kg avelumab escalation cohort, resolved and did not recur in that same subject or additional subjects in any cohort.
• The most frequent related AEs still remain at grades 1 or 2 fatigue, pyrexia, or chills.
• Two (2) Immune Related Adverse Event (irAE) occurred during the Expansion Cohort (immune related myositis and immune mediated pneumonitis).
• No deaths (grade 5) have been reported that were related to study treatment (pepinemab and avelumab) (14 Jan 2020)
• Overall immunogenicity does not appear to be a concern with this combination.

November, 2019 I 8

Percent Change in Target Lesion Diameter by Weeks (IO Naïve)

6 Months		1 Year

Lines are color coded base on best overall response

Partial Response

Stable Disease

Progressive Disease

End of Treatment

Ongoing Response

5 Partial Responses

3 Subjects on study ≥ 1 year

Disease control rate (PR+SD): 81%

Note: Patient on single agent pepinemab for the last 8 months due to rash deemed related to avelumab

Evaluable patients are shown (n=21)

November, 2019 I 9

Percent Change in Target Lesion Diameter by Weeks (IO Failure)

6 Months

1 Year

Partial Response

Stable Disease

Progressive Disease

End of Treatment

Ongoing Response

2 PR + 3 SD on study

≥ 6 months

59% (17/29) benefited from combo (SD or PR)

Lines are color coded base on best overall response

Evaluable patients are shown (n=29)

November, 2019 I 10

CLASSICAL- Lung: IO Failure

Increase in CD8+ T cell infiltration

		PR
	002-012	002-025
Pre-Treatment
On-Treatment
Density	1	1
0.5	0.5
CD8	0	0

		SD
002-016	002-015	002-019	007-002	007-003
1	1		1	1
0.5	0.5	NE	0.5	0.5
0	0		0	0

PD

002-034002-013

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0.50.5

00

No or low tumor detected in	No tumor detected in these 3 biopsies from	Tumor (Cytokeratin+)
these 2 biopsies from	CD8+ T cells
patients with stable disease
Pembrolizumab refractory
patients with PR

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Time on Study in Evaluable Subjects

IO Naïve Subjects

• 81% of evaluable patients (17/21) have experienced disease control (PR+SD) while receiving the combination.

• Durable clinical benefit of ≥1 year has been achieved in 3 subjects and ≥6 months in 7 subjects

						79% of PR & SD subjects were
						reported to have Negative or Low
						PD-L1 expression*
++
					IO Failure Subjects
						*PD-L1 analysis was performed via Dako 73-10 pharmDx. PD-L1 status
						reported (44/50 subjects) is from data available at cut off (10 Jan
						2020). A total of 29 SD and PR subjects were analyzed and 23 were
						reported to be PD-L1 negative or low (0-49%); 10 of these were PD-L1
						negative (<1%).
						• 59% of evaluable patients (17/29) whose tumors had progressed during or
						following treatment with anti-PD-x antibodies benefited from switching to
						the combination therapy, which appears to induce a halt or reversal of
						tumor progression.
						• Three (3) subjects were IO refractory before entering trial ( )
						• Two (2) subjects who failed pembro have attained PRs with 66% and 52%
						tumor reduction at most recent scan.
						• Durable response of ≥1 year has been achieved in 1 subject and ≥6
						months in 6 subjects
				++

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CD8 Density generally increased following treatment

CLASSICAL-Lung

• CD8+ T cell density increased in most tumors following treatment with pepinemab + avelumab in patients experiencing a PR (5/5) or SD (4/5).
• CD8+ T cell levels in tumor appear to correspond with response. Higher T cell densities and largest increases in density were observed in patients with PR or SD, while low T cell density was observed in tumor tissue from subjects with rapidly progressing disease (PD).

• Matched pre and on-treatment from the same lesion
• On-treatmentbiopsies collected after ~ 5 weeks of treatment
• Core or needle biopsies
• Quantification of tumor bed across the entire biopsy section, excluding necrotic regions. Tumor bed was verified by pathologist review

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Summary

• Anti-SEMA4Dshifts the immune balance in the TME to overcome immune exclusion and myeloid suppression
• • Increased T cell penetration and T cell activity
  • Reduced myeloid cells and reduced immune suppression
• The combination of pepinemab + avelumab is well tolerated in CLASSICAL-Lung trial.
• Extent and duration of treatment benefit.
• • ION: Among evaluable IO naïve subjects (n=21) enrolled in either dose escalation or dose expansion, 5 immunotherapy naïve patients experienced a PR, 3 patients have durable benefit over 1 year, and the Disease Control Rate (PR+SD) was 81%.
     Quality of enrollment in this cohort suffered from 30% non-evaluable and low PD-L1 expression.
  • IOF: 59% of evaluable patients (17/29) whose tumors had progressed during or following treatment with anti-PD-x antibodies benefited from switching to the combination of pepinemab + avelumab, which appeared to induce a halt or reversal of tumor progression (PR or SD).
  • Clinical response or disease stabilization was observed in majority of patients despite low PD-L1 expression. 82% (18/22) of all subjects with either PR or SD subjects were reported to have negative or low positive PD-L1 expression (Dako 73-10 pharmDx assay)
• Exploratory:
• • Increased CD8+ T cell density was observed in most tumors following treatment with pepinemab + avelumab. CD8+ T cell levels in tumor appear to correspond with response.
  • Tumor was absent or greatly reduced in 10/11 biopsies from subjects analyzed with PR or SD. Interestingly, no tumor was detected in biopsies analyzed from 4/5 subjects with PR and 3/6 subjects with SD.

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Acknowledgements

Vaccinex, Research:

• Elizabeth Evans
• Crystal Mallow
• Holm Bussler, PhD
• Sebold Torno
• Christine Reilly
• Maria Scrivens
• Leslie Balch
• Alan Howell

Vaccinex, Clinical Development:

• Terrence Fisher, PhD
• Desa Rae Pastore
• Alisha Reader
• Robert Parker
• Jason Condon
• William Bigham
• Cindy Dawson

Vaccinex, Executive Management:

• Maurice Zauderer, CEO
• Ernest Smith, CSO
• John Leonard, SVP
• Raymond Watkins, COO
• Scott Royer, CFO

Merck KGaA, Darmstadt, Germany/EMD Serono; a business of Merck KGaA Andreas Schröder, Kevin Chin, Pam Kaur, Shruti Vasudev, Dongzi Yu

CLASSICAL-Lung Investigators

Michael Shafique (Moffitt Cancer Center), Jonathan W. Goldman (UCLA Medical Center), J. Thaddeus Beck (Highlands Oncology Group), Megan Ann Baumgart (University of Rochester), Ramaswamy Govindan (Washington University School of Medicine, St. Louis, MO), Nashat Gabrail (Gabrail Cancer Center), Rachel E. Sanborn (Earle A. Chiles Research Institute, Providence Cancer Institute); Alexander I. Spira (Virginia Cancer Center Specialists); Aaron S. Mansfield (Mayo Clinic, Rochester, MN), Yanyan Lou (Mayo Clinic, Jacksonville, FL), Nagashree Seetharamu (Feinstein Institutes for Medical Research, Northwell Health).

Moffitt Co-investigators Alberto Chiappori, Benjamin Creelan, Jhanelle E.

Gray, Eric Haura, Andreas Saltos, Tawee Tanvetyanon

Moffitt Clinical Trial Coordinator Ashley Derigo

Moffitt Research Data Specialists Faranak Esfahani, Brittany Gore,

Mariana Castellano-Fornelli

Patients and	Funding: This study receives funding from Vaccinex, Rochester, NY,
their families	and from Merck KGaA as part of the alliance between Merck KGaA,
Darmstadt, Germany and Pfizer, Inc, New York, NY, USA

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