Abstract #3011: Interim subgroup analysis for response by PD-L1 status of CLASSICAL-Lung, a phase 1b/2 study of pepinemab (VX15/2503) in combination with avelumab in advanced NSCLC.

Authors: Michael Rahman Shafique, Terrence Lee Fisher, Elizabeth E. Evans, John E. Leonard, Desa Rae Electa Pastore, Crystal L. Mallow, Ernest Smith, Andreas Schröder, Kevin M. Chin, Joseph Thaddeus Beck, Megan Ann Baumgart, Ramaswamy Govindan, Nashat Y. Gabrail, Rachel E. Sanborn, Alexander I. Spira, Nagashree Seetharamu, Yanyan Lou, Aaron Scott Mansfield, Jonathan W Goldman, Maurice Zauderer

IO naïve, negative and low PD-L1 patients achieved

higher response rates with pepinemab combination,

than historical patient treated with single agent

avelumab1

• Tumor biopsies showed increased T cell infiltration & less tumor in both PR & SD patients.

• Durable clinical responses have been achieved in both IO Naïve & Failure patient populations

• Combination is safe & tolerable in all dose levels tested

Background: • Semaphorin 4D signals through Plexin receptors to regulate cellular

cytoskeleton and its function in cell migration and differentiation

• Pepinemab binds to SEMA4D and blocks it’s signaling, which promotes T cell infiltration and reverses myeloid suppression

• Anti-SEMA4D antibodies neutralize the SEMA4D barrier at the tumor margin and “open the gates” of the tumor to the immune system.

Methods: • First in human combination study designed to evaluate the combination of

pepinemab with avelumab in NSCLC patients who were IO naïve or who progressed on anti-PDx therapy

anti-PD-L1 Combination: Colon26

Dose Escalation 15 mg/kg pepinemab*

(n = 3)

Dose Escalation 210 mg/kg pepinemab*

(n = 6)

Dose Escalation 320 mg/kg pepinemab*

(n = 3)DSMB DSMB

ScreeningNSCLC Immunotherapy

Naïve Stage IIB/IV

Phase Ib(3+3 Design)

n = 12

NSCLC Stage IIB/IV10 mg/kg pepinemab +

10 mg/kg avelumabQ2W

Phase IIn =50

Immunotherapy Naïve(n = 18)

Immunotherapy Failure (n = 32)

*in combination with 10 mg/kg of avelumab Q2W

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Time on Study in Evaluable Subjects (Weeks)

A. IO Naïve Subjects• Disease control rate: 81% (17/21) experienced PR or SD• Durable clinical benefit of ≥1 year has been achieved in 4 subjects and ≥6

months in 6 subjects

B. IO Failure Subjects, whose tumors had progressed during or following treatment with anti-PD-x antibodies • Disease control rate: 59% (17/29) IOF subjects benefited from switching to

the combination therapy, which appears to induce a halt or reversal of tumor progression.

• Three (3) subjects were IO primary refractory before entering trial ( )• Two (2) subjects who failed pembro have attained PRs with 65% and 52%

tumor reduction at most recent scan.• Durable benefit of ≥1 year has been achieved in 1 subject and ≥6 months in

5 subjects

9 subjects experienced durable clinical benefit of ≥ 6 months, including patients who had previously progressed on anti-PDx therapy

→ 97% of PR & SD subjects had negative or low PD-L1 expression in tumor*

Results:

Following treatment, tumors have more T cells & less tumor in both responders and patients with stable disease

Pre

-Tre

atm

en

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n-T

reat

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No tumor detected in these 3 biopsies from patients with stable disease

No or low tumor detected in these 2 biopsies from patients with PR

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CD

8 D

ensi

ty

NE

PR-01 PR-02 SD-01 SD-03 SD-04 SD-05 SD-06 PD-01 PD-02

71 32 23 18 26 16 18 11 6

Tumor (Cytokeratin+)CD8+ T cellsPembrolizumab refractory

Weeks on Study:

Matched tumor biopsies from IOF cohort of CLASSICAL-Lung

(<1%) (1-49%) (50-79%)

0

10

20

30

40

50

Javelin Solid TumorObjective Response Rate by PD-L1 status

PD-L1 expression, % of tumor(Dako 73-10 pharmDx)

% O

RR

10%(2/20)

Study n=184PD-L1 evaluable n=142

13.2%(9/68)

15.4%(2/13)

Negative Low Low(<1%) (1-49%) (50-79%)

0

10

20

30

40

50

CLASSICAL-LungObjective Response Rate by PD-L1 status

PD-L1 expression, % of tumor(Dako 73-10 pharmDx)

% O

RR

Study n=30PD-L1 evaluable n=22

25%(2/8) 20%

(2/10)

33%(1/3)

Negative Low Low

Overall Response Rate by PD-L1 Comparison of Javelin Solid Tumor to CLASSICAL-Lung

1. Calculated from previously published data (See references 5,6 on detailed poster)2. 27% (8/30) subjects did not have PD-L1 status reported and 9.5% (2/21) subjects were non-evaluable for post dose scans (included in ORR calculation) due to withdrawal prior to first scan.

PD-L1 negative and low (<1-79%) pts. responded better to the combination therapy, than previously observed single agent study1

A.

B.

Control IgG

αSema4D Mab67

Inflammatory DC’s migrate into tumor

Increase in Pro-inflammatory

APC

The Sema4D gradient is neutralized

SEMA4D CD11c F4/80

Preclinical Model - Colon26

CD8+ CTL

(vessel)

Increase in CD8+ T cell infiltration and activity

QR Code for detailed poster, acknowledgements and

references

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*PD-L1 analysis was performed via Dako 73-10 pharmDx. PD-L1 status was available for 51/62 subjects. A total of 29 SD and PR subjects were analyzed and 28 were reported to be PD-L1 negative or low (0-80%); 10 of these were PD-L1 negative (<1%).

ENROLLMENT COMPLETE

Author Contact: Michael Shafique, MD Michael.Shafique@moffitt.org

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