Anti-CD27 Agonist Antibody Varlilumab with Nivolumab for ...Anti-CD27 Agonist Antibody Varlilumab...

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Anti-CD27 Agonist Antibody Varlilumab with Nivolumab for Colorectal and Ovarian Cancer: Phase 1/2 Clinical Trial Results Rachel E. Sanborn 1 , Michael J. Pishvaian 2 , Margaret K. Callahan 3 , Amy Weise 4 , Branimir I. Sikic 5 , Osama Rahma 6 , Daniel Cho 7 , Naiyer Rizvi 8 , Jose Lutzky 9 , Rhonda L. Bitting 10 , Alexander Starodub 11 , Antonio Jimeno 12 , Michael Yellin 13 , Tracey Rawls 13 , Laura Vitale 13 , Abdel Halim 13 , Hui Zhang 13 and Tibor Keler 13 1 Rachel E. Sanborn 1 Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Cancer Center, Portland, OR, 2 Georgetown University, Washington, DC, 3 Memorial Sloan Kettering Cancer Center, New York, NY, 4 Karmanos Cancer Institute, Detroit, MI, 5 Stanford Medical Center, Stanford, CA, 6 Dana Farber Cancer Institute, Boston, MA, 7 Laura & Isaac Perlmutter Cancer Center, NY, NY, 8 Columbia University Medical Center, NY, NY, 9 Mount Sinai Comprehensive Cancer Center, Miami Beach, FL, 10 Wake Forest Baptist Heath, Winston-Salem, NC, 11 Parkview Research Center, Fort Wayne, IN, 12 University of Colorado Cancer Center, Aurora CO, 13 Celldex Therapeutics, Hampton, NJ

Transcript of Anti-CD27 Agonist Antibody Varlilumab with Nivolumab for ...Anti-CD27 Agonist Antibody Varlilumab...

Page 1: Anti-CD27 Agonist Antibody Varlilumab with Nivolumab for ...Anti-CD27 Agonist Antibody Varlilumab with Nivolumab for Colorectal and Ovarian Cancer: Phase 1/2 Clinical Trial Results

Anti-CD27 Agonist Antibody Varlilumab with Nivolumabfor Colorectal and Ovarian Cancer:

Phase 1/2 Clinical Trial Results

Rachel E. Sanborn1, Michael J. Pishvaian2, Margaret K. Callahan3, Amy Weise4, Branimir I. Sikic5, Osama Rahma6, Daniel Cho7, Naiyer Rizvi8, Jose Lutzky9, Rhonda L. Bitting10, Alexander Starodub11, Antonio Jimeno12, Michael Yellin13, Tracey Rawls13, Laura Vitale13, Abdel Halim13,

Hui Zhang13 and Tibor Keler13

1Rachel E. Sanborn

1 Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Cancer Center, Portland, OR, 2 Georgetown University, Washington, DC, 3 Memorial Sloan Kettering Cancer Center, New York, NY, 4 Karmanos Cancer Institute, Detroit, MI, 5Stanford Medical Center, Stanford, CA, 6Dana Farber Cancer Institute, Boston, MA, 7Laura & Isaac Perlmutter Cancer Center, NY, NY, 8Columbia University Medical Center, NY, NY, 9Mount Sinai Comprehensive Cancer Center, Miami Beach, FL, 10Wake Forest Baptist Heath, Winston-Salem, NC, 11Parkview Research Center, Fort Wayne,

IN, 12University of Colorado Cancer Center, Aurora CO, 13Celldex Therapeutics, Hampton, NJ

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Combo CD27 PD-(L)1

DNA replication genes

Cytotoxicity andProliferation genes

Combination of CD27 Costimulation with PD-(L)1 Blockade

1 Buchan. et al. Clin Can Res 20182 Bullock, et al. SITC 20143 Infante, et al. ASCO 20144 Burris, et al. JCO 2017

BCL1 lymphoma

Cooperative roles of anti-CD27 and PD-(L)1 drives proliferation and cytotoxicity of T cells1

Adoptive transfer of Pmel-TgT cells stimulated in vivo with

peptide and Abs

Combining CD27 agonist Abs with PD-(L)1 blockade improves antitumor responses in several preclinical models1

CD27: Member of the TNF-receptor superfamily • Single ligand is CD70 (tightly regulated)• Constitutively expressed on most T cells/subset of B and NK cells1

• CD27 activation:– Signaling through Traf2, Traf 5– Activation of the NF-κB pathway– Cell survival, activation, proliferation– Role in generation and long-term maintenance of T cell immunity– Role in NK cell differentiation/activation

Varlilumab: Fully human IgG1 CD27 agonist mAb• Well tolerated as single agent, no MTD identified• Single-agent antitumor activity demonstrated in advanced,

refractory solid tumors or hematologic malignancies (n=90) 2, 3, 4

(varlilumab)

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Phase 2 Cohorts*

Nivolumab flat dose (240 mg) q 2 weeks

CRC (n=18)** Varlilumab3 mg/kg q 2 weeks

** Planned enrollment

Phase 1/2 Study of Varlilumab in Combination with Nivolumab

Colorectal and Ovarian Cancer ExperienceActual Enrollment Status

(cut-off 13Apr18)Phase 1 Phase 2 Overall

Ovarian Cancer 8 58 66 7 continue treatment

CRC 21 21 42 2 continue treatment

Primary objective: Estimation of objective response rate (ORR)ORR observed with nivolumab monotherapy:

CRC: MSI− -low 0-5%2, MSI-high 31%3

Ovarian: − 6-15%4,5

Additional objectives: PFS, OS, Immunogenicity, PK, PD

CNS, central nervous system; CRC, colorectal cancer; MTD, maximum tolerated dose; MSI, microsatellite instability; OS, overall survival; PD, pharmacodynamics; PFS, progression free survival; PK, pharmacokinetics

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Varlilumab3 mg/kg q 2 weeks (n=18)3 mg/kg q 12 weeks (n=18)0.3 mg/kg q 4 weeks (n=18)

Ovarian (n=54)**

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0.3 mg/kg Q4wk3 mg/kg Q2wk 3 mg/kg Q12wk

Days

Varl

ilum

ab, µ

g/m

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Predicted PK: Alternate dosing regimens/Intermittent CD27 signaling

Key Eligibility Criteria• Progressive, recurrent or refractory ovarian

cancer, CRC, SCCHN, melanoma, or NSCLC• No prior anti-PD-(L)1 • ≥ 3 month washout for T cell directed mAbs

(inc. anti-CTLA-4) • ≤ 5 prior regimens for advanced disease• No active CNS metastases • No autoimmune disease• CRC: Progression or intolerant to

fluoropyrimidine, oxaliplatin, and irinotecan plus bevacizumab, cetuximab or panitumumab (if KRAS wild type), and regorafenib.

• Ovarian cancer: platinum-taxane frontline therapy

* Varlilumab administered for up to ~32 weeks (q2w and q4w schedules) or ~48 weeks (q12w schedule); nivolumab continues until progression

Phase 1 Dose Escalation/Expansion*

Nivolumab 3 mg/kg q 2 weeksVarlilumab escalating doses

q 2 weeks:

• Well tolerated, MTD not identified1

• No clear varlilumab dose response1

0.1 mg/kg (n=6)

10 mg/kg (n=15)

1 mg/kg (n=15)

1. Sanborn, ASCO 20172. Overman, ASCO 20163. Overman, Lancet 2017

4. Brahmer, NEJM 20125. Hamanishi, JCO 2015

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Baseline Patient Characteristics

ECOG, Eastern Cooperative Oncology Group; MSI, microsatellite instability; N/A, not applicable1 Denominator represents patients with tumor assessed for PD-L1 status. PD-L1+ criteria: ≥ 1% tumor cells staining positive, using the BMS

developed PD-L1 IHC method at a central lab

Ovarian Cancer (n=66)

CRC (n=42)

Age, years (median [range]) 64 (40-89) 55 (29-76)Female (n [%]) 66 (100%) 16 (38%)ECOG performance status (n [%])

0 22 (33%) 18 (43%)1 44 (67%) 24 (57%)

Stage IV at study entry (n [%]) 60 (91%) 42 (100%)No. of prior treatment regimens (median [range]) 3 (1-8) 4 (1-9)

Immunotherapy/cytokine 2 (3%) 5 (12%)

PD-L1+ tumor (n/n [%])1 20/59 (34%) 5/38 (13%)

MSI Status (n [%])MSI-High N/A 1 (2%)MSI-Low or MMR proficient N/A 21 (50%) MSI unknown N/A 20 (48%)

4Rachel E. Sanborn Data cut-off as of April 13, 2018

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• No evidence of additive toxicity for the combination

• Toxicity profile similar across varlilumab dosing regimens

• 10% of patients with CRC and ovarian cancer discontinued study treatment due to toxicity

• 10 patients with treatment-related SAEs

• One treatment-related death (pneumonitis in a patient with pulmonary metastases and prior history of chemotherapy-induced pneumonitis)

Varlilumab & Nivolumab Combination Therapy is Well Tolerated

Data shown as N (%). Table includes adverse events assessed as related to either varlilumab or nivolumab for > 10% of patients overall and treatment-related SAEs (*)

Treatment-Related Adverse Events Ovarian Cancer (n=66) CRC (n=42)All Grade

3-4Grade

5All Grade

3-4Grade

5Infusion Reaction 11 (17) 0 0 13 (31) 0 0Pruritus 12 (18) 0 0 6 (14) 0 0Rash 12 (18) 0 0 6 (14) 0 0Fatigue 5 (8) 0 0 5 (12) 0 0Rash maculo-papular 8 (12) 0 0 4 (10) 1 (2) 0Lymphopenia 4 (6) 2 (3) 0 7 (17) 5 (12) 0Nausea 4 (6) 0 0 7(17) 0 0ALT increased* 4 (6) 1 (2) 0 2 (5) 1 (2) 0Lipase increased * 4 (6) 4 (6) 0 1 (2) 1 (2) 0Abdominal pain * 3 (5) 1 (2) 0 0 0 0Acute kidney injury * 3 (5) 2 (3) 0 0 0 0Pneumonitis * 0 0 0 2 (5) 0 1 (2)Tumor lysis syndrome * 1 (2) 1 (2) 0 0 0 0Hepatitis * 1 (2) 1 (2) 0 0 0 0Colitis * 1 (2) 1 (2) 0 0 0 0Small intestinal obstruction * 1 (2) 1 (2) 0 0 0 0Diarrhea * 4 (6) 0 0 5 (12) 0 0Peripheral sensory neuropathy * 1 (2) 0 0 0 0 0

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Tumor Response: Ovarian Cancer

Nivolumab dosing: 3 mg/kg q2w in Phase 1 and 240 mg q2w in Phase 2 ORR, Objective response rate; DCR, Disease control rate (best response of SD or better for ≥ 3 months). Analyses based on response-evaluable population (includes patients with symptomatic deterioration or death in absence of post-treatment tumor assessment).

Rachel E. Sanborn 6

Best Response: Partial Response (PR)Single time-point PR (uPR)Stable Disease (SD)Progressive Disease (PD) Not Evaluable (NE)

PD-L1 Status: Negative

Numerical values represent % cells positive

Patient continues treatment-* Includes data provided after the analysis cut-off date

Response rate by PD-L1 status: PDL-1 positive: 20% (n=4 of 20; 3 PR, 1 uPR)PDL-1 negative: 14% (n=5 of 37; 4 PR, 1 uPR)

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Tumor Response: CRC

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Nivolumab dosing: 3 mg/kg q2w in Phase 1 and 240 mg q2w in Phase 2 ORR, Objective response rate; DCR, Disease control rate (best response of SD or better for ≥ 3 months). Analyses based on response-evaluable population (includes patients with symptomatic deterioration or death in absence of post-treatment tumor assessment)

Nivolumab + Varlilumab q2w

0.1-10 mg/kg 3 mg/kg

ORR: 1/21 (5%) 1/20 (5%)

DCR: 4/21 (19%) 4/20 (20%)

-100%

-75%

-50%

-25%

0%

25%

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75%

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Best Response: Partial Response (PR)Single time-point PR (uPR)Stable Disease (SD)Progressive Disease (PD) Not Evaluable (NE)

PD-L1 Status: Negative

Numerical values represent % cells positive

Patient continues treatment

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-- -- - -- - -2 - - - --

1 mg/kgMMR-proficient

MSI high

Phase 1 Phase 2

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70-

Rachel E. Sanborn

Molecular analysis on baseline tumor • Tissue from 2 patients with progressive disease used for comparison• Strong pattern of differentially expressed genes

• Similar expression of DNA repair enzymes• High mutational burden likely contributed to response

• May be result of mutations in MLH-1 and MSH-6

CRC pt: PR PD PD

Differentially ExpressedGenes

Patient with CRC initially considered MMR-proficientExperienced near• -CR (95% tumor shrinkage), continues at 35 monthsPath IHC report: PMS• 2, hMLH-1, hMSH-2, hMSH-6 all present

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Analysis of Immune Monitoring and Correlations with Outcome Immune Monitoring Parameters:• Peripheral blood: serum factors by multiplex; flow cytometry on whole blood/PBMC• Tumor biopsies: baseline and on-treatment (day 29) immunohistochemistry• Molecular profiling (in progress)

Benefit No BenefitCorrelative analysis:• Patients with ovarian cancer sorted by:

− “Benefit” = SD ≥ 16wks, uPR, PR or CR − “No Benefit” = PD and SD < 16 wks− Correlative analysis included all ovarian

patients • Patients with CRC; Too few “Benefit” for

analysis

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0 1 6 3 2 4 8 6 4

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0

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PD-L1 testing was performed using the BMS developed PD-L1 IHC method (Dako PD-L1 IHC 28-8 pharmDx assay); PD-L1+ defined as ≥ 1% of tumor cells

PD-L1 Expression of Baseline Biopsy Samples

Patients with Ovarian CancerOnly • 34% had any tumor PD-L1 expressionSimilar PD• -L1 expression in Benefited and No Benefit groups

Patient with CRC • Only 13% had any tumor PD-L1 expression

Includes all patients with ovarian cancer and CRC

This patient had 28% reduction in tumor, then PD

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Generally Low TIL Levels in Baseline Biopsy SamplesOvarian Cohort (all pts) - Baseline CRC Cohort (all pts)- Baseline

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Benefit (n = 16) No Benefit (n=37)

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(n=39)

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5.0

(n=39)

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Combination Treatment Increases Tumor PD-L1 and CD8 in Patients with Ovarian Cancer

IHC analysis of all patients with ovarian cancer and CRC with paired biopsies (On• -study ̴day 29)

Patients with ovarian cancer had significant increase in tumor expression of PD• -L1 and CD8+ TIL14 • of 23 patients (61%) had increase in PD-L1 and 14 of 24 patients (58%) had increase in CD8

These changes were rarely observed in CRC patient samples•

(dashed line represents mean)

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CD8

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Enhanced PD-L1 Expression and CD8 TIL is Associated with Better Outcome in Ovarian Patients

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All ovarian patients with paired biopsy samples (Day 29)Benefit/No Benefit PFS

Median (mos) PR+uPR7.4 38%3.5 13%

HR 0.32p-value 0.066

Median (mos) PR+uPR7.4 42%2.6 0%

HR 0.24p-value 0.015

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Expression of TIM-3, LAG-3 Does Not Distinguish Refractory Ovarian Patients

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The inhibitory/exhaustion markers TIM-3 and LAG-3 increased in correlation with CD8 T cells independent of outcome

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Analysis of peripheral blood

T cells and NK cells had marked up• -regulation of HLA-DR

Stark • Treg decreases were seen in majority of patients

Rapid increase in chemokines (CCL• 2, CCL4, CXCL9)

Changes observed across all varlilumab dose cohorts and •similar between patients with CRC and Ovarian cancer

No apparent correlation of peripheral blood parameters that •we investigated with clinical outcome

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ConclusionsVarlilumab and nivolumab combination therapy was generally well tolerated at all varlilumab •dose levels testedPatients’ baseline tumor biopsies were mostly “cold” (PD• -L1 neg. or low and low TIL) with low expectation of responding to check-point inhibition monotherapy Uniquely in ovarian cancer cohort, increased PD• -L1 and CD8 TIL were observed in ̴ 60% of patients with paired biopsy samples

The increase in PD− -L1 and CD8 TIL is associated with better clinical outcome3 • mg/kg dosing of varlilumab may have more clinical activity than other doses studied. Among CRC patients, durable clinical responses were observed in a patient with MSI• -High tumor and one with a high mutational burdenOpportunities for further evaluation of varlilumab/nivolumab:•

Molecular analysis may identify biomarkers in baseline biopsies of ovarian patients whose −tumors can be predicted to change from “cold” to “hot”Expanding the experience in CRC (or other tumors) with MSI− -High or high mutational burden

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Acknowledgments

• Study CDX1127-02 investigators and their staff

Thank you to the patients and their families who participated in this study

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Rachel SanbornMichael PishvaianMargaret CallahanAmy WeiseBranimir I SikicOsama Rahma

Daniel ChoNaiyer RizviJose LutzkyRhonda L. BittingAlexander StarodubAntonio Jimeno

• Celldex Therapeutics

• Bristol-Myers Squibb