Durability and Characteristics of Objective Tumor Responses with the Innate Immune Cell Modulator Imprime PGG in Combination with Standard of Care Frontline Treatment for Patients (Pts) with Metastatic Non-Squamous NSCLC

Walburga Engel-Riedel1, Folker Schneller2, Martin Wolf3, Wolfgang Schuette4, Bo Ma5, Paulette Mattson5, Jamie Lowe5, Ada Braun5

1Kliniken der Stadt Köln gGmbH, Köln, Germany; 2Klinikum Rechts der Isar, Technical University Munich, Munich, Germany; 3Klinikum Kassel GmbH, Kassel, Germany; 4Krankenhaus Martha-Maria Halle Dölau, Halle (Saale), Germany; 5Biothera, Eagan, MN, United States of America

Rationale

Lung cancer affects approximately 1.8 million people each year worldwide1 and is the leading cause of cancer-related deaths.2 Non-small cell lung cancer (NSCLC) accounts for approxi-mately 85% of these cases2

Standard treatment for advanced or metastatic NSCLC consists of platinum-based doublet chemotherapy, which improves symptom control and prolongs overall survival (OS)3

Bevacizumab, a vascular endothelial growth factor (VEGF)-targeted monoclonal antibody (Ab), can further prolong OS4 and is approved in Europe and the United States in combination with platinum-based chemotherapy for the first-line treatment of patients (pts) with non-squa-mous NSCLC5,6

- In pts receiving carboplatin/paclitaxel backbone therapy, bevacizumab improved ob-jective response rates (ORR) from 15% to 35%, and was associated with median progres-sion-free survival (PFS) of 6.2 months and OS of 12.3 months (HR=0.79; ECOG4599)7

Imprime PGG is a novel innate immune cell modulator, consisting of soluble beta-1,3/1,6 glucan derived from a proprietary strain of yeast. Imprime PGG is a pathogen-associated molecular pattern (PAMP) that binds complement receptor 3 (CR3) on innate immune cells (neutrophils, monocytes and macrophages), priming them to exert anti-tumor activity against comple-ment (iC3b) opsonized tumor cells8-13

- In a recent randomized phase 2 trial in pts with stage IV NSCLC, Imprime PGG in combina-tion with carboplatin/paclitaxel chemotherapy and an EGFR-targeted antibody (cetuxi-mab) resulted in a 48% ORR compared to 23% ORR with chemotherapy plus cetuximab alone14

- Imprime PGG is currently in phase 3 clinical development for the treatment of metastatic colorectal cancer in combination with cetuximab

- Many human cancers, including NSCLC, overexpress VEGF which has been associated with poor clinical prognosis15,16

- Although VEGF is secreted, a significant fraction remains bound to the cell surface and the extracellular matrix by virtue of its heparin-binding affinity, and its bioavailability is regulated by proteolytic cleavage17-20

- Bevacizumab is a humanized IgG1 antibody that binds to all human VEGF-A isoforms and bio-active proteolytic cleavage fragments.20 Bevacizumab has been shown to accumulate in the tumor microenvironment due to local accretion of cell- and matrix-associated VEGF21-26

- Binding of bevacizumab to surface-retained VEGF can induce complement (C3) deposition (opsonization),27,28 but does not result in cell- or complement-mediated cytotoxicity28

- Imprime PGG is a novel innate immune cell modulator that primes neutrophils, monocytes and macrophages through a complement receptor 3 (CR3)-dependent mechanism to exert an-ti-tumor activity against complement opsonized tumor cells8-13

- In human lung cancer xenograft studies, the combination of Imprime PGG with bevacizumab reduced tumor growth and prolonged survival compared to either agent alone12,13

- Thus, combining Imprime PGG with bevacizumab is a rational investigational strategy to in-crease tumor response and improve clinical outcomes for patients with NSCLC

Abstract 3070

Methods

Results

Hypothesis: Imprime PGG in combination with standard of care chemotherapy and bevaci-zumab will improve ORR in previously untreated patients with stage IV non-squamous NSCLC compared to carboplatin, paclitaxel and bevacizumab alone

Primary objective: To assess the ORR of Imprime PGG in combination with carboplatin/pacl-itaxel and bevacizumab compared to the ORR with carboplatin/paclitaxel and bevacizumab alone in patients with previously untreated stage IV non-squamous NSCLC

Study Design: Multicenter, open-label, randomized (2:1) phase 2 trial. Simon 2-stage optimal flexible design30 with 90% power to detect an improvement in ORR from ≤ 30 to ≥ 50%

The primary analysis of the study occurred when all patients had either progressed or had the opportunity to complete at least 18 treatment cycles (approximately 1 year)

Primary endpoint: Objective response rate (based on modified* RECIST 1.0)31

Secondary endpoints included:- Duration of Response (DoR) - Progression-free Survival (PFS) - Time to progression (TTP) - Overall survival (OS) - Safety

- Between 29 Sep 2009 and 08 Mar 2013, 92 subjects were enrolled across 12 centers in Germany and the United States of America

- The primary analysis data cutoff date was 21 March 2014, the pre-specified time point at which all subjects had either progressed or had the opportunity to complete at least 18 treatment cycles

- The primary analysis is ongoing; outcomes from the investigator review as well as exploratory analyses will be reported separately

Patient Eligibility: - Histologically or cytologically confirmed, previously untreated stage IV non-squamous NSCLC- Measurable disease*- Adequate organ function (hematologic, hepatic, renal, coagulation)- ECOG performance status of 0 or 1- Life expectancy > 3 months- Documented informed consent- No central nervous system metastases- No history of recent or severe thromboembolic disorders- No recent surgery, fracture or severe bleeding- No concurrent anticoagulation therapy * RECIST modification: consistent with RECIST 1.1,32 confirmation of a response after the initial response assessment was not required

by repeat assessment. No other criteria were modified

Treatment:- Carboplatin (AUC 6), Paclitaxel (200 mg/m2) IV Day 2 of each 3-week treatment cycle for 4 to

6 cycles (investigator discretion)

- Bevacizumab (15 mg/kg) IV Day 1 of each cycle

- Imprime PGG (4 mg/kg) IV Days 1, 8 and 15 of each cycle

Imaging assessments: - CT of chest and abdomen every 6 weeks. CT of pelvis if pelvic involvement was suspected.

Bone scans if skeletal metastasis was suspected

- All images were assessed by an independent, blinded central radiology facility

Analysis sets:- Efficacy analyses: all patients who received at least 1 dose of any study drug, had an evalua-

ble baseline scan and at least one evaluable post-baseline scan

- Safety, exposure and survival analyses: all patients who received at least 1 dose of study drug

Statistical analysis:- ORR was defined as the proportion of subjects experiencing a best overall tumor response of

complete response (CR) or partial response (PR) at any time on study, as assessed by independ-ent central radiology review, based on modified RECIST v1.0. ORR was compared between groups using Fisher’s Exact test. For determination of stable disease (SD), on-study assessments must have met SD criteria at least once, at least 6 weeks after randomization

- For time-to-event endpoints, hazard ratios (HR) of the treatment effect along with 95% confi-dence intervals (CIs) were calculated using a Cox proportional hazards model with treatment as a factor. Kaplan-Meier curves, estimates of medians and associated 95% CIs were gener-ated, and differences between groups were assessed using a log-rank test

- Adverse events were coded using the Medical Dictionary for Regulatory Activities (MedDRA) version 15.0. No formal testing was performed for between-group differences in adverse events

- Results from the independent, blinded review are reported for all efficacy endpoints

Duration of Response

Duration of Response by Subject Overall Survival

Patient Disposition

Background Dura%on  of  Response  by  Subject  

Control  

Imprime  PGG  

→  

 *  

Ongoing    Censored    

*  →

*  *  

*  

 *  

*  *  

→

→

 *    *  

 *    *  

 *    *  

 *    *  

 *  

 *  

 *  

 *  

 *  

 *  

 *  

 *    *  

Dura%on  of  Response  (months)  

Efficacy Results

Subject Responses on Carboplatin/Paclitaxel and Bevacizumab + Imprime PGG

Baseline Demographics and Disease Characteristics

- Overall, patient baseline demographics and disease characteristics were balanced between groups. A slightly higher proportion of patients in the control group had good performance sta-tus (ECOG 0) at baseline. More patients in the Imprime PGG group than in the control group had a history of surgery or radiotherapy for NSCLC

- Imprime PGG increased ORR by approximately 17% percentage points and increased the duration of response by 4.7 months, as assessed by an independent, blinded central imaging facility

- There was continued regression of lesions on maintenance therapy with Imprime PGG and bevacizumab

Additionally, In the PGG group, OTR were observed regardless of baseline tumor burden (up to >30cm SLD) or lesion location (incl. lung, lymph nodes, adrenals, liver).

- Although the study was not powered for time-to-event endpoints, there was a trend towards im-proved progression-free and overall survival, with an increase in median survival of 4.5 months, and a 34% reduction in the risk of death

- Rates of overall and serious (e.g. life threatening or requiring hospitalization) AEs were similar between groups. Events were mostly reflective of expected toxicities with the standard of care backbone therapy (carboplatin/paclitaxel and bevacizumab) or were complications of the patients’ underlying cancer

- The incidence of severe (CTCAE grade ≥ 3) AEs was higher in the Imprime PGG group overall, with no clear preponderance of any specific system organ class. Fatal AEs in the Imprime PGG group were generally associated with progression of the patients’ lung cancer

- Fewer patients in the Imprime PGG group compared to the control group discontinued the study due to AEs

- With the exception of proteinuria as well as events potentially associated with infusion reac-tions, there was no difference between groups in the incidence of AEs associated with beva-cizumab treatment

- Events potentially associated with hypersensitivity reactions occurred more frequently with Imprime PGG, including one grade 3 event of anaphylactic reaction deemed related to the drug

- Premedication with low dose corticosteroids and anti-histamines is recommended prior to Im-prime PGG administration

- Of interest, both overall and grade 3 or 4 events of infection occurred at a lower frequency in the Imprime PGG group compared to control (47.5% vs 63.3% overall; 5.1% vs 10.0% grade 3 or 4)

- Immune-mediated adverse reactions (e.g. immune-mediated hepatitis or endocrinopathies) reported with T-cell modulators (e.g. CTLA-4, PD-1, PD-L1)33,34 were not observed at increased incidence with Imprime PGG Tumor Reduction During Maintenance Therapy

- Following completion of chemotherapy (on maintenance bevacizumab +/- Imprime alone), further meaningful (>10mm) reductions in tumor burden were observed in 6 (20%) patients in the Imprime PGG group, but none in the control group.

Drug Exposure

- The proportion of pts who discontinued chemotherapy after 4 treatment cycles was greater in the Imprime PGG group than in the control group (31.8% versus 10%, respectively)

Study Schema

Safety Results

SMQ, Standard MedDRA Query. *event categories are based upon Bevacizumab USPI Warnings and Precautions6 and are listed if any preferred term (PT) in the category is reported for ≥ 1 patient; PTs are listed when reported for >1 patient, or if only 1 PT is reported in the category; **included events of cerebrovascular insufficiency (n=1; Imprime PGG) and myocardial infarction (n=1; control); #search strategy per statistical analysis plan and available upon request; ## included PTs of rash (n=5, Imprime PGG; n=1, control), rash maculo-papular (n=1, control), and rash pustular (n=1, Gr 3; control); × included PTs of “proteinuria” and “protein urine”

SMQ, Standard MedDRA Query. #included PTs of rash (n=5, Imprime PGG; n=1, control), rash maculo-papular (n=1, control), and rash pustular (n=1, Gr 3; control); *search strategy per statistical analysis plan, based on key terms listed in the Warnings and Pre-cautions and the Adverse Drug Reactions sections of the Ipilimumab USPI as of 02 July 201433 and available upon request; **PTs are listed when reported for >1 patient in either treatment group

- Most AEs deemed related to Imprime PGG were potentially associated with infusion related reactions and occurred within the first 6 months of treatment

Conclusions

References

Acknowledgements

Disclosures

Corresponding Author

- Imprime PGG in combination with carboplatin, paclitaxel and bevacizumab therapy resulted in substantial numerical increases in objective response rate and duration of response in pa-tients with non-squamous non-small cell lung cancer

- Although the study was not powered for survival, treatment with Imprime PGG was associated with a 4.5-month median increase in survival, and a 34% reduction in the risk of death

- Combined use of chemotherapy, bevacizumab and Imprime PGG mediated rapid and dura-ble responses of metastatic NSCLC regardless of baseline tumor burden or lesion location and further regression of lesions on maintenance Imprime PGG plus bevacizumab was observed

- Overall, Imprime PGG was well tolerated; adverse events mostly reflected expected toxicities with the backbone chemotherapy and bevacizumab or were complications of the patients’ lung cancer. Premedication with low-dose corticosteroids and antihistamines is recommended

- Imprime PGG is a novel innate immune modulator that holds promise as an adjunct to anti-body-based therapy for patients with non-small cell lung cancer

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Statistical analyses were performed by independent biostatistician J. Richard Trout, Ph.D., Professor Emeritus, Rutgers, The State University of New Jer-sey. Biostatistical programming was performed by Susan C. Goebel, M. S., Statistical Consultant Independent central radiology review was performed at VirtualScopics, Inc Corina Taitt, M.D., contributed to data cleaning and analysisWe would like to thank all patients, investigators and study staff for their participation in this clinical trial

The trial was sponsored by Biothera (ClinicalTrials.gov NCT 00874107, EudraCT 2008-006780-37)W. Engel-Riedel, F. Schneller, M. Wolf, W. Schuette: No financial disclosuresM. Bo, J. Lowe, P. Mattson and A. Braun: Employees of Biothera and hold stock options/ grants

Ada Braun (abraun@biothera.com)

American Society of Clinical Oncology May 29-Jun 2 2015, Chicago, IL

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