Slide 1: Transformational Science Advancing Oncology
Cedars-Sinai Medical Center, Los Angeles CA; 2BeyondSpring Pharmaceuticals, New York, NY; 3Univ Calif. San Diego, San Diego, CA Transformational Science Advancing Oncology
Slide 2: Plinabulin's Target is Tubulin in Microtubules
Plinabulin’s Target is Tubulin in Microtubules Cell Cytoskeleton Consists of Polymerized Tubulin a1Tub Immune – Related Anticancer Effects GTP b1Tub GDP Plinabulin Neutrophil Rescue Effects a2Tub Vascular Disruptive Effects b2Tub Wang Y et al. FEBS J. 2016; 283: 102-111 2 Singh AV et al. Blood 2011l
Slide 3: Plinabulin Anti-Cancer MOA: Immune-Enhancing and Apoptosis
Plinabulin Anti-Cancer MOA: Immune-Enhancing and Apoptosis Cancer Cells Tumor Antigen Tumor Killing MHCII Apoptosis Caspase-3 Activation RhoB Dendritic Cell .. Plinabulin Tubulin JNK ActivationC-Jun CD80 CD86 Co-Stimulation T-Cell Activation T-Cell Heasman et al. Coordinated RhoA sign
Slide 4: Plinabulin MOA for Neutrophil Protection
Plinabulin MOA for Neutrophil Protection IL-1β IL-6 IL-12 Dendritic Cell IL-6 Plinabulin Tubulin JNK-ActivationC-Jun IL-12 Apoptosis Prevention Shear stress-induced neutrophil migration * Neutrophil *Fine et al. GEF-H1 is necessary for neutrophil shear stress-induced migration during infl
Slide 5: Plinabulin: Immune-Oncology Effects
Plinabulin: Immune-Oncology Effects • Induces Maturation of Dendritic Cells (DCs) – ↑Phenotypic Cell Surface Markers: – CD-40, CD-80, CD-86, MHCII • Release of Neutrophil-Protective Cytokines – IL-1β, IL-6, IL-12 • Synergistic Antitumor Effects in Combination with PD1- and CTLA4- inhibitor in Tumor
Slide 6: Plinabulin + Nivolumab Breast Cancer Animal Model Data
Plinabulin + Nivolumab Breast Cancer Animal Model Data Improved Anti-Cancer Efficacy when Plinabulin is Combined with: • PD1-Inhibitor • PD1-Inhibitor +CTLA-4 Inhibitor 6 - Dr. Zippelius Lab at Univ. of Basel
Slide 7: Plinabulin + Docetaxel in NSCLC: Phase 2 Trial Design
Plinabulin + Docetaxel in NSCLC: Phase 2 Trial Design Cohort 1: 30mg/m2 Docetaxel 75mg/m2 n=55 Docetaxel 75mg/m2 + Plinabulin 30mg/m2 Endpoints: n=50 • Primary: Overall Patients included: 2nd/3rd line Survival (OS) NSCLC, stage 3b/4 Cohort 2: 20mg/m2 • Secondary: PFS, n=163 ORR, DOR Docetaxel 75mg/m
Slide 8: Plinabulin: NSCLC Phase 2 Efficacy Summary
Plinabulin: NSCLC Phase 2 Efficacy Summary ITT Patient Population Endpoints Plinabulin + Docetaxel (DN) Docetaxel alone (D) (D) 75mg/m2 75mg/m2 + (N) 30 mg/m2 N=50 N=55 Median OS, Months 8.7 (6.6,12.6) 7.5 (6.3, 10.5) (90% CI) Median Duration of Response (DOR)* 12.7 (4.0, 13.9) 1.5 (1.1, 3.1) Months
Slide 9: Phase 2 Study of Docetaxel +/- Plinabulin in NSCLC
Phase 2 Study of Docetaxel +/- Plinabulin in NSCLC Encouraging Activity in Measurable Lung Lesion Durable Response and Extended Survival Benefit of 4.6 Month Plinabulin + Docetaxel Docetaxel alone (D) (DN) N=38 N=38 mOS 11.3 M 6.7 M P = 0.29 DOR 12.7 M 1.0 M P<0.05 ORR 18.4% 10.5% PFS 3.7 M 2.9 M 9
Slide 10: Plinabulin: NSCLC Phase 2 Safety Summary
Plinabulin: NSCLC Phase 2 Safety Summary Common (>=20%) AEs (% Grade 1-4;% Grade 3-4) 30 D (n=55） 30 DP (n=50） 20 D (n=18） 20 DP (n=40) Nausea 44;0 48;4 22;0 40;0 Fatigue 40;11 52;4 39;6 30;3 Diarrhea 33;4 58;8 33;11 35;5 Constipation 33;0 36;0 17;6 28;0 Anorexia 31;0 34;0 39;0 25;3 Pyrexia 29;2 30;
Slide 11: Phase 2 Data: Grade 4 Neutropenia in Cycle 1 Day 8
Phase 2 Data: Grade 4 Neutropenia in Cycle 1 Day 8 Plinabulin ITT Population Proportion of Patients with Grade 4 Neutropenia Plinabulin + Adverse Docetaxel Docetaxel events (n=73) (n=90) Sepsis 0% 3.6 % Severe P<0.0003 infections 0% 3.6 % Docetaxel dose reduction due 6.7 % 19.2 % to toxicity n=65 n=
Slide 12: Phase 2 Data Summary and Global Phase 3 Study
• Phase 2 Data Plinabulin/Docetaxel vs Docetaxel alone: • mOS benefit of 4.6 months in pts with a measurable lung lesions • Prolonged DOR • Prevention of Grade 4 Neutropenia • No increase in immune-related AEs vs Docetaxel alone • A Global Phase 3 Study in NSCLC Patients with a Measurable Lung Lesio
Slide 13: Conclusions
CONCLUSIONS (2) • Plinabulin Has Potent Immune-Enhancing Effects • Preclinical Evidence • Clinical Evidence • Two IIT Phase 1/2 Trials Plinabulin/Nivolumab Combination Trials have been Initiated in NSCLC UCSD Phase 1/2 Trial Design: Fred Hutchinson Phase 1/2 Trial Design: • 28 days per cycle • 28 da
Slide 14: Acknowledgements
Acknowledgements • We like to thank: – All patients in this study and their families – Study Investigators: – Lyudmila Bazhenova, MD – Osvaldo Rudy Aren MD – Jonathan Polikoff, MD, – William Mikrut, PhD, – Steven D. Reich, MD, – Matthew A. Spear, MD – Lihua Du – Rebecca Suk Heist, MD 14 14
Slide 15: Less Grade 3 Respiratory Symptoms with Plinabulin
Less Grade 3 Respiratory Symptoms with Plinabulin Baseline Docetaxel Monotherapy Docetaxel + Plinabulin 30 mg/m2 (n=38) (n=38) Patients (%) with 65.8% 73.7% Respiratory Symptoms A n y P u lm o n a r y /R e s p ir a to r y A d v e r s e E v e n t : In c id e n c e in S tu d y N P I-2 3 5 8 -1 0 1 P 2