Scientific Perspectives of Olaratumab Beyond the Approval Indication

Transcription

1 Scientific Perspectives of Olaratumab Beyond the Approval Indication William D. Tap, MD Chief, Sarcoma Medical Oncology Service Memorial Sloan Kettering Cancer Center GEIS XVI International Symposium October 2018

2 Disclosures Consulting/Advisory Role: Eli Lilly, Novartis, Eisai, Janssen, Eisai, Immune Design, Adaptimmune, Daiichi Sankyo Plexxikon, Blueprint, Loxo, GlaxoSmithKline, Agios

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5 Mesenchymal Tide

6 Olaratumab Fully human monoclonal antibody of immunoglobulin G class 1 (IgG1) that selectively binds PDGFRα Blocks PDGF binding and PDGF-induced PDGFRα activation Demonstrated activity in both in vitro and in vivo cancer models known to be driven by a PDGF-PDGFRα autocrine loop Demonstrated antitumor activity alone or in combination with Dox in human sarcoma xenograft models Tap W et al, ASCO Annual Meeting 2015

7 How is olaratumab acting Disrupting Cell Autonomous Signaling Chemo is necessary prolonged better.why? Hanahan and Weinberg, Cell 144(5): , 2011

8 Open-label, Multicenter, Phase 1b/2 Trial Phase 2 Same entry criteria as Phase 1b Stratification: PDGFRα (IHC) Lines of prior treatment ECOG PS Histology (leiomyosarcoma, synovial sarcoma, other) R A N D O M I Z E Olaratumab 15 mg/kg D1,8 + Dox 75 mg/m 2 D1 8 cycles (21 days)* Dox 75 mg/m 2 D1 8 cycles Olaratumab monotherapy until progression Optional olaratumab monotherapy after progression Primary endpoint: Progression-free survival (PFS) (predefined statistical significance: 2-sided alpha = 0.2) Secondary end points: Overall survival (OS), objective response rate, PFS at 3 months Biomarker: PDGFRα (IHC) and related ligands * During Cycles 5-8, patients receiving Dox could receive dexrazoxane, at the investigator s discretion. Tap W et al, ASCO Annual Meeting 2015; Tap WD, et al. Lancet 2016; 388:

9 Overall Tumor Response (ITT) (Phase 2) Olaratumab + Dox (N=66) Dox (N=67) Objective response rate (CR + PR) % (95% CI) 18.2 (9.8, 29.6) 11.9 (5.3, 22.2) p-value 0.34* * 2-sided Fisher s exact test Tap W et al, ASCO Annual Meeting 2015; Tap WD, et al. Lancet 2016; 388:

10 Overall Survival Overall Survival Progression Free Survival Tap W et al, ASCO Annual Meeting 2015; Tap WD, et al. Lancet 2016; 388:

11 Overall Survival 2yr survival 50-60% Tap W et al, ASCO Annual Meeting 2015; Tap WD, et al. Lancet 2016; 388:

12 Tap W et al, ASCO Annual Meeting 2015; Tap WD, et al. Lancet 2016; 388: months of PFS and 11.8 months of Survival Patients on the combination seemed to get a few more cycles of doxorubicin Median 7 for the combination vs 4 for doxorubicin alone? Olara augmented chemo vs investigator bias Patients on combo generally progressed 1-2 scans after chemo.censoring RECIST Progression Dox alone progressed on chemo Olara monotherapy post chemo median 9 infusions Chemo necessary to control the disease we see Some activity of olara post chemo vs residual chemo effect Olara monotherapy control 4 infusions little activity against growing disease

13 Next Steps Accelerated approval Phase 2 Confirmatory Phase 3 Completed Rapid Accrual 450+ patients

14 Phase 3 Study - ANNOUNCE What would be considered a positive study? Only an OS benefit If so what degree? A PFS benefit If so what degree? What if positive in only a few subtypes? If a negative trial, should all current clinical trials stop? If a negative trial Why Olara does not work in sarcoma Clinical trial design Over interpretation of the Phase 2 data Thoughts?

15 ANNOUNCE Critical Data from ANNOUNCE Secondary Endpoints Differential response patterns specific subtypes (LMS, UPS, DDLS) locally advanced vs. metastatic first vs subsequent line patients Why patients came off study Progression current disease or new disease Time to new mets; pattern of new disease Mechanism of Action Biomarkers Other thoughts for discussion?

16 Olaratumab Mechanism of Action Cell Autonomous Hanahan and Weinberg, Cell 144(5): , 2011

17 ? Olaratumab Mechanism of Action Cell Autonomous Interaction with the tumor/stroma microenvironment Through PDGFR signaling Immune Regulation Prevention of new disease or metastases if so, how PDGFR signaling in mesenchymal stem cells Other? Multiple MOA, Different in each Subtype? How does MOA influence patient selection and clinical application?

18 Next Steps Accelerated approval Phase 2 Confirmatory Phase 3 Completed Rapid Accrual 450+ patients Mechanism of Action Perioperative Study Backbone study Pediatric Sarcomas (Appropriate Regimen) Bone Sarcomas (Appropriate Regimen) Novel Combinations

19 Hanahan and Weinberg, Cell 144(5): , 2011

20 Pediatric Indication Ongoing Clinical Trial Olaratumab plus Ifosfamide, Irinotecan, Vincristine, Doxorubicin How to position in the Pediatric Malignancies With upfront treatment? Refractory Patients? Gemcitabine-based regimens, eg osteo/ewings Trabectedin-based combinations

21 Novel Combinations Immunotherapy Rationale? Olaratumab and Pembrolizumab ongoing Other Lilly Drugs Remucirumab, abemaciclib, prexasertib Thoughts?

22 Translational Research Pre-clinical work needs to be done, to define MOAs Biomarker analyses from the Phase 3 Study

23 Thank You