ONT-380 and HER2+ Breast Cancer

Transcription

1 ONT-380 and HER2+ Breast Cancer Diana F. Hausman, MD CMO, VP Clinical Development Oncothyreon Inc. PNW Bio February Copyright 2014 Copyright Oncothyreon 2014 Oncothyreon

2 Oncothyreon Leading Oncology Product Candidates and Cutting-Edge Technology ONT-380 Potential best-in-class small molecule HER2 inhibitor Ongoing Phase 1b development program Exclusive license from Array BioPharma ONT-10 MUC1 liposomal vaccine Collaboration with Celldex for combination Phase 1b trial with varlilumab Building a leading product discovery capability Protocells for targeted nanoparticle delivery Novel immunotherapeutic antibodies Small molecule inhibitor of Chk1 2

3 HER2 Forms Active Dimers in Absence of Ligand 3

4 Major Clinical Advances in HER2+ Disease 4

5 Approved HER2 Targeted Agents Murphy and Morris (2012) Recent advances in novel targeted therapies for HER2+ breast cancer Anti-Cancer Drugs 23:

6 Current Treatment Paradigm for HER2+ Breast Cancer Adjuvant/NeoAdjuvant Chemotherapy (taxane containing regimen) + trastuzumab +/- pertuzumab (trastuzumab x 1 year) Metastatic Breast Cancer 1 st Line Trastuzumab, pertuzumab, docetaxel (CLEOPLATRA) 2 nd line Trastuzumab emantasine (T-DM1) (EMILIA) 3 rd line If no prior T-DM1 T-DM1 (if no prior treatment) (TH3RESA) If prior T-DM1: Lapatinib + capecitabine Trastuzumab + chemo (capecitabine or vinorelbine) Trastuzumab + lapatinib PFS 18.5 mos, OS 56.5 mos, ORR 80%, PFS 9.6 mos, OS 31 mos, ORR 44%, Med PFS 6.2, mos, ORR 31% Time to progression 3-6 mos 6

7 CNS Metastases The Greatest Unmet Need in HER2+ Breast Cancer CNS metastases develop in up to 50% of patients with metastatic disease Better control of systemic metastases associated with increased overall survival HER2 tropism for brain CNS as sanctuary from antibody-based therapies Management approaches Mainstay of treatment is local management Surgery, radiation (whole brain, stereotactic) No recommended HER2-targeted/chemotherapy regimen Limited efficacy and significant toxicity Capecitabine/lapatinib most commonly used 7

8 ONT-380: The TKI of Choice for Use in HER2+ Breast Cancer Exceptional potency and selectivity profile Single digit nanomolar potency for HER2 with 500-fold selectivity vs. EGFR Drug selectivity results in reduced incidence and severity of diarrhea/rash compared with lapatinib and neratinib Synergy with chemotherapy and trastuzumab in preclinical models Improved tolerability positions ONT-380 as the preferred drug to combine with other HER2-targeted agents or chemotherapy Potential for improved CNS activity ONT-380 shows superior activity compared with lapatinib and neratinib in CNS tumor models Superior CNS activity and drug tolerability supports evaluation of ONT-380 in treating this key unmet medical need 8

9 ONT-380 is the Only Selective HER2 Inhibitor in Clinical Development ONT-380 Compound ONT-380 Neratinib Lapatinib HER2 IC 50 (nm) 8 7 Cellular Selectivity Data EGFR IC 50 (nm) HER2 IC 50 (nm) 50% Human erum

10 ONT-380 Shows Superior Activity in Preclinical CNS Tumor Model ONT-380 produced superior therapeutic benefit compared with lapatinib and neratinib when dosed at MTD in mice bearing intracranial HER2+ tumors BT-474 HER2+ breast carcinoma ONT-380 (75 mg/kg, BID PO) 10

11 ONT-380 Shows Single-Agent Activity in HER2+ Breast Cancer Patients after Trastuzumab and Lapatinib Phase 1 single agent study powder in 50 patients Good tolerability, with minimal EGFR-like toxicity Maximal tolerated dose 600 mg BID powder in capsule formulation No treatment related Grade 3 diarrhea Dose limiting toxicity reversible liver transaminase elevation Single agent anti-tumor activity seen in patients with progression after trastuzumab and lapatinib based therapies At 600 mg, 27% clinical benefit rate 100% pats with prior trastuzumab, 88% with prior lapatinib 11

12 ONT-380 Presentations at San Antonio Breast Cancer Symposium A phase 1b study of ONT-380, an oral HER2-specific inhibitor, combined with capecitabine and/or trastuzumab, in HER2+ metastatic breast cancer (MBC) Erika Hamilton a, Denise A. Yardley a,b, Gabriel Hortobagyi c, Luke Walker d, Virginia F. Borges e, Stacy Moulder c a Sarah Cannon Research Institute, Nashville, TN; b Tennessee Oncology, Nashville, TN; c MD Anderson Cancer Center, Houston, TX; d Oncothyreon Inc., Seattle, WA; e University of Colorado Cancer Center, Aurora, CO A phase 1b study of ONT-380, an oral HER2-specific inhibitor, combined with ado-trastuzumab (T-DM1), in HER2+ metastatic breast cancer (MBC) Virginia F. Borges a, Erika Hamilton b,c, Denise A. Yardley b,c, Jorge Chaves d, Nathalie Aucoin e, Cristiano Ferrario f, Luke Walker g, Ian Krop h a University of Colorado Cancer Center, Aurora, CO; b Sarah Cannon Research Institute, Nashville, TN; c Tennessee Oncology, Nashville, TN; d Northwest Medical Specialties, Tacoma, WA; e Hôpital Cité-de-la-Santé, Laval, QC; f Jewish General Hospital, Montreal, QC; g Oncothyreon Inc., Seattle, WA; h Dana Farber Cancer Institute, Boston, MA 12

13 ONT Capecitabine + Trastuzumab Study Overview Design Parallel 3+3 dose escalation of ONT-380 tablets in combination with capecitabine alone or trastuzumab alone, followed by evaluation of ONT-380 maximum tolerated dose (MTD) / recommended dose (RD) in combination with both capecitabine and trastuzumab Dose Escalation Cohorts ONT-380 Capecitabine Trastuzumab Enrollment Status Combo mg BID X Complete 350 mg BID X Ongoing Combo mg BID X Complete 350 mg BID X Ongoing Combo 2 CNS Cohort 300 mg BID X Ongoing Expansion cohorts in patients with and without CNS metastases Combo mg BID X X Complete Combo 3 CNS Cohort 300 mg BID X X Ongoing 13

14 ONT Capecitabine + Trastuzumab Selected Patient Characteristics Combo 1 +C (n = 7) ONT-380 (300 mg BID) Combo 2 +T (n = 8) Combo 3 +C +T (n = 4) a CNS Cohort +T (n = 2) Age, mean (range) 54 (38, 70) 46 (35, 63) 41 (36, 50) 65 (63, 67) ECOG 0/1, n 3/4 3/5 4/0 2/0 Hormone receptor positive, n b 2 Number of prior systemic treatments for metastatic disease, median (range) 3 (2, 5) 5 (2, 7) 3 (2, 3) b -- (9, 11) Patients with prior pertuzumab, n b 2 Patients with prior T-DM1, n b 2 Patients with prior lapatinib, n b 2 CNS metastases, n History of prior treatment for CNS metastases, n Treatment of CNS metastases within 6 months of study entry, n a Does not include 2 additional safety-evaluable patients enrolled after the data cut-off b Data unavailable for 1 patient 14

15 ONT Capecitabine + Trastuzumab Safety Overview ONT-380 well-tolerated Most common AEs ( 4 patients overall), regardless of relationship to study drug: Diarrhea, nausea, constipation, fatigue, headache, AST increased, dizziness, palmar-plantar erythrodysesthesia syndrome, hot flush, and dyspepsia Majority Grade 1 or Grade 2 in severity No Grade 3 diarrhea No significant changes in left ventricular ejection fraction 15

16 ONT Capecitabine + Trastuzumab Anti-Tumor Activity Best response (RECIST 1.1) Combo 1 +C (n = 7) Combo 2 +T (n = 8) ONT-380 (300 mg BID) Combo 3 +C +T (n = 4) CNS Cohort +T (n = 2) Evaluable patients, n CR PR SD a PD -- 1 b 1 -- Clinical Benefit Rate (PR or SD >6 months) 7/7 (100%) 4/6 (67%) c 1/2 (50%) c NE NE = Not evaluable a SD also includes patients with non-target lesions only without progression. b Patient with clinical progression c Two active patients each in Combo 2 and Combo 3 with SD on study for <6 months. 16

17 ONT Capecitabine + Trastuzumab Maximum Change in Sum of Longest Diameter 40% 30% 20% 10% 0% -10% T, L T L P, T P, T, L T, L P, T, L T, L P, L T, L T, L P, T, L T, L P, T P, T T Ca Tr Ca Tr Tr CN -20% Tr -30% -40% -50% -60% -70% -80% -90% -100% P L T +Capecitabine +Trastuzmab +Capecitabine +Trastuzmab CNS Cohort (+Trastuzmab) Prior Pertuzumab Prior Lapatinib Prior T-DM1 Discontinued from the study due to investigator decision Hashed bars indicate a patient is off treatment Tr Ca Ca CN Tr Ca Ca Ca 17

18 ONT Capecitabine + Trastuzumab Case Study: ONT mg BID + Trastuzumab Baseline: Patient with history of wholebrain radiation 15 months prior to study entry and SRS of cerebellar lesion 8 months prior to study entry with evidence of CNS lesion shrinkage after 2 cycles of ONT trastuzumab Post-Cycle 2: Images selected to demonstrate longest axis of lesions 18

19 ONT T-DM1 Selected Patient Characteristics ONT mg + T-DM1 (n = 17) Age, mean (range) 52.5 (31, 71) ECOG 0/1, n 6/11 Hormone receptor positive, n 12 Number of prior systemic treatments for metastatic disease, median (range) 2 (1, 6) Patients with prior pertuzumab, n 6 Patients with prior lapatinib, n 5 CNS metastases, n 9 History of prior treatment for CNS metastases, n 7 Treatment of CNS metastases within 6 months of study entry, n 6 19

20 ONT T-DM1 Safety Overview ONT-380 well-tolerated Most common AEs, regardless of relationship to study drug Nausea, diarrhea, vomiting, fatigue, thrombocytopenia, decreased appetite, hypokalemia, constipation Majority Grade 1 or Grade 2 in severity No Grade 3 diarrhea or rash No significant changes in left ventricular ejection fraction (LVEF) 20

21 ONT T-DM1 Anti-Tumor Activity ONT mg + T-DM1 (n = 17) Best response (RECIST 1.1) m Evaluable patients a, n 16 PR 5 SD b 7 PD 4 Clinical Benefit Rate (PR or SD >6 months) 6/13 c (46%) a One patient on study but without evaluable follow-up scans b SD includes patients measurable disease or with non-target lesions only without progression c Three active patients with SD on study for <6 months; 3 patients with SD as best response, now off study due to progression. 21

22 ONT T-DM1 Best Response in Measurable Disease per RECIST % Maximum Change in SLD 50% 40% 30% 20% 10% 0% -10% -20% P L P L P, L P, L -30% -40% -50% -60% -70% -80% -90% -100% P L On Treatment Off Treatment Prior Pertuzumab Prior Lapatinib Clinical progression PD Non-target Lesion New lesion 22

23 ONT T-DM1 CNS Disease Control 9 of 17 patients with history of CNS metastases 4 patients with evaluable target CNS lesions per modified RECIST 1.1 Best CNS response: SD in 3 patients; PD in 1 patient Decrease in target lesions in 2 of 3 patients with SD 23

24 ONT Summary of Phase Ib Clinical Data ONT-380 in combination with capecitabine and/or trastuzumab, or T-DM1, has been well tolerated in patients with HER2+ metastatic breast cancer Majority of AEs were Grade 1 or 2 in severity No Grade 3 diarrhea, with no mandatory concomitant medication Encouraging signs of preliminary efficacy in heavily pre-treated patients Many patients receiving 3rd-line or greater treatment Clinical benefit and response seen in patients previously treated with pertuzumab, lapatinib and T-DM1 History of treated and/or active CNS metastases in >50% of patients Evaluation of CNS anti-tumor activity ongoing; disease stabilization and evidence for CNS lesion shrinkage seen Data support further development of ONT-380 in patients with advanced metastatic breast cancer 24

25 ONT Capecitabine + Trastuzumab CNS Disease Control 14 of 21 patients with history of CNS metastases 6 patients with evaluable CNS target lesions per modified RECIST 1.1 Best CNS response SD in all 6 patients, with decrease in target lesions in 4 patients 5 remain active on study 25

26 Mean (ng/ml) AUC_daily ONT-380 Improved Pharmacokinetics with Tablet Formulation ONT mg BID Mean Plasma Concentration ONT mg BID Individual Patient AUC Daily Individual patient AUC Daily Mean 600 mg BID PIC Mean 300 mg BID Tablet IC90 exposure PK Summary Nominal Time (h) Individual Patient ONT-380 AUC_daily at Steady State (n=11) At steady state, dosing with 300 mg BID tablets yielded similar drug exposure to the original PIC formulation at 600 mg BID (single agent study MTD) PK parameters (AUC, C max & T max ) show reduced variability at steady state using the tablet formulation compared to PIC formulation (data not shown) Drug exposure using 300 mg tablets BID is well above the level corresponding to 90% inhibition of HER2 (cellular potency in 50% human serum) 26

27 ONT-380 Demonstrates Activity in Combination with Trastuzumab ONT-380 combined with trastuzumab resulted in 100% CRs in animal model with HER2+ cell line BT