R&D DAY. June 14, PDF Free Download

R&D DAY June 14, 2016

Forward Looking Statement This written and oral presentation contains forward-looking statements, including statements concerning preclinical results and anticipated research, preclinical and clinical development activities, the potential benefits and tolerability of product candidates, development plans, the anticipated announcement of clinical data, and clinical milestone dates. All statements other than statements of historical fact are statements that could be deemed forward-looking statements. Any statements in this presentation that are not statements of historical fact may be deemed to be forward-looking statements. Words such as believes, anticipates, plans, expects,, will, intends, potential, possible, and similar expressions are intended to identify forward-looking statements. Forward-looking statements involve risks and uncertainties related to Cascadian s business and the general economic environment, many of which are beyond its control. These risks, uncertainties and other factors could cause Cascadian s actual results to differ materially from those projected in forward-looking statements. These risks and uncertainties include, among others, the possibility that preclinical and clinical trials of product candidates will not be successful, or be completed, or confirm earlier results, risks associated with obtaining additional financing, risks related to obtaining and protecting intellectual property rights, risks related to the receipt of regulatory strategies and approvals, and risks related to general economic factors. Although Cascadian believes that its forward-looking statements are reasonable, it can give no assurance that its expectations are correct. All forward-looking statements are expressly qualified in their entirety by this cautionary statement. For a detailed description of Cascadian s risks and uncertainties you are encouraged to review the documents filed with the securities regulators in the United States on EDGAR and in Canada on SEDAR. Except as required by law, the company undertakes no obligation to publicly update its forward-looking statements based on events or circumstances after the date hereof. 2

Agenda & Presenters Company Strategy & Opportunity Scott Myers President, Chief Executive Officer, Cascadian Therapeutics HER2+ Therapies: Past, Present & Future Pamela Klein, MD PMK BioResearch, Former CMO Intellikine, VP Clinical Development, Genentech Research Director, NCI Navy Breast Center ONT-380 Clinical Data Overview Luke Walker, MD VP, Clinical Development, Cascadian Therapeutics Triplet Phase 2 Trial (HER2CLIMB) Design & Regulatory Strategy Luke Walker, MD VP, Clinical Development, Cascadian Therapeutics 3

Agenda & Presenters Panel Q/A Discussion Doug Blayney, MD Professor, Stanford School of Medicine Erika Hamilton, MD Director, Breast and Gynecologic Cancer Research, Sarah Cannon Research Institute Pamela Klein, MD PMK BioResearch, Former CMO Intellikine, VP Clinical Development, Genentech Research Director, NCI Navy Breast Center Luke Walker, MD VP Clinical Development, Cascadian Therapeutics Key Takeaways & Wrap-Up Scott Myers President, Chief Executive Officer, Cascadian Therapeutics 4

Company Strategy & Opportunity Scott Myers, President, Chief Executive Officer

NASDAQ Stock Symbol: CASC www.cascadianrx.com 6

Transforming into a Differentiated, Targeted Therapeutics Company Focused in Oncology The name and image reflect the Company s Pacific Northwest roots and headquarters Transforming from cancer vaccine legacy programs to cancer therapeutics that are differentiated, including orally available small molecules Dedicated to helping oncology patients live longer with a good quality of life HER2CLIMB, our Phase 2 trial, was named in the spirit of our mission to help women with advanced, metastatic HER2+ breast cancer Chk1: Potential to treat solid and hematological tumors 7

Our Pipeline DISCOVERY PRE- CLINICAL PHASE 1 PHASE 2 PHASE 3 ONT-380 HER2+ Breast Cancer HER2CLIMB Study Randomized Phase 2 Trial ONT-380 + capecitabine (C) + trastuzumab (T) vs. placebo + C + T Triplet Study Phase 1b ONT-380 + C + T Enrolling (Planned sites in US, CAN, W. Europe) Enrolled and Active TDM-1 Study Phase 1b ONT-380 + T-DM1 Enrolled and Active Data Update at ASCO 16 Chk1 Inhibitor Cell Cycle Inhibitor Orally Available Preclinical Models 8

Chk1 Inhibitor: DNA Damage Response (DDR) and Cell Cycle Control Represent Attractive Cancer Targets Targeting cell cycle regulation and DDR is a clinically validated approach to cancer therapy DDR / cell cycle regulation compromised due to gene mutations Approach validated with CDK and PARP inhibitor development Next generation - ATR, Chk1 and Wee1 inhibitors Adapted from Nature Reviews Cancer 4, 216-225 Chk1 inhibitors inhibit tumor growth as single agents and in combination with chemotherapeutics 9

Novel Chk1 Inhibitor: A Potential Best-in-Class Oral Drug Candidate Cascadian s novel Chk1 inhibitors are highly potent and selective for Chk1 Sub-nanomolar potency (IC50 ~100 pm) vs. Chk1 with limited off-target kinase activity (>1000x selective vs. Chk2) Single digit nanomolar cellular potency (IC50 = 1 nm) against Chk1 Attractive pharmaceutical properties Oral bioavailability and low efflux ratio allows for flexible dose schedule, potential for treating MDR resistant and CNS metastasized cancers Good metabolic stability, no CYP inhibition liabilities and excellent herg inhibition index Compelling single agent and combinatorial anti-tumor activity Potent single agent activity in select tumor cell lines and synergistic potentiation of chemotherapeutics and other DDR targeted drugs in vitro Well tolerated with anti-tumor activity in vivo as a single agent and in combination with gemcitabine 10

ONT-380 Offers a Unique Profile and Opportunity to Address Several Unmet Needs Selective HER2 Mechanism ONT-380 Profile and Opportunity Active in Patients with Brain Metastases Well Tolerated with Existing Regimens High Potential for Broader Application 11

Initial Positioning Would Be Post T-DM1 Progression with Potential to Move Up in the Treatment Paradigm 1 st Line Therapy trastuzumab + pertuzumab + docetaxel (chemotherapy) Disease Progression 2 nd Line Therapy T-DM1 Disease Progression 3 rd Line Therapy (No standard of care) ONT-380 + trastuzumab + capecitabine 12

Agenda & Presenters Company Strategy & Opportunity Scott Myers President, Chief Executive Officer, Cascadian Therapeutics HER2+ Therapies: Past, Present & Future Pamela Klein, MD PMK BioResearch, Former CMO Intellikine, VP Clinical Development, Genentech Research Director, NCI Navy Breast Center ONT-380 Clinical Data Overview Luke Walker, MD VP Clinical Development, Cascadian Therapeutics Triplet Phase 2 Trial (HER2CLIMB) Design & Regulatory Strategy Luke Walker, MD VP Clinical Development, Cascadian Therapeutics 13

HER2+ Therapies: Past, Present and Future Pamela Klein, MD

Overview History and Biology of HER2 Breast Cancer Treatment Paradigms The Evolution of HER2 Therapies Unmet Needs Remain Outcomes of Patients with Metastatic Breast Cancer Future of HER2 Targeted Therapies 15

Topic History and Biology of HER2 Breast Cancer Treatment Paradigms The Evolution of HER2 Therapies Unmet Needs Remain Outcomes of Patients with Metastatic Breast Cancer Future of HER2 Targeted Therapies 16

History and Biology of HER2+ Breast Cancer Historically, HER2+ breast cancer is associated with shorter survival times and higher risk of recurrence driven by HER2 overexpression Higher incidence of CNS metastasis Higher incidence of de novo diagnosis (metastatic, Stage IV) The advent of HER2 targeted therapies is changing the treatment paradigm Longer overall survival Longer duration of treatments Unmet medical needs Tolerable, chronic therapies Therapies that treat CNS disease 17

Targeting HER2+ Breast Cancer with Small Molecule Kinase Inhibitors and Antibodies trastuzumab pertuzumab T-DM1 TKI Block tumor cell growth signaling Internalization of toxin payload HER2 is a receptor tyrosine kinase that provides cell growth and survival signaling Amplified HER2 drives breast cancer progression Antibody and small molecule HER2 targeted drugs in combination with chemotherapy are therapeutically effective in early and metastatic disease settings 18

History of HER2 Targeted Therapy Approvals for the Treatment of Breast Cancer 1998 2007 2012 2013 2015 trastuzumab approved for treatment of HER2+ MBC lapatinib approved for treatment of HER2+ MBC pertuzumab approved for treatment of HER2+ MBC T-DM1 approved for treatment of HER2+ MBC pertuzumab approved as neoadjuvant treatment CLEOPATRA EMILIA TH3RESA* Approved therapies in HER2 setting have doubled overall survival Unmet needs remain T-DM1 and pertuzumab were developed simultaneously *Note: TH3RESA study published in 2014, supportive trial/not registration 19

Outline History and Biology of HER2 Breast Cancer Treatment Paradigms The Evolution of HER2 Therapies Unmet Needs Remain Outcomes of Patients with Metastatic Breast Cancer Future of HER2 Targeted Therapies 20

Current Early- to Late-Stage HER2 Treatment Paradigm EARLY-STAGE HER2 BREAST CANCER LATE-STAGE HER2 BREAST CANCER de novo MBC trastuzumab + chemo trastuzumab chemo +/- pertuzumab metastatic trastuzumab/ pertuzumab + chemo T-DM1 lapatinib + capecitabine trastuzumab + lapatinib 21

Treatment of Metastatic Breast Cancer Post Pertuzumab and T-DM1, No Single Standard of Care Physician's Choice/ No Standard of Care trastuzumab + chemo (e.g. capecitabine) trastuzumab/ pertuzumab + chemo T-DM1 lapatinib + capecitabine trastuzumab + lapatinib 22

HER2+ Metastatic Breast Cancer Patients Living Longer Survival has increased with new drugs Initial OS in first HER2+ MBC trial was 25.1 months and, more recently, CLEOPATRA demonstrated OS of 56.5 months As therapies continue to improve, patients need tolerable treatment for longer periods of time HER2 therapies are cytostatic agents Treatment Goals Prolongation of progression-free survival and overall survival Low toxicity Amelioration of symptoms and improvement in quality of life A treatment paradigm that maximizes efficacy and minimizes toxicity is therefore of paramount importance 24

Brain Metastases: Significant Unmet Need in HER2+ Breast Cancer With longer survival and better control of systemic disease, brain metastases remain an unmet need Estimated 30-50% of patients with metastatic disease develop brain metastases CNS acts as sanctuary from HER2 antibody-based therapies Current mainstay of treatment is local management of brain metastases Surgery Radiation Whole brain radiation associated with significant neurocognitive effects Stereotactic surgery associated with high distant brain relapse rates No approved anti-her2 systemic regimen Capecitabine/lapatinib most commonly used for HER2+ CNS disease Limited efficacy data exists Use limited by toxicity 25

Limited Data Exists on the Treatment Outcomes of HER2+ Patients with Brain Metastases Limited existing data from registries enrolling patients with brain metastases demonstrate shorter survival registher (2003-2006) examination of the natural history of patients with new diagnosed HER2+ MBC found: Worse outcomes with presence of brain mets Median survival 26.3 months in patients with brain metastases vs. 44.6 months without 37% of patients with HER2+ MBC had brain mets detected over the study 7% at diagnosis 30% over the course of their disease Adam M. Brufsky et al. Clin Cancer Res 2011;17:4834-4843 Historically, most pivotal trials exclude patients with brain metastases With increasing incidence of brain metastases, trials do not accurately represent real world patients 26

Are Historical Treatment Outcomes a Guide for Current Clinical Trials? Treatment Arm (n=402) CLEOPATRA Control Arm (n=406) Treatment Arm (n = 495) EMILIA Control Arm (n = 496) Treatment Arm (n = 404) TH3RESA Control Arm (n = 198) Study Treatment T + P + docetaxel T + docetaxel T-DM1 C + L T-DM1 Physician's choice # of prior HER2 therapies 0-1 a 0-1 a 1 1 2 2 Median PFS (95% CI) ORR 80% 69% 44% 31% 31% 9% 18.5 12.4 9.6 6.4 6.2 3.3 Median PFS declines as patients experience additional treatments All patients in these trials assumed to be pertuzumab naïve P = pertuzumab C = capecitabine T = trastuzumab L = lapatinib a In the subset of patients who received adjuvant or neoadjuvant therapy, 25.5% of patients in the PERJETA + Herceptin + docetaxel arm and 21.4% of patients in the Herceptin + docetaxel alone arm received prior Herceptin. Source: Baselga J, Cortés J, Kim S-B, et al; CLEOPATRA Study Group. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012;366:109-119. 28

What are the Expectations for Treatment Outcomes After Pertuzamab and T-DM1? General concept of decreasing benefit with anti-cancer therapies as you go from one line of tx to the next PFS usually decreases with each line TH3RESA control arm Most patients received chemotherapy plus trastuzumab; similar to modern treatment paradigm in 3rd line or greater Patients had received two prior anti-her2 therapies (trastuzumab, lapatinib) No patients with progressing or untreated brain metastases mpfs (median progression-free survival) was 3.3 months Response = 9% ASCO 2016* T-DM1 treatment post pertuzumab showed reduced benefit compared to previous T-DM1 benchmarks Median duration of therapy = 4 months (mpfs not provided) Response rate = 18% First report of T-DM1 outcomes in contemporary treatment setting * Dzimitrowicz, et al : ASCO 2016, Abstract #585 29

Summary: The Future of HER2+ Targeted Treatment The advent of HER2 targeted therapies is changing the treatment paradigm Longer overall survival Longer duration of treatments No standard of care post pertuzumab and T-DM1 Chemo + trastuzumab therapy yield low response rates and PFS Unmet needs remain Tolerable, chronic therapies Therapies that treat HER2+ brain metastases Novel, well tolerated therapeutic approaches are needed in later line settings 30

Agenda & Presenters Company Strategy & Opportunity Scott Myers President, Chief Executive Officer, Cascadian Therapeutics HER2+ Therapies: Past, Present & Future Pamela Klein, MD PMK BioResearch, Former CMO Intellikine, VP Clinical Development, Genentech Research Director, NCI Navy Breast Center ONT-380 Clinical Data Overview Luke Walker, MD VP Clinical Development, Cascadian Therapeutics Triplet Phase 2 Trial (HER2CLIMB) Design & Regulatory Strategy Luke Walker, MD VP Clinical Development, Cascadian Therapeutics 31

ONT-380 Clinical Data Overview Luke Walker, MD, VP of Clinical Development

ONT-380 Clinical Data Review Clinical Study Results to Date Background of ONT-380 Clinical Overview of the 380 program Phase 1b Study of T-DM1 + ONT-380 Phase 1b Study of TRIPLET ONT-380 + capecitabine + trastuzumab Summary of Phase 1b Studies Note: All data subject to review and modification the event of new information 33

Background of 380 Molecule ONT-380 is an orally bioavailable, highly potent HER2 selective tyrosine kinase inhibitor Designed to be highly selective for HER2 > EGFR; decreased potential for EGFR-related toxicities (e.g. diarrhea, skin rash) Tolerability may lead to better compliance, ability to dose for longer periods of time Superior activity compared to lapatinib or neratinib in preclinical models of HER2+ brain metastases Initial Phase 1 single-agent study showed objective responses with no treatment-related Grade 3 diarrhea 34

Approximately 200 Patients Have Been Treated with ONT-380 in 5 Studies ARRY-380-101 Study Treatment Trial Type Status ONT-380 (single agent) Phase 1 ONT-380-004 ONT-380 + T-DM1 Phase 1b ONT-380-005 ONT-380-206 Investigator Trials DFCI Investigator Sponsored Trial (Nancy Lin PI) ONT-380 +/-cape+/-tras ONT-380 vs placebo +cape/tras ONT-380 + tras Phase 1b Phase 2 Randomized, blinded study Phase 1b CNS only Study completed (n=50) Enrollment completed (n=57) Last patient enrolled July 2015 Enrollment completed (n=60) Last patient enrolled December 2015 Enrollment ongoing (n=180) First patient enrolled February 2016 Enrollment completed (n=40) 36

Introduction and Rationale of Combination Design HER2 agents have historically been combined with other therapies in an effort to maximize activity Combinations with cytotoxic chemotherapy most common More recently, importance of dual blockade of HER2 demonstrated in CLEOPATRA study (pertuzumab and trastuzumab) Phase 1b studies designed to: Demonstrate safety of ONT-380 in combination with other standard therapies Explore potential efficacy of ONT-380 combination regimens Explore activity in patients with brain metastases 37

Metastatic HER2+ Breast Cancer Treatment Algorithm trastuzumab + capecitabine trastuzumab/ pertuzumab + chemo T-DM1 lapatinib + capecitabine trastuzumab + lapatinib 38

Metastatic HER2+ Breast Cancer Treatment Algorithm +ONT-380 +ONT-380 trastuzumab + capecitabine trastuzumab/ pertuzumab + chemo T-DM1 lapatinib + capecitabine trastuzumab + lapatinib 39

Rationale for Combining ONT-380 and T-DM1 METASTATIC HER2 BREAST CANCER Patients with brain metastases included trastuzumab + chemo (e.g. capecitabine) trastuzumab/ pertuzumab + chemo T-DM1 +ONT-380 lapatinib + capecitabine Rationale for combination: Combine ONT-380 with HER2-targeted cytotoxic therapy Improving overall outcome of patients treated with 2 nd line SOC Demonstrate activity in patients with brain metastases trastuzumab + lapatinib 41

T-DM1 Combination: Phase 1b Study Overview T-DM1 Combination Treatment Patient Population ONT-380 300 mg BID + T-DM1 Prior trastuzumab + taxane required; patients with brain metastases eligible Status Last patient enrolled 7/2015 Enrollment at MTD n=50 42

T-DM1 Combination: Patients Treated with Multiple Prior HER2 Agents, with High Incidence of Brain Mets Patients Treated (n = 50) Age, median (range) 51 (30-72) ECOG 0/1, n (%) 20 (40%)/30 (60%) Hormone receptor positive, n (%) 34 (68%) Time since metastatic diagnosis (mos), median (range) 20 (1-93) Prior HER2 agents, median (range) 2 (1-3) trastuzumab, n (%) pertuzumab, n (%) lapatinib, n (%) 50 (100%) 23 (46%) 10 (20%) Brain mets, n (%) 30 (60%) Stable, treated brain mets, n (%) Untreated brain mets, n (%) Progressing brain mets, n (%) 9 (18%) 11 (22%) 10 (20%) 43

T-DM1 Combination: Manageable Adverse Events, Grade 3/4 Events Uncommon N = 50 Grade 1/2 Grade 3 Grade 4 Total AEs ( 20%) Nausea 35 (70%) 1 (2%) 0 36 (72%) Diarrhea 28 (56%) 2 (4%) 0 30 (60%) Fatigue 22 (44%) 6 (12%) 0 28 (56%) Headache 20 (40%) 2 (4%) 0 22 (44%) Thrombocytopenia 7 (14%) 11 (22%) 3 (6%) 21 (42%) Vomiting 20 (40%) 1 (2%) 0 21 (42%) Constipation 20 (40%) 0 0 20 (40%) Decreased appetite 20 (40%) 0 0 20 (40%) Hypokalaemia 13 (26%) 7 (14%) 0 20 (40%) Epistaxis 20 (40%) 0 0 20 (40%) Cough 13 (26%) 0 0 13 (26%) Dyspepsia 12 (24%) 0 0 12 (24%) Additional Gr 4 or 5 AEs: Gr 4 anemia (n=1) Gr 4 pneumonia, sepsis, and neutropenia (n=1) Gr 5 accidental drowning (n=1) Gr 5 respiratory distress (n=1) Patient data as of May 2, 2016 44

T-DM1 Combination: Manageable Adverse Events, Grade 3/4 Events Uncommon N = 50 Grade 1/2 Grade 3 Grade 4 Total AEs ( 20%) Urinary Tract Infection 12 (24%) 0 0 12 (24%) Vision Blurred 10 (20%) 0 0 10 (20%) Dizziness 10 (20%) 0 0 10 (20%) Insomnia 10 (20%) 0 0 10 (20%) LFT Abnormalities Increased AST 37 (74%) 6 (12%) 1 (2%) 44 (88%) Increased ALT 32 (64%) 8 (16%) 40 (80%) Increased Bilirubin 16 (32%) 2 (4%) 18 (36%) Patient data as of May 2, 2016 45

Patients T-DM1 Combination: Encouraging Progression-Free Survival (8.2 months) Median PFS: 8.2 months (95% CI: 5.1-10.2) Best Overall Response Complete response Partial response Stable disease Progressive disease Stable, non-measurable disease Patient still on study Patient data as of May 2, 2016 0 6 12 18 24 Progression-Free Survival (Months) 46

T-DM1 Combination: 47% Objective Response Rate Best Response in Patients with Measurable Lesions (n = 34) Objective Response Rate 16/34 (47%) Complete Response 1 Partial Response 15 Stable Disease 14/34 (41%) Progressive Disease 4/34 (12%) Patient data as of May 2, 2016 47

Maximum Change in Sum of Diameters in Target Lesions Similar ORR in Patients Previously Treated with Pertuzumab 60% 40% 20% 0% -20% -40% -30% -60% With prior pertuzumab use Without prior pertuzumab use -80% -100% Patient data as of May 2, 2016 Recent data (Dzimitrowicz, ASCO 2016) have reported ORR <20% for T-DM1 in patients with prior pertuzumab ORR for patients with measurable lesions treated with T-DM1 + ONT-380 with prior pertuzumab was 8/15 (53%); includes one patient with no follow-up scan 48

Patients Without Brain Mets Patients With Brain Mets T-DM1 Combination: Similar PFS in Patients with and without Brain Metastases With brain mets Treated, stable With brain mets Untreated asymptomatic With brain mets Progressive after prior tx Patient still on study Median PFS: 6.7 months (CI: 5.1-9.2) Without brain mets Median PFS: 8.2 months (CI: 3.1-n/a) Patient data as of May 2, 2016 0 6 12 18 24 Progression-Free Survival (Months) 49

Maximum Change in Sum of Diameters (%) T-DM1 Combination: Responses Have Been Seen in Patients with and without Brain Metastases 60% 40% 20% 0% -20% -40% -30% -60% -80% -100% Without Brain Mets With Brain Mets Patient data as of May 2, 2016 50

T-DM1 Combination: Durable Response in Untreated Brain Metastases Screening Cycle 2 Study Patient History Disposition ONT-380 + T-DM1 Metastatic disease at diagnosis, treated in first line with carboplatin, trastuzumab, pertuzumab and docetaxel, with progression after 7 months of therapy Found to have new asymptomatic CNS metastases at time of study screening with target lesions located in cerebellum No history of prior CNS XRT Post 2 cycles: -50% CNS target lesions Active on therapy at 235 days 51

T-DM1 Combination: Untreated/Asx CNS Metastases Study Patient History Disposition ONT-380 + T-DM1 Prior systemic regimens for metastatic disease including T combined with: vinorelbine, C, and paclitaxel Found to have new asx CNS mets at time of study screening with target lesions located in cerebellum No history of prior CNS XRT Post 2 cycles: -68% CNS target lesions Post 6 cycles -100% CNS target lesions Durable partial response; on treatment for 317 days 52

ASCO 2016 SUMMARY: T-DM1 Combination Encouraging Data Systemically, Including Patients with Brain Metastases Combination of ONT-380 and T-DM1 in this Phase 1b study demonstrates encouraging anti-tumor activity in a patient population with a median of two prior HER2 agents, including almost half treated previously with pertuzumab Objective Response Rate of 47% Median PFS 8.2 months in overall population Combination was well tolerated Majority of AEs were Grade 1 Most patients who required an ONT-380 dose reduction maintained disease control at lower dose Most common reason for dose reductions of ONT-380 due to reversible lab abnormalities 53

ASCO 2016 SUMMARY: T-DM1 Combination Encouraging Data Systemically, including Patients with Brain Metastases Clinical benefit in patients with brain mets Outcomes of patients with brain mets similar to patients without brain mets Response rate of brain lesions 36%, with long-term stable brain mets in many patients Study included patients previously treated with pertuzumab and patients with brain mets Reflects HER2+ patients seen in contemporary clinical practice Encouraging activity and tolerability warrant further study in these populations We plan to develop this combination ourselves or in collaboration at a later date 54

Rationale for Triplet Combination Metastatic HER2+ Breast Cancer Treatment Algorithm Combine ONT-380 with HER2 therapy and cytotoxic therapy Improving overall outcome of patients treated with 3rd line SOC Demonstrate activity in patients with brain metastases Study activity in patients after T-DM1 trastuzumab + capecitabine +ONT-380 trastuzumab / pertuzumab + chemo T-DM1 lapatinib + capecitabine trastuzumab + lapatinib 56

Change in Sum of Diameters (%) Encouraging Data in ONT-380 Doublet Arms 40% ONT-380 + C 40% ONT-380 + T 20% 0% -20% -40% -60% -80% -100% 20% 0% -20% -40% -60% -80% -100% Best Response in Patients with Measurable Lesions + C (n = 6) + T (n = 15) Objective Response Rate 5 (83%) 6 (40%) Complete response 0 0 Partial response 5 6 Stable disease 1 (17%) 7 (47%) Progressive disease 0 (0%) 2 (13%) 57

Triplet Combination: Phase 1b Study Overview TRIPLET Study Treatment Patient Population ONT-380 + capecitabine + trastuzumab Prior trastuzumab + taxane + T-DM1 required; patients with brain metastases eligible Status Last patient enrolled 12/2015 Enrollment at MTD n=27 58

Triplet Combination: Pretreated Patient Population with High Incidence of Brain Mets C + T (n = 27) Age, median (range) 50 (35-67) ECOG 0/1, n (%) 14 (52%)/13 (48%) Hormone receptor positive, n (%) 15 (56%) # of prior HER2 agents, median (range) 3 (2-4) trastuzumab, n (%) pertuzumab, n (%) T-DM1, n (%) lapatinib, n (%) 27 (100%) 20 (74%) 27 (100%) 10 (37%) Brain metastases, n (%) 11 (41%) Stable, treated brain mets, n (%) Untreated brain mets, n (%) Progressing brain mets, n (%) 4 (15%) 4 (15%) 3 (11%) 59

Triplet Combination: Severity of Most Common Adverse Events and LFT Abnormalities AEs ( 20%) C+T (n = 27) Grade 1 Grade 2 Grade 3 Total Diarrhea 14 (52%) 4 (15%) 3 (11%) 21 (78%) Nausea 11 (41%) 6 (22%) 0 17 (63%) Palmar-Plantar Erythrodysaesthesia Syndrome 2 (7%) 13 (48%) 3 (11%) 18 (67%) Vomiting 9 (33%) 2 (7%) 0 11 (41%) Fatigue 5 (19%) 3 (11%) 3 (11%) 11 (41%) Decreased Appetite 2 (7%) 4 (15%) 0 6 (22%) Upper Respiratory Tract Infection 3 (11%) 3 (11%) 0 6 (22%) Hypokalaemia 4 (15%) 2 (7%) 0 6 (22%) LFT Abnormalities Increased AST 15 (56%) 6 (22%) 2 (7%) 23 (85%) Increased ALT 15 (56%) 2 (7%) 2 (7%) 19 (70%) Increased Bilirubin 8 (30%) 4 (15%) 2 (7%) 14 (52%) Note: Two Grade 4 AEs were reported for cerebral edema and breast implant infection and no Grade 5 events were reported Patient data as of May 27, 2016 60

Patients Triplet Combination: Discontinuations Uncommon; Patients with Dose Reduction Had Continued Disease Control C+T (n = 27) Patients requiring dose reduction Each color change indicates dose reduction Patient still on study ONT-380 6 capecitabine 14 Patients requiring discontinuation of study drug due to AE ONT-380 2 capecitabine 3 trastuzumab 2 0 6 12 18 24 Time on Study (Months) Note: Two additional patients discontinued from the study due to adverse events but did not have a dose reduction Patient data as of May 27, 2016 61

Patients Triplet Combination: Impressive Duration of Treatment in Multiple High Risk Patients Progression Free Survival C + T (n = 27) Median (months) 6.3 95% CI (4.1-n/a) 0 6 12 18 24 6.3 mos Progression-Free Survival (Months) Best Overall Response Complete response Partial response Stable disease Progressive disease Stable, non-measurable disease Patient still on study Patient data as of May 27, 2016 62

Triplet Combination: 58% Objective Response Rate in Pretreated Patients with Measurable Disease Best Response in Patients with Measurable Lesions C+T (n=24) Objective Response Rate 14 (58%) Complete Response 1 Partial Response 13 Stable Disease 6 (25%) Progressive Disease 4 (17%) Patient data as of May 27, 2016 63

Maximum Change in Sum of Diameters (%) Triplet Combination: Responses Were Seen in Patients Pretreated with Multiple HER2 Agents 40% 20% 0% -20% -30% -40% -60% ORR: 14/24 (58%) 2 prior HER2 agents 3 prior HER2 agents 4 prior HER2 agents -80% -100% Patient data as of May 27, 2016 64

Patients Triplet Combination: Encouraging PFS in Patients with and without Brain Metastases Without Brain Mets With Brain Mets Without brain mets With brain mets Treated, stable With brain mets Untreated asymptomatic With brain mets Progressive after prior tx Patient still on study Patient data as of May 27, 2016 0 6 12 18 24 Progression-Free Survival (Months) 65

Maximum Change in Sum of Diameters (%) Triplet Combination: Responses Were Seen in Patients with and without Brain Metastases 40% 20% 0% -20% -30% -40% -60% ORR: 14/24 (58%) Patients without Brain Mets Patients with Brain Mets -80% -100% Patient data as of May 27, 2016 66

Triplet Combination: Durable Response in Progressing Brain Metastases after Prior Local Therapy Screening Cycle 2 Study Treatment Patient History Disposition ONT-380 + capecitabine + trastuzumab Metastatic disease at diagnosis, treated in first line with carboplatin, trastuzumab, and pertuzumab followed by T-DM1 Found to have new CNS metastases five months prior to study entry, treated with WBRT Progressive and new CNS lesions found at time of study entry Post 2 cycles: significant reduction in all lesions Durable partial response; still active on therapy after 430 days of treatment 67

Response in Brain Metastases with Trastuzumab + ONT-380 Screening Post-cycle 2 Screening Study Treatment Patient History Disposition ONT-380 + trastuzumab Prior treatment with trastuzumab and pertuzumab History WBRT 15 months before study entry and SRS of cerebellar lesion 8 months before study entry Progression in CNS after 3 months with C + L just prior to study entry Post 2 cycles: 26% reduction in CNS lesion 68

Triplet Combination: Summary and Conclusions The combination of ONT-380 with C + T demonstrates encouraging anti-tumor activity in patients treated with multiple anti-her2 agents, many with brain mets Objective Response Rate of 58% Median PFS >6 months overall in a pretreated population with a median of three prior HER2 agents, including majority with pertuzumab Combination was well tolerated Majority of AEs were Grade 1, with most patients able to continue on full dose of ONT-380 Activity and tolerability warrant continuing efforts to explore combination in a randomized trial 69

Phase 1b Studies: Summary and Conclusions The data from ONT-380 Phase 1b combination studies demonstrate encouraging systemic anti-tumor activity in patients treated with multiple anti-her2 agents Combination therapies in both the T-DM1 and Triplet studies were well tolerated Consistent with HER2 selectivity vs. EGFR Majority of AEs were Grade 1 Patients with dose reductions had continued disease control Clinical benefit in patients with brain metastases Outcomes in patients with brain metastases similar to those without T-DM1 combination warrants further exploration either with a collaborator or by ourselves at a later date Triplet combination results continue to be encouraging; provided basis for Phase 2 program 71

Agenda & Presenters Company Strategy & Opportunity Scott Myers President, Chief Executive Officer, Cascadian Therapeutics HER2+ Therapies: Past, Present & Future Pamela Klein, MD PMK BioResearch, Former CMO Intellikine, VP Clinical Development, Genentech Research Director, NCI Navy Breast Center ONT-380 Clinical Data Overview Luke Walker, MD VP Clinical Development, Cascadian Therapeutics Triplet Phase 2 Trial (HER2CLIMB) Design & Regulatory Strategy Luke Walker, MD VP of Clinical Development, Cascadian Therapeutics 72

Triplet HER2CLIMB Phase 2 Trial Design & Regulatory Strategy Luke Walker, VP, Clinical Development

HER2CLIMB: (HER2+ InCLuding Patients with CNS Metastases with Metastatic Breast Cancer) Study of ONT-380 vs. Placebo in Combination with Capecitabine & Trastuzumab in Patients with Metastatic HER2+ Breast Cancer Study Objective Assess the effect of ONT-380 vs. placebo in combination with capecitabine and trastuzumab on progression-free survival based on independent central review Source: clinicaltrials.gov 74

HER2CLIMB: Phase 2 Study Details Population Locally advanced or metastatic HER2+ breast cancer with prior treatment with a taxane, trastuzumab, pertuzumab, and T-DM1 Patients with and without brain metastases Progression after last systemic therapy Study Design Randomized, double-blinded study of ONT-380 or placebo with capecitabine and trastuzumab 2:1 randomization Global Trial Approx. 100 clinical sites in U.S., Canada and Western Europe 180 patients First patient enrolled in February 2016 75

HER2CLIMB: Study Design Prior pertuzumab, T-DM1, trastuzumab and a taxane 2:1 capecitabine + trastuzumab + ONT-380 capecitabine + trastuzumab + placebo All patients screened at baseline for brain metastases Patients with asymptomatic brain metastases eligible Primary endpoint PFS as assessed by central review Unblinded Data Monitoring Committee for safety review; no interim analyses planned 76

Assumptions for Control Arm of HER2CLIMB CLEOPATRA EMILIA TH3RESA ASCO 16* Treatment Arm (n=402) Control Arm (n=406) Treatment Arm (n=496) Control Arm (n=495) Treatment Arm (n = 404) Control Arm (n = 198) Treatment Group (n=82) Study Treatment T + P + docetaxel T + docetaxel T-DM1 C + L T-DM1 Physician's choice T-DM1 # of prior HER2 therapies 0-1 0-1 1 1 2 2 2 ORR 80% 69% 44% 31% 31% 9% 18% Median PFS (months) 18.5 12.4 9.6 6.4 6.2 3.3 4 (Time on Treatment**) Estimates suggest a PFS of 3-4.5 months for capecitabine + trastuzumab post both pertuzumab + T-DM1 *Dzimitrowicz et al. ASCO 2016, Abstract # 585 ** Time on treatment, not PFS 77

Assumptions for Control Arm of HER2CLIMB CLEOPATRA EMILIA TH3RESA ASCO 16* ONT-380 + Treatment Arm (n=402) Control Arm (n=406) Treatment Arm (n=496) Control Arm (n=495) Treatment Arm (n = 404) Control Arm (n = 198) Treatment Group (n=82) Treatment C + T Cohort (n = 27) Study Treatment T + P + docetaxel T + docetaxel T-DM1 C + L T-DM1 Physician's choice T-DM1 ONT-380 + C + T # of prior HER2 therapies 0-1 0-1 1 1 2 2 2 3 (1-4) ORR 80% 69% 44% 31% 31% 9% 18% 54% Median PFS (months) 18.5 12.4 9.6 6.4 6.2 3.3 4 (Time on Treatment**) 6.3 (3.4-N/A) Estimates suggest a PFS of 3-4.5 months for capecitabine + trastuzumab post both pertuzumab + T-DM1 HER2CLIMB uses these assumptions along with input from steering committee KOLs, and then is powered conservatively with an assumption of 4.5 months in the control arm *Dzimitrowicz et al. ASCO 2016, Abstract # 585 ** Time on treatment, not PFS 78

HER2CLIMB Phase 2 trial has been rigorously designed to allow for possible transition to a pivotal registrational trial Central review of scans Double-blinded trial with placebo control Unblinded DMC Originally, RANO-BM used as novel criteria to allow for better assessment of activity in brain metastases However, new criteria have not yet been used to support NDA Given continued encouraging activity and safety of the Triplet combination, our intention is to work toward transition of HER2CLIMB to a registrational trial. Changes include: Change from RANO-BM to RECIST 1.1 for primary and secondary endpoints Continue to use RANO-BM as an exploratory endpoint to assess activity in brain metastases Consider other statistical changes necessary for registrational trial 79

Proposed HER2CLIMB Endpoints Modifications in Process to Reflect RECIST 1.1 Primary Endpoints Progression-free survival based upon independent central review Secondary Endpoints Investigator-assessed PFS Objective Response Rate Duration of Response Clinical Benefit Rate Overall Survival Safety Exploratory CNS Endpoints CNS response rate by RANO-BM PFS in subset of patients with brain metastases To be further discussed with FDA 80

Pathway for Transition to Registration Trial Ongoing review of input from investigators, independent advisors and the ONT-380 development team to inform potential transition of the current trial to a registrational study design Plan for questions to be submitted to FDA summer 2016, including: Discuss changes in trial design and statistical assumptions required for transition to registrational size Powering, trial size Potential endpoints to demonstrate efficacy in patients with brain metastases Based on these discussions, plan to provide further information on this registration pathway by year-end 81

Panel Intros & Q/A Scott Myers, President, Chief Executive Officer

Panel Q/A Discussion Doug Blayney, MD Professor, Stanford School of Medicine Erika Hamilton, MD Director, Breast and Gynecologic Cancer Research, Sarah Cannon Research Institute Pamela Klein, MD PMK BioResearch, Former CMO Intellikine, VP Clinical Development, Genentech Research Director, NCI Navy Breast Center Luke Walker, MD VP Clinical Development, Cascadian Therapeutics 83

Key Takeaways & Wrap-Up Scott Myers, President, Chief Executive Officer

Key Takeaways Focused on developing orally active agents for cancers, with a first indication for ONT- 380 combination therapy in HER2+ metastatic breast cancer Also in our pipeline: A potentially differentiated, early stage Chk1 inhibitor moving to expected IND in 2017 ONT-380, in combination, has demonstrated activity and a favorable safety profile in two Phase 1b trials in advanced MBC patients previously treated with multiple HER2 therapies Will provide updated clinical results from Phase 1b trials by year-end HER2CLIMB, our Phase 2, randomized, blinded trial is currently enrolling patients in the U.S., Canada and Western E.U. Strong investigator and KOL support to develop the Triplet combination Exploring the potential of transitioning HER2CLIMB to a pivotal trial We would like to thank investigators and patients for supporting our efforts to develop a new, potentially very exciting therapy for breast cancer patients 85

R&D DAY. June 14, 2016