Supplementary appendix

Transcription

1 Supplementary appendix This appendix formed part of the original submission and has been peer reviewed. We post it as supplied by the authors. Supplement to: Murthy R, Borges V F, Conlin A, et al. Tucatinib with capecitabine and trastuzumab in advanced HER2-positive metastatic breast cancer with and without brain metastases: a non-randomised, open-label, phase 1b study. Lancet Oncol 218; published online May 24.

2 Patients Entered on Study by Site Site Principal Investigator Patients Entered on Study MD Anderson Rashmi Murthy 3 Tennessee Oncology (SCRI) Erika Hamilton 14 University of Colorado Cancer Center Virginia Borges 1 Providence Cancer Center Alison Conlin 5 Northwest Medical Specialties Jorge Chaves 1 Page 1

3 Prior HER2 Therapies at RP2D Tucatinib + Capecitabine (N = 7) Tucatinib + Trastuzumab (N = 18) Tucatinib + Capecitabine + Trastuzumab (N = 27) Overall (N= 52) Prior HER2 Therapy Trastuzumab 1% 1% 1% 1% Pertuzumab 57% 5% 74% 65% T-DM1 1% 89% 1% 97% Lapatinib 29% 94% 37% 55% Patients with measurable disease Number of responders Median Prior Unique HER2 Agents in nonresponders vs responders 3/3 3.5/3.5 3/3 3/3 Page 2

4 Drug Modifications due to Adverse Events Treatment Modifications Tucatinib + Capecitabine (N = 7) Tucatinib 3 mg + Trastuzumab (N = 18) + Capecitabine + Trastuzumab (N = 27) + Capecitabine (N = 4) Tucatinib 35 mg + Trastuzumab (N = 4) Total (N = 6) Any dose reduction 2 (29%) 6 (22%) 9 (15%) 1 dose reduction 2 (29%) 5 (19%) 7 (12%) 2 dose reductions 1 (4%) 2 (3%) Any drug interruption 5 (71%) 6 (33%) 18 (67%) 3 (75%) 2 (5%) 34 (57%) 1 drug interruptions 3 (43%) 4 (22%) 1 (37%) 18 (3%) 2 drug interruptions 1 (14%) 1 (6%) 2 (7%) 6 (1%) 3 drug interruptions 1 (14%) 1 (6%) 6 (22%) 1 (17%) Resumed dosing after interruption 1 5 (71%) 4 (22%) 17 (63%) 2 (5%) 28 (47%) At same dose 4 (57%) 4 (22%) 13 (48%) 2 (5%) 23 (38%) At reduced dose 1 (14%) 4 (15%) 5 (8%) Capecitabine 2 Any dose reduction 6 (86%) N/A 17 (63%) 2 (5%) N/A 25 (42%) 1 dose reduction 6 (86%) N/A 7 (26%) N/A 14 (23%) 2 dose reductions N/A 6 (22%) N/A 6 (1%) 3 dose reductions N/A 4 (15%) N/A 5 (8%) Any drug interruption 5 (71%) N/A 2 (74%) 3 (75%) N/A 28 (47%) 1 drug interruptions 4 (57%) N/A 4 (15%) N/A 9 (15%) 2 drug interruptions N/A 3 (11%) 2 (5%) N/A 5 (8%) 3 drug interruptions 1 (14%) N/A 13 (48%) N/A 14 (23%) Resumed dosing after interruption 1 5 (71%) N/A 18 (67%) 2 (5%) N/A 25 (42%) At same dose 3 (43%) N/A 14 (52%) N/A 17 (28%) At reduced dose 2 (29%) N/A 4 (15%) 2 (5%) N/A 8 (13%) Trastuzumab 3 Any drug interruption N/A N/A 7 (26%) N/A N/A 7 (12%) 1 drug interruptions N/A N/A 6 (22%) N/A N/A 6 (1%) 2 drug interruptions N/A N/A 1 (4%) N/A N/A 1 (2%) Resumed dosing after interruption 1 N/A N/A 6 (22%) N/A N/A 6 (1%) At same dose N/A N/A 6 (22%) N/A N/A 6 (1%) 1 For patients with multiple interruptions, determination of whether dosing was resumed is relative to last dose interruption. 2 Capecitabine dose not applicable (N/A) for the combination of tucatinib with trastuzumab. 3 Trastuzumab dose reduction not applicable throughout the study. Trastuzumab dose interruptions were allowed in the Triplet cohort only. Page 3

5 Steady state pharmacokinetics parameters of capecitabine (Cycle 1 Day 14) Analyte Half-Life (h) T max (h) C max (ng/ml) AUC last (h*ng/ml) AUC inf (h*ng/ml) Literature AUC 1 Capecitabine dfcr dfur FU FBAL Reigner et al., Clin Pharmacokinet (21) 4(2): dfcr (5 -deoxy-5-fluorocytidine); 5 -dfur (5 -deoxy-5-fluorouridine); 5-FU (5-fluorouracil); FBAL ( -fluoro- -alanine) Page 4

6 Mean plasma tucatinib concentration vs. time with and without capecitabine Page 5

7 Response in Patients with Brain Metastases at Baseline Patients with baseline BM at the RP2D N=29 Patients with baseline BM in the triplet cohort N=11 Treated stable Treated progressive Untreated asymptomatic Treated stable Treated progressive Untreated asymptomatic Number Measurable (target) brain disease Objective Response Rate N/A 5/12 (42%) /1 (%) N/A 2/2 (1%) N/A Page 6

8 Incidence of Treatment-Emergent Adverse Events Regardless of Causality; All Grades Event Total Patients with any AE Grade 3 Grade 4 Diarrhea Grade 3 Nausea Grade 3 Palmar-plantar erythrodysaesthesia syndrome Grade 3 Fatigue Grade 3 Vomiting Grade 3 Headache Grade 3 Decreased appetite Grade 3 Dizziness Aspartate aminotransferase increased Grade 3 Alanine aminotransferase increased Grade 3 Arthralgia Upper respiratory tract infection Urinary tract infection Hypokalemia Grade 3 Neuropathy peripheral + Capecitabine (N = 7) 7 (1%) 3 (43%) 3 (43%) 1 (14%) 5 (71%) 5 (71%) 5 (71%) 5 (71%) 5 (71%) 4 (57%) 1 (14%) 5 (71%) 5 (71%) 2 (29%) 2 (29%) 2 (29%) 2 (29%) 2 (29%) 2 (29%) 2 (29%) 2 (29%) 4 (57%) 3 (43%) 1 (14%) 4 (57%) 3 (43%) 1 (14%) 1 (14%) 1 (14%) 2 (29%) 2 (29%) Tucatinib 3 mg + Trastuzumab (N = 18) 18 (1%) 14 (78%) 3 (17%) 1 (6%) 1 (56%) 1 (56%) 6 (33%) 6 (33%) 3 (17%) 3 (17%) 4 (22%) 3 (17%) 1 (6%) 3 (17%) 3 (17%) 4 (22%) 4 (22%) 4 (22%) 4 (22%) 3 (17%) 3 (17%) 3 (17%) 3 (17%) 1 (6%) 1 (6%) + Capecitabine + Trastuzumab (N = 27) 27 (1%) 9 (33%) 16 (59%) 2 (7%) 2 (74%) 17 (63%) 3 (11%) 2 (74%) 2 (74%) 18 (67%) 15 (56%) 3 (11%) 12 (44%) 8 (3%) 4 (15%) 14 (52%) 14 (52%) 6 (22%) 6 (22%) 9 (33%) 9 (33%) 3 (11%) 3 (11%) 7 (26%) 5 (19%) 2 (7%) 6 (22%) 4 (15%) 2 (7%) 5 (19%) 5 (19%) 6 (22%) 6 (22%) 7 (26%) 7 (26%) 6 (22%) 5 (19%) 1 (4%) 4 (15%) 4 (15%) + Capecitabine (N = 4) 4 (1%) 3 (75%) 4 (1%) 4 (1%) 2 (5%) 2 (5%) 2 (5%) 2 (5%) 2 (5%) Tucatinib 35 mg + Trastuzumab (N = 4) 4 (1%) 2 (5%) 2 (5%) 2 (5%) 4 (1%) 3 (75%) 2 (5%) 2 (5%) Total (N = 6) 6 (1%) 31 (52%) 24 (4%) 5 (8%) 38 (63%) 34 (57%) 4 (7%) 33 (55%) 32 (53%) 1 (2%) 27 (45%) 23 (38%) 4 (7%) 26 (43%) 21 (35%) 5 (8%) 23 (38%) 21 (35%) 2 (3%) 13 (22%) 13 (22%) 12 (2%) 12 (2%) 12 (2%) 12 (2%) 11 (18%) 8 (13%) 3 (5%) 1 (17%) 7 (12%) 3 (5%) 1 (17%) 1 (17%) 1 (17%) 1 (17%) 1 (17%) 1 (17%) 9 (15%) 8 (13%) 1 (2%) 9 (15%) 9 (15%) Page 7

9 Event + Capecitabine (N = 7) Tucatinib 3 mg + Trastuzumab (N = 18) + Capecitabine + Trastuzumab (N = 27) + Capecitabine (N = 4) Tucatinib 35 mg + Trastuzumab (N = 4) Total (N = 6) Edema peripheral Grade 3 3 (17%) 2 (11%) 1 (6%) 3 (11%) 3 (11%) 2 (5%) 2 (5%) 8 (13%) 7 (12%) 1 (2%) Hot flush 2 (29%) 2 (29%) 2 (11%) 2 (11%) 3 (11%) 3 (11%) 8 (13%) 8 (13%) Rash 1 (14%) 1 (14%) 2 (11%) 2 (11%) 5 (19%) 5 (19%) 8 (13%) 8 (13%) Cough 2 (29%) 2 (29%) 2 (11%) 2 (11%) 3 (11%) 3 (11%) 7 (12%) 7 (12%) Dyspnea 2 (11%) 2 (11%) 5 (19%) 5 (19%) 7 (12%) 7 (12%) Local swelling 1 (14%) 1 (14%) 3 (17%) 3 (17%) 2 (7%) 2 (7%) 7 (12%) 7 (12%) Pruritus 1 (14%) 1 (14%) 2 (11%) 2 (11%) 4 (15%) 4 (15%) 7 (12%) 7 (12%) Abdominal pain 3 (17%) 3 (17%) 3 (11%) 3 (11%) 6 (1%) 6 (1%) Anemia Grade 3 1 (14%) 1 (14%) 5 (19%) 3 (11%) 2 (7%) 6 (1%) 4 (7%) 2 (3%) Dry skin 2 (29%) 2 (29%) 4 (15%) 4 (15%) 6 (1%) 6 (1%) Muscular weakness 2 (11%) 2 (11%) 3 (11%) 3 (11%) 6 (1%) 6 (1%) Stomatitis 2 (11%) 2 (11%) 3 (11%) 3 (11%) 6 (1%) 6 (1%) Weight decreased 5 (19%) 5 (19%) 6 (1%) 6 (1%) Convulsion Grade 3 1 (6%) 1 (6%) 2 (7%) 2 (7%) 5 (8%) 4 (7%) 1 (2%) Mucosal inflammation Grade 3 1 (14%) 1 (14%) 4 (15%) 3 (11%) 1 (4%) 5 (8%) 4 (7%) 1 (2%) Asthenia Grade 3 1 (6%) 1 (6%) 3 (11%) 1 (4%) 2 (7%) 4 (7%) 2 (3%) 2 (3%) Hyperbilirubinemia Grade 3 1 (6%) 1 (6%) 2 (7%) 2 (7%) 4 (7%) 2 (3%) 2 (3%) Cellulitis Grade 3 2 (7%) 2 (7%) 3 (5%) 1 (2%) 2 (3%) Hyponatremia Grade 3 3 (11%) 2 (7%) 1 (4%) 3 (5%) 2 (3%) 1 (2%) Hypophosphatemia Grade 3 1 (6%) 1 (6%) 1 (4%) 1 (4%) 3 (5%) 1 (2%) 2 (3%) Page 8

10 Event + Capecitabine (N = 7) Tucatinib 3 mg + Trastuzumab (N = 18) + Capecitabine + Trastuzumab (N = 27) + Capecitabine (N = 4) Tucatinib 35 mg + Trastuzumab (N = 4) Total (N = 6) Lymphoedema Grade 3 1 (6%) 1 (6%) 2 (5%) 3 (5%) 2 (3%) 1 (2%) Neutropenia Grade 3 1 (14%) 1 (14%) 2 (7%) 2 (7%) 3 (5%) 2 (3%) 1 (2%) Pneumonia Grade 3 1 (6%) 1 (6%) 1 (4%) 1 (4%) 3 (5%) 1 (2%) 2 (3%) Weight increased Grade 3 1 (6%) 1 (6%) 1 (4%) 1 (4%) 3 (5%) 2 (3%) 1 (2%) Brain edema Grade 3 Grade 4 1 (4%) 1 (4%) 2 (3%) 2 (3%) Breast pain Grade 3 2 (7%) 1 (4%) 1 (4%) 2 (3%) 1 (2%) 1 (2%) Disease progression Grade 3 Grade 4 2 (11%) 1 (6%) 1 (6%) 2 (3%) 1 (2%) 1 (2%) Pleural effusion Grade 3 1 (14%) 1 (14%) 1 (4%) 1 (4%) 2 (3%) 1 (2%) 1 (2%) Visual field defect Grade 3 1 (4%) 1 (4%) 2 (3%) 1 (2%) 1 (2%) Ascites Grade 3 1 (4%) 1 (4%) 1 (2%) 1 (2%) Complicated migraine Grade 3 1 (6%) 1 (6%) 1 (2%) 1 (2%) Device leakage Grade 3 1 (4%) 1 (4%) 1 (2%) 1 (2%) Dysarthria Grade 3 1 (4%) 1 (4%) 1 (2%) 1 (2%) Hypertension Grade 3 1 (2%) 1 (2%) Influenza Grade 3 1 (4%) 1 (4%) 1 (2%) 1 (2%) Page 9

11 Leukopenia Grade 3 Event Mental status changes Grade 3 Pericardial effusion Grade 3 Peritonitis bacterial Grade 3 Soft tissue infection Grade 3 Spinal pain Grade 3 Tumor pain Grade 3 Cardiac arrest Grade 3 Grade 4 Device-related infection Grade 3 Grade 4 + Capecitabine (N = 7) 1 (14%) 1 (14%) 1 (14%) 1 (14%) Tucatinib 3 mg + Trastuzumab (N = 18) 1 (6%) 1 (6%) + Capecitabine + Trastuzumab (N = 27) 1 (4%) 1 (4%) 1 (4%) 1 (4%) 1 (4%) 1 (4%) 1 (4%) 1 (4%) 1 (4%) 1 (4%) + Capecitabine (N = 4) Tucatinib 35 mg + Trastuzumab (N = 4) Total (N = 6) Note: AEs reported in 1% of patients; Grade 3-4 any AE; no Grade 5 AEs were observed. In instances where higher grade is not indicated, none was seen for that event. 1 (2%) 1 (2%) 1 (2%) 1 (2%) 1 (2%) 1 (2%) 1 (2%) 1 (2%) 1 (2%) 1 (2%) 1 (2%) 1 (2%) 1 (2%) 1 (2%) 1 (2%) 1 (2%) 1 (2%) 1 (2%) Page 1

12 Protocol Number: Protocol Title: Investigational Product: Amendment No.: Previous Versions: Clinical Study Protocol Signature Page ONT-38-5 A Phase 1b, open-label study to assess the safety and tolerability of ONT-38 combined with capecitabine and trastuzumab, alone and in combination in HER2+ metastatic breast cancer Tucatinib (ONT-38) 7 (18-JUL-217) 6 (6-JUL-216) 5 (7-MAY-215) 4 (12-SEP-214) Please REMOVE and send to sponsor. 3 (11-JUL-214) 2 (27-MAR-214) 1 (3-JAN-214) Original (31-OCT-213) By signing this protocol, the investigator agrees to conduct the clinical trial in accordance with this protocol, generally accepted standards of good clinical practice, and all applicable federal, state, and local laws, rules, regulations, requirements, and guidelines (including all foreign laws and governmental requirements as applicable) relating to the conduct of the clinical trial. In addition, the investigator agrees to provide the sponsor with such information and certifications as the sponsor shall reasonably request from time to time regarding direct and indirect financial interests and other arrangements between sponsor and investigator, to allow the sponsor to submit complete and accurate certification and disclosure statements as required by FDA regulations. The sponsor agrees to be responsible for implementing and maintaining quality control and quality assurance systems with written procedures to ensure that the clinical trial is conducted and data are generated, documented, and reported in compliance with this protocol, accepted standards of good clinical practice, and all applicable federal, state, and local laws, rules, regulations, requirements, and guidelines (including all foreign laws and governmental requirements as applicable) relating to the conduct of the clinical trial. Principal Investigator s Signature Site Address and Telephone Print Name Date Tucatinib (ONT-38) Cascadian Therapeutics, Inc. 18-JUL-217 Protocol ONT-38-5 Amendment 7 CONFIDENTIAL Page 1 of 15

13 Protocol Number: Protocol Title: Investigational Product: Amendment No.: Previous Versions: Clinical Study Protocol Signature Page ONT-38-5 A Phase 1b, open-label study to assess the safety and tolerability of ONT-38 combined with capecitabine and trastuzumab, alone and in combination in HER2+ metastatic breast cancer Tucatinib (ONT-38) 7 (18-JUL-217) 6 (6-JUL-216) 5 (7-MAY-216) 4 (12-SEP-214) 3 (11-JUL-214) 2 (27-MAR-214) 1 (3-JAN-214) Original (31-OCT-213) Please KEEP with protocol. By signing this protocol, the investigator agrees to conduct the clinical trial in accordance with this protocol, generally accepted standards of good clinical practice, and all applicable federal, state, and local laws, rules, regulations, requirements, and guidelines (including all foreign laws and governmental requirements as applicable) relating to the conduct of the clinical trial. In addition, the investigator agrees to provide the sponsor with such information and certifications as the sponsor shall reasonably request from time to time regarding direct and indirect financial interests and other arrangements between sponsor and investigator, to allow the sponsor to submit complete and accurate certification and disclosure statements as required by FDA regulations. The sponsor agrees to be responsible for implementing and maintaining quality control and quality assurance systems with written procedures to ensure that the clinical trial is conducted and data are generated, documented, and reported in compliance with this protocol, accepted standards of good clinical practice, and all applicable federal, state, and local laws, rules, regulations, requirements, and guidelines (including all foreign laws and governmental requirements as applicable) relating to the conduct of the clinical trial. Principal Investigator s Signature Site Address and Telephone Print Name Date Tucatinib (ONT-38) Cascadian Therapeutics, Inc. 18-JUL-217 Protocol ONT-38-5 Amendment 7 CONFIDENTIAL Page 2 of 15

14 Clinical Study Protocol Effective Date: 7-MAY-215 Protocol Number: Protocol Title: Investigational Product: Amendment No.: Previous Versions: Indication: Sponsor: Sponsor Monitor: Serious Adverse Event Reports: ONT-38-5 A Phase 1b, open-label study to assess the safety and tolerability of ONT-38 combined with capecitabine and trastuzumab, alone and in combination in HER2+ metastatic breast cancer Tucatinib (ONT-38) 7 (18-JUL-217) 6 (6-JUL-216) 5 (7-MAY-216) 4 (12-SEP-214) 3 (11-JUL-214) 2 (27-MAR-214) 1 (3-JAN-214) Original (31-OCT-213) HER2-positive Metastatic Breast Cancer Cascadian Therapeutics, Inc th Avenue, Suite 5 Seattle, WA Luke Walker, MD Senior Vice President, Clinical Development Office: Fax: Cascadian Therapeutics, Inc. Fax: Confidentiality Statement This document contains proprietary information which shall not be reproduced, transferred to other documents, disclosed to others, used for manufacturing or any other purpose without prior written permission of Cascadian Therapeutics, Inc. Tucatinib (ONT-38) Cascadian Therapeutics, Inc. 18-JUL-217 Protocol ONT-38-5 Amendment 7 CONFIDENTIAL Page 3 of 15

15 Protocol Synopsis Protocol Synopsis Protocol Number: ONT-38-5 Version: Amendment 7 (18-JUL-217) Phase: 1b Product Name: Tucatinib (ONT-38) Sponsor: Cascadian Therapeutics, Inc th Avenue, Suite 5 Seattle, WA Protocol Title A Phase 1b, open-label study to assess the safety and tolerability of tucatinib (ONT-38) combined with capecitabine and trastuzumab, alone and in combination in HER2+ metastatic breast cancer Study Objectives Primary: Determine the maximum tolerated dose/recommended Phase 2 dose (MTD/RP2D) of tucatinib to Secondary: be given in combination with capecitabine alone, with trastuzumab alone, and with both trastuzumab and capecitabine. Evaluate the safety of tucatinib given at the MTD/RP2D in combination with capecitabine alone, with trastuzumab alone, and with both trastuzumab and capecitabine. Examine the effects of combination therapy on the pharmacokinetics (PK) of tucatinib and capecitabine when given in combination. Evaluate the preliminary anti-tumor activity of tucatinib given in combination with capecitabine Exploratory: alone, with trastuzumab alone, and with both trastuzumab and capecitabine. Assess p95 expression and the presence of other potential biomarkers of response in archived tumor biopsy specimens. Evaluate the preliminary anti-tumor activity of tucatinib in combination with capecitabine alone, with trastuzumab alone, and with both trastuzumab and capecitabine on central nervous system (CNS) metastases. Tucatinib (ONT-38) Cascadian Therapeutics, Inc. 18-JUL-217 Protocol ONT-38-5 Amendment 7 CONFIDENTIAL Page 4 of 15

16 Protocol Synopsis Study Population Patients with progressive HER2+ metastatic breast cancer who have received prior treatments with both trastuzumab and ado-trastuzumab emtansine (T-DM1) (unless deemed intolerant to or ineligible for T-DM1 by the investigator) for metastatic disease. Inclusion Criteria Patients must meet the following criteria to be eligible for the study: 1) Metastatic breast cancer, documented as HER2+ by fluorescence in situ hybridization (FISH) and/or 3+ staining by immunohistochemistry (IHC). 2) Progressive disease, with a history of prior treatment with both trastuzumab and T-DM1 (unless deemed intolerant to or ineligible for T-DM1 by the investigator) for metastatic disease. 3) 18 years at time of consent. 4) If female and of child-bearing potential, has negative pregnancy test within 14 days prior to treatment. 5) If a sexually active male or a sexually active female of child-bearing potential, agrees to use dual (two concurrent) forms of medically accepted contraception from the time of consent until 6 months after the last dose of tucatinib, capecitabine, or trastuzumab, whichever is longest. 6) Signed an informed consent document that has been approved by an institutional review board or independent ethics committee (IRB/IEC). 7) Must have target or non-target lesions as per Response Evaluation Criteria In Solid Tumors (RECIST) ) All toxicity related to prior cancer therapies must have resolved to Grade 1, with the following exceptions: alopecia; neuropathy, which must have resolved to Grade 2; and congestive heart failure (CHF), which must have been Grade 1 in severity at the time of occurrence and must have resolved completely. 9) Eastern Cooperative Oncology Group (ECOG) performance status of or 1 at screening. 1) In the opinion of the Investigator, life expectancy > 6 months. 11) Adequate hematologic function as defined by: a) Hemoglobin 9 g/dl b) Absolute neutrophil count (ANC) 1 cells/µl c) Platelets 1,/µL Tucatinib (ONT-38) Cascadian Therapeutics, Inc. 18-JUL-217 Protocol ONT-38-5 Amendment 7 CONFIDENTIAL Page 5 of 15

17 Protocol Synopsis 12) Adequate hepatic function as defined by the following: a) Total bilirubin 1.5 X upper limit of normal (ULN), unless a known history of Gilbert s disease b) Transaminases (aspartate aminotransferase/serum glutamic oxaloacetic transaminase [AST/SGOT] and alanine aminotransferase/serum glutamic pyruvic transaminase [ALT/SGPT]) 2.5 X ULN (< 5 X ULN if liver metastases are present) 13) International normalized ratio (INR) and activated partial thromboplastin time (aptt) 1.5 X ULN unless on medication known to alter INR and aptt. 14) Creatinine clearance 5 ml/min. 15) Left ventricular ejection fraction (LVEF) must be within institutional limits of normal as assessed by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA) documented within 4 weeks prior to first dose of study drug. Exclusion Criteria Patients will be excluded from the study for any of the following reasons: 1) Medical, social, or psychosocial factors that, in the opinion of the Investigator, could impact safety or compliance with study procedures. 2) Patient is breastfeeding. 3) Previous treatment with any experimental agent within 14 days or five half-lives of study treatment, whichever is greater. 4) Previous treatment with trastuzumab or other antibody-based therapy within three weeks of starting study treatment or with chemotherapy or hormonal cancer therapy within two weeks of starting study treatment. 5) Previous treatment with cumulative dose of doxorubicin > 36 mg/m 2 or previous treatment with another anthracycline with cumulative dose equivalent to > 36 mg/m 2 doxorubicin. 6) Previous treatment with: a) Capecitabine for metastatic disease at any time, for patients assigned to cohorts using capecitabine plus tucatinib (Combination 1) or capecitabine plus trastuzumab plus tucatinib (Combination 3). However, patients who have previous treatment with capecitabine for metastatic disease are eligible for enrollment into cohorts using trastuzumab plus tucatinib (Combination 2). Patients who have received capecitabine for adjuvant or neoadjuvant treatment at least 12 months prior to starting study treatment are eligible to enroll into all cohorts (Combination 1, 2, or 3). b) Any small molecule HER2 inhibitors including (but not limited to) lapatinib, neratinib, or afatinib Tucatinib (ONT-38) Cascadian Therapeutics, Inc. 18-JUL-217 Protocol ONT-38-5 Amendment 7 CONFIDENTIAL Page 6 of 15

18 Protocol Synopsis within the last 4 weeks prior to initiation of study therapy. 7) CNS disease: a) Patients with leptomeningeal disease are excluded. b) Dose escalation and expansion cohorts: Patients with symptomatic CNS metastases are excluded. Patients with treated CNS metastases or untreated asymptomatic CNS metastases not requiring immediate local therapy may be eligible. Enrollment of patients with metastases must be approved by the study medical monitor. c) Optional CNS disease expansion cohorts: Patients with untreated asymptomatic CNS metastases not requiring immediate local therapy or patients with progressive CNS disease following local therapy may be eligible with medical monitor approval. 8) History of allergic reactions to compounds of similar chemical or biological composition to capecitabine (for patients assigned to Combination 1 or 3 only), trastuzumab (for patients assigned to Combination 2 or 3 only), or tucatinib, except for a history Grade 1 or Grade 2 Infusion Related Reaction to trastuzumab which has been successfully managed. 9) Patients with uncorrectable electrolyte abnormalities. 1) Known to be HIV positive. HIV testing is not required for those patients who are not known to be positive. 11) Known carrier of Hepatitis B and / or Hepatitis C (whether active disease or not). 12) Known liver disease, autoimmune hepatitis, or sclerosing cholangitis. 13) Inability to swallow pills or any significant gastrointestinal diseases, which would preclude adequate absorption of oral medications. 14) Use of a strong CYP3A4 inducer or inhibitor within three elimination half-lives of the inhibitor or inducer prior to the start of study treatment. (See Appendix G). 15) Use of strong CYP2C8 inducer or inhibitor within three elimination half-lives of the inducer or inhibitor prior to the start of study treatment. (See Appendix F). 16) Radiotherapy within 14 days of first dose of tucatinib; patient must have recovered from acute effects of radiotherapy to baseline. 17) Known impaired cardiac function or clinically significant cardiac disease such as ventricular arrhythmia requiring therapy, congestive heart failure, and uncontrolled hypertension (defined as systolic blood pressure >15 mmhg and/or diastolic blood pressure > 1 mmhg on antihypertensive medications). 18) Myocardial infarction or unstable angina within 6 months prior to the first dose of study drug. 19) Patient with known dihydropyrimidine dehydrogenase deficiency (for patients assigned to Tucatinib (ONT-38) Cascadian Therapeutics, Inc. 18-JUL-217 Protocol ONT-38-5 Amendment 7 CONFIDENTIAL Page 7 of 15

19 Protocol Synopsis Combination 1 or 3 only). 2) Patients requiring warfarin therapy with known history of difficulty in management of maintaining INR within therapeutic range. Patients on warfarin may be included if on a stable dose with a therapeutic INR. Study Design and Number of Planned Patients This is a Phase 1b, open-label, multiple dose study to assess the safety, tolerability, and MTD/RP2D of tucatinib combined with 1) capecitabine alone, 2) trastuzumab alone, and 3) capecitabine and trastuzumab. The combinations, cohorts and dose levels to be studied are described in the table below, and in Table 7. The study will use a 3+3 dose escalation design to evaluate escalating dose levels of tucatinib in each of these three different combinations. 3 6 evaluable patients will be enrolled in each cohort in the dose escalation phase, unless that dose is found to be intolerable (i.e., 2 or more evaluable patients experience DLT) prior to completion of enrollment. At least 6 evaluable patients are to be treated at a dose level in order for an MTD/RP2D for that combination to be determined. The MTD/RP2D of tucatinib to be used in combination with either capecitabine alone (Combination 1) or trastuzumab alone (Combination 2) will be determined prior to evaluating tucatinib in combination with both capecitabine and trastuzumab (Combination 3). If Combination 1 and Combination 2 are found to be tolerable, then tucatinib will be evaluated in Combination 3, using the lowest MTD/RP2D or other SMCrecommended dose of tucatinib determined for either of the two drug combinations. This will be followed by enrollment of an expansion cohort of patients treated at the MTD/RP2D for Combination 3 (cohort 3A). Additional expansion cohorts for either Combination 1 (tucatinib and capecitabine) or Combination 2 (tucatinib and trastuzumab) may also be enrolled. Refer to Section 5.4 for details regarding the methods of assigning patients to cohorts. Provided that only seven dose cohorts are needed for dose escalation and only the expansion cohort for Combination 3 is enrolled up to 66 evaluable patients may be enrolled (i.e., 6 patients each in cohorts 1A, 1B, 1C, 2A, 2B, 2C and up to 3 in cohort 3A). Additional patients may be enrolled if additional expansion cohorts are opened. Following approval of Amendment 7, patients who are on study treatment may continue to receive study drug. Tucatinib (ONT-38) Cascadian Therapeutics, Inc. 18-JUL-217 Protocol ONT-38-5 Amendment 7 CONFIDENTIAL Page 8 of 15

20 Protocol Synopsis Planned Dose Escalation and Expansion Cohorts Combination Cohort Tucatinib Capecitabine Trastuzumab a,b Comment Combination 1 (Tucatinib + Capecitabine) 1A 1B 1C 3 mg BID 35 mg BID 4 mg BID 1 mg/m 2 BID days mg/m 2 BID days mg/m 2 BID days 1-14 NA NA NA 1D TBD TBD NA Optional cohort to evaluate alternative dose of tucatinib and/or capecitabine. Combination 2 (Tucatinib + Trastuzumab) Combination 3 (Tucatinib + Capecitabine + Trastuzumab) 1E TBD TBD NA Optional expansion cohort. 1F TBD TBD NA 2A 3 mg BID NA 2B 35 mg BID NA 2C 4 mg BID NA 2D TBD NA 2E TBD NA 2F 3 mg BID NA 3A 3 mg BID 3B TBD TBD 3C TBD TBD 3D TBD TBD 3E 3 mg BID 1 mg/m 2 BID days mg/m 2 BID days mg/kg IV C1 D1, then 6 mg/kg q 21 days starting C2 8 mg/kg IV C1 D1, then 6 mg/kg q 21 days starting C2 8 mg/kg IV C1 D1, then 6 mg/kg q 21 days starting C2 8 mg/kg IV C1 D1, then 6 mg/kg q 21 days starting C2 8 mg/kg IV C1 D1, then 6 mg/kg q 21 days starting C2 8 mg/kg IV C1 D1, then 6 mg/kg q 21 days starting C2 8 mg/kg IV C1 D1, then 6 mg/kg q 21 days starting C2 8 mg/kg IV C1 D1, then 6 mg/kg q 21 days starting C2 8 mg/kg IV C1 D1, then 6 mg/kg q 21 days starting C2 8 mg/kg IV C1 D1, then 6 mg/kg q 21 days starting C2 8 mg/kg IV C1 D1, then 6 mg/kg q 21 days starting C2 Optional CNS disease cohort. Optional cohort to evaluate alternative dose of tucatinib. Optional expansion cohort. Optional CNS disease cohort. Dose escalation and MTD/RP2D Expansion Optional cohort to evaluate alternative dose of tucatinib and/or capecitabine. Optional cohort to evaluate alternative dose of tucatinib and/or capecitabine. Optional cohort to evaluate alternative dose of tucatinib and/or capecitabine. Optional CNS disease cohort. Abbreviations: twice daily (BID); cycle (C); central nervous system (CNS); day (D); maximum tolerated dose/recommended Phase 2 dose (MTD/RP2D); oral (PO); intravenous (IV); to be determined (TBD). Cohorts in bold are non-optional cohorts. a. Trastuzumab may be given at a weekly dose at 2 mg/kg q 7 days under certain circumstances, see section 5.1 b. If patient has received trastuzumab within four weeks of first trastuzumab dose on study, loading dose is not required, and patient will begin with 6 mg/kg q 21 days on C1. Tucatinib (ONT-38) Cascadian Therapeutics, Inc. 18-JUL-217 Protocol ONT-38-5 Amendment 7 CONFIDENTIAL Page 9 of 15

21 Protocol Synopsis Test Product, Dose, and Mode of Administration All treatments will be given on a 21-day cycle. Tucatinib will be administered twice daily at escalating doses in each cohort. Capecitabine will be given at 1 mg/m 2 PO BID on Days 1 14 of each 21-day cycle. Trastuzumab will be given as a loading dose of 8 mg/kg intravenously (IV) followed by 6 mg/kg once every 21 days, except in specific circumstances outlined in detail in section 5.1. Duration of Treatment Patients will be assessed for progression every 2 cycles through cycle 6, and then every 3 cycles. Treatment will continue until unacceptable toxicity, disease progression, withdrawal of consent, or Sponsor decision. Efficacy Assessments Efficacy will be measured by contrast computed tomography (CT) and/or contrast magnetic resonance imaging (MRI) of the body done at baseline, every 2 cycles through Cycle 6, and then every 3 cycles. All known sites of disease will be assessed at time of restaging. Additional imaging, such as nuclear bone scans, may also be done as appropriate at the discretion of the Investigator. Imaging will be assessed per RECIST 1.1 by the Investigator. Patients with CNS disease may also be assessed by modified CNS RECIST 1.1 criteria (See Appendix A). Contrast brain MRI images for patients with CNS metastases may be collected for additional independent review. However, all treatment decisions will be made by local review of radiologic imaging. Following approval of Amendment 7, patients on study treatment will be assessed for efficacy based upon institutional policy without protocol mandated efficacy time points Safety Assessments Safety assessments will include surveillance and documentation of adverse events (AEs) (including dose limiting toxicities [DLTs]), laboratory assessments, physical exam findings, and cardiac assessments. Following approval of Amendment 7, patients on study treatment will be assessed for safety based upon institutional policy. Only serious adverse events (SAEs) and adverse events of interest (AOIs) will be collected by the Sponsor (AST or ALT elevations that are > 3 X ULN with concurrent elevation [within 21 days of AST and/or ALT elevations] of total bilirubin > 2 X the ULN, except in patients with documented Gilbert s syndrome, asymptomatic decline in LVEF leading to a change in study treatment or discontinuation of study treatment, any event of cerebral edema not clearly attributable to progression of disease, CTCAE Grade 3 diarrhea). Statistical Methods The study will utilize a standard 3+3 dose escalation design to determine the MTD/RP2D of tucatinib to be given in combination with capecitabine alone, trastuzumab alone, and both capecitabine and trastuzumab. Other safety, efficacy and exploratory endpoints will be summarized descriptively. Endpoints Tucatinib (ONT-38) Cascadian Therapeutics, Inc. 18-JUL-217 Protocol ONT-38-5 Amendment 7 CONFIDENTIAL Page 1 of 15

22 Protocol Synopsis Primary: Incidence and severity of AEs Secondary: Incidence and severity of clinical laboratory abnormalities Frequency of dose reductions in tucatinib Frequency of dose reductions in capecitabine Plasma concentrations of tucatinib and metabolite Plasma concentrations of capecitabine and metabolites Objective response rate (ORR) Duration of response Disease control rate (best response of complete response [CR], partial response [PR], or stable disease [SD]) Clinical benefit rate (CBR) (SD for 6 months, PR, or CR) Progression-free survival (PFS) Exploratory: p95 expression and the presence of other potential biomarkers of response in archived tumor biopsy specimens CNS response rate Tucatinib (ONT-38) Cascadian Therapeutics, Inc. 18-JUL-217 Protocol ONT-38-5 Amendment 7 CONFIDENTIAL Page 11 of 15

23 Table of Contents Table of Contents 1 INTRODUCTION HER2+ Breast Cancer Treatment of HER2+ Breast Cancer Ongoing Medical Need in HER2+ Breast Cancer ONT-38: Product Description and Mechanism for Action Preclinical Studies Summary of Clinical Data for ONT Phase 1 Single-Agent Study (ARRAY-38-11) Patient Characteristics Dose Escalation and Determination of Maximum Tolerated Dose Adverse Events Efficacy Results Clinical Pharmacokinetic Results Ongoing Studies with ONT Summary of ONT Trastuzumab Efficacy of Trastuzumab Safety of Trastuzumab Capecitabine Efficacy of Capecitabine Safety of Capecitabine Purpose of the Study OBJECTIVES Primary Objective Secondary Objectives Exploratory Objectives Endpoints Primary Endpoint Secondary Endpoints Exploratory Endpoints INVESTIGATIONAL PLAN Summary of Study Design Dose Escalation Phase Expansion Phase Rationale for Selection of Doses Potential Food Effects Potential Drug Interactions between ONT-38, Capecitabine, and Trastuzumab Tucatinib (ONT-38) Cascadian Therapeutics, Inc. 18-JUL-217 Protocol ONT-38-5 Amendment 7 CONFIDENTIAL Page 12 of 15

24 Table of Contents 3.7 Potential Risks of Combination Therapy with ONT-38, Capecitabine, and Trastuzumab STUDY POPULATION Inclusion Criteria Exclusion Criteria Criteria for Patient Withdrawal and Replacement TREATMENTS Treatments Administered Dose Modifications and Discontinuations Identity of Investigational Products Packaging and Labeling Preparation and Administration Storage and Handling Study Drug Accountability Method of Assigning Patients to Treatment Groups Concomitant Therapy Required Concomitant Therapy Permitted and Prohibited Concomitant Therapy Treatment Compliance SCHEDULE OF EVENTS Screening/Baseline (Days -28 to 1) Cycle 1 Day Cycle 1 Day 8 (± 48 hours) Cycle 1 Day 14 (±24 hours) Cycle 2 Day 1 (± 24 hours) Cycle 2 Day 8 (± 48 hours) Cycle 2 Day 15 (± 48 hours) Cycle 2 Day 21 (± 7 days) Cycle 3 Day 1, and Day 1 of all Subsequent Cycles (± 24 hours) Cycle 3 Day 1 and Cycle 4 Day 1 (± 72 hours) Cycle 4 Day 21 (± 7 days) Cycle 6 Day 21 (and thereafter at the end of every third cycle; ± 7 days) Cycle 8 Day 21 (and thereafter at the end of every fourth cycle; ± 7 days) End of Study (3 days, ± 7, after last dose of capecitabine, trastuzumab, or ONT-38, whichever is latest) 67 7 STUDY ASSESSMENTS Efficacy Measures Biomarker Assessments Pharmacokinetic Measures Safety Assessments... 7 Tucatinib (ONT-38) Cascadian Therapeutics, Inc. 18-JUL-217 Protocol ONT-38-5 Amendment 7 CONFIDENTIAL Page 13 of 15

25 Table of Contents Clinical Laboratory Evaluation Adverse Events Definitions of Adverse Events Documenting and Monitoring Adverse Events Assessment of Adverse Events Serious Adverse Events Definition and Reporting Procedures Follow-up of Adverse Events and Laboratory Test Abnormalities Pregnancy Reporting Overdose Other Safety Measures Appropriateness of Measurements DATA QUALITY CONTROL AND QUALITY ASSURANCE Study Monitoring Data Management Quality Assurance Audits STATISTICAL METHODS Determination of Sample Size Statistical Analysis Patient Analysis Sets Statistical and Analytical Plans General Considerations Adjustments for Covariates Handling of Missing Data Patient Characteristics Safety Analyses Adverse Events Serious Adverse Events Clinical Laboratory Results Other Safety Analyses Efficacy Analyses Primary Efficacy Endpoint Secondary Efficacy Endpoints Exploratory Efficacy Endpoints Concomitant Medications Subject Disposition Subject Characteristics Protocol Deviations Tucatinib (ONT-38) Cascadian Therapeutics, Inc. 18-JUL-217 Protocol ONT-38-5 Amendment 7 CONFIDENTIAL Page 14 of 15

26 Table of Contents Extent of Exposure Interim Analyses INFORMED CONSENT, ETHICAL REVIEW, AND ADMINISTRATIVE AND REGULATORY CONSIDERATIONS Informed Consent Ethical Review Administrative and Regulatory Considerations Investigator Information Protocol Amendments and Study Termination Study Documentation, Privacy, and Records Retention Clinical Trial Agreement ABBREVIATIONS AND DEFINITIONS OF TERMS LITERATURE REFERENCES List of Tables Table 1 Studies Evaluating Capecitabine and Lapatinib in CNS Metastases Table 2 HER2 and HER1 Inhibition Table 3 Summary of Completed Clinical Studies using ONT Table 4 Treatment-emergent Adverse Events by Preferred Term and Severity Reported in Patients (Study ARRAY-38-11), Regardless of Relationship to Drug Table 5 RECIST Response by Dose Level in Evaluable Patients Table 6 Ongoing ONT-38 Clinical Trials Table 7 Planned Dose Escalation and Expansion Cohorts... 4 Table 8 Recommended ONT-38 Dose Reduction Schedule* Table 9 Dose Modifications of ONT-38 and Trastuzumab for Clinical Adverse Events Other Than Left Ventricular Dysfunction Related to Either ONT-38 and/or Trastuzumab, or Hepatocellular Toxicity Table 1 Dose Modification of Capecitabine for Clinical Adverse Events Considered Related to Capecitabine a Table 11 Dose Modifications of ONT-38 and Capecitabine for Liver Function Abnormalities Table 12 Dose Modifications for Left Ventricular Dysfunction Table 13 PK Schedule of ONT-38 (Only in Patients Receiving Combination 1 and Combination 3 in Dose Escalation and Expansion Cohorts)... 7 Table 14 Adverse Event Severity Grading Scale (CTCAE Version 4.3) Table 15 Adverse Event Relationship to Study Drug Table 16 Adverse Event Outcomes Table 17 Definition of Serious Adverse Events Tucatinib (ONT-38) Cascadian Therapeutics, Inc. 18-JUL-217 Protocol ONT-38-5 Amendment 7 CONFIDENTIAL Page 15 of 15

27 Table of Contents List of Figures Figure 1 Effect of Treatment with ONT-38 (± Docetaxel) on BT-474 HER2+ Breast Cancer Model Figure 2 Effect of Treatment with ONT-38 (± Trastuzumab) on BT-474 HER2+ Breast Cancer Model Figure 3 BT-474 HER2+ Breast Carcinoma: Intracranial Tumor Implantations Figure 4 Change in Measurable Disease (Study ARRAY-38-11) List of Appendices Appendix A: Modified RECIST 1.1 and Volumetric Response Criteria for CNS Disease Appendix B: Schedule of Events for Screening and Cycle Appendix C: Schedule of Events for Cycle Appendix D: Schedule of Events for Cycle 3 and All Subsequent Cycles Appendix E: Schedule of Events for End of Study Visit Appendix F: List of Selected Strong Inhibitors and Inducer of CYP2C8 and Their Elimination Half-Lives... 1 Appendix G: List of Selected Strong Inhibitors or Inducers of CYP3A4 and Their Elimination Half-Lives Tucatinib (ONT-38) Cascadian Therapeutics, Inc. 18-JUL-217 Protocol ONT-38-5 Amendment 7 CONFIDENTIAL Page 16 of 15

28 Section 1 Introduction 1 INTRODUCTION 1.1 HER2+ Breast Cancer Breast cancer is the most common form of cancer in women worldwide, 1 and the second leading cause of cancer-related death in the United States. 2 Approximately 2% of breast cancers overexpress the human epidermal growth factor receptor 2 (HER2). 3 HER2 is a trans-membrane tyrosine kinase receptor that mediates cell growth, differentiation, and survival. Tumors that overexpress HER2 are more aggressive and historically have been associated with poorer overall survival (OS) compared to HER2 negative cancers, 4 although the introduction of HER2 targeted therapies has led to ongoing improvements in clinical outcomes. HER2 belongs to a family of four related receptor tyrosine kinases, which also include HER1 (also referred to as epidermal growth factor receptor [EGFR]), HER3, and HER4. These are single-pass transmembrane glycoprotein receptors containing an extracellular ligand binding region and an intracellular signaling domain. In addition, all receptors contain an intracellular active tyrosine kinase domain with the exception of HER3, whose kinase domain does not exhibit enzymatic activity. The activation process is initiated by ligand binding to the extracellular domain of the receptor by one of a number of different hormones such as EGF, transforming growth factor (TGF), and the neuregulins. Upon ligand binding, homo- or heterodimerization is induced, which results in the activation of the tyrosine kinase domains and phosphorylation of tyrosines on the intracellular signaling domains. As no known ligand for HER2 has been described and HER3 lacks an active kinase domain, these receptors heterodimerize to elicit a response, and it has been demonstrated that HER2 is typically the preferred dimerization partner for the other HER family receptors. Receptor activation leads to initiation of different signaling cascades including the Ras/Raf/MEK/MAPK, PI3K/AKT, Src, and STAT pathways. These signaling pathways lead to both cell proliferation and cell survival through inhibition of apoptosis Treatment of HER2+ Breast Cancer HER2 targeted therapy using either antibody-based therapy or a small molecule tyrosine kinase inhibitor (TKI) has led to significant and ongoing improvements in disease-free survival (DFS), progression-free survival (PFS), and OS in both the adjuvant and metastatic settings Trastuzumab (HERCEPTIN ), a humanized anti-her2 antibody that binds to the HER2 extracellular domain, was the first anti-her2 agent approved by the FDA for use in the treatment of HER2+ breast cancer, and remains the backbone of treatment in the adjuvant and first-line metastatic settings, usually in combination with a taxane. The approval of trastuzumab was followed by the approval of lapatinib (TYKERB ), a small molecule tyrosine kinase inhibitor (TKI) that targets both HER2 Tucatinib (ONT-38) Cascadian Therapeutics, Inc. 18-JUL-217 Protocol ONT-38-5 Amendment 7 CONFIDENTIAL Page 17 of 15

29 Section 1 Introduction and EGFR. Lapatinib is approved for use in combination with capecitabine in patients with metastatic disease who have progressed following prior trastuzumab and taxane therapy, or in combination with letrozole in patients with ER+/PR+ metastatic disease. In addition, pertuzumab (PERJETA ), another antibody-based therapy which binds to HER2 at a site different than trastuzumab and inhibits HER2 dimerization, has also been approved for use in combination with trastuzumab and docetaxel as first-line therapy for patients with HER2+ metastatic disease. Finally, ado-trastuzumab emtansine (KADCYLA, also known as T-DM1), an antibody-drug conjugate composed of trastuzumab, a thioether linker, and a derivative of the antimitotic agent maytansine, was approved by the United States Food and Drug Administration (FDA) in February 213 for patients who progress following prior therapy with trastuzumab and a taxane, either separately or in combination, as either treatment for metastatic disease, or following progression within 6 months of completing as adjuvant therapy. Anti-HER2 therapy has been approved for use in combination with cytotoxic chemotherapy including taxanes, platinum agents, or capecitabine, or in the case of lapatinib, in combination with hormonal therapy such as letrozole. T-DM1 has been approved as a single agent, but is a conjugate with the cytotoxic agent, maytansine. The use of these cytotoxic agents in combination with anti-her2 therapy such as trastuzumab or lapatinib allows for concurrent treatment with agents having two different mechanisms of action, leading to greater efficacy than with either agent alone. 11,15 16 Current standard of care for metastatic HER2+ breast cancer is evolving, and depends in part upon what treatment patients received previously. 213 NCCN guidelines 17 recommend the following: a) 1 st line treatment of HER2+ metastatic disease i) Trastuzumab + pertuzumab + taxane ii) T-DM1 (Preferred regimen for trastuzumab-exposed disease) iii) Trastuzumab + taxane iv) Trastuzumab + other chemo (vinorelbine, capecitabine) b) After prior trastuzumab and chemotherapy i) T-DM1 ii) Lapatinib + capecitabine iii) Continue trastuzumab and change chemotherapy (e.g., vinorelbine or capecitabine) iv) Trastuzumab + lapatinib Tucatinib (ONT-38) Cascadian Therapeutics, Inc. 18-JUL-217 Protocol ONT-38-5 Amendment 7 CONFIDENTIAL Page 18 of 15

30 Section 1 Introduction Ongoing Medical Need in HER2+ Breast Cancer Despite the improvements in outcomes for HER2+ breast cancer, up to a quarter of all patients treated with anti-her2 therapy in the adjuvant setting relapse, and essentially all patients in the metastatic setting ultimately progress, including those treated with the newest agents such as pertuzumab and T-DM1. Treatment failures may result from primary or acquired resistance to HER2 blockade. Potential mechanisms of resistance to trastuzumab-based therapy may include increased dimerization with other HER2 family members, cross-talk with insulin-like growth factor-1 receptor, 18 expression of a truncated form of HER2 (p95her2) which lacks the extracellular trastuzumab binding domain, 19 and changes in expression of surface glycopeptides such as MUC4 which may block access to the trastuzumab binding site. Other mechanisms of resistance may include increased signaling through non-her family growth factor receptors, increased signaling through the PI3K pathway either due to kinase activating mutations or PTEN deficiency, or increased activation of Rac1, a GTPase that affects trastuzumab-mediated endocytosis of the HER2 receptor There is increasing evidence that dual targeting of HER2, either through combination of two different HER2 targeted antibodies such as trastuzumab and pertuzumab, or through use of an antibody-based therapy such as trastuzumab and a TKI, can lead to further improvements in efficacy in metastatic disease. 13,22 In particular, combination of a small molecule TKI with an antibody-based therapy may be effective. This combination may help overcome resistance to antibody-mediated inhibition through utilization of an alternative mechanism of receptor inhibition, as well as through inhibition of the p95 form of HER2. Lapatinib, a dual EGFR/HER2 oral TKI, has been shown to have increased activity in combination with trastuzumab compared to lapatinib alone, even when given to patients who have previously progressed on prior trastuzumab-based therapy Use of lapatinib, however, has been limited by the anti-egfr/her1 activity of the drug, which results in toxicities such as rash, diarrhea, and fatigue. There is therefore a need for a more selective small molecule inhibitor of HER2 which could be combined with other anti-her2 therapies to improve clinical outcomes. Perhaps the greatest unmet medical need in the post-trastuzumab era is treatment and prevention of central nervous system (CNS) metastases. Recent data suggest that the incidence of first relapse occurring in the CNS is increasing in patients who have received trastuzumab-based adjuvant therapy, 25 and approximately 3% of HER2+ patients with metastatic disease will develop CNS metastases. 26 The increasing prevalence of CNS metastases in HER2+ breast cancer patients may be due to several factors. First, HER2+ breast cancer appears to display tropism for the CNS. Second, with better control of non-cns disease, patients may be living longer allowing CNS metastases to become more of a critical clinical issue. Finally, and perhaps most Tucatinib (ONT-38) Cascadian Therapeutics, Inc. 18-JUL-217 Protocol ONT-38-5 Amendment 7 CONFIDENTIAL Page 19 of 15

31 Section 1 Introduction importantly, the CNS may represent a sanctuary site for HER2+ disease as large molecules such as trastuzumab do not penetrate the blood-brain barrier. 27 Treatment options for CNS metastases are limited. There is currently no specific treatment regimen approved for CNS disease. Treatment of CNS metastases currently consists of use of whole brain or stereotactic radiation. Patients may also receive chemotherapy alone, or capecitabine and lapatinib, although response rates are generally modest as described below. Use of a small molecule HER2 inhibitor such as lapatinib offers a theoretically attractive approach to the treatment of CNS disease. Results with single-agent lapatinib have been disappointing, with response rates below 1%. Response rates for lapatinib and capecitabine have been variable, in part due to differences in patient populations studied and methodology used to assess response. Of note, several of these studies use volumetric response rather than RECIST to measure response. Response rates using the former method tend be higher than those using the latter. Use of lapatinib/capecitabine is limited, due to concerns regarding toxicity and limited efficacy. A summary of studies looking at capecitabine and lapatinib is presented in Table 1. Tucatinib (ONT-38) Cascadian Therapeutics, Inc. 18-JUL-217 Protocol ONT-38-5 Amendment 7 CONFIDENTIAL Page 2 of 15