Tucatinib

Tucatinib is an investigational, orally bioavailable, potent tyrosine kinase inhibitor (TKI) that is selective for HER2 without  inhibition of EGFR. Inhibition of EGFR has been associated with significant toxicities, including skin rash and diarrhea.  Tucatinib has shown activity as a single agent and in combination with both chemotherapy and other HER2 directed agents such as trastuzumab.1,2 Studies of tucatinib in these combinations have shown activity both systemically and in brain metastases.

Compound

Cellular Selectivity Data

HER2 

IC50 (nM)

EGFR

IC50 (nM)

tucatinib

8

>10,000

Unmet Need in HER2+ Metastatic Breast Cancer

With longer survival and better control of systemic disease, brain metastases remain an unmet need. It is estimated that ~20% of patients with invasive breast cancer have overexpression of HER2. HER2+ metastatic breast cancer will spread to the brain in up to 50% of patients.3 Brain metastases have become a major limitation of life expectancy and quality of life for many patients. Tucatinib is the only investigational HER2-selective small molecule in clinical development for patients with HER2+ metastatic breast cancer with or without brain metastases.

Preclinical Results

In preclinical studies, tucatinib is highly active as a single agent and in combination with both chemotherapy and trastuzumab in mouse tumor models of HER2+ breast cancer, including models of brain metastases that were less efficacious with lapatinib or the investigational agent neratinib.

Phase 1b Results

In a Phase 1b trial, the triplet combination of tucatinib with capecitabine + trastuzumab demonstrated encouraging anti-tumor activity in patients with HER2+ metastatic breast cancer. Patients were previously treated with a median of 3 anti-HER2 agents. Approximately 40% of patients had brain metastases at baseline (included stable treated brain metastases, untreated brain metastases or progressive brain metastases) after prior treatment.

Patient Population

  • HER2+ metastatic breast cancer with progression after prior therapy with trastuzumab, taxane, and T-DM1 (unless contraindicated)
  • Baseline brain MRIs; patients with brain metastases eligible, including untreated or progressive brain metastases after prior CNS-directed treatment
  • Prior pertuzumab or lapatinib permitted

Treatment

  • Tucatinib was studied in doublet cohorts in combination with capecitabine or trastuzumab, followed by a triplet cohort in combination with capecitabine and trastuzumab
    • Tucatinib 300 mg PO BID (all combinations) or 350 mg PO BID (doublets)
    • Capecitabine 1000 mg/m2 PO BID for 14 days of a 21-day cycle
    • Trastuzumab (8 mg/kg) IV loading dose; (6 mg/kg) IV once every 21 days
  • No anti-diarrheal prophylaxis required

Baseline Patient Characteristics

 

Tucatinib 300 mg BID

+ capecitabine

(N = 7)

Safety Cohort

+ trastuzumab

(N = 18)

Safety Cohort

+ capecitabine and trastuzumab

(N = 27)

Age, median (range)

52 (38-70)

46 (35-67)

50 (35-67)

ECOG 0/1, n (%)

3 (43%)/4 (57%)

9 (50%)/9 (50%)

14 (52%)/13 (48%)

Hormone receptor positive, n (%)

5 (71%)

14 (78%)

15 (56%)

# of prior regimens for metastatic disease,
median (range)

3 (1-5)

6 (2-13)

3 (0-8)

# of prior HER2 agents, median (range)

2 (2-3)

3 (2-4)

3 (2-4)

Trastuzumab, n (%)

7 (100%)

18 (100%)

27 (100%)

Pertuzumab, n (%)

4 (57%)

9 (50%)

20 (74%)

T-DM1, n (%)

7 (100%)

16 (89%)*

27 (100%)

Lapatinib, n (%)

2 (29%)

17 (94%)

10 (37%)

Brain mets, n (%)

2 (29%)

16 (89%)

11 (41%)

Stable, treated mets, n (%)

1 (14%)

7 (39%)

4 (15%)

Untreated mets , n (%)

0

1 (6%)

4 (15%)

Progressive mets after prior tx, n (%)

1 (14%)

8 (44%)

3 (11%)

Source: Hamilton E, et al. Phase 1b Triplet Study update presented at 2016 SABCS.

Most Common Treatment-Emergent Adverse Events Reported

Most Common Adverse Events Reported in Patients in Cohort

Tucatinib 300 mg BID

+ C

(N = 7)

+ Tz

(N = 18)

+ C + Tz

(N = 27)

Diarrhea

Grade 1

Grade 2

Grade 3

5 (71%)

4

1

0

10 (56%)

7

3

0

21 (78%)

14

4

3

Nausea

Grade 1

Grade 2

Grade 3

5 (71%)

4

1

0

6 (33%)

6

0

0

20 (74%)

13

7

0

PPE

Grade 1

Grade 2

Grade 3

5 (71%)

1

3

1

0

0

0

0

18 (67%)

2

13

3

Vomiting

Grade 1

Grade 2

Grade 3

2 (19%)

2

0

0

4 (22%)

2

1

1

13 (48%)

11

2

0

Source: Hamilton E, et al. Phase 1b Triplet Study update presented at 2016 SABCS.

Elevated Liver Function by Grade by Cohort

LFT Abnormalities

Tucatinib 300 mg BID

+ C

(N = 7)

+ Tz

(N = 18)

+ C + Tz

(N = 27)

Increased ALT

Grade 1

Grade 2

Grade 3

5 (71%)

3

1

1

5 (28%)

4

1

0

19 (70%)

15

2

2

Increased AST

Grade 1

Grade 2

Grade 3

6 (86%)

3

2

1

9 (50%)

9

0

0

23 (85%)

15

6

2

Increased Bilirubin

Grade 1

Grade 2

Grade 3

3 (43%)

3

0

0

4 (22%)

3

1

0

14 (52%)

7

5

2

Source: Hamilton E, et al. Phase 1b Triplet Study update presented at 2016 SABCS.

The triplet combination was well tolerated; the majority of adverse events were Grade 1, with most patients able to continue at full dose of tucatinib.

Summary of Data from Phase 1b Triplet Combination Reported in 2016

Evaluated by Independent Central Review

June 2016
N = 27

December 2016

N = 27

Progression-free survival (PFS)

6.3 months

7.8 months

Overall response rate (ORR)

58%

61%

Median duration of response

NA

10 months

Source: Hamilton E, et al. Phase 1b Triplet Study update presented at 2016 SABCS.

response in patients chart

Best Response in Patients with Measurable Lesions

(n=24)

Objective Response Rate (ORR)

14 (61%)

        Complete Response

1

        Partial Response

13

Stable Disease

6 (26%)

Progressive Disease

4

Source: Hamilton E, et al. Phase 1b Triplet Study update presented at 2016 SABCS.

Tucatinib is now being evaluated in a pivotal randomized, double-blind, placebo controlled trial that is currently enrolling in North America, Western Europe, Israel, and Australia.

HER2CLIMB Trial

Pivotal Phase 2 randomized, double-blind, controlled study of tucatinib vs. placebo, each in combination with capecitabine and trastuzumab in patients with pretreated unresectable locally advanced or metastatic HER2+ breast carcinoma.

Treatment Schedule

Treatment is double-blinded, placebo-controlled; all patients receive a 21-day cycle:

  • Study participants will take tucatinib 300 mg or placebo orally twice daily (PO BID) in cycles of 21 days.
  • All participants will also take capecitabine orally on days 1-14 of each 21-day cycle and trastuzumab once every 21 days.
  • No anti-diarrheal prophylaxis required.
  • Study participants will be evaluated throughout the study for safety.
  • At the start of the study, participants will receive a brain MRI as well as any other appropriate scans to measure metastatic disease. These scans will be repeated every 6 weeks for the first 24 weeks and then every 9 weeks.
  • Treatment will continue until unacceptable toxicity, disease progression, or study closure.

Study Population

Patients with progressive, unresectable locally recurrent or metastatic HER2+ breast cancer who have had prior treatment with Herceptin® (trastuzumab), Perjeta® (pertuzumab), and Kadcyla® (T-DM1: ado-trastuzumab emtansine or trastuzumab emtansine).

Number of Planned Patients

It is anticipated that the study will enroll approximately 480 patients at sites in North America, Western Europe, Australia, and Israel.

Study Objectives

Primary Outcome Measure

To assess the effect of tucatinib vs. placebo in combination with capecitabine and trastuzumab on progression-free survival (PFS) based on independent central review

Secondary Outcome Measures

  • PFS in the subgroup of patients with baseline brain metastases based on central review
  • Effect of tucatinib in combination with capecitabine and trastuzumab on overall survival

Eligibility Criteria

*except in cases of negligible exposure.

For a complete list of eligibility criteria, please visit https://clinicaltrials.gov/ct2/show/NCT02614794?term=tucatinib&rank=3

 

Healthcare Provider Contact:
If you have further questions regarding the protocol please contact HER2CLIMBinquiries@cascadianrx.com

Study Locations

      Publications

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      Contact Cascadian Therapeutics

      Cascadian Therapeutics Inc.

      2601 Fourth Avenue, Suite 500
      Seattle, WA 98121

      Main: (206) 801-2100
      Fax: (206) 801-2101

      References

      1. Moulder, S. et al., Phase 1 Study of ONT-380, a HER2 Inhibitor, in Patients with HER2+ Advanced Solid Tumors, with an Expansion Cohort in HER2+ Metastatic Breast Cancer. Clin Cancer Res, May 2017.
      2. Hamilton, E. et al., Efficacy of a Phase 1b Study of Tucatinib (ONT-380), an Oral HER2-Specific Inhibitor, in Combination with Capecitabine and Trastuzumab in HER2+ Metastatic Breast Cancer, Including Patients with Brain Metastases. Presented at the San Antonio Breast Cancer Symposium (SABCS) Annual Meeting 2016, San Antonio, TX, December 9, 2016 (Poster P4-21-01).
      3. ASCO Cancer.Net, Treatment of Metastatic HER2-Positive Breast Cancer.