Updated data from tucatinib (Tukysa®; Seagen), a reversible, highly specific HER2 tyrosine kinase inhibitor which is approved for the treatment of its HER2-positive metastatic breast cancer therapy, will be presented at the 43th San Antonio Breast Cancer Symposium (SABCS) Virtual Symposium, taking place December 8-11, 2020.

A total of 9 abstracts, including two spotlight posters and new analyses from the pivotal HER2CLIMB trial describe outcomes by hormone receptor status, will be addressing unmet needs in breast cancer.[1]

“Following this year’s FDA approval of tucatenib, we continue to broadly study if more patients may benefit from this important medicine,” said Roger Dansey, M.D., Chief Medical Officer at Seagen.

“Data presented at the meeting from the HER2CLIMB trial demonstrate the efficacy of tucatenib regardless of patients’ hormone receptor status, while other clinical and preclinical findings provide new insights about the potential of tucatenib to help patients living with HER2-positive metastatic breast cancer,” Dansey added.

Efficacy Outcomes by Hormone Receptor Status from HER2CLIMB Trial
Outcomes for tucatinib in combination with trastuzumab and capecitabine in patients with HER2-positive metastatic breast cancer from the pivotal HER2CLIMB trial (NCT02614794), a randomized (2:1), double-blind, placebo-controlled trial that enrolled 612 patients with HER2-positive unresectable locally advanced or metastatic breast cancer who had previously received, either separately or in combination, trastuzumab, pertuzumab, and ado-trastuzumab emtansine (T-DM1), by hormone receptor (HR) status will be featured in a spotlight poster (Abstract #PD3-08). The results will be presented by Erika P. Hamilton, M.D., Director, Breast Cancer, and Gynecologic Cancer Research Program at the Sarah Cannon Research Institute.

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Health-related quality of life
Patients with HER2+ MBC who have brain metastases have limited treatment options and lower health-related quality of life (hrQoL) compared with patients without brain metastases. Andrew Wardley, MD,  of the NIHR Manchester Clinical Research Facility at The Christie NHS Foundation & Trust Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology Medicine & Health, University of Manchester, Manchester, United Kingdom, will present the results of an evaluation of the impact of tucatinib on hrQoL in patients with stable and active brain metastases (Abstract #PD13-04)

Compared to the placebo arm, pts on the tucatinib arm had an approximately 49% reduction in the risk of deterioration (hazard ratio: 0.51; 95% CI: 0.28, 0.93); the median time to deterioration has not been reached in the tucatinib arm with available follow-up and was 5.5 months (95% CI; 4.2, -) in the placebo arm. Decline in all domains of the EQ-5D-5L and the EQ-VAS scores were seen once patients discontinued their therapy, particularly on the ‘usual activities’ domain.

Tucatinib + trastuzumab emtansine
Results from a study designed to determine the maximal tolerated dose (MTD) or recommended dose (RD) and to assess the safety and tolerability of tucatinib in combination of ado-trastuzumab emtansine (T-DM1; Kadcyla®; Genentech/Roche) in patients with HER2+ breast cancer (NCT01983501) shows that simultaneous dual HER2 inhibition with tucatinib and trastuzumab emtansine, along with the results of the phase Ib/II clinical trial demonstrating preliminary safety and efficacy of the combination, confirms that further clinical development of the combination of tucatinib +  trastuzumab emtansine is warranted. These results also support the evaluation of tucatinib in combination with other HER2-targeted ADCs in patients with HER2+ MBC.[2]

Meaningful improvements
As previously reported, the addition of tucatinib to trastuzumab and capecitabine resulted in clinically meaningful improvements in overall survival (OS), progression-free survival (PFS) and objective response rate (ORR) compared to the addition of placebo. The new exploratory analyses presented at SABCS demonstrated that the PFS, OS, and ORR improvements with tucatinib were observed consistently across hormone receptor status subgroups, including in patients with brain metastases.

Title#AbstractPresentationPresented by
Tucatinib versus placebo in combination with trastuzumab and capecitabine for patients with locally advanced unresectable or HER2-positive metastatic breast cancer (HER2CLIMB): outcomes by hormone receptor status #PD3-08 Spotlight Poster Discussion 3 – Wednesday, Dec. 9 from 6:45 – 7:45 p.m. CT Hamilton EP, Reinisch M, Loi S, Okines A, Pohlmann PR, Harder Brix E, Bourgeois H, et al.
Impact of tucatinib on health-related quality of life in patients with HER2+ metastatic breast cancer with stable and active brain metastases #PD13-04Spotlight Poster Discussion 13 – Friday, Dec. 11 from 1 – 2:15 p.m. CT Wardley A, Mueller V,  Paplomata E, Crouzet L, Iqbal N, Aithal S, Block M, et al.
Tucatinib favourably modulates the immune microenvironment and synergizes with anti-PD1 therapy in a trastuzumab resistant HER2+ murine model #PS10-04 Poster Session 10 / Wednesday, Dec. 9 at 8 a.m. CT Li R, Sant S, Brown E, Caramia F, Byrne A, Clarke K, Neeson M, et al.
Tucatinib potentiates the activity of the antibody-drug conjugate T-DM1 in preclinical models of HER2-positive breast cancer #PS10-08 Poster Session 10 / Wednesday, Dec. 9 at 8 a.m. CT Kulukian A, Taylor J, Jain N, Olson D, Zaval M, Thurman R, Hengel S, et al.
Real world treatment patterns and healthcare resource utilization among HER2+ metastatic breast cancer patients with and without brain metastases: a retrospective cohort study #PS14-15 Poster Session 14 / Wednesday, Dec. 9 at 8 a.m. CT Ike C, Schwartz N, Surinach A, Liu Y, DeBusk K and Walters T.
Interim safety and efficacy analysis of phase IB/II clinical trial of tucatinib, palbociclib and letrozole in patients with hormone receptor and HER2-positive metastatic breast cancer #PS10-03 Poster Session 10 / Wednesday, Dec. 9 at 8 a.m. CT Shagisultanova E, Gradishar W,  Brown-Glaberman U, Chalasani P, Brenner AJ, Stopeck A, Mayordomo J, et al.
HER2CLIMB-02: A randomized, double-blind, phase 3 study of tucatinib or placebo with T-DM1 for unresectable locally-advanced or metastatic HER2+ breast cancer #OT-28-01Ongoing Trials Posters / Wednesday, Dec. 9 at 8 a.m. CT Hurvitz S,  Vahdat L, Harbeck N, Wolff AC, Tolaney SM, Loi S, Masuda N, et al.
SGNLVA-001: a phase 1 open-label dose-escalation and expansion study of SGN-LIV1A administered weekly in breast cancer #OT-03-03Ongoing Trials Posters / Wednesday, Dec. 9 at 8 a.m. CT Beckwith HC,  Medgyesy DC, Abraham J, Nanda R, Tkaczuk KHR, Krop IE, Pusztai L, et al.


Clinical trials
A Study of Tucatinib vs. Placebo in Combination With Capecitabine & Trastuzumab in Patients With Advanced HER2+ Breast Cancer (HER2CLIMB) – NCT02614794
A Study of Tucatinib (ONT-380) Combined With Ado-trastuzumab Emtansine (T-DM1) in Patients With HER2+ Breast Cancer – NCT01983501

Highlights of prescribing information
Tucatinib (Tukysa®; Seagen) [Prescribing Information]

[1] Hurvitz SA, O’Shaugnessy J, Mason G, et al. Central NervousSystem Metastasis in Patients with HER2-Positive Metastatic Breast Cancer: Patient Characteristics, Treatment, and Survival from SystHERs. ClinCancer Res. 2019;25(8):2433-2441.Murthy RK, Loi S, Okines A, et al. Tucatinib, Trastuzumab, and Capecitabine for HER2-Positive Metastatic BreastCancer. N Engl J Med. 2020;382(7):597-609
[2] Kulukian A, Lee P, Taylor J, Rosler R, de Vries P, Watson D, Forero-Torres A, Peterson S. Preclinical Activity of HER2-Selective Tyrosine Kinase Inhibitor Tucatinib as a Single Agent or in Combination with Trastuzumab or Docetaxel in Solid Tumor Models. Mol Cancer Ther. 2020 Apr;19(4):976-987. doi: 10.1158/1535-7163.MCT-19-0873. PMID: 32241871.

Featured image: Attendees during morning sessions during the 42th Annual San Antonio Breast Cancer Symposium in 2019. Photo courtesy: © 2019 – 2020 American Association for Cancer Research (AACR). Used with permission.

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