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HER2-Positive Metastatic Breast Cancer: Current Status and Promising Agents
  • CME
  • CE

Adam M. Brufsky, MD, PhD
Released: April 13, 2020

Future Directions for ADCs in HER2-Positive MBC

DESTINY-Breast03: Second-line T-DXd vs T-DM1 in HER2-Positive MBC After Progression on Trastuzumab/Taxane

DESTINY-Breast03 is an ongoing randomized, open-label phase III trial of second-line T-DXd vs T-DM1 in patients with HER2-positive, unresectable and/or metastatic breast cancer who had progressed on treatment with trastuzumab and a taxane (planned N = 500).[47] Patients with CNS metastases are permitted to enroll, but the trial excludes those with previous HER2 ADCs. The primary endpoint is PFS with secondary endpoints including OS and responses.

This trial is probably going to have a slower accrual, mainly because of the widespread use of T-DXd as third-line therapy.

Efficacy of Trastuzumab Deruxtecan in HER2-Low MBC

As suggested by results from the DESTINY-Breast01 trial,[45] T-DXd is highly active in HER2-low MBC. In this 2018 study by Modi and colleagues,[48] the response rate in patients with HER2 IHC 1+ expression was 33.3%, and 54.5% in patients with HER2 IHC 2+ expression. In these subgroups, the median PFS was 5.7 months and 13.6 months, respectively.

Of note, approximately one third of patients had previously received a CDK4/6 inhibitor. Even in this group, 33% of patients responded to T-DXd, with a fairly impressive median PFS of 7.1 months and a median duration of response not yet reached.

DESTINY-Breast04: T-DXd vs Chemotherapy in Unresectable HER2-Low Breast Cancer

DESTINY-Breast04 is an ongoing, randomized phase III trial of T-DXd vs chemotherapy in patients with HER2-low unresectable and/or metastatic breast cancer who progressed on endocrine therapy and have no history of high HER2 expression (planned N = 540).[49] Patients could not have received previous HER2-targeted therapy.

Participants are being randomized to T-DXd at 5.4 mg/kg every 3 weeks or to physician’s choice of standard chemotherapies (capecitabine, eribulin, gemcitabine, paclitaxel or nab-paclitaxel). The primary endpoint is PFS with secondary endpoints including OS and responses.

HER2-Targeted ADC: Trastuzumab Duocarmazine (SYD985)

What about other HER2-targeted ADCs? Trastuzumab duocarmazine (SYD985) comprises a HER2 antibody very similar to trastuzumab conjugated to the DNA alkylator DUBA.[50,51] The linker is cleavable, which means this agent can also act via the bystander killing effect.

Phase I Study: Trastuzumab Duocarmazine in Locally Advanced or Metastatic HER2-Positive Breast Cancer

In a phase I trial in patients with HER2-positive advanced or metastatic breast cancer (N = 48), trastuzumab duocarmazine was associated with responses in 33% of participants.[52] Most drug-related toxicity was mild to moderate, with grade 3 neutropenia in 6 patients, and grade 3 fatigue and grade 3 conjunctivitis in 3 patients each.

Ocular toxicity was seen in two thirds of patients and was the main reason for discontinuation. Furthermore, ocular toxicity and neutropenia were the main reasons for dose modification.

TULIP: Trastuzumab Duocarmazine vs Physician’s Choice of Chemotherapy in Locally Advanced or Metastatic Breast Cancer

TULIP is a randomized phase III trial of trastuzumab duocarmazine vs chemotherapy in patients with HER2-positive, unresectable, locally advanced and/or metastatic breast cancer who had progressed on at least 2 HER2-targeted regimens including T-DM1 (planned N = 345).[53] Patients will be randomized to either trastuzumab duocarmazine every 3 weeks or physician’s choice of standard regimens: lapatinib/capecitabine, trastuzumab/capecitabine, trastuzumab/vinorelbine, or trastuzumab/eribulin. The primary endpoint is PFS with secondary endpoints including OS, responses, and quality of life.

This registration study is currently ongoing, and hopefully we will see the results soon.

Provided by Clinical Care Options, LLC

Clinical Care Options, LLC
12001 Sunrise Valley Drive
Suite 300
Reston, VA

Sophia Kelley
(203)-316-2125
skelley@clinicaloptions.com
www.clinicaloptions.com

Supported by educational grants from
Daiichi Sankyo, Inc.
Puma Biotechnology, Inc.
Seattle Genetics

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