Trastuzumab Deruxtecan Added to Pertuzumab May Improve Efficacy in HER2+ Breast Cancer

The phase 3 DESTINY-Breast09 clinical trial is examining the potential for trastuzumab deruxtecan (Enhertu; T-DXd) combined with pertuzumab (Perjeta) to improved efficacy compared with T-DXd alone in patients with HER2-positive metastatic breast cancer (mBC) based on earlier research.

According to information in a poster made available as part of the 2021 San Antonio Breast Cancer Symposium, many patients with HER2-positive mBC eventually develop resistance to standard of care therapy comprised of a taxane, trastuzumab (Herceptin), and pertuzumab, underscoring the need for new therapies in the frontline setting. Specifically, new therapies for HER2-positive mBC must be able to address resistance to SOC and improve clinical outcomes overall.

T-DXd, an antibody-drug conjugate (ADC) composed of an anti-HER2 antibody along with a tetrapeptide-based cleavable linker, and a topoisomerase I inhibitor payload, demonstrated antitumor activity in patients with HER2-positive mBC treated in the phase 2 DESTINY-Breast01 clinical trial (NCT03248492). In 184 heavily-pretreated patients who were on treatment for a median duration of 11.1 months (range, 0.7-19.9), the objective response rate (ORR) observed was 60.9%. Findings from the trial led to the FDA approval of T-DXd for the treatment of patients with unresectable or metastatic HER2-positive BC that have progressed on 2 or more prior therapies.²

In a later study, DESTINY-Breast03 (NCT03529110), T-DXd was compared with trastuzumab emtansine (Kadcyla; T-DM1), another ADC, and demonstrated improved efficacy in terms of objective responses. The trial included 524 patients with HER2-positive mBC. The ORR observed with T-DXd was 79.7% versus 34.2% with T-DM1.^1,4 Other research has also shown that the addition of pertuzumab to an ADC can facilitate the internalization of the agent.

DESTINY-Breast09 is an open-label phase 3 trial of patients with HER2-positive mBC. Patients enrolled in the study will be randomized 1:1:1 to receive either T-DXd with placebo, TDX-d with pertuzumab, or SOC treatment. Recruitment for the study began on April 26, 2021, to enroll 1134 patients who meet the inclusion criteria. Patients were assessed at study sites in 29 countries across North America, South America, Europe, Asia, Africa, the Middle East, and the Oceania.

To be eligible, patients aged 18 years of age or older are required to have advanced and/or mBC, have HER2 -positive disease confirmed by immunohistochemistry or in situ hybridization, have adequate organ and bone marrow function, have left ventricular ejection fraction of at least 50% within 28 days before randomization, and be naïve to chemotherapy or HER2-targeted therapy for advanced or mBC. Patients must also have an adequate tumor tissue sample from the metastatic setting available for assessment of HER2 and PIK3CA status.

The study will exclude patients who are ineligible to be treated with any of the study drugs, or who have spinal cord compression or clinically active central nervous system metastases unless they are clinically inactive/treated brain metastases, active or previously documented interstitial lung disease, or pneumonitis, suspicion of interstitial lung disease or pneumonitis, any substance abuse. Per investigator discretion, any medical condition that may interfere with study treatment is ground for exclusion. In addition, patients previously randomized or treated in a previous study of T-DXd are not permitted to enroll in the study.

Stratified by prior treatment status of de novo versus recurrent, negative, or positive HR status, and detection of PIK3CA mutation, patients with HER2-positive mBC in DESTINY-Breast09 will be evaluated for the primary end point of progression-free survival (PFS) per blinded independent central review (BICR).

The study will also explore multiple secondary end points to test the efficacy and safety of the T-DXd in all 3 arms, including pharmacokinetics, immunogenicity, and safety/tolerability. The secondary end points are either assessed per BICR or investigator assessment. Quality-of-life (QOL) measurements are assessed per European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) core 30 or QLQ core B or QLQ BR45.

The study is actively recruiting at select locations around the world. Some locations have not yet begun recruitment. The prospective primary completion date for DESTINY-Breast09 is July 24, 2025.⁵

References

1. Tolaney SM, Barroao-Sousa R, Jiang Z, et al. Phase 3 study of trastuzumab deruxtecan (T-DXd) with or without pertuzumab vs a taxane, trastuzumab and pertuzumab in first-line (1L), human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (mBC): DESTINY-Breast09. Presented at: San Antonio Breast Cancer Symposium. December 7-10, 2021. San Antonio, TX. Abstract OT1-14-02.
2. Modi S, Saura G, Yamashita T, et al., Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. N Engl J Med. 2020; 382:610-62. doi: 10.1056/NEJMoa1914510
3. Narayan P. Osgoog CL, Singh H, et al. FDA approval summary: fam-trastuzumab deruxtecan-nxki for the treatment of unresectable or metastatic HER2-positive breast cancer. Clin Cancer Res. 2021;27(16):4478-4485. doi: 10.1158/1078-0432.CCR-20-4557
4. DS-8201a versus T-DM1 for human epidermal growth factor receptor 2 (HER2)-positive, unresectable and/or metastatic breast cancer previously treated with trastuzumab and taxane [DESTINY-Breast03]. Clinicaltrials.gov. Accessed December 9, 2021. https://bit.ly/3EH8OTI
5. Trastuzumab deruxtecan (T-DXd) with or without pertuzumab versus taxane, trastuzumab and pertuzumab in HER2-positive metastatic breast cancer (DESTINY-Breast09). Clinicaltrials.gov. Accessed December 9, 2021. https://bit.ly/3ItLM53