DESTINY-Breast04

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Clinical Question

In patients with HER2-low metastatic breast cancer, does trastuzumab-deruxtecan compared to physician's (protocol-limited) choice of chemotherapy improve progression-free survival?

Bottom Line

Trastuzumab-deruxtecan improved median progression-free survival in patients with HER2-low metastatic breast cancer compared to the patients who received chemotherapy.

Major Points

Human Epidermal Growth Factor Receptor 2 (HER2)is overexpressed in about 20-30% of breast cancers. [1] Although the expression of HER2 is associated with more aggressive disease, it can also be a target for therapies like Trastuzumab. HER2-low breast cancers, defined as, breast cancers with a score of 1+ on immunohistochemistry (IHC) or 2+ on IHC but negative results on in-situ hybridization (ISH) comprise about 60% of HER2-negative breast cancers. [2] They constitute both hormone receptor-positive and hormone receptor-negative breast cancers. HER2-low metastatic breast cancers were treated the same as HER2-negative breast cancers as the current HER2-targeted therapies did not improve clinical outcomes in HER2-low metastatic breast cancers.

Trastuzumab-deruxtecan is an antibody-drug conjugate with a potent cytotoxic payload; the drug-to-antibody ratio is 8:1. Even for tumors that express low HER2 levels, this antibody-drug conjugate can deliver its payload via the bystander effect. [3] After promising phase 1 and 2 studies results in heavily pretreated patients, the DESTINY-Breast04 study, a phase 3 clinical trial was conducted a evaluate the safety and efficacy of trastuzumab-deruxtecan compared to physician's choice of chemotherapy.

Guidelines

Design

  • Multicenter, open-label, two-group, randomized, active-controlled trial
  • Parallel model, with randomization at 2:1
  • N=557
    • Trastuzumab-deruxtecan group (n=373)
    • Physician's choice group (n=184)
  • Hormone receptor-positive cohort: 331 (88.7%) in the Trastuzumab-deruxtecan group and 163 (88.6%) in the physician's choice group
  • Setting: 208 centers across the world
  • Enrollment: December 27, 2018, through December 31, 2021
  • Median duration of follow-up for survival: 18.4 months (95% CI, 17.7 to 18.9)
  • Analysis: Intention-to-treat
  • Primary endpoint: Progression-free survival among patients with hormone receptor-positive disease

Population

Inclusion Criteria

  • Is at least 18 years or the age of majority in their respective country
  • Must have had chemotherapy for metastatic disease or disease recurrence within 6 months after completing adjuvant chemotherapy
  • Has pathologically documented breast cancer that:
    • Is unresectable or metastatic
    • Has low-HER2 expression defined as IHC 2+/ISH- or IHC 1+ (ISH- or untested)
    • Is HR-positive or HR-negative
    • Has progressed on, and would no longer benefit from, endocrine therapy
    • Has been treated with 1 to 2 prior lines of chemotherapy/adjuvant in the metastatic setting
    • Was never previously HER2-positive (ICH 3+ or ISH+) on prior pathology testing
  • Has documented radiologic progression (during or after most recent treatment)
  • Has at least 1 protocol-defined measurable lesion

Exclusion Criteria

  • Not eligible for any options in the physician's choice chemotherapy arm
  • Previous diagnosis of breast cancer with high HER2 expression
  • Previous treatment with any anti-HER2 therapy or any antibody-drug conjugate
  • Presence of significant or uncontrolled cardiovascular disease
  • Presence of active (clinically) central nervous system metastases or spinal cord compression
  • History of interstitial lung disease (ILD)/pneumonitis that was non-infectious requiring steroid, or suspected ILD/pneumonitis that could not be ruled out by imaging at screening

Baseline Characteristics

  • Median age in years:
    • Trastuzumab-deruxtecan group: 57.5 (31.5-80.2)
    • Physician's choice of Chemotherapy group: 55.9 (28.4–80.5)
  • Female sex:
    • Trastuzumab-deruxtecan group: 371 (99.5%)
    • Physician's choice of Chemotherapy group: 184 (100%)
  • Race
    • Trastuzumab-deruxtecan group: White: 176 (47.2%); Black: 7 (1.9%); Asian: 151 (40.5%)
    • Physician's choice of Chemotherapy group: White: 91 (49.5%); Black: 3 (1.6%); Asian: 72 (39.1%)
  • Hormone receptor-positive:
    • Trastuzumab-deruxtecan group: 333 (89.3%)
    • Physician's choice of Chemotherapy group: 166 (90.2%)
  • ECOG performance-status score:
    • Trastuzumab-deruxtecan group: ECOG 0: 200 (53.6%); ECOG 1: 173 (46.4%)
    • Physician's choice of Chemotherapy group: ECOG 0: 105 (57.1%); ECOG 1: 79 (42.9%)
  • Median number of lines of therapy for metastatic disease:
    • Trastuzumab-deruxtecan group: 3 (1-9)
    • Physician's choice of Chemotherapy group: 3 (1-8)

Interventions

  • Patients randomized in a ratio of 2:1 to receive either:
    • Trastuzumab deruxtecan or
    • physician's choice of capecitabine, eribulin, gemcitabine, paclitaxel, or nab-paclitaxel
  • Randomization was further stratified according to:
    • HER2 low status (IHC 1+ vs IHC 2+/ISH-negative)
    • Number of previous lines of chemotherapy (1 vs 2)
    • Hormone-receptor status (positive [with vs without previous CDK 4/6 inhibitor therapy] vs negative)

Outcomes

Comparisons are trastuzumab-deruxtecan group vs physician's choice chemotherapy group.

Primary Outcomes

Median progression-free survival in the hormone receptor-positive cohort
10.1 months (95% CI, 9.5 to 11.5) vs 5.4 months (95% CI, 4.4 to 7.1) (HR 0.51; 95% CI, 0.40 to 0.64; P<0.001)

Secondary Outcomes

Median progression-free survival among all patients
9.9 months (95% CI, 9.0 to 11.3) vs 5.1 months (95% CI, 4.2 to 6.8) (HR 0.50; 95% CI, 0.40 to 0.63; P<0.001)
Median overall survival in the hormone receptor-positive cohort
23.9 months (95% CI, 20.8 to 24.8) vs 17.5 months (95% CI, 15.2 to 22.4) (HR 0.64; 95% CI, 0.48 to 0.86; P=0.003)
Median overall survival among all patients
23.4 months (95% CI, 20.0 to 24.8) vs 16.8 months (95% CI, 14.5 to 20.0) (HR 0.64; 95% CI, 0.49 to 0.84; P=0.001)
Percentage of patients with a confirmed objective response in the hormone receptor-positive cohort
52.6% (95% CI, 47.0 to 58.0) vs 16.3% (95% CI, 11.0 to 22.8)
Median duration of response
10.7 months vs 6.8 months

Subgroup Analysis

Among the patients treated with trastuzumab-deruxtecan, patients who had previous treatments with CDK4/6 inhibitors had a median PFS of 10 months; for patients without previous treatments with CDK4/6 inhibitors, PFS was 11.7 months.

Among the patients treated with trastuzumab-deruxtecan, patients with HER2 IHC score of 1+ had a median PFS of 10.3 months; for patients with a HER2 IHC score of 2+ and negative results on ISH, PFS was 10.1 months.

Adverse Events

Incidence of serious adverse events
27.8% vs 25.0%
Incidence of grade 3 or higher adverse events
52.6% vs 67.4%
Incident of adverse events associated with discontinuation of treatment
16.2% vs 8.1%
Incidence of adverse events associated with dose reductions
22.6% vs 38.4%
Adverse events associated with death
3.8% vs 2.9%

Criticisms

Severe underrepresentation of the black population (1.8% of the trial population).

Inadequate data regarding treatments received before randomization and after progression. Patients who had previously received anthracycline, for example, may have led to an imbalance in group assignments.

Funding

Supported by Daiichi Sankyo and AstraZeneca.

Further Reading

  1. ↑ Mitri Z et al. The HER2 Receptor in Breast Cancer: Pathophysiology, Clinical Use, and New Advances in Therapy. Chemother Res Pract 2012. 2012:743193.
  2. ↑ Schettini F et al. Clinical, pathological, and PAM50 gene expression features of HER2-low breast cancer. NPJ Breast Cancer 2021. 7:1.
  3. ↑ Ogitani Y et al. DS-8201a, A Novel HER2-Targeting ADC with a Novel DNA Topoisomerase I Inhibitor, Demonstrates a Promising Antitumor Efficacy with Differentiation from T-DM1. Clin Cancer Res 2016. 22:5097-5108.
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