Drugs Xagena
DESTINY-Breast04 was a phase III, randomized, open-label multicenter, global trial in adult patients with unresectable or metastatic HER2-low breast cancer, which was defined as tumors scoring 1+ or 2+ by IHC and no evidence of HER2 gene amplification by ISH, as determined at a central laboratory.
Patients must have received chemotherapy in the metastatic setting or have developed disease recurrence during or within 6 months of completing (neo)adjuvant chemotherapy and were randomly assigned in a 2:1 ratio to receive Trastuzumab deruxtecan or treatment of physician's choice (TPC) of Capecitabine, Eribulin, Gemcitabine, Paclitaxel, or Paclitaxel protein-bound. T-DXd was administered at the previously approved dose for breast cancer of 5.4 mg/kg intravenously once every 3 weeks while TPC options were administered in accordance with labeling information or National Comprehensive Cancer Network guidelines. Random assignment was stratified according to HER2-low status (IHC 1+ v IHC 2+/ISH-negative), the number of previous lines of chemotherapy for metastatic disease (one vs two), and hormone receptor status (positive [with vs without previous CDK 4/6 inhibitor therapy] vs negative). Patients with HR+ disease must have received at least one endocrine therapy in the metastatic setting or have been ineligible for endocrine therapy. Patients were assessed for disease progression every 6 weeks until progression, death, withdrawal of consent, or loss to follow-up.
IHC scores for HER2 expression were determined through central testing of archived or recent fresh tumor biopsy specimens with the use of an investigational IHC assay, the PATHWAY anti-HER-2/neu (4B5) Rabbit Monoclonal Primary Antibody (PATHWAY anti-HER2 [4B5] antibody) assay. Patients whose tumors were found to be HER2-positive (IHC 3+ or IHC 2+/ISH-positive) on prior pathology testing or who had received prior anti-HER2 therapy were not eligible. Hormone receptor testing was conducted locally at study sites.
The intent-to-treat (ITT) population included all patients who were randomly assigned into the study regardless of the tumor hormone receptor status, including those who did not receive any dose of study drug.
The primary efficacy end point was progression-free survival (PFS) on the basis of blinded independent central review (BICR) assessment using RECIST v1.1 in patients with HR+ breast cancer. The key secondary efficacy end points were BICR-assessed progression-free survival in all randomly assigned patients, overall survival (OS) in the HR+ cohort, and overall survival in all randomly assigned patients. These end points were tested hierarchically in this order to maintain the overall two-sided type I error rate to 0.05 or less. Up to three analyses for overall survival were planned, and the first interim analysis was performed at the time of the final analysis of progression-free survival (provided progression-free survival was significant in both the HR+ cohort and the ITT).
If the first interim analysis was not significant, a second interim analysis was planned when approximately 233 overall survival events (70% information fraction) in the HR+ cohort were documented. If the second interim analysis was not significant, a final analysis of overall survival was planned after approximately 333 overall survival events in the HR+ cohort were documented. Objective response rate and duration of response were considered exploratory end points by the FDA, as no alpha was allocated to these end points in this study.
Efficacy
A total of 557 patients were randomly assigned 2:1 with 373 patients in the T-DXd arm and 184 patients in the TPC arm. Among these patients, 331 were HR+ and 42 were HR− in the T-DXd arm and 163 were HR+ and 21 were HR− in the TPC arm.
Approximately 70% of patients with HR+ disease had received a prior CDK 4/6 inhibitor. In the TPC group, the majority of patients received Eribulin (51%), followed by Capecitabine (20%), Paclitaxel protein-bound (10%), Gemcitabine (10%), or Paclitaxel (8%).
The primary end point of progression-free survival by BICR in the HR+ cohort showed a statistically significant and clinically meaningful improvement with an estimated progression-free survival hazard ratio (HR) of 0.51 (95% CI, 0.40 to 0.64), and the two-sided P value was less than 0.0001.
The observed median progression-free survival was 10.1 months (95% CI, 9.5 to 11.5) in the T-DXd arm and 5.4 months (95% CI, 4.4 to 7.1) in the TPC arm, on the basis of 211 events (64%) in the T-DXd arm and 110 events (67%) in the TPC arm at the data cutoff date of january 11, 2022.
A statistically significant and clinically meaningful improvement was also demonstrated in the other key end points in the statistical hierarchy. For BICR-assessed progression-free survival in the ITT, the stratified hazard ratio was 0.50 (95% CI, 0.40 to 0.63) with two-sided P value less than 0.0001. The median progression-free survival was 9.9 months (95% CI, 9.0 to 11.3) in the T-DXd arm and 5.1 months (95% CI, 4.2 to 6.8) in the TPC arm.
As the analyses of BICR-assessed progression-free survival were significant in both the HR+ cohort and the ITT population, the first interim analysis of overall survival was performed at the time of the data cutoff, when there were 199 overall survival events (approximately 60% of the events planned for the final overall survival analysis) in the HR+ cohort and 239 overall survival events in the ITT population.
In the HR+ cohort, the stratified hazard ratio for overall survival was 0.64 (95% CI, 0.48 to 0.86) with two-sided P value of .0028 that crossed the prespecified interim analysis efficacy stopping boundary of 0.0075. The median overall survival was 23.9 months (95% CI, 20.8 to 24.8) in the T-DXd arm and 17.5 months (95% CI, 15.2 to 22.4) in the TPC arm.
In the ITT population, the stratified hazard ratio for overall survival was 0.64 (95% CI, 0.49 to 0.84) with two-sided P value of 0.0010 that crossed the prespecified interim analysis efficacy stopping boundary of 0.0075. The median overall survival was 23.4 months (95% CI, 20.0 to 24.8) in the T-DXd arm and 16.8 months (95% CI, 14.5 to 20.0) in the TPC arm.
For the primary end point and all three key secondary end points, consistent benefit was observed across the prespecified subgroups in the study, including HER2 status, number of prior lines of chemotherapy in metastatic setting, prior CDK 4/6 inhibitor use, age, race, region, lines of prior endocrine therapy in the metastatic setting, best response to the last prior cancer systemic therapy, reported history of CNS metastases, renal function at baseline, hepatic function at baseline, baseline visceral disease, and ECOG performance status.
Safety
The pooled safety analysis for all patients who had received at least one dose of Trastuzumab deruxtecan 5.4 mg/kg once every 3 weeks across multiple studies including Study DS8201-A-J101, DESTINY-Breast01, DESTINY-Breast03, DESTINY-Breast04, and DESTINY-Lung02 was reviewed, but the focus of the FDA safety analysis for this indication was from DESTINY-Breast04.
The evaluation of safety of Trastuzumab deruxtecan for metastatic HER2-low breast cancer was assessed in 371 patients in the T-DXd arm who received at least one dose of Trastuzumab deruxtecan 5.4 mg/kg once every 3 weeks, as compared with 172 patients treated in the TPC arm in DESTINY-Breast04.
The median duration of treatment with Trastuzumab deruxtecan was 8.2 months (range, 0.2-33).
The most common (greater than or equal to 20%) adverse events were nausea, fatigue, alopecia, vomiting, anemia, constipation, decreased appetite, diarrhea, and musculoskeletal pain.
Serious adverse events (frequency more than 1%) occurred in 28% of patients receiving Trastuzumab deruxtecan and were for interstitial lung disease (ILD) / pneumonitis, pneumonia, dyspnea, musculoskeletal pain, sepsis, anemia, febrile neutropenia, hypercalcemia, nausea, pyrexia, and vomiting.
Sixteen percent of patients in the T-DXd arm experienced treatment-emergent adverse events leading to study drug discontinuation, of which interstitial lung disease / pneumonitis accounted for 8%.
Interstitial lung disease / pneumonitis is a known risk of Trastuzumab deruxtecan and remains in the Warnings and Precautions section of the United States Prescribing Information (drug label).
Treatment emergent adverse events that were reported at an incidence that was greater than or equal to 10 percentage points higher in the T-DXd arm than the TPC arm include vomiting, thrombocytopenia, hemorrhage, and pneumonitis.
Left ventricular dysfunction was reported in 4.6% of patients in theTrastuzumab deruxtecan and no patients in the TPC arm. As left ventricular dysfunction is a known class effect of HER2-directed therapies and a potential risk of therapy, it continues to be included as a warning in the United States Prescribing Information for Trastuzumab deruxtecan. ( Xagena )
Narayan P et al, J Clin Oncol 2023;41(11):2108-2116
XagenaMedicine_2023
