CME
Physicians: Maximum of 0.75 AMA PRA Category 1 Credit™
Released: February 22, 2024
Expiration: February 21, 2025
Datopotamab Deruxtecan (DS-1062; Dato-DXd): TROP-2‒Directed ADC in TNBC
Dato-DXd is a novel, investigational TROP-2‒directed ADC. Like all ADCs, Dato-DXd is made of 3 components: a humanized anti‒TROP-2 monoclonal antibody (datopotamab), a cytotoxic TOPO-I inhibitor payload (an exatecan derivative; DXd) and a tetrapeptide-based cleavable linker.10-12 Dato-DXd specifically binds to TROP-2 on the surface of tumor cells and gets internalized and trafficked to lysosomes for the release of its cytotoxic payload, which triggers DNA damage and apoptosis. It has a drug-to-antibody ratio of 4:1. Dato-DXd has shown promising activity in trials for patients with relapsed/refractory advanced breast cancer.
TROPION-PanTumor01: Dato-DXd in Advanced Solid Tumors
TROPION-PanTumor01 is an open-label, 2-part, phase I trial for patients with advanced solid tumors, including those with advanced breast cancer (NCT03401385). The trial was performed in 2 parts, including a dose-escalation phase and a dose-expansion phase. Both phases included patients with unresectable advanced non-small-cell lung cancer and TNBC with disease that is refractory to or relapsed from standard treatment or with disease for which no standard treatment is available. The dose-expansion phase included patients with HR-positive/HER2-negative breast cancer, HR-positive/HER2-low breast cancer, HER2-positive breast cancer, small-cell lung cancer, endometrial cancer, pancreatic adenocarcinoma, HER2-negative gastric/gastroesophageal junction cancer, esophageal cancer, and head and neck cancer, among many other solid tumor types. Patients with disease harboring any TROP-2 expression level were allowed on the trial. The primary endpoints were safety and tolerability, and the secondary endpoints included ORR, survival, and pharmacokinetic analysis.
TROPION-PanTumor01: Efficacy in Advanced TNBC Cohort
In the TNBC dose-expansion cohort, 42 patients received 6 mg/kg of Dato-DXd administered intravenously on Day 1 of 21-day cycles, and 2 patients received Dato-DXd in the dose-escalation phase at 8 mg/kg.13 In this cohort of 44 patients with relapsed/refractory advanced TNBC, the ORR by BICR was 32%; however, in the subgroup of 27 patients with TOPO-I inhibitor‒naive disease, the ORR by BICR was 44%. The median duration of response for all patients was 16.8 months. The median PFS was 4.4 months in all patients vs 7.3 months in patients with TOPO-I inhibitor‒naive disease. The median OS was 13.5 months in all patients vs 14.3 months in patients with TOPO-I inhibitor‒naive disease. These data suggest that Dato-DXd may have activity in patients even after prior exposure to a TOPO-I inhibitor.
TROPION-PanTumor01: Efficacy in Advanced HR-Positive/HER2-Negative Breast Cancer
Among patients with HR-positive/HER2-negative advanced breast cancer, the ORR was 27% (all partial responses), and the median duration of response was not reached at the time of data analysis.14 Several responses were ongoing at the time of data analysis. The disease control rate was 85%, and the median PFS in this cohort was 8.3 months. These encouraging results led to the registrational TROPION‑Breast01 trial (NCT05104866).
TROPION-Breast01: Dato-DXd vs TPC in Inoperable or Metastatic HR-Positive/HER2-Negative Breast Cancer
TROPION‑Breast01 is a randomized phase III trial of Dato-DXd vs physician’s choice of single-agent chemotherapy (capecitabine, eribulin, gemcitabine, or vinorelbine) for patients with HR-positive/HER2-negative inoperable or metastatic breast cancer with disease progression after receiving 1 or 2 prior lines of systemic therapy. Dato-DXd was intravenously administered at 6 mg/kg on Day 1 of 21-day cycles. The primary endpoints were PFS by BICR and OS, and the secondary endpoints included ORR, duration of response, and disease control rate.
TROPION-Breast01: Primary Analysis of PFS, ORR, and OS
At the time of primary analysis (after a median follow-up of 9.7 months), data from TROPION-Breast01 showed that the study had met one of its primary endpoints (PFS by BICR).15 The median PFS by BICR was 6.9 months with Dato-DXd vs 4.9 months with chemotherapy (hazard ratio: 0.63; 95% CI: 0.52-0.76; P <.0001). Investigator-assessed PFS demonstrated a median PFS of 6.9 months vs 4.5 months with chemotherapy (hazard ratio: 0.64; 95% CI: 0.53-0.76). At the median follow-up of 9.7 months, the OS data were immature, but the OS rates favored Dato-DXd (hazard ratio: 0.84; 95% CI: 0.62-1.14). The confirmed ORR with Data-DXd was 36.4% (complete response of 0.5%) vs 22.9% with chemotherapy (no complete responses).
TROP-2‒Directed ADCs: Sacituzumab Govitecan vs Dato-DXd
Although both sacituzumab govitecan and Dato-DXd are TROP-2‒directed ADCs with bystander antitumor effects, there are differences in their technologies. With sacituzumab govitecan, the cytotoxic TOPO-I inhibitor payload is a camptothecin derivative (SN-38) linked to the RS7 monoclonal antibody via a proprietary cleavable hydrolyzable linker.3-5 With Dato-DXd, the cytotoxic TOPO-I inhibitor payload is an exatecan derivative (DXd) linked to the monoclonal antibody (datopotamab) via a tetrapeptide-based cleavable linker.10-12 A key difference between sacituzumab govitecan and Dato-DXd is that the CL2A linker in sacituzumab govitecan (but not Dato-DXd) is hydrolysable; therefore, it can be cleaved during trafficking, bypassing the requirement for lysosomal delivery for the release of its cytotoxic payload.5
TROPiCS-02 Trial of Sacituzumab Govitecan vs TROPION-Breast01 Trial of Dato-DXd
The TROPiCS-02 trial of sacituzumab govitecan vs chemotherapy and the TROPION-Breast01 trial of Dato-DXd vs chemotherapy are both randomized phase III trials of TROP-2‒directed ADCs for patients with HR-positive/HER2-negative recurrent inoperable or metastatic breast cancer, but there are differences in the trial designs.8,15
The TROPiCS-02 trial of sacituzumab govitecan included patients who had previously received 2-4 lines of chemotherapy in the metastatic setting, but patients on the TROPION-Breast01 trial had received only 1 or 2 prior lines of systemic therapy. On the TROPiCS-02 trial, the eligibility criteria included prior exposure to a CDK4/6 inhibitor in any setting, whereas there was no requirement for progression on a CDK4/6 inhibitor on the TROPION-Breast01 trial. Also, the stratification factors for TROPiCS-02 were visceral metastases (yes vs no), endocrine therapy exposure in the metastatic setting within 6 months of trial entry (yes vs no), and the number of prior therapy lines (2 vs 3-4). On the other hand, the stratification factors for TROPION-Breast01 were the number of prior therapy lines of therapy (1 vs 2), prior use of a CDK4/6 inhibitor (yes vs no), and the geographic location (United States/Canada/Europe vs rest of world). Both sacituzumab govitecan and Dato-DXd are administered intravenously, but sacituzumab govitecan is given on Days 1 and 8 of 21-day cycles, and Dato-DXd is given on Day 1 of 21-day cycles. There are also differences in their toxicity profiles, in that diarrhea and neutropenia are the 2 most common serious adverse events associated with sacituzumab govitecan, whereas stomatitis is more commonly observed with Dato-DXd, and neutropenia and diarrhea occur with less severity.
As the treatment landscape for patients with relapsed/refractory HR-positive/HER2-negative breast cancer continues to evolve and expand, the differences in the design of these 2 trials of 2 different TROP-2‒targeted ADCs, as well as the differences in their treatment schedules and toxicity profiles, will significantly contribute to the determination of how these agents will be selected and used if Dato-DXd receives FDA approval in the future.
Ongoing Phase I/II Single-Arm Basket Trial of SKB264 in Pretreated HR-Positive/HER2-Negative Metastatic Breast Cancer: Efficacy
SKB264 is another novel TROP-2‒directed ADC in early-phase development and is currently under investigation for patients with HR-positive/HER2-negative metastatic breast cancer. SKB264 comprises an anti‒TROP-2 monoclonal antibody, a sulfonyl pyrimidine-CL2A-carbonate linker, and a cytotoxic TOPO-I inhibitor payload (a belotecan derivative). Its drug-to-antibody ratio is 7.4:1.16
SKB264 is being investigated in a single-arm phase I/II basket trial for patients with advanced unresectable or metastatic solid tumors (NCT04152499). In a cohort of 38 evaluable patients with pretreated HR-positive/HER2-negative metastatic breast cancer, 25 (65.8%) had received a CDK4/6 inhibitor, and 30 (78.9%) had received ≥2 prior lines of chemotherapy in the metastatic setting. In this patient cohort, the confirmed ORR was 36.8%, with a disease control rate of 89.5% and a median duration of response of 7.4 months. The median PFS was 11.1 months, with a 6-month PFS rate of 61.2%. The 6-month OS rate was 81.4%, and the median OS has not yet been reached.
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