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TROP2 ADCs for Oncology Nurses
TROP-2–Targeting Antibody–Drug Conjugates: Perspectives for the Oncology Nurse Specialist

Released: July 26, 2023

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Key Takeaways
  • TROP-2–targeting antibody–drug conjugates, such as sacituzumab govitecan and datopotamab deruxtecan, are an emerging class of anticancer drugs being studied across multiple solid tumor types.
  • Sacituzumab govitecan is approved by the FDA for the treatment of previously treated locally advanced/metastatic triple-negative breast cancer, HR-positive/HER2-negative breast cancer, and urothelial cancer.
  • An update of the phase III TROPiCS-02 trial at ASCO 2023 showed durable efficacy with sacituzumab govitecan in patients with HR-positive/HER2-negative metastatic breast cancer, including continued improvements in overall response rate, duration of response, progression-free survival, and overall survival compared with single-agent chemotherapy.
  • There are distinct toxicities between sacituzumab govitecan and datopotamab deruxtecan to be aware of, likely attributable to their different chemotherapy payloads.

TROP-2–targeting antibody–drug conjugates (ADCs) are an emerging and expanding class of anticancer drugs being studied across multiple solid tumors. ADCs are composed of a monoclonal antibody attached to a cytotoxic drug (ie, payload) using a cleavable linker and are designed such that the payload is released directly within tumor cells. The transmembrane glycoprotein TROP-2 was chosen as a target for these agents because of its overexpression in multiple solid tumors and association with poor prognoses. The 2 TROP-2 ADCs furthest along in development are sacituzumab govitecan and datopotamab deruxtecan. The primary difference between these 2 agents is their cytotoxic payload: For sacituzumab govitecan, SN-38 (an irinotecan derivative) is attached to the TROP-2 antibody at a drug:antibody ratio of 7.6:1 by a pH-sensitive linker, and for datopotamab deruxtecan, the TOP1 inhibitor deruxtecan (an exatecan derivative) is attached at a drug:antibody ratio of 4:1 with a cleavable linker.

FDA-Approved Indications for TROP-2 ADCs
Sacituzumab govitecan was the first TROP-2 ADC to have received approval from the FDA and is now approved for the treatment of adults with (1) Unresectable locally advanced or metastatic triple-negative breast cancer in adults who have received ≥2 prior systemic therapies (≥1 for metastatic disease), (2) unresectable locally advanced or metastatic hormone receptor (HR)–positive/HER2-negative (IHC 0, IHC 1+, or IHC 2+/ISH-) breast cancer in adults who have received endocrine-based therapy and ≥2 additional systemic therapies in the metastatic setting, and (3) locally advanced or metastatic urothelial cancer in adults who have received platinum-containing chemotherapy and either a PD-1 or PD-L1 inhibitor. Datopotamab deruxtecan has not yet received FDA approval but is furthest along in development for the treatment of non-small-cell lung cancer.

ASCO 2023 Update of Phase III TROPiCS-02 Trial: Sacituzumab Govitecan vs Single-Agent Chemotherapy for HR-Positive/HER2-Negative MBC
The randomized phase III TROPiCS-02 trial (NCT03901339) is evaluating sacituzumab govitecan (n = 272) vs physician’s choice of single-agent chemotherapy (ie, capecitabine, eribulin, gemcitabine, or vinorelbine) (n = 271) in patients with HR-positive/HER2-negative metastatic breast cancer (MBC). Of the 543 patients enrolled, 95% had visceral metastasis, and the median number of prior chemotherapy regimens received in the metastatic setting was 3. In preliminary reports of TROPiCS-02, sacituzumab govitecan demonstrated significantly improved overall response rate, duration of response, progression-free survival, and overall survival (OS) in patients with pretreated, endocrine-resistant HR-positive/HER2-negative MBC. The safety profile was also manageable. These data led to the approval of sacituzumab govitecan by the FDA in this setting.

Updated data from this study were presented at the 2023 ASCO Annual Meeting. With 12.8 months of follow-up, efficacy with sacituzumab govitecan was shown to be durable, with continued improvements in overall response rate, duration of response, progression-free survival, and OS compared with single-agent chemotherapy. Of note, median OS was 14.5 months vs 11.2 months (HR: 0.79; P = .0133), respectively, with OS rates of 60.9% vs 47.1% at 12 months, 39.2% vs 31.7% at 18 months, and 25.7% vs 21.1% at 24 months. No new safety signals were observed.

In a subgroup analysis, sacituzumab govitecan demonstrated improved OS with sacituzumab govitecan vs chemotherapy regardless of TROP-2 expression level: For an H-score <100 (42% of patients), median OS was 14.9 months vs 11.3 months, respectively (HR: 78). For an H-score ≥100 (58% of patients), median OS was 14.4 months vs 11.2 months, respectively (HR: 82). This also was true regardless of whether the patient had HER2-negative disease (IHC 0) (median OS: 13.6 months vs 10.8 months with chemotherapy; HR: 0.85) or HER2-low disease (IHC 1+ or IHC 2+/ISH-) (median OS: 15.4 months vs 11.5 months with chemotherapy; HR: 0.75).

These data confirm the clinically meaningful survival benefit of sacituzumab govitecan in patients with pretreated, endocrine-resistant HR-positive/HER2-negative MBC compared with single-agent chemotherapy.

Comparing Toxicities Between Datopotamab Deruxtecan and Sacituzumab Govitecan
As with most anticancer agents, efficacy and toxicity go hand in hand, and it is crucial to understand the risk vs benefit profile of any given drug. For the TROP-2 ADCs, there are distinct toxicities between sacituzumab govitecan and datopotamab deruxtecan to be aware of, likely attributable to their different chemotherapy payloads. Diarrhea and neutropenia are among the most common notable adverse events (AEs) associated with sacituzumab govitecan, whereas stomatitis, dry eye, and interstitial lung disease are associated with datopotamab deruxtecan. Sacituzumab govitecan and datopotamab deruxtecan also share a suite of AEs common to chemotherapy that nurses are familiar with managing, including nausea and vomiting, fatigue, and alopecia, along with the potential for hypersensitivity reactions during their infusion.

Early recognition of treatment-related AEs is critical, as optimal AE management ultimately maximizes patients’ treatment benefit in addition to maintaining their quality of life. For guidance on monitoring for and managing AEs associated with TROP-2 ADC therapy, watch this on-demand webcast of a live symposium developed for oncology nurse specialists or download this associated slideset.

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