Hormone receptor-positive/human epidermal growth factor negative (HR+/HER2-) breast cancer accounts for approximately 70% of all breast cancers, with close to 40,000 new cases diagnosed each year worldwide. Although many patients are diagnosed with early-stage disease, almost a third progress to metastatic disease, with a five-year survival rate of just 30%. Once patients become resistant to standard of care (Soc ) endocrine-based therapies and CDK 4/6 inhibitors, the prognosis is poor, with treatment options limited to single-agent chemotherapies.
Gilead’s Trodelvy (sacituzumab govitecan-hziy) is a first-in-class Trop-2 directed antibody-drug conjugate (ADC ), with a potent topoisomerase I inhibitor payload. Trop-2 is highly expressed across multiple cancer types, with expression detected in more than 90% of breast cancers. Trodelvy has already received regulatory approval for previously treated triple-negative breast cancer (TNBC) across the eight major markets (8MM – US, France, Germany, Italy, Spain, UK, Japan and China).
A global Phase III TROPiCS-02 study evaluated the use of Trodelvy in comparison to physicians’ choice of chemotherapy in 543 HR+/HER2- metastatic breast cancer patients who were previously treated with endocrine therapy, CDK 4/6 inhibitors and at least two lines of chemotherapy. Findings of the study, reported at the ESMO Congress 2022, demonstrated a 3.2-month overall survival (OS) benefit for patients receiving Trodelvy (14.4 months) versus physicians’ choice chemotherapy (11.2 months). A superior overall response rate (ORR ) of 57% for Trodelvy in comparison to 38% for chemotherapy-treated patients was also announced. Although the clinical benefit of Trodelvy in the HR+/HER2- breast cancer setting is not as dramatic as the approximately six-month OS benefit observed in TNBC patients, the results from the TROPiCS-02 study show a clinically meaningful impact for patients with very limited therapeutic options.
While Trodelvy is expected to be the first ADC approved in the HR+/HER2-negative breast cancer setting, Daiichi/AstraZeneca’s Enhertu (trastuzumab deruxtecan) received US Food and Drug Administration (FDA ) approval just last month for patients with HER2-low expressing breast cancers. Patients with HER2-low-expressing tumours were historically treated as those with HER2-negative disease, but with the approval of the HER2 targeting ADC in this setting, these patients are expected to receive Enhertu in the second line and beyond.
Approximately 60% of previously classified HR+/HER2- patients, as well as 34% of TNBC patients, are now considered as HER2-low expressing patients, making them candidates for Enhertu therapy, which demonstrated a 6.6-month OS benefit compared to Soc chemotherapy in the DESTINY-Breast04 trial. While cross-trial comparisons must be made with caution, the OS benefit reported for Enhertu surpasses that observed for Trodelvy and may give Enhertu an advantage in patients who are candidates for both ADCs.
It remains to be investigated whether Trodelvy may be utilised in patients previously treated with Enhertu. While the two ADCs have differential targets, the payloads belong to the same class, with Trodelvy carrying SN38 and Enhertu bearing deruxtecan, both topoisomerase I inhibitors. With deruxtecan having a topoisomerase I inhibition potency ten times greater than that of SN38, it is expected that at least a proportion of those treated with Enhertu will have developed resistance to topoisomerase inhibition and will not derive benefit from subsequent Trodelvy exposure. In patients who fail to respond or progress on Enhertu therapy due to loss of HER2 expression, utilising an ADC with a different target may be a therapeutic option.
Last month, Gilead submitted a supplemental biologics licensing application (BLA) to the FDA for Trodelvy, seeking regulatory approval for previously treated metastatic HR+/HER2-breast cancer. While Trodelvy is expected to become the new Soc for previously treated HR+/HER2- patients who do not have sufficient HER2 expression to receive Enhertu, it remains to be seen whether HR+/HER2-low patients will be treated with the anti-TROP2 ADC . In addition to Enhertu, Trodelvy may also experience competition from Daiichi/AstraZeneca’s anti-TROP2 ADC , datopotamab deruxtecan (dato-DXd), which is being investigated in the Phase III TROPION-Breast01 trial for previously treated HR+/HER2- patients. As Trodelvy will have the first-in-class advantage in the HER2-negative setting, dato-DXd would have to demonstrate superior efficacy to dominate this market.