The antibody–drug conjugate sacituzumab govitecan, or SG, may be a viable option for patients with metastatic HR-positive/HER2-negative breast cancer who have developed resistance to endocrine drugs. In the phase III TROPiCS-02 trial, compared with standard chemotherapy, SG extended both progression-free and overall survival, besides improving quality of life.

For patients with metastatic hormone receptor (HR)–positive/HER2-negative breast cancer, sacituzumab govitecan (SG; Trodelvy; Gilead) not only cuts the risk of disease progression but also improves overall survival (OS). As such, this TROP2-targeting antibody–drug conjugate (ADC) could boost their otherwise limited therapeutic arsenal, especially once resistance to endocrine agents sets in.

“The optimal sequencing of drugs following endocrine resistance is still unclear,” said Hope Rugo, MD, of the University of California, San Francisco. “Single-agent chemotherapy is standard but associated with poor disease control, increased toxicity, and declining quality of life. We really need new and effective options.”

In June, during the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting, Rugo disclosed results from the first interim analysis of TROPiCS-02, a phase III trial evaluating SG in patients whose disease had worsened after endocrine therapy, CDK4/6 inhibitors, and up to four prior lines of chemotherapy. Among 543 patients randomly assigned to receive SG or their physician's treatment of choice—capecitabine, vinorelbine, gemcitabine, or eribulin—the median progression-free survival (PFS) was 5.5 months and 4 months, respectively.

A second interim analysis followed, which Rugo presented at the ESMO 2022 Congress in September. SG extended the median OS to 14.4 months, she noted, compared with 11.2 months in the control arm. Objective response rates were 21% and 14%, and the median duration of response was 8.1 months versus 5.6 months. Patients given SG reported a significantly better quality of life, including less fatigue, appetite loss, and insomnia.

“We also saw that dyspnea improved” with SG versus chemotherapy, added TROPiCS-02 investigator Aditya Bardia, MD, of Massachusetts General Hospital Cancer Center in Boston. “It likely reflects better disease control, particularly with pulmonary metastases.”

“At ASCO, the PFS data provoked some debate about SG's magnitude of benefit in this population,” remarked Meritxell Bellet, MD, PhD, of Vall d'Hebron University Hospital in Barcelona, Spain. “The new OS findings are clinically meaningful in my opinion and should lead to regulatory approval” that would expand SG's label beyond its current second-line indication for metastatic triple-negative breast cancer.

However, that practice-changing data from DESTINY-Breast04, which featured a different ADC, trastuzumab deruxtecan (T-DXd; Enhertu; Daiichi Sankyo), likely complicates the landscape, Bellet observed. The landmark phase III trial, highlighted at ASCO, has set the stage for redefining approximately 65% of patients with metastatic HR-positive/HER2-negative breast cancer as having HER2-low tumors.

In light of this new definition, the TROPiCS-02 researchers retrospectively examined patients’ ISH or IHC results if available. They found that 52% of patients were in fact HER2-low and 40% were HER2-negative (IHC score 0). SG outperformed chemotherapy in both subgroups—improving the median PFS from 4.2 months to 6.4 months and from 3.4 months to 5.0 months, respectively—Frederik Marmé, MD, PhD, of the University of Heidelberg in Germany, reported at ESMO.

When it comes to HER2, though, concordance between pathology scores of IHC 0 and 1+ “is actually pretty bad,” cautioned Shom Goel, MBBS, PhD, of Peter MacCallum Cancer Centre in Melbourne, Australia. “As more ADCs come on the market, we should be careful to not get caught up chasing our tail, trying to classify and reclassify breast cancer using blunt, imperfect tools.”

Comparing SG with T-DXd may be tempting but “is really hard,” Goel added, “given that [TROPiCS-02] patients were so much more heavily pretreated. The best we can do is to be pragmatic.” For HER2-low patients, “it's hard to ignore the large OS benefit” T-DXd provides; meanwhile, based on the subgroup findings Marmé presented, “I think SG could be a reasonable choice for HER2-negative patients if approved.” –Alissa Poh

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©2022 American Association for Cancer Research
2022
American Association for Cancer Research