Barbara Pistilli, MD, Head of the Breast Cancer Unit in the Medical Oncology Department of Gustave Roussy Cancer Center, Villejuif, France, was invited to discuss the TROPiCS-02 updated analysis. She began by pointing out that the target landscape of antibody-drug conjugates is “expanding rapidly,” and newer agents require lower expression of the target. However, although TROPiCS-02 found that sacituzumab govitecan-hziy may be effective regardless of TROP-2 expression—and it is approved for metastatic triple-negative breast cancer regardless of TROP-2 expression—she cautioned against interpreting this as a rationale for the drug’s unselective use in hormone receptor–positive, HER2-negative breast cancer.
In the updated analysis of TROPiCS-02, based on an additional median 13 months of follow-up, sacituzumab govitecan significantly reduced the risk of disease progression by 35% and the risk of death by 21% in heavily pretreated patients unselected for TROP-2 expression, she noted.
Barbara Pistilli, MD
Should TROP-2 Expression Guide Treatment?
“My question is, with the different-generation antibody-drug conjugates showing activity across a wide range of target expression, do we still need to know the tumor target expression level? If you look at the ASCO biomarker guidelines, you see the expert panel does not recommend using TROP-2 expression to guide treatment because of a lack of evidence,” Dr. Pistilli said.
However, in preclinical and clinical studies, the level of TROP-2 expression did correlate with the drug’s magnitude of benefit, she pointed out. In vitro cytotoxic studies have shown an enhanced ability to internalize sacituzumab govitecan when more antigen is present.1 The ASCENT trial “clearly showed” numerically higher efficacy outcomes in high and medium TROP-2 expression subgroups.2 And the absence of TROP-2 expression by RNA and immunohistochemistry has been associated with de novo resistance to sacituzumab govitecan,3 she noted.
The current TROPiCS-02 analysis is in line with these findings in showing a numerically shorter progression-free survival in patients with lower TROP-2 expression (5.0 vs 5.8 months), which is consistent with the biomarker analysis presented at the 2022 San Antonio Breast Cancer Symposium.4 It showed less benefit among patients with an H-score of up to 10 (hazard ratio [HR] = 0.89), she said. “These findings suggest that the few patients with tumors that have low or absent TROP-2 expression are less likely to benefit from sacituzumab govitecan,” Dr. Pistilli stated.
“TROP-2 expression is preferable, though the optimal threshold for activity is unknown,” Dr. Pistilli concluded.
How About Expression of HER2 [and HER3]?
Commenting on two other studies from the same session, Dr. Pistilli further noted: “Likewise, the assessment of HER2 [and HER3] expression matters.”
The recent DESTINY clinical trials have shown that the magnitude of benefit from fam-trastuzumab deruxtecan-nxki (T-DXd) is higher in patients with increasing levels of HER2 expression and is very low in HER2-negative breast cancer,5 she noted. Similarly, for the HER3-targeting antibody-drug conjugate patritumab deruxtecan, activity has been seen across a broad range of HER3 membrane expression.6 However, few patients with low HER3 expression have been evaluated, and activity is lacking in HER3-low–expressing tumor xenografts.7
Clinical Implications
“The new antibody-drug conjugates work across a broad range of tumor expression, and they work beyond target expression, such as through the bystander effect and by immune modulation of the tumor environment—but they are less likely to work when the target is low or absent,” Dr. Pistilli commented. “These patients are more likely to have de novo resistance to the antibody-drug conjugate. So, in the expanding antibody-drug conjugate landscape, I think that target assessment may support the choice of the most suitable drug for each patient and may help us to avoid using the antibody-drug conjugate that has little chance of working,” Dr. Pistilli concluded.
DISCLOSURE: Dr. Pistilli has served as a consultant or advisor to or has received travel funding from AstraZeneca, Daiichi Sankyo/UCB Japan, Myriad Genetics, Novartis, Pierre Fabre, Puma Biotechnology, and MSD Oncology.
REFERENCES
1. Cardillo TM, Govindan SV, Sharkey RM, et al: Humanized anti-Trop-2 IgG-SN-38 conjugate for effective treatment of diverse epithelial cancers: Preclinical studies in human cancer xenograft models and monkeys. Clin Cancer Res 17:3157-3169, 2011.
2. Bardia A, Hurvitz SA, Tolaney SM, et al: Sacituzumab govitecan in metastatic triple-negative breast cancer. N Engl J Med 384:1529-1541, 2021.
3. Coates JT, Sun S, Leshchiner I, et al: Parallel genomic alterations of antigen and payload targets mediate polyclonal acquired clinical resistance to sacituzumab govitecan in triple-negative breast cancer. Cancer Discov 11:2436-2445, 2021.
4. Rugo HS, Bardia A, Marmé F, et al: Sacituzumab govitecan vs treatment of physician’s choice: Efficacy by Trop-2 expression in the TROPiCS-02 study of patients with HR+/HER2– metastatic breast cancer. 2022 San Antonio Breast Cancer Symposium. Abstract GS1-11. Presented December 6, 2022.
5. Modi S, Jacot W, Yamashita T, et al: Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer. N Engl J Med 387:9-20, 2022.
6. Krop IE, Masuda N, Mukohara T, et al: Results from the phase 1/2 study of patritumab deruxtecan, a HER3-directed antibody-drug conjugate, in patients with HER3-expressing metastatic breast cancer. 2022 ASCO Annual Meeting. Abstract 1002. Presented June 4, 2022.
7. Koganemaru S, Kuboki Y, Koga Y, et al: U3-1402, a novel HER3-targeting antibody-drug conjugate, for the treatment of colorectal cancer. Mol Cancer Ther 18:2043-2050, 2019.
