Sacituzumab govitecan effective for triple-negative breast cancer regardless of biomarkers
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Women with metastatic triple-negative breast cancer benefited from sacituzumab govitecan irrespective of their Trop-2 expression level and BRCA1/BRCA2 mutation status, according to data from the phase 3 ASCENT study.
However, results presented at the virtual San Antonio Breast Cancer Symposium also showed sacituzumab govitecan-hziy (Trodelvy, Immunomedics) — an antibody-drug conjugate composed of an anti-Trop-2 antibody and SN-38, the metabolite of irinotecan — had higher efficacy compared with physician’s choice of therapy among those with medium or high Trop-2 expression vs. low expression.
“Trop-2 is expressed in all breast cancer subtypes, including triple-negative breast cancer, and has been linked to poor prognosis and decreased survival,” Sara A. Hurvitz, MD, medical oncologist at UCLA Health - Santa Monica Medical Center, associate professor at David Geffen School of Medicine at UCLA, medical director of the Jonsson Comprehensive Cancer Center Clinical Research Unit, and director of the breast cancer clinical trials program at UCLA, said during her presentation. “Triple-negative breast cancer has been shown to have high membrane expression of Trop-2, with up to 88% of primary and metastatic triple-negative breast cancer tumors having moderate to strong Trop-2 staining. Sacituzumab govitecan has demonstrated activity in translation models of triple-negative breast cancer with relatively high Trop-2 expression.”
Also, BRCA mutations occur in approximately 10% of patients with triple-negative breast cancer, which may make the cancers cells susceptible to agents that block DNA repair mechanisms, Hurvitz said.
“Sacituzumab govitecan has demonstrated activity in BRCA-mutant translational models ... and may confer synthetic lethality to triple-negative breast cancer tumors,” she said.
ASCENT, a confirmatory study of sacituzumab govitecan for metastatic triple-negative breast cancer, included 529 patients randomly assigned 1:1 to 10 mg/kg IV sacituzumab govitecan on days 1 and 8 of each 21-day cycle, or treatment of physician’s choice of eribulin (Halaven, Eisai), vinorelbine, gemcitabine or capecitabine. Results reported at this year’s ESMO Virtual Congress 2020 showed a significant PFS (median, 5.6 months vs. 1.7 months; HR = 0.41; P < .0001) and OS (median, 12.1 months vs. 6.7 months; HR = 0.48; P < .0001) benefit with the study drug vs. chemotherapy.
Hurvitz and colleagues conducted an exploratory biomarker analysis of the trial to determine whether Trop-2 expression and BRCA mutations correlated with efficacy among 468 patients without brain metastases.
Their analysis included 149 patients with known BRCA status assigned sacituzumab govitecan, 7% of whom were BRCA1/BRCA2 positive, and 143 assigned chemotherapy, 8% of whom were BRCA1/BRCA2 positive.
Histochemical scores (H-score) for Trop-2 expression were available for 151 patients assigned sacituzumab govitecan and 139 assigned chemotherapy. Most patients had a high H-score of 200 to 300 (sacituzumab govitecan, 56%; chemotherapy, 52%), followed by a medium H-score of 100 to 200 (26%; 25%) and a low H-score of less than 100 (18%; 23%).
Median PFS favored the sacituzumab govitecan group for those with high (6.9 months vs. 2.5 months), medium (5.6 months vs. 2.2 months) and low (2.7 months vs. 1.6 months) Trop-2 H-scores. Median OS followed the same trend, with longer OS observed among those with medium and high expression (high, 14.2 months vs. 6.9 months; medium, 14.9 months vs. 6.9 months; low, 9.3 months vs. 7.6 months).
“Due to small sample size, the efficacy data should be interpreted with caution for the Trop-2-low subgroup,” Hurvitz said.
Overall response rates also were higher with sacituzumab govitecan for those with Trop-2 high (44% vs. 1%), medium (38% vs. 11%) or low (22% vs. 6%) expression.
Sacituzumab govitecan demonstrated a similar safety profile across the three Trop-2 expression subgroups.
Sacituzumab govitecan also appeared to outperform chemotherapy regardless of germline BRCA mutation status as measured by ORR (BRCA1/BRCA2 positive, 19% vs. 6%; BRCA1/BRCA2 negative, 33% vs. 6%), median PFS (positive, 4.6 months vs. 2.5 months; negative, 4.9 months vs. 1.6 months) and median OS (positive, 15.6 months vs. 4.4 months; negative, 10.9 months vs. 7 months).
“This biomarker evaluation confirmed that the clinical benefit of sacituzumab govitecan vs. treatment of physician’s choice in previously treated metastatic triple-negative breast cancer is irrespective of Trop-2 expression,” Hurvitz said. “The highest efficacy outcomes were seen in sacituzumab govitecan-treated patients from the Trop-2-high and Trop-2-medium subgroups. Sacituzumab govitecan also outperformed treatment of physician’s choice regardless of germline BRCA1/BRCA2 mutation status at study entry.”
Although there is a prognostic association with Trop-2, it may not be appropriate to use this biomarker to determine who should receive sacituzumab govitecan, Hurvitz said during the Q&A session.
“Low Trop-2 expression, if you look at the Kaplan-Meier curve, is associated with worse outcome regardless of treatment, so there does appear to be a better outcome associated with higher levels of expression,” she said. “That said, we don’t see a differential benefit. The Trop-2-low group was such a small group of patients; it’s too small for us to be saying they do or don’t respond significantly with sacituzumab govitecan. But, the trend at each different H-score level is indicating that sacituzumab govitecan benefits all patients, regardless of Trop-2 expression. I don’t think Trop-2 should be used to identify patients who would or wouldn’t benefit from sacituzumab govitecan. That said, it is potentially a prognostic marker based on these data, but I don’t see how that would help an individual patient.”
Perspective
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Trop-2 is very commonly expressed in triple-negative breast cancer. Although the benefit varied with the degree of Trop-2 expression, there was a benefit at every level of expression. There weren’t enough patients in this analysis who had no Trop-2 expression to say anything about that group.
But because it is so common — around 85% of triple-negative breast cancers express Trop-2 — and there was a benefit across the spectrum of Trop-2 expression, I don’t think at this point we should limit sacituzumab govitecan treatment to only Trop-2-high expressors or require testing for Trop-2 prior to giving this drug.
This area of antibody-drug conjugates is so interesting because it is brand new, and it’s not clear how much of the protein you need to have on the tumor surface in order to get some degree of benefit from the payload. You could have very little expression of the protein to which the antibody is docking, but if you’ve got a lot of drug loaded up on that antibody, it could still potentially get into the cell and benefit the patient. We still have to learn more about this balance of how much protein you need to get the antibody to dock, and how much payload you need on the antibody to get a benefit.
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Hurvitz SA, et al. Abstract GS3-06. Presented at: San Antonio Breast Cancer Symposium (virtual meeting): Dec. 8-11, 2020.
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