Clinical Benefit of Sacituzumab Govitecan in Metastatic TNBC Observed Irrespective of TROP-2 Expression

Sara A. Hurvitz, MD

Sacituzumab govitecan (Trodelvy), an antibody-drug conjugate (ADC), demonstrated clinical benefit compared with physician’s choice of therapy (PCT) as treatment of patients with metastatic triple-negative breast cancer (TNBC), irrespective of Trop-2 expression, but greater efficacy was seen in patients with a medium or high Trop-2 score in the phase 3 ASCENT study (NCT02574455), according to data from an exploratory biomarker analysis presented during the 2020 San Antonio Breast Cancer Symposium.¹

Results showed that the median progression-free survival (PFS) was higher in patients who received the ADC versus those who were given PCT, across all subgroups of Trop-2 analyzed. In the Trop-2 High subgroup, the median PFS in the investigative and control arms was 6.9 months vs 2.5 months, respectively; in the Trop-2 medium subgroup, median PFS was 5.6 months and 2.2 months, respectively, while in the Trop-2 low subset, the median PFS was 2.7 months vs 1.6 months, respectively.

Furthermore, sacituzumab govitecan also outperformed TPC with regard to median overall survival (OS), across all Trop-2 subgroups. The median OS was longest in the Trop-2 High (14.2 months vs 6.9 months, respectively) and Trop-2 Medium (14.9 months vs 6.9 months, respectively) subgroups. In the Trop-2 Low subgroup, the median OS with the ADC was 9.3 months vs 7.6 months with PCT.

“The biomarker evaluation in the phase 3 ASCENT trial confirmed that the clinical benefit with sacituzumab govitecan vs TPC in previously treated patients with metastatic TNBC is irrespective of the level of Trop-2 expression,” Sara A. Hurvitz, MD, director of Breast Cancer Clinical Research Program an co-director of the Santa Monica University of California Los Angeles (UCLA) Outpatient Hematology/Oncology Practice, and an assistant professor of medicine in the Division of Hematology/Oncology of the David Geffen School of Medicine at UCLA, said during an oral presentation during the meeting.

“The highest efficacy outcomes were seen in sacituzumab govitecan–treated patients from the Trop-2 High and Trop-2 median subgroups compared with TPC,” Hurvitz added. “Sacituzumab govitecan also outperformed TPC, regardless of germline BRCA1/2 mutation status.”

Sacituzumab govitecan is a first-in-class ADC that is highly specific for Trop-2. The antibody is conjugated via a hydrolysable linker to SN-38, which represents an active metabolite of irinotecan in a high drug to antibody ratio of 7.6:1, explained Hurvitz. To release SN-38 from the antibody, internalization and enzymatic cleavage by the tumor cells is not needed. Hydrolysis of the linker liberates SN-38 extracellularly to elicit a bystander effect in patients who receive the ADC.

In April 2020, sacituzumab govitecan was granted an accelerated approval from the FDA for use in adult patients with metastatic TNBC who have received at least 2 previous therapies for metastatic disease based on data from a phase 1/2 study of the agent. Here, the ADC demonstrated an objective response rate (ORR) of 33.3% via local assessment (95% CI, 24.6%-43.1%), and a median duration of response (DOR) of 7.7 months (95% CI, 4.9-10.8) at a median follow-up of 9.7 months.²

Data from ASCENT, which is the confirmatory trial of the ADC, were presented during the 2020 ESMO Virtual Congress and showed that the median PFS with sacituzumab govitecan versus PCT was 5.6 months vs 1.7 months, respectively (HR, 0.41; P <.0001).³ Moreover, the median OS was 12.1 months vs 6.7 months (HR, 0.48; P <.0001). The ORR with the ADC was 35% vs just 5% with PCT. These benefits were observed across all subgroups analyzed on the trial.

“Trop-2 is expressed in all breast cancer subtypes, including TNBC, and has been linked with poor prognosis and decreased survival,” said Hurvitz. “TNBC has been shown to have high membrane expression of Trop-2, with up to 88% of primary and metastatic tumors having moderate to strong Trop-2 staining. Sacituzumab govitecan has demonstrated activity in translational models of TNBC with relatively high Trop-2 expression.”

Additionally, BRCA mutations are detected in approximately 10% of patients with TNBC, according to Hurvitz. These mutations are known to be involved with deficiencies in homologous repair of double-stranded DNA beaks and may make cells susceptible to other agents that block such mechanisms.

“Topoisomerase I inhibitors, including SN-38, and the payload in the ADC, increases single-strand DNA breaks irrespective of BRCAmutations. Sacituzumab govitecan has demonstrated activity in BRCA-mutant translational models of TNBC and may confer synthetic lethality to TNBC tumors.”

In the confirmatory phase 3 trial, a total of 529 patients with metastatic TNBC who had received at least 2 prior lines of chemotherapy for advanced disease were randomized 1:1 to receive either intravenous sacituzumab govitecan at a dose of 10 mg/kg on days 1 and 8 of every 21-day treatment cycle or TPC of single-agent chemotherapy in the form of either eribulin, vinorelbine, gemcitabine, or capecitabine. Patients were stratified based on the number of prior lines of chemotherapy received (2-3 vs more than 3), geographic region (North America vs Europe), and the presence vs absence of known brain metastases (yes vs no).

The primary end point of the trial was PFS measured by central review, while key secondary end points comprised PFS for the full patient population, OS, ORR, DOR, time to response, and safety. Biomarker assessments, including Trop-2 expression and BRCA mutation status were examined as exploratory end points.

For the exploratory biomarker analysis, investigators set out to examine the link between efficacy and Trop-2 expression or germline BRCA1/2 mutation status. For the analysis, subgroups were defined by Trop-2 expression and germline BRCA1/2 mutation status. To determine Trop-2 expression, investigators requested primary or metastatic archival biopsy or surgical specimens at the time of study entry; however, this was not a requirement for eligibility. From these samples, Trop-2 expression was examined using a validated immunohistochemistry assay; it was categorized based on histochemical score.

Patients who had a H score of less than 100 were determined to be Trop-2 Low, while those with a score between 100 and 200 were Trop-2 Medium, and those with a score of 200 to 300 were Trop-2 High.

If known, germline BRCA1/2 mutation status was collected at baseline, noted Hurvitz.

For the analysis, the link between efficacy and biomarkers was examined in the primary population of patients who were negative for brain metastases and only those with known Trop-2 expression or BRCA1/2 data were included in the assessment. The data cutoff was March 11, 2020 for the analysis.

A total of 468 patients were included in the assessment; 235 were in the ADC arm and 233 were in the TPC arm. Trop-2 expression was known for 64% of those in the sacituzumab arm versus 60% in the TPC arm. “More than 50% of evaluable patients in both arms had high Trop-2 expression by age score,” said Hurvitz. BRCA mutation status was collected for 63% of those in the ADC arm vs 61% in the TPC arm at baseline. Only 7% to 8% of patients had BRCA1/2 positivity, noted Hurvitz.

Additional results from the analysis revealed that sacituzumab govitecan also outperformed TPC in terms of ORR, across all Trop-2 subgroups examined. “Notably, a significant difference in response rate was noted for the Trop-2 High subgroup,” said Hurvitz.

The ORRs with the ADC and TPC in the Trop-2 High subgroup were 44% vs just 1%, respectively. In the Trop-2 Medium subgroup, these rates were 38% vs 11%, respectively; in the Trop-2 Low subgroup, the ORR rates were 22% vs 6%, respectively.

Moreover, efficacy outcomes proved to be numerically higher for the ADC vs TCP in the subgroup of patients with BRCA1/2 positivity, although this benefit did not reach statistical significance. “Due to the low patient number, however, these data should be interpreted with caution,” said Hurvitz.

Sacituzumab govitecan showcased a similar toxicity profile across all Trop-2 subgroups examined. “This shows that Trop-2 expression did not affect toxicity,” noted Hurvitz. The key grade 3 or higher treatment-associated adverse effects of special interest for the Trop-2 High subgroup with the ADC vs TPC included neutropenia (47% vs 32%, respectively), diarrhea (12% vs 0%), and anemia (10% vs 5%).

“Sacituzumab govitecan was generally well tolerated in the Trop-2 subgroups and had a safety profile consistent with previous reports,” concluded Hurvitz.

_References

_{1. Hurvitz SA, Tolaney SM, Punie K, et al. Biomarker evaluation in the phase 3 ASCENT study of sacituzumab govitecan versus chemotherapy in patients with metastatic triple-negative breast cancer. Presented at: 2020 San Antonio Breast Cancer Symposium; December 8-11, 2020; Virtual.}

_{2. Immunomedics Announces ASCENT study to be stopped for compelling efficacy. News release. Immunomedics, Inc. April 6, 2020. Accessed December 10, 2020. https://bit.ly/3lQ7i7C.}

_{3. Bardia A, Tolaney SM, Loirat D, et al. ASCENT: a randomized phase III study of sacituzumab govitecan (SG) vs treatment of physician’s choice (TPC) in patients (pts) with previously treated metastatic triple-negative breast cancer (mTNBC). Ann Oncol. 2020;31(suppl 4):S1149-S1150. doi:10.1016/j.annonc.2020.08.2245}