Sacituzumab Govitecan Benefit in HR+/HER2– Breast Cancer Not Determined by Trop-2 Levels

Hope S. Rugo, MD

Treatment with sacituzumab govitecan (Trodelvy) led to improved survival outcomes compared with treatment of physician’s choice (TPC) in patients with pretreated, endocrine-resistant hormone receptor–positive, HER2-negative metastatic breast cancer, according to updated results from the phase 3 TROPiCS-02 trial (NCT03901339). Additionally, the results of a post hoc analysis showed that benefit from sacituzumab govitecan was seen regardless of the level of Trop-2 expression.¹

“We found that there was an improvement in progression-free and overall survival regardless of whether you fell into the lower Trop-2 expression or higher Trop-2 expression [group],” Hope S. Rugo, MD, professor of medicine and director of breast oncology and clinical trials education at the University of California San Francisco Helen Diller Family Comprehensive Cancer Center, said in an interview with Targeted Oncology™ during the 2022 San Antonio Breast Cancer Symposium.

Sacituzumab govitecan is a first-in-class Trop-2–directed antibody-drug conjugate (ADC), which has already been approved for use in patients with locally advanced or metastatic triple-negative breast cancer who have received at least 2 prior systemic therapies.²

High expression of Trop-2, an epithelial antigen, is reported in about 85% to 90% of all subtypes of breast cancer.

Sacituzumab govitecan has already demonstrated efficacy in patients with hormone receptor–positive, HER2-negative metastatic breast cancer in earlier results from the TROPiCS-02 trial. Results from the first interim analysis presented at the 2022 American Society for Clinical Oncology Annual Meeting showed that the median PFS was 5.5 months with sacituzumab govitecan (n = 272) and 4.0 months with TPC (n = 271; HR, 0.66; 95% CI, 0.53-0.83; P = .0003).³

At the European Society for Medical Oncology Congress 2022, findings from the second interim analysis demonstrated that the median OS was 14.4 months with sacituzumab govitecan compared with 11.2 months with TPC (HR, 0.79; 95% CI, 0.65-0.96; P = .02).⁴ The objective response rate (ORR) was 21% with the ADC compared with 14% with TPC (odds ratio, 1.63; 95% CI, 1.03-2.56; P = .035).

Efficacy By Trop-2 Expression Level

For the Trop-2 post hoc analysis,1 expression was determined on primary or metastatic archival tumor tissue samples using a validated immunohistochemistry assay. Patients were given an H-score to represent the total percent staining weighted by the intensity of the staining (range, 0-300).

Eighty-eight percent of the investigational arm and 83% of the control arm had evaluable samples for Trop-2 level testing. Overall, 5% of patients had an H-score of 0, 12% had a score between 0 and 10, 24% had a score between 10 and 100, and 58% had a score of at least 100.

Among patients with Trop-2 expression of 100 or more, the median PFS was 6.4 months (95% CI, 4.0-8.3) with sacituzumab govitecan and 4.1 months (95% CI, 2.1-4.5) with TPC (HR, 0.60; 95% CI, 0.44-0.81). In those with an H-score below 100, the median PFS was 5.3 months (95% CI, 4.1-6.0) in the sacituzumab govitecan arm and 4.0 months (95% CI, 2.8-5.6) in the TPC arm (HR, 0.77; 95% CI, 0.54-1.09). More specifically, the median PFS in patients with a score of 10 or below was 5.5 months (95% CI, 2.8-9.5) with the ADC and 4.3 months (95% CI, 1.7-6.4) with standard therapy (HR, 0.89; 95% CI, 0.51-1.57), and for those with a score between 10 and 100, the median PFS was 5.0 months (95% CI, 4.1-7.1) and 3.5 months (95% CI, 1.6-5.6), respectively (HR, 0.67; 95% CI, 0.42-1.07).

Median OS in patients with a Trop-2 expression of 100 or more was 14.4 months (95% CI, 12.7-16.4) with sacituzumab govitecan and 11.2 months (95% CI, 9.9-12.9) with TPC (HR, 0.83; 95% CI, 0.62-1.11). Patients with a score below 100 had a median OS of 14.6 months (95% CI, 12.7-18.1) with the ADC and 11.3 months (95% CI, 10.0-13.3) with standard therapy (HR, 0.75; 95% CI, 0.54-1.04). More specifically, among patients with a score of 10 or below, the median OS was 17.6 months (95% CI, 11.5-not evaluable) with sacituzumab govitecan compared with 12.3 months (95% CI, 8.0-15.3) with TPC (HR, 0.61; 95% CI, 0.34-1.08), and for those with a score between 10 and 100, the median OS was 13.7 months (95% CI, 10.9-16.3) and 11.0 months (95% CI, 9.0-13.5), respectively (HR, 0.81; 95% CI, 0.54-1.23).

“It appeared there was a PFS and OS benefit in these very low scores, with a H-score up to 10—Trop-2 expression didn’t impact response or safety as well. So I think that confirms the fact that sacituzumab is effective regardless of Trop-2 expression, and that you don’t need to test for Trop-2 to determine which patients are eligible for benefit from sacituzumab,” Rugo said, though she noted in her presentation that the sample size was small and so caution should be given to interpreting these data.

In patients with a score of up to 10, the ORR was 24% and the clinical benefit rate (CBR) was 32%. The median duration of response (DOR) in this subgroup was 7.5 months (95% CI, 2.5-not reached [NR]). In the 10 to 100 Trop-2 expression level group, the ORR was 18%, the CBR was 27%, and the median DOR was 7.4 months (95% CI, 4.1-NR). In the 100 or more expression level group, the ORR was 23%, the CBR was 39%, and the median DOR was 8.5 months (95% CI, 5.9-16.9).

The safety profile by treatment was not impacted by Trop-2 expression levels. With sacituzumab govitecan specifically, the rate of grade 3 or higher treatment-emergent adverse events (TEAEs) was 79% in patients with an H-score below 100 and 74% in those with a score of 100 or higher. TEAEs led to treatment discontinuation in 2% of patients with a score below 100 and 8% with a score of at least 100. Serious TEAEs were reported in 26% of patients with a score below 100 and in 30% with a score of at least 100; TEAEs led to death in 1% and 3% of patients, respectively.

Neutropenia of grade 3 or higher was reported in 58% and 54% of patients in the sacituzumab govitecan arm who had H-scores below and above 100, respectively, and in 46% and 35% of patients in the TPC arm. Grade 3 or higher febrile neutropenia was observed in 7% and 6% of patients in the sacituzumab govitecan arm who had H-scores below and above 100, respectively, and in 4% and 5% of patients in the TPC arm. Diarrhea of grade 3 or higher was reported in 10% and 9% of patients in the sacituzumab govitecan arm who had H-scores below and above 100, respectively, and in 1% of patients in each group in the TPC arm.

Trial Design

TROPiCS-02 is a randomized, open-label phase 3 study that enrolled 543 patients with locally recurrent or metastatic, inoperable hormone receptor–positive, HER2-negative breast cancer that has progressed after at least 1 prior endocrine therapy, a taxane, and a CDK4/6 inhibitor in any setting. Patients had received between 2 and 4 prior lines of chemotherapy for metastatic disease.

Enrolled patients were randomly assigned 1:1 to intravenous sacituzumab govitecan at 10 mg/kg administered on days 1 and 8 of every 3-week cycle or TPC, which consisted of capecitabine, vinorelbine, gemcitabine, or eribulin. Patients were stratified by the presence of visceral metastases, endocrine therapy use in the metastatic setting at 6 months or more, and the number of prior lines of chemotherapy.

The primary end point was PFS by blinded independent central review, and secondary end points included OS, ORR, DOR, CBR, patient-reported outcomes, and safety.

_References:

_{1. 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. Abstract presented at: 2022 San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, TX. Abstract GS1-11.}

_{2. FDA grants regular approval to sacituzumab govitecan for triple-negative breast cancer. FDA. April 8, 2021. Accessed December 9, 2022. https://bit.ly/3Fd1wbP}

_{3. Rugo HS, Bardia A, Marme F, et al. Primary results from TROPiCS-02: A randomized phase 3 study of sacituzumab govitecan (SG) versus treatment of physician’s choice (TPC) in patients (Pts) with hormone receptor–positive/HER2-negative (HR+/HER2-) advanced breast cancer. J Clin Oncol. 2022;40(suppl 17):LBA1001. doi:10.1200/JCO.2022.40.17_suppl.LBA1001}

_{4. Rugo HS, Bardia A, Marme F, et al. Overall survival (OS) results from the phase III TROPiCS-02 study of sacituzumab govitecan (SG) vs treatment of physician's choice (TPC) in patients (pts) with HR+/HER2- metastatic breast cancer (mBC). Ann Oncol. 2022;33(suppl 7):LBA76. doi:10.1016/annonc/annonc1089}