Sacituzumab Govitecan Approaches EU Approval for Pretreated HR+ Metastatic Breast Cancer

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion regarding sacituzumab govitecan-hziy (Trodelvy) for use as a single agent in adult patients with unresectable or metastatic hormone receptor–positive, HER2-negative breast cancer who have previously received endocrine therapy and at least 2 additional systemic treatments for advanced disease.¹

The recommendation is supported by findings from the phase 3 TROPiCS-02 study (NCT03901339) in which the antibody-drug conjugate (ADC; n = 272) resulted in improved overall survival (OS) over physician’s choice of single-agent chemotherapy (TPC; n = 271) in this population. At a median follow-up of 12.75 months, the median OS was 14.5 months (95% CI, 13.0-16.0) in the ADC arm and 11.2 months (95% CI, 10.2-12.6) in the chemotherapy arm (HR, 0.79; 95% CI, 0.65-0.95; P = .0133).²

Sacituzumab govitecan also improved progression-free survival (PFS) over TPC, at a median of 5.5 months (95% CI, 4.2-6.9) vs 4.0 months (95% CI, 3.0-4.4), respectively (HR, 0.65; 95% CI, 0.53-0.81; P = .0001). The 1-year PFS rates in the investigative and control arms were 21% and 7%, respectively.¹

“This positive opinion from the Committee confirms the clinical benefit and value of sacituzumab govitecan in pretreated hormone receptor–positive/HER2-negative metastatic breast cancer and is a positive step toward bringing this treatment option to patients in Europe,” Javier Cortes, MD, PhD, head of the International Breast Cancer Center in Madrid and Barcelona, Spain, stated in a press release. “Too many people living with pretreated hormone receptor–positive/HER2-negative metastatic breast cancer are without treatment options after their cancer progresses, and this positive opinion is a significant step forward for patients and their loved ones across Europe.”

The phase 3 TROPiCS-02 study enrolled patients with metastatic or locally recurrent inoperable hormone receptor–positive/HER2-negative breast cancer that progressed following at least 1 endocrine therapy, taxane, and CDK4/6 inhibitor in any setting, and at least 2 but no more than 4 lines chemotherapy for metastatic disease. Patients were also required to have metastatic disease by RECIST v1.1 criteria.

Study participants were randomly assigned 1:1 to receive sacituzumab govitecan at 10 mg/kg intravenously on days 1 and 8 of every 21-day cycle or TPC in the form of capecitabine, vinorelbine, gemcitabine, or eribulin.

Patients were stratified by visceral metastases (yes vs no), endocrine therapy in the metastatic setting of 6 months or more (yes vs no), and number of prior lines of chemotherapy (2 vs 3 or 4).

PFS by blinded independent central review served as the primary end point, and secondary end points comprised OS, objective response rate (ORR), duration of response (DOR), clinical benefit rate (CBR), and patient-reported outcomes. OS by HER2 immunohistochemistry (IHC) status served as an exploratory end point.

Data from the primary analysis of the trial showed that sacituzumab govitecan significantly improved PFS (HR, 0.66; 95% CI, 0.53-0.83; P = .0003), prolonged OS (HR, 0.79; 95% CI, 0.65-0.96; P = .020) and median DOR (8.1 months vs 5.6 months) and induced a higher ORR (odds ratio [OR], 1.63; 95% CI, 1.03-2.56; P = .035) than TPC.

At the 2023 ASCO Annual Meeting, investigators shared updated safety and efficacy data from the trial.

The median age across the ADC and chemotherapy arms was 56 years (range, 27-86), and most patients were female (99%, both), White (68% vs 66%), and from Europe (58%, both) with the remainder from North America (42%, both). Most patients had an ECOG performance status of 1 (57% vs 54%) and the remainder had a status of 0 (43% vs 46%). The majority of patients had baseline visceral metastases (95%, both) and liver metastases (84% vs 87%). De novo metastatic disease was present in 29% and 22% of patients, respectively.

More than half of patients in the investigative and control arms previously received chemotherapy in the neo(adjuvant) setting (64% vs 68%) and only 8% of patients in both arms has a disease-free interval that was shorter than 1 year. Additionally, 42% and 44% of patients, respectively, received up to 2 prior lines of chemotherapy, and 58% and 56% of patients, respectively, received 3 or more prior lines. The median number of prior chemotherapy regimens was 3 in both arms (range, 0-8).

Eighty-six percent of patients in both arms previously received endocrine therapy in the metastatic setting for 6 months or longer, and more than half of patients received a previous CDK4/6 inhibitor for up to 12 months (59% vs 61%).

Additional data showed that the PFS benefit provided with sacituzumab govitecan over TPC was generally observed spanning all predefined subgroups.

The 12-month OS rate with the ADC was 60.9% (95% CI, 54.8%-66.4%) vs 47.1% (95% CI, 41.0%-53.0%) with TPC; at 18 months, these rates were 39.2% (95% CI, 33.4%-45.0%) and 31.7% (95% CI, 26.2%-37.4%), respectively. The 24-month OS rates in the investigative and control arms were 25.7% (95% CI, 20.5%-31.2%) and 21.1% (95% CI, 16.3%-26.3%), respectively.

Notably, the OS benefit with the ADC over TPC was also generally noted across key predefined patient subsets.

When evaluating PFS by HER2 IHC status, sacituzumab govitecan consistently improved PFS over TPC in those with HER2-low disease (IHC 1+, IHC2+/ISH–; unstratified HR, 0.60; 95% CI, 0.44-0.82), and in those with HER2 IHC0 disease (HR, 0.70; 95% CI, 0.51-0.98) with longer follow-up. This was also true for OS; the unstratified HR for OS in those with HER2-low disease was 0.75 (95% CI, 0.57-0.97) and 0.85 (95% CI, 0.61-1.14) in those with HER2 IHC0 disease.

With longer follow-up, the ADC induced an ORR of 21% vs 14% with TPC (OR, 1.66; 95% CI, 1.06%-2.61%; P = .027). Among those who responded in the sacituzumab arm, the complete response rate was 1%, the partial response rate was 21%, and the stable disease rate was 52%; 21% of patients had progressive disease and 6% were not evaluable for response. The CBRs in the investigative and control arms were 34% and 22%, respectively (OR, 1.80; 95% CI, 1.23%-2.63%; P = .0025). The median DOR was 8.1 months (95% CI, 6.7-8.9) and 5.6 months (95% CI, 3.8-7.9), respectively.

Overall, the toxicity profile of the ADC proved to be consistent with what has previously been reported. No new safety signals were observed with longer follow-up.

The most common treatment-emergent toxicities with sacituzumab govitecan that were grade 3 or higher in severity were neutropenia (52%), diarrhea (10%), and fatigue (6%). In the TPC arm, the most frequent grade 3 or higher effects were neutropenia (39%), thrombocytopenia (4%), fatigue (4%), and dysgeusia (4%).

The final decision on the additional indication for sacituzumab govitecan is anticipated later this year.¹

References

1. Gilead receives CHMP positive opinion for Trodelvy in pre-treated HR+/HER2- metastatic breast cancer. News release. Gilead Sciences, Inc. June 23, 2023. Accessed June 23, 2023. https://www.gilead.com/news-and-press/press-room/press-releases/2023/6/gilead-receives-chmp-positive-opinion-for-trodelvy-in-pretreated-hrher2-metastatic-breast-cancer
2. Tolaney SM, Bardia A, Marmé F, et al. Final overall survival (OS) analysis from the phase 3 TROPiCS-02 study of sacituzumab govitecan (SG) in patients (pts) with hormone receptor–positive/HER2-negative (HR+/HER2–) metastatic breast cancer (mBC). J Clin Oncol. 2023;41(suppl 16):1003. doi:10.1200/JCO.2023.41.16_suppl.1003