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The European Commission granted marketing authorization for sacituzumab govitecan-hziy for use as a monotherapy in the treatment of adult patients with unresectable or metastatic triple-negative breast cancer who have previously received 2 or more systemic therapies, at least 1 of them for advanced disease.
The European Commission has granted marketing authorization for sacituzumab govitecan-hziy (Trodelvy) for use as a monotherapy in the treatment of adult patients with unresectable or metastatic triple-negative breast cancer (TNBC) who have previously received 2 or more systemic therapies, at least 1 of them for advanced disease.1
The regulatory decision was supported by findings from the phase 3 ASCENT trial (NCT02574455), in which the antibody-drug conjugate (ADC) resulted in a 49% reduction in the risk of death compared with physician’s choice of chemotherapy. The median overall survival (OS) with sacituzumab govitecan was 11.8 months vs 6.9 months with chemotherapy (HR, 0.51; 95% CI, 0.41-0.62; P < .0001).
The agent was also found to result in a 57% reduction in the risk of death or disease worsening compared with chemotherapy. The median progression-free survival (PFS) was 4.8 months and 1.7 months in the investigative and control arms, respectively, in all-randomized patients, including those with brain metastases (HR, 0.43; 95% CI, 0.35-0.54; P < .0001).
“The metastatic stage of TNBC is particularly challenging to treat and until now we have urgently needed new treatment options for people in Europe living with this condition,” Véronique Diéras, MD, senior medical oncologist head of the Breast Cancer Group in the Department of Medical Oncology at the Centre Eugène Marquis, stated in a press release. “Today’s approval including second-line metastatic TNBC is significant for the community as it’s another important step forward in helping women with this disease live longer.”
ASCENT enrolled patients with metastatic TNBC that was relapsed or refractory to 2 or more prior standard chemotherapy regimens for unresectable, locally advanced or metastatic disease. Prior therapy had to include a taxane.2 Notably, those with stable brain metastases for 4 weeks prior to treatment were permitted to enroll; however, they were excluded from the primary end point analysis of the trial.
Participants were randomized 1:1 to receive the ADC at 10 mg/kg on days 1 and 8 of each 21-day treatment cycle or single-agent chemotherapy. Those in the control arm could have received eribulin at 1.4 mg/m2 on days 1 and 8 of a 21-day cycle, vinorelbine at 25 mg/m2 on day 1 weekly, capecitabine at 1000 to 1250 mg/m2 twice daily on days 1 to 14 of a 21-day cycle, or gemcitabine at 800 to 1200 mg/m2 on days 1, 8, and 15 of a 28-day cycle.
Stratification factors included number of prior chemotherapy regimens received for advanced disease (2 or 3 vs more than 3), presence of known brain metastases at baseline (yes vs no), and geographic region (North America vs the rest of the world).
Treatment was given until progressive disease, intolerable toxicity, withdrawal from the trial, or death, whichever occurred first. Crossover to the sacituzumab arm was not allowed upon disease progression on chemotherapy.
The primary end point of the trial was PFS per blinded independent central review in patients without known brain metastases. Key secondary end points comprised OS, PFS per investigator assessment, objective response, and safety.
A total of 529 patients were enrolled to the trial. Sixty-one patients had brain metastases at baseline, and 468 did not have evidence of brain metastases. Of these patients, 235 received sacituzumab govitecan and 233 were given single-agent chemotherapy chosen by an investigator. Of those in the control arm, 54% received eribulin, 20% were given vinorelbine, 13% received capecitabine, and 12% received gemcitabine.
Thirty-two patients assigned to the control arm did not receive treatment (n = 26) or withdrew consent (n = 6) prior to treatment. These patients were included in the efficacy analysis of the trial, but not the safety analyses.
Across the arms, patients had a median age of 54 years (range, 27-82), and prior treatments included taxanes (100%), anthracyclines (82%), carboplatin (66%), PD-1 or PD-L1 inhibitors (27%), and PARP inhibitors (7%). The most common reason for discontinuation of prior treatment was progressive disease (78%); 3% of patients discontinued because of toxicities. Approximately 30% of patients did not have triple-negative disease at initial diagnosis.
Additional data published in the New England Journal of Medicine showed that the PFS benefit with the ADC over chemotherapy was observed across all predefined subsets, including those aged 65 years and older (median 7.1 months vs 2.4 months, respectively), those who received more than 3 prior therapies (5.6 months vs 2.5 months), those who previously received a PD-1 or PD-L1 inhibitor (4.2 months vs 1.6 months), those with TNBC at initial diagnosis (5.7 months vs 1.6 months), and those with liver metastasis (4.2 months vs 1.5 months).2
Sacituzumab govitecan was also found to elicit an objective response of 35% vs 5% with chemotherapy in this population. Clinical benefit was observed in all subsets examined. The median DOR in the investigative and control arms was 6.3 months (95% CI, 5.5-9.0) and 3.6 months (95% CI, 2.8–not estimated), respectively (HR, 0.39; 95% CI, 0.14-1.07). The median TTR was 1.5 months (range, 0.7-10.6) with the ADC vs 1.5 months (range, 1.3-4.2) with chemotherapy.
In all randomly assigned patients, with or without brain metastases, the median PFS was 4.8 months (95% CI, 4.1-5.8) with sacituzumab govitecan vs 1.7 months (95% CI, 1.5-2.5) with chemotherapy (HR, 0.43; 95% CI, 0.35-0.54). The median OS in these patients was 11.8 months (95% CI, 10.5-13.8) in the investigative arm vs 6.9 months (95% CI, 5.9-7.7) in the control arm (HR, 0.51; 95% CI, 0.41-0.62).
Regarding safety, the most common grade 3 or higher adverse effects included neutropenia (49.5%), leukopenia (12.0%), diarrhea (10.7%), anemia (10.1%), febrile neutropenia (6.6%), fatigue (5.2%), hypophosphatemia (5.2%), nausea (4.1%), and vomiting (3.0%).
Previously, in April 2020, the FDA granted an accelerated approval to the ADC for the treatment of adult patients with metastatic TNBC who have received at least 2 prior therapies for metastatic disease.3 The decision was based on findings from a phase 1/2 study, which showed that at a median follow-up of 9.7 months, the ADC elicited an objective response rate of 33.3% (95% CI, 24.6%-43.1%) per local assessment, with a median DOR of 7.7 months (95% CI, 4.9-10.8).4
A year later, in April 2021, the FDA granted a regular approval to sacituzumab govitecan for use in patients with unresectable locally advanced or metastatic TNBC who received 2 or more prior systemic therapies, at least 1 for metastatic disease.5 The decision was based on findings from the confirmatory ASCENT trial.