Sacituzumab Govitecan Significantly Improves Survival in Metastatic TNBC

Treatment with sacituzumab govitecan (Trodelvy) led to a 59% reduction in the risk of disease progression or death compared with physician’s choice of single-agent chemotherapy in patients with previously treated metastatic triple-negative breast cancer (TNBC), according to the results of the phase 3 ASCENT trial that were presented during the 2020 ESMO Virtual Congress.¹

Findings showed that the median progression-free survival (PFS) by blinded independent central review (BICR) was 5.6 months (95% CI, 4.3-6.3) in the sacituzumab govitecan arm compared with 1.7 months (95% CI, 1.5-2.6) with standard treatment (HR, 0.41; 95% CI, 0.32-0.52; P <.0001).

Sacituzumab govitecan also nearly doubled the median overall survival (OS) at 12.1 months (95% CI, 10.7-14.0) compared with physician’s choice of therapy at 6.7 months (95% CI, 5.8-7.7), an improvement that was determined to be statistically significant (HR, 0.48; 95% CI, 0.38-0.59; P <.0001).

“The phase 3 ASCENT trial is the first phase 3 study to demonstrate a significant improvement in efficacy with a first-in-class Trop-2–directed antibody-drug conjugate (ADC) compared with standard chemotherapy in patients with previously treated metastatic triple-negative breast cancer,” lead study author Aditya Bardia, MBBS, MPH, director of precision medicine at the Center for Breast Cancer at Massachusetts General Hospital Cancer Center, stated in a virtual presentation during the meeting. “The clinical benefit here confirms the use of sacituzumab govitecan as a standard therapy for patients with pretreated metastatic triple-negative breast cancer.”

Immunomedics Inc., the manufacturer of the ADC, announced the topline findings in July 2020.2 ASCENT is the confirmatory trial for the April 2020 FDA accelerated approval of sacituzumab govitecan as a treatment for use in adult patients with metastatic TNBC who have received at least 2 prior therapies for metastatic disease, based on phase 1/2 data.

The ASCENT study was halted in April 2020 due to “compelling evidence of efficacy³” per a unanimous recommendation by the Data Safety Monitoring Committee.

Trop-2 is expressed in all breast cancer subtypes and is associated with poor prognosis. Sacituzumab govitecan is a first-in-class Trop-2–directed ADC, with an antibody that is highly specific for Trop-2 and a high drug-to-antibody ratio. Additionally, it has a SN-38 payload, which is more potent than irinotecan, the parent compound.

The international, open-label confirmatory ASCENT trial enrolled 529 patients with metastatic TNBC who had received 2 or more prior chemotherapies for advanced disease. Patients were randomized 1:1 to receive either sacituzumab govitecan (n = 267) or physician’s choice of treatment (n = 262) until disease progression or unacceptable toxicity. Sacituzumab govitecan was administered at 10 mg/kg intravenously on days 1 and 8 in 21-day cycles. Physician’s choice of treatment included eribulin (n = 139), vinorelbine (n = 52), gemcitabine (n = 38), and capecitabine (n = 33).

Patients were stratified by the number of prior chemotherapies received (2-3 vs more than 3), geographic region, and the presence or absence of known brain metastases.

The primary end point of the trial was PFS; secondary end points included PFS for the full population, OS, ORR, DOR, time to response, and safety. The PFS analysis was based on a central assessment in the brain metastases–negative population using a stratified log-rank test; there was a pre-defined maximum 15% cap for patients with brain metastases. Additionally, the safety population included all patients, regardless of brain metastases status, who received at least 1 dose of study treatment (n = 258 for sacituzumab govitecan; n = 224 for chemotherapy). The data cutoff date was March 11, 2020.

Demographics and patient characteristics were well balanced between the 2 arms. The majority of patients were female (99.5%), the median age was 53.5 years, and 79.5% of patients were white. More than half (56%) of patients had an ECOG performance status of 1, and 7.5% of patients harbored BRCA1/2 mutations.

The median number of prior anticancer therapies was 4, the most common of which being taxane (100%), anthracycline (82%), cyclophosphamide (82%), carboplatin (66%), and capecitabine (65.5%). PARP inhibitors and checkpoint inhibitors were previously administered in 7.5% and 27.5% of patients, respectively. The most common sites of disease were in the lung (44%), liver (42.5%), and bone (22%).

A total 213 and 201 patients in the sacituzumab govitecan and chemotherapy arms discontinued treatment, respectively, most of which were due to disease progression (n = 199 and 166, respectively). Fifteen patients receiving sacituzumab govitecan and 0 patients on chemotherapy remain on treatment.

Additional results showed that through investigator assessment, sacituzumab govitecan led to a 65% reduction in the risk of disease progression or death (HR, 0.35); in the overall population, which included brain metastasis–positive patients, the HR was 0.42, Bardia noted.

The PFS benefit was observed across prespecified subgroups, including age, race, number of prior therapies, geographic region (HR, 0.44 for North America vs HR, 0.36 for rest of world), prior immunotherapy (HR, 0.37), liver metastases (HR, 0.48), and initial diagnosis of TNBC (HR, 0.38). In detail, the race subgroup comprised white (HR, 0.39), black (HR, 0.45), and Asian (HR, 0.40) patients. Patients who received 2 to 3 prior therapies had improved PFS (HR, 0.39) as did those who received more than 3 treatments (HR, 0.48).

The ORR was 35% with sacituzumab govitecan, which comprised a 4% complete response (CR) rate and a 31% partial response (PR) rate; the ORR with standard treatment was 5% with a 1% CR rate and 4% PR rate (P <.0001). The clinical benefit rate was 45% with sacituzumab govitecan and 9% with standard treatment (P <.0001). The median DOR was 6.3 months (95% CI, 5.5-9.0) and 3.6 months (95% CI, 2.8–not estimable), respectively (P = .057).

Sacituzumab govitecan was given for a median 7 treatment cycles and a median treatment duration of 4.4 months (range, 0.03-22.9). Regarding safety, the most common, all-grade treatment-related adverse effects (TRAEs) with sacituzumab govitecan and chemotherapy included neutropenia (63% vs 43%, respectively), anemia (34% vs 24%), diarrhea (59% vs 12%), nausea (57% vs 26%), fatigue (45% vs 30%), and alopecia (46% vs 16%).

The key grade 3 or higher TRAEs in the sacituzumab govitecan and chemotherapy arms were neutropenia (46% vs 27%, respectively), diarrhea (10% vs less than 1%), leukopenia (10% vs 5%), anemia (8% vs 5%), and febrile neutropenia (5% vs 2%). Granulocyte colony stimulating factors were used in 49% and 23% of patients on the sacituzumab govitecan and standard therapy arms, respectively. Additionally, no severe cardiovascular toxicity was reported, nor reports of neuropathy above grade 2 and interstitial lung disease above grade 3, with sacituzumab govitecan.

Adverse effects that led to treatment discontinuation occurred in 4.7% and 5.4% of patients on sacituzumab govitecan and on chemotherapy, respectively; 0 and 1 treatment-related deaths, respectively, were reported.

A supplemental biologics application seeking full approval for the agent is planned for later this year, according to Immunomedics, Inc.

Ongoing studies are exploring sacituzumab govitecan in the neoadjuvant and adjuvant treatment settings and in combination with other targeted agents. Additionally, the ongoing, phase 3 TROPiCS-02 trial (NCT03901339) is evaluating the ADC in patients with hormone receptor–positive, HER2-negative breast cancer.

References

1. Bardia A, Tolaney SM, Loirat D, et al. ASCENT: A randomized phase 3 study of sacituzumab govitecan (SG) vs treatment of physician’s choice (TPC) in patients (pts) with previously treated metastatic triple-negative breast cancer (mTNBC). Presented at: 2020 ESMO Virtual Congress; September 19-21, 2020; Virtual. Abstract LBA17.
2. Immunomedics announces positive results from phase 3 ASCENT study of Trodelvy. News release. Immunomedics. July 6, 2020. Accessed September 19, 2020. bit.ly/2Z5PSeI.
3. Immunomedics announces ASCENT study to be stopped for compelling efficacy Published April 6, 2020. Accessed September 19, 2020. https://bit.ly/2RgJ3mu.