Sacituzumab Govitecan Meets Primary End Point in Phase 3 ASCENT Trial

The novel antibody-drug conjugate (ADC) sacituzumab govitecan-hziy (Trodelvy) demonstrated significant improvement in survival in patients with triple-negative breast cancer (TNBC) without brain metastases who previously received at least 2 prior therapies for metastatic disease, meeting the primary end point of the phase 3 ASCENT trial (NCT02574455).¹

Results from the pivotal trial showed a statistically significant improvement in progression-free survival (PFS) with the ADC compared with chemotherapy (HR, 0.41; 95% CI, 0.32-0.52), according to Immunomedics, the developer of the agent. Specifically, the median PFS with sacituzumab govitecan was 5.6 months (95% CI, 4.3-6.3) versus 1.7 months (95% CI, 1.5-2.6) with chemotherapy (P <.0001).

Notably, the agent also met key secondary end points of the trial, such as overall survival (OS) and objective response rate (ORR). The safety profile observed with the agent proved to be consistent with the FDA-approved label. Full results from the trial will be revealed at an upcoming medical meeting.

“The results of the global phase 3 ASCENT study confirm our initial observations that sacituzumab govitecan has the potential to change the standard management of metastatic TNBC,” said Aditya Bardia, MD, MPH, director of Precision Medicine at the Center for Breast Cancer at Massachusetts General Cancer Center and assistant professor of medicine at Harvard Medical School, in a recent press release.

“Based on these data, sacituzumab govitecan has set a new benchmark in scientific and clinical innovation for patients with metastatic TNBC by offering a novel alternative to the common drugs currently in clinical practice,” Bardia added. “Importantly, the ASCENT topline data also validate the manageable safety profile of sacituzumab govitecan, rendering it a good partner candidate for combination with other therapies, including immunotherapy.”

The international, open-label confirmatory trial enrolled over 500 patients with metastatic TNBC who had received at last 2 prior therapies for metastatic disease. In the trial, patients were randomized to receive either sacituzumab govitecan or physician’s choice of chemotherapy. The primary endpoint of the trial was PFS and secondary end points included OS, ORR, DOR, time to onset of response, and other measures of safety and tolerability.²

The phase 3 ASCENT trial, designed to validate the favorable safety and efficacy data of sacituzumab govitecan, was stopped in April 2020 due to “compelling evidence of efficacy.³” The company decided to halt the trial based on a unanimous recommendation from the Independent Data Safety Monitoring Committee.

Later that month, the FDA granted an accelerated approval to sacituzumab govitecan for use in adult patients with metastatic TNBC who have received at least 2 prior therapies for metastatic disease based on data from a phase 1/2 study.

Results from the trial showed that at a median follow-up of 9.7 months, the ORR with the ADC was 33.3% via local assessment (95% CI, 24.6%-43.1%), and the median duration of response (DOR) was 7.7 months (95% CI, 4.9-10.8). The clinical benefit rate, comprised of the ORR plus stable disease, was 45.4% with sacituzumab govitecan. Moreover, the ORR and median DOR was 34.3% (95% CI, 25.4%-44.0%) and 9.1 months (95 CI, 4.6-11.3), respectively.

The phase 1/2 trial enrolled a total of 108 patients with TNBC. The majority of participants, or 80%, had visceral metastases. The ADC was given at 10 mg/kg on days 1 and 8 of each 28-day treatment cycle. Thirty percent of patients had an ECOG performance status of 0, while 70% had a status of 1. Moreover, the median time from metastatic diagnosis to treatment was 1.5 years. A total of 57 patients were observed to have TROP-2 expression by immunohistochemistry ranging from moderate (2+) to strong (3+). Five patients had either weak or absent staining for the marker. Data were unavailable for the remaining patients on the trial.

Additionally, the median number of prior regimens was 3; 16.7% of patients had received previous treatment with checkpoint inhibitors. Just under half of the participants, or 41%, were treated in the third-line setting and 59% received treatment in the fourth-line or greater setting. The most common therapies that had previously been received included taxanes (98%), anthracyclines (86%), cyclophosphamide (85%), and platinum agents (75%).

The median PFS observed with the agent was 5.5 months (95% CI, 4.1-6.3), and the estimated 6-month PFS rate was 41.9%. By 12 months, the PFS rate with the ADC was estimated at 15.1%. The median OS with sacituzumab govitecan was 13.0 months (95% CI, 11.2-13.7). The estimated 6-month OS rate with the agent was 78.5% and the estimated 12-month OS was 51.3%.

With regard to safety, 85% of patients experienced grade 3/4 adverse events (AEs) with the ADC. Serious AEs were experienced by 35% of study participants. However, only 3 patients discontinued treatment with sacituzumab govitecan because of toxicities; 2 of these cases were deemed to be caused by the study drug. Dose reductions of the ADC to 7.5 mg/kg occurred in 25% of patients, and the rest of the patients were able to continue treatment at the 10 mg/kg dose.

The most common grade 3/4 AEs reported by patients on the trial included neutropenia (41.7%), anemia (11%), reduced white-cell count (11%), hypophosphatemia (9%), diarrhea (8%), as well as fatigue and asthenia (8%). Approximately 9% of patients developed febrile neutropenia over the course of the trial. Four deaths were reported during treatment.

Notably, the ADC carries a black box warning for severe neutropenia and diarrhea.

“It is gratifying to see the final confirmatory results of [sacituzumab govitecan] in a randomized study supporting the previously reported phase 2 data that formed the basis of the accelerated approval of [the agent],” stated Behzad Aghazadeh, PhD, executive chairman of Immunomedics in a press release. “Importantly, the strong ASCENT data reinforce the promise of our unique ADC technoloigy and embolden us to continue our work to change the treatment paradigm for patients with difficult-to-treat cancers.”

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

References

1. Immunomedics announces positive results from phase 3 ASCENT study of Trodelvy. News release. Immunomedics. July 6, 2020. Accessed July 6, 2020. bit.ly/2Z5PSeI.
2. ASCENT-study of sacituzumab govitecan in relapsed/refractory triple-negative breast cancer (ASCENT). ClinicalTrials.gov. Updated June 2, 2020. Accessed July 6, 2020. https://clinicaltrials.gov/ct2/show/NCT02574455.
3. Immunomedics announces ASCENT study to be stopped for compelling efficacy. News release. Immunomedics. April 6, 2020. Accessed July 6, 2020. bit.ly/2RgJ3mu.