Sacituzumab Govitecan in Patients With Metastatic TNBC

Editor’s Note: An analysis of data from the phase 3 ASCENT trial has been presented and results show that Black women with metastatic triple-negative breast cancer have outcomes in response to the antibody–drug conjugate sacituzumab govitecan (SG) comparable to those of the overall patient population with progression-free survival improved by 56% and an overall survival increased by a nonsignificant 36% when receiving SG versus single-agent chemotherapy.^[1]

This transcript has been edited for clarity.

I'm excited to update you on some of the progress that's been made about sacituzumab govitecan over the past couple of weeks. So, sacituzumab govitecan is an antibody-drug conjugate. The antibody part is targeting something called Trop-2 (trophoblast cell-surface antigen 2) and the chemo part of it is SN 38, a derivative of irinotecan. 

So, we were very excited when we saw that this compound had activity in refractory triple-negative breast cancer (TNBC) several years ago. And we published our first paper in metastatic triple-negative breast cancer back in February 2019 highlighting its activity in 108 metastatic triple-negative breast cancer patients, in which we saw that the response rate was 36% with a higher clinical benefit rate, and the median duration of response was almost 8 months.^[2]

Of course, that's something you never really see in triple-negative breast cancer. So, that led to the accelerated approval of sacituzumab govitecan, and the phase 3 ASCENT trial was designed and executed. And my colleague Aditya Bardia from MGH (Massachusetts General Hospital) presented the initial results of this clinical trial at ESMO (European Society for Medical Oncology) a couple of weeks ago.^[3]

And I'd like to share those results with you. So, the ASCENT trial is a phase 3 confirmatory study of sacituzumab govitecan in refractory triple-negative breast cancer. Eligible patients were those who had received at least two chemotherapies for advanced disease. There was no upper limit on the number of regimens that could be prescribed or had prior. 

Patients were randomized one to one to sacituzumab govitecan at the FDA (Food and Drug Administration)-approved dose of 10 mg/kg IV (intravenous), 2 weeks on, 1 week off versus treatment of physician's choice (TPC). And treatments of physician's choice could be either eribulin, vinorelbine, capecitabine, or gemcitabine. 

Patients were allowed to continue until disease progression or unacceptable toxicity, and the primary endpoint was progression-free survival. Secondary endpoints were PFS (progression-free survival) for the full population—overall survival, response rate, duration of response, and safety. Patients were stratified according to a number of prior regimens, two or three versus more than three where they lived—North America versus Europe—or presence or absence of known brain metastasis. 

As patients could have stable brain meds and still be enrolled in this clinical trial. When you looked at the demographics of the trial, what you can see is that it's actually fairly well balanced. The median age for both patients was around 54 years. When you looked at the performance status, the median performance status was one in both arms of the trial. 

They also looked at whether or not patients had a BRCA-1 (breast cancer gene) or a BRCA-2 mutational status, and a very small proportion—7% and 8%—were positive and the rest were negative with a small proportion unknown. 70% of patients had triple-negative breast cancer as their initial diagnosis and 30% of those had recurrent disease. 

The median number of prior regimens in the metastatic setting was four, so heavily pretreated population. And when you looked at patients' prior regimens, you could see that almost everyone had received a prior taxane, prior AC (anthracycline). Roughly between 65% received prior carboplatin and roughly 67% received prior capecitabine. 

Approximately 27% of patients had received prior checkpoint inhibitors. And when you looked at the most common sites of a disease out of the demographics in the trial, what you can see is that lung, liver, and bone—lung and liver were present in more than 40% of patients and bone in only about 20%, reflecting the kinds of tropism that we see in patients. 

So, the primary endpoint was progression-free survival and it was a positive study. The median progression-free survival for patients to receive sacituzumab govitecan was 5.6 months versus 1.7 months for patients who received TPC. The hazard ratio is 0.41 and it's highly significant at P being less than .0001. 

When we looked at forest plots, looking at them, was there a group that benefited more or less? You could see that, basically, all subgroups benefited, including age, race, prior therapies more or less, region, prior PD-L1 (programmed death-ligand 1) use, de novo stage IV breast cancer, as well as those with liver mass. 

So, a benefit was really seen across all of the different subgroups looked at. And when we looked at overall survival, I'm happy to report that the median overall survival for patients who receive sacituzumab govitecan was 12.1 months versus 6.7 months in the TPC arm. That hazard ratio is 0.48, and it's highly statistically significant at less than 0.0001. 

So, this actually reflects our clinical experience with sacituzumab govitecan as really great to see it in a randomized controlled trial. When we looked at some of the treatment-related adverse events as expected, grade 3 or 4 neutropenia was around 60% in the sacituzumab govitecan, very similar to what we've seen in the TPC arm. 

Grade 3-4 anemia was approximately 8%. Diarrhea of any grade was about 59%, with grade 3-4 diarrhea being about 10%. GI (gastrointestinal) toxicity, generally speaking, was fairly low. Alopecia, of course, was seen with this drug. 

So, in summary, ASCENT is the first phase 3 study with the Trop-2-directed antibody-drug conjugate in pretreated metastatic triple-negative breast cancer to demonstrate significant improvements over standard single-agent chemotherapy. The median PFS improved from 1.7 months to 5.6 months, hazard ratio of 0.41. 

The median overall survival improved from 6.7 months to 12.1 months with a hazard ratio of 0.48. There is an overall response rate of 35% versus 5%. It was well tolerated with a manageable safety profile, with no new toxicities being observed. So just generally speaking, I would say that I'm very happy that this drug is finally approved and available to all of our patients, as I believe that it really represents a very large step forward in our treatment of metastatic triple-negative breast cancer.^[4,5,6]