At virtual ESMO 2020, on behalf of the co-authors, I presented the results from the ASCENT trial, a randomised phase III study of sacituzumab govitecan versus treatment of physician’s choice for patients with previously treated metastatic triple negative breast cancer.
As a brief background, triple negative breast cancer represents the aggressive form of breast cancer. It tends to affect young women, African-Americans, and is associated with poor prognosis. Chemotherapy is the standard of care for the treatment of metastatic triple negative breast cancer but the response rate with standard chemotherapy is in the range of 10% and median progression free survival is in the range of two months. So clinically there is an unmet need for better therapies for patients with metastatic triple negative breast cancer.
We evaluated sacituzumab govitecan, a novel Trop-2 directed antibody-drug conjugate for triple negative breast cancer. It’s an antibody-drug conjugate that targets Trop-2, which is overexpressed in the majority of triple negative breast cancers, as a hydrolysable linker and it’s linked to SN-38, the active metabolite of irinotecan. This antibody-drug conjugate has three unique properties. The first is that it’s highly specific for Trop-2. Second, it has a high drug to antibody ratio: 7.6:1. So for every antibody on average there are 7.6 molecules of SN-38. Third, the hydrolysis of the linker also releases SN-38 extracellularly in the tumour microenvironment, providing a bystander effect, thus it can even affect cells that have low or no expression of Trop-2 because of the bystander effect.
We were involved with the phase I/phase II clinical trial with this agent. Activity was seen with this agent early on for patients with metastatic triple negative breast cancer with a response rate of 33% and the drug was granted accelerated approval by the FDA for the treatment of patients with metastatic triple negative breast cancer. So ASCENT was the confirmatory phase III trial.
The ASCENT trial was for patients with pre-treated metastatic triple negative breast cancer. They were randomised one to one to sacituzumab govitecan versus treatment of physician’s choice. Eligibility included metastatic triple negative breast cancer and also patients must have received at least two prior chemotherapies for advanced disease. If someone had progression within 12 months of neoadjuvant adjuvant therapy that would count as one line. The primary endpoint of the study was progression free survival. 529 patients were randomised to sacituzumab govitecan versus treatment of physician’s choice. This was a global study that enrolled at multiple centres throughout the world.
What did the results show? The study was positive. The study met its primary endpoint. Patients who received sacituzumab govitecan had a median progression free survival of 5.6 months as compared to 1.7 months with standard chemotherapy. This corresponded to a hazard ratio of 0.41 and this was highly statistically significant with a p-value of less than 0.0001. So, in other words, patients who received sacituzumab govitecan had a 59% lower risk of disease progression as compared to the chemotherapy.
How about overall survival? Again, patients who received sacituzumab govitecan had an overall survival of 12.1 months as compared to 6.7 months with standard chemotherapy. So there was almost a doubling of overall survival with sacituzumab govitecan. This corresponded to a hazard ratio of 0.48 and this was highly statistically significant with a p-value of less than 0.0001.
Then finally in terms of objective response rate, patients who received sacituzumab govitecan had a response rate of 35% as compared to 5% in the chemotherapy arm. This was statistically significant as well. In terms of AEs, or adverse events, the common adverse events seen with this agent included neutropenia, diarrhoea, anaemia, alopecia, all side effects that were seen in the phase I/phase II trial as well. So there were no surprises. No greater than grade 2 neuropathy or greater than grade 3 interstitial lung disease was noted.
So, in summary, in conclusion, ASCENT is the first phase III study to demonstrate activity of an antibody-drug conjugate that is superior to standard chemotherapy, both in terms of median progression free survival and overall survival. Patients had a doubling of overall survival with sacituzumab govitecan as compared to standard chemotherapy. Sacituzumab govitecan was well tolerated with a manageable safety profile consistent with previous reports. Discontinuation because of adverse events was low, less than 5%, and there were no treatment related deaths reported.
The randomised phase III trial confirms that sacituzumab govitecan should be considered as the new standard of care for patients with pre-treated metastatic triple negative breast cancer. However, the future ongoing studies are evaluating sacituzumab govitecan in earlier lines of therapy, including in the neoadjuvant and adjuvant setting, combination with other targeted agents as well as evaluation in other breast cancer subtypes such as hormone receptor positive metastatic breast cancer. The TROPiCS-02 trial is currently ongoing and is looking at activity of sacituzumab govitecan in hormone receptor positive metastatic breast cancer.
In terms of my concluding remarks, I would say thank you to patients and their caregivers for their valuable contribution and commitment as well as thank you to the dedicated clinical trial investigators and devoted team members for contributing to the ASCENT trial. Thank you.