Aditya Bardia, MD, MPH, discusses phase I/II trial of sacituzumab govitecan which showed favorable clinical activity in patients with relapsed or refractory metastatic triple-negative breast cancer who have received at least 2 prior treatment regimens.
Aditya Bardia, MD, MPH
Aditya Bardia, MD, MPH
A phase I/II trial of sacituzumab govitecan demonstrated favorable clinical activity in patients with relapsed or refractory metastatic triple-negative breast cancer (mTNBC) who have received at least 2 prior treatment regimens.
Sacituzumab govitecan is an antibodydrug conjugate that consists of the active metabolite of irinotecan, SN-38, which is linked with a humanized IgG antibody targeted against TROP-2, a cell-surface glycoprotein that is expressed in more than 90% of TNBCs. Already the agent has shown promise and had received a breakthrough therapy designation from the FDA in February 2016 for the treatment of patients with heavily pretreated mTNBC. Thus the confirmed efficacy seen in the phase I/II trial are all the more exciting, as they could help to fill an unmet need in TNBC, according to lead investigator Aditya Bardia, MD, MPH.
“We observed an objective response rate (ORR) of 34%...[and] complete responses were also noted with sacituzumab govitecan. So, it was quite impressive to see the efficacy results with this agent in patients with mTNBC,” said Bardia, an attending physician of medical oncology at Massachusetts General Hospital and an assistant professor of medicine at Harvard Medical School.
In an interview withTargeted Oncology, Bardia discusses the results of this study, which he presented at the 2017 San Antonio Breast Cancer Symposium, and touches upon the next steps in research with the antibodydrug conjugate, including the submission of a biologics license agreement to the FDA in the first quarter of 2018.
TARGETED ONCOLOGY: What did the trial of sacituzumab govitecan in patients with mTNBC demonstrate?
Bardia:This was a study looking at the efficacy of this antiTROP-2 antibody–drug conjugate. As a brief background, patients with mTNBC tend to have an aggressive tumor biology. They also tend to have visceral and brain metastases. The response to standard chemotherapy agents usually ranges from 10% to 15% in the second-line and beyond setting. The progression-free survival (PFS) is usually in the range of 2 to 3 months with standard chemotherapy agents. Consequently, there is an unmet clinical need for patients with mTNBC.
This compound, sacituzumab govitecan, is an antibody drug conjugate that has an antiTROP-2 antibody that is linked with SN-38, which is the active metabolite of irinotecan. The intent was that it would target the mTNBC cells, but also the microenvironment. We have previously reported results from 69 patients who were treated with this drug and had mTNBC. In February of 2016, the drug was awarded breakthrough therapy designation status by the FDA; the protocol was modified and a more homogeneous population, which was third-line and plus mTNBC, was enrolled.
We treated these patients with sacituzumab govitecan at day 1 and 8 every 21 days intravenously. The main adverse event (AE) that was noticed in this trial was neutropenia. Besides neutropenia, nausea, vomiting, and diarrhea were also seen. But the incidence of grade 3 gastrointestinal AEs was in the single digits. The side effects were manageable with supportive therapy. Only 2 patients, so that is 1.8%, discontinued because of AEs and the others were able to stay on this treatment and continue the treatment until disease progression or unacceptable toxicity.
In terms of efficacy, we observed an objective response rate (ORR) of 34%. This was a confirmed ORR in an intention-to-treat analysis. Complete responses were also noted with sacituzumab govitecan. So, it was quite impressive to see the efficacy results with this agent in patients with mTNBC. We also looked at the durability of responses and the responses were durable.
In summary, sacituzumab govitecan demonstrated single-agent activity in patients with mTNBC [in the] third-line setting [and beyond]. The side effects were manageable with supportive therapy. The phase III confirmatory trial, called the ASCENT trial, is currently enrolling patients in the United States [NCT02574455] and will start enrolling patients in Europe in 2018.
TARGETED ONCOLOGY: How do your findings have the potential to change the treatment of mTNBC?
Bardia:Based on these findings, the sponsor (Immunomedics) is going to apply for a biologics license application to the FDA. If this gets approved, this could potentially be a therapeutic option for patients with mTNBC.
TARGETED ONCOLOGY: This study was in the third-line and plus setting. Is it being considered in the first- or second-line setting, or should it be?
Bardia:Those studies are being planned to look at this agent in earlier lines, as well as in [patients with] early breast cancer.
TARGETED ONCOLOGY: Can you discuss the role of the microenvironment in cancer treatment for mTNBC?
Bardia:There is not too much that we know, but we do know from preclinical models that the tumor microenvironment plays a very important role in tumor progression. The stromal and cancer cell interaction is an important piece. In terms of therapeutic approach, there is not much known as to what would be the best strategy to really target the tumor microenvironment.
There is interest in immunotherapy, and with PD-1 inhibitors they affect the cancer cells and also the T cells, but a lot more needs to be done to really target the microenvironment, including the macrophages and the fibroblast, all of which play an important role in the progression of cancer.
TARGETED ONCOLOGY: Are there currently any other unanswered questions that you would like to see answered in the future?
Bardia:From a therapeutic perspective, we need combination therapies. It was good to see the response rates, but we need to improve the response rates even further. We need to work towards a cure for mTNBC. I think those would be the key issues that we need to tackle.
We are really excited about this study. Clinically, there is an unmet need [for patients with mTNBC] and I think our patients really need better therapies. I would like also to thank and acknowledge the patients and the families that participated in this study, and we just need to continue to build on the progress we’ve made.
Bardia A, Vahdat LT, Diamond J, et al. Sacituzumab govitecan (IMMU-132), an anti-Trop-2-SN-38 antibody-drug conjugate, as ≥3rd-line therapeutic option for patients with relapsed/refractory metastatic triple-negative breast cancer (mTNBC): efficacy results. Presented at: 2017 San Antonio Breast Cancer Symposium; December 5-9, 2017, San Antonio, TX. Abstract GS1-07.