Hopes on the rise in wake of ASCENT data

MORRIS PLAINS, N.J.—Triple-negative breast cancer (TNBC) accounts for up to 20 percent of all breast cancer cases, and at present, there is no approved standard of care for women with previously treated TNBC. But biopharmaceutical company Immunomedics Inc. is hoping to change that, having recently reported on promising data from its confirmatory Phase 3 ASCENT study of Trodelvy (acituzumab govitecan-hziy). Trodelvy met its primary endpoint of progression-free survival (PFS) and secondary endpoints in brain metastasis-negative patients with metastatic TNBC who had previously received at least two therapies for their disease.

Patients treated with Trodelvy in the ASCENT study saw a median PFS of 5.6 months (95 percent CI, 4.3-6.3), compared to 1.7 months (95 percent CI, 1.5-2.6) for those who received chemotherapy (p<0.0001). Trodelvy also met its secondary endpoints of boosting overall survival and objective response rate. As for safety, the safety profile remained consistent, with neutropenia (an abnormally low number of neutrophils, a type of white blood cell) and diarrhea as the most common Grade 3 or 4 adverse events. In ASCENT, 2 percent of patients discontinued Trodelvy discontinued treatment due to adverse events, but there were no severe cases of neuropathy or interstitial lung disease and no treatment-related deaths.

“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 mTNBC. Based on these data, sacituzumab govitecan has set a new benchmark in scientific and clinical innovation for patients with mTNBC by offering a novel alternative to the common drugs currently in clinical practice. Importantly, the ASCENT top-line data also validate the manageable safety profile of sacituzumab govitecan, rendering it a good partner candidate for combination with other therapies, including immunotherapy,” stated Dr. Aditya Bardia, who is the study’s principal investigator; director of Precision Medicine at the Center for Breast Cancer, Mass General Cancer Center; and Assistant Professor of Medicine at Harvard Medical School.

Trodelvy targets Trop-2, a cell-surface protein found in multiple solid tumors. Beyond TNBC, Immunomedics is also evaluating the drug as a treatment for metastatic urothelial cancer, hormone receptor-positive/human EGFR2-negative metastatic breast cancer, and metastatic non-small cell lung cancer, either as a monotherapy or as part of a combination therapy regimen.

The U.S. Food and Drug Administration recently approved Trodelvy as a third-line treatment for adults with metastatic TNBC under its Accelerated Approval Program based on the results from a Phase 2 study. ASCENT, designed under the FDA’s Special Protocol Assessment, was intended to validate the results that led to accelerated approval.

According to Usama Malik, Immunomedics’ chief financial officer and chief business officer, “In triple-negative breast cancer, the accelerated approval that we received in April was on the basis of response rate and duration of response. We saw a response rate of 33 percent—generally you’re looking at, with standard of care, anywhere between 8 and 10 percent response rate.”

He explains that Immunomedics uses SN-38, a “moderately strong” cytotoxin, while “generally other ADC companies use very highly toxic compounds that create additional toxicities that sometimes may not be manageable or are irreversible.”

“In our case there are obviously toxicities, but generally they’re well managed with prophylactics, and all of them are reversible,” he continues. “And we also have something called the bystander effect, where not only are we targeting a specific tumor cell, but also the tumor microenvironment and other tumors around there; even if the ADC attaches onto a specific tumor, it releases the cytotoxin in the tumor microenvironment, so we get this bystander effect. So we do believe we have a very differentiated and unique ADC platform that gives us the ability to drive efficacy significantly different than standard of care, but also provide for manageable toxicities that are reversible.”

Malik tells DDN that ADCs “have been seeing a resurgence” in the last two or three years, and adds that there is a significant amount of interest and investment in the field of immuno-oncology.

“As it pertains to having very directed oncological therapies for patients, I think the industry’s been thinking about this for quite some time—to be able to segment and target patient populations based on biomarkers so you can have a much more targeted efficacy response and you can have much more managed toxicity, because you are putting into the patient that which is accepted by the biology of that patient,” he remarks. “That has kind of been the panacea that the industry has been working towards, but we’re still a ways away from there.”

In terms of Trodelvy, Malik says the results “potentially allow us to effectuate a new standard of care here in triple-negative breast cancer.”

“It was clear to us going into the approval, and now with the benefit of the last three months, that there’s a significant unmet need here and the demand is very, very high because patients just don’t have other good options,” he adds. “The other options are highly toxic and patients progress from those options very quickly, so there’s a lot of hope and excitement and optimism—both from oncologists and from patients and their caregivers—that Trodelvy is an option that can really provide a clinical benefit rate that has not been seen in this indication for a long time.”

Moving forward, he reports that Immunomedics intends to submit an sBLA with the full ASCENT study data in the fourth quarter of 2020.