Clinical Challenges: ADCs and Triple-Negative Breast Cancer

In Clinical Studies News by Barbara Jacoby

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By: Mike Bassett

From: medpagetoday.com

The development of antibody drug conjugates adds a much needed option for women with TNBC

Triple-negative breast cancer (TNBC) — i.e., breast cancer that does not express estrogen, progesterone, or HER2 receptors — comprises approximately 10%-20% of all breast cancers and represents “an unmet need in the field of breast oncology,” said Aditya Bardia, MD, MPH, director of precision medicine at the Center for Breast Cancer at Massachusetts General Hospital Cancer Center and Harvard Medical School in Boston.

“Triple-negative breast cancer has an aggressive tumor biology, a higher risk of disease recurrence, and poor prognosis,” he told MedPage Today. “And standard therapies, including standard chemotherapy, are not very effective in metastatic triple-negative breast cancer, with the median progression-free survival with standard therapies in the range of 3 to 4 months in the second-line and beyond setting.”

This situation is further compounded by the fact that TNBC tends to be more prevalent in younger patients and African-American women, Bardia added.

While options are limited for women with TNBC, the potential of antibody drug conjugates (ADCs) as an effective therapy for these patients has been gaining traction.

One of these, sacituzumab govitecan-hziy (Trodelvy), was recently granted accelerated approval by the FDA for treatment of adults with TNBC who had previously received two lines of therapy.

ADCs have three components — an antibody that targets antigens that are overexpressed in cancer cells, a stable linker, and the toxic payload that is linked to the antibody.

“And the idea of the antibody drug conjugate is that the antibody binds to cancer cells that express the antigen, is internalized, and once it is inside the cell releases the payload, so it selectively delivers high doses of toxic payload to cancer cells, while sparing normal cells,” Bardia explained. “It is what we call a ‘smart bomb’ — a selective way of delivering high doses of toxic payload to the cancer cells, and thereby have a better efficacy-to-toxicity ratio.”

The concept of ADCs is not a new one, he noted. More than 100 years ago the German scientist Paul Ehrlich proposed the idea of a targeted delivery of a toxic agent to kill cells – a “magic bullet.” And the first approved ADC was gemtuzumab ozogamicin (2000).

“But what has made them more usable is the improvement in linker technology,” said Debu Tripathy, MD, of the University of Texas MD Anderson Cancer Center in Houston, referring to the link between the antibody and the payload. “This link is designed to be broken, but only once the antibody drug conjugate has been internalized into the cell.”

Regarding sacituzumab govitecan, the antibody targets Trop-2, a glycoprotein that is overexpressed in the majority of TNBCs and is linked to SN-38, the active metabolite of the topoisomerase inhibitor irinotecan. The concept is that the ADC binds to Trop-2 in cancer cells, is internalized, and releases SN-38.

“Part of the reason it works well in breast cancer patients who have been extensively pretreated is that most of these patients have not seen a topoisomerase inhibitor before, and now they are getting it at very high concentrations,” explained Tripathy. “And the side effects of antibody drug conjugate are similar to those seen in topoisomerase inhibitors, and to a much lower degree, because there is much less of the drug floating around than if you had given it just as a naked drug.”

Another feature of sacituzumab govitecan is that it exhibits a “bystander effect,” said Bardia. “The SN-38 can permeate outside the cancer cells and affect the cells in the nearby region, some of which might not express Trop-2, and thereby impact the cells in the tumor microenvironment.”

FDA approval of sacituzumab govitecan was based on results from a phase I/II trial, of which Bardia was the lead investigator. In that single-arm study of 108 patients, sacituzumab govitecan demonstrated an overall response rate of 33.3% and a median duration of response of 7.7 months.

Of those patients with a response, 55.6% maintained their response for 6 or more months, while 16.7% maintained the response for 12 or more months. Median progression-free survival was 5.5 months (95% CI 4.1 to 6.3), and overall survival was 13.0 months (95% CI 11.2 to 13.7).

Results from the confirmatory phase III ASCENT trial are pending, but the biopharmaceutical company Immunomedics halted the trial in April “due to compelling evidence of efficacy.”

“The approval of this agent is a big win for patients,” Bardia said. “To have a promising therapeutic option gives physicians another tool to fight this disease.”

There are other ADCs in development that are showing activity in TNBC. For example, ladiratuzumab vedotin is a LIV-1-targeted monoclonal antibody linked to the potent microtubule-disrupting agent monomethyl auristatin E, and results from a phase I study of 60 patients with heavily pretreated TNBC found a response rate of 25% and median progression-free survival of 11.0 weeks

Another ADC under development is U3-1402 — “an antibody drug conjugate that targets HER3, that tends to be overexpressed in triple-negative breast cancer,” said Bardia. “The phase I results for that agent appear to be quite promising and it is being developed further for patients with triple negative breast cancer.”

“Moving forward, we need to accelerate our efforts to fight this devastating disease,” he continued. “We need to build further combination therapies with sacituzumab govitecan as the backbone, and move this agent into earlier lines in order to reduce the risk of metastatic breast cancer recurrence.”

“There are already designs of trials for patients who are in earlier lines of therapy, and even in the early-stage setting there are some trials where these drugs are going to be given to patients who have already been treated — for example, with preoperative standard chemotherapy in the early stage, but are not having a good response,” said Tripathy. “And that’s because we know those patients are at a high risk for recurrence later.”

Immunomedics has entered into a collaboration with the German Breast Group to develop sacituzumab govitecan as a treatment for newly diagnosed breast cancer patients who do not achieve a pathologic complete response following standard neoadjuvant therapy.