'It's Not Every Day' This Response Rate Seen in TNBC

New Agent for Aggressive Breast Cancer in NEJM

Nick Mulcahy

February 20, 2019

A novel targeted therapy has shown activity in an aggressive type of breast cancer.

The investigational drug sacituzumab govitecan (Immunomedics) yielded a 33% response rate among patients with metastatic triple-negative breast cancer (TNBC) who were heavily pretreated.

For such patients, the current standard of treatment is chemotherapy, which historically has been associated with low response rates of 10% to 15%.

The new data come from a phase 1/2 trial published online February 21 in the New England Journal of Medicine.

TNBC, an aggressive disease that is associated with relatively poor prognosis, lacks three cellular targets present in more common forms of breast cancer. The lack of actionable mutations and molecular targets for drugs to act upon is part of the reason for the poorer outcomes of patients with TNBC, say the authors.

Sacituzumab govitecan may represent a change — it has a target.

Given intravenously, the experimental agent is an antibody–drug conjugate in which SN-38, an active metabolite of the chemotherapy drug irinotecan (multiple brands), is coupled to a monoclonal antibody that targets an antigen that has high expression in TNBC and induces cancer cell growth, explain the study authors.

The new study included 108 patients (median age, 56 years) who had undergone a median of three previous lines of therapy. There were 36 responses (three complete and 33 partial). The median duration of response was 7.7 months; 45.4% of patients, including those with stable disease, derived clinical benefit.

Median progression-free survival was 5.5 months, and overall survival was 13.0 months.

"It's not every day that we see this sort of clinical activity in this aggressive subtype of breast cancer," said senior study author Kevin Kalinsky, MD, in an interview with Medscape Medical News. He is a medical oncologist at New York–Presbyterian Hospital and Columbia University Medical Center in New York City.

Among such heavily pretreated patients, progression-free survival with standard chemotherapy is just 2 to 3 months, the study authors say.

Kalinsky added that the new data demonstrate "impressive results," despite the fact that it is an early-phase trial.

Sactizumab represents one of the most promising new drugs for TNBC. Dr Charles Shapiro

"I think this drug has the potential to change practice, because the data look so compelling, even with the relatively small number of patients in the trial," Kalinsky said speculatively in a press statement.

Approached for comment, Charles Shapiro, MD, director of translational breast cancer research, Tisch Cancer Institute at Mount Sinai, New York City, said that on the basis of the new report, "sactizumab represents one of the most promising new drugs for TNBC."

If the current results are confirmed, the agent will likely be tested in the first-line metastatic setting and perhaps also in early-stage disease, Shapiro commented to Medscape Medical News.

He also pointed out that the drug model of a bispecific antibody drug conjugate has already been shown to be effective in breast cancer. Among such drugs is trastuzumab emtansine (TDM-1), which has shown efficacy in the treatment of HER2+ disease.

Trop-2 Target

The new drug targets humanized antitrophoblast cell-surface antigen 2 (Trop-2), which is a "transmembrane calcium signal transducer" that stimulates cancer cell growth, the authors explain. It has limited expression in normal tissue and is overexpressed in many epithelial cancers, including TNBC, they add.

"High expression of Trop-2 in triple-negative breast cancer and its association with a poor prognosis suggest that it is a rational therapeutic target in this patient population," write the study authors, citing other research.

Trop-2 expression was not measured in the current study. It will be assessed retrospectively in a confirmatory randomized, phase 3 trial (ASCENT) that is currently recruiting patients in North America and Europe. In that trial, sacituzumab govitecan will be compared with physicians' choice of chemotherapy.

New treatments are needed for all metastatic TNBC patients, inasmuch as overall survival has not changed in 20 years, the study authors point out.

Low Rate of Treatment Discontinuation

In the study, patients received sacituzumab govitecan intravenously (10 mg/kg body weight) on days 1 and 8 of each 21-day cycle until disease progression or unacceptable toxicity.

The 108 participants received a mean of 18.7 doses of sacituzumab govitecan, or 9.6 cycles. The median duration of exposure was 5.1 months.

Three patients discontinued treatment because of adverse events, and two patients discontinued because of drug-related events.

The most common adverse events were nausea, diarrhea, fatigue, neutropenia, and anemia, write the investigators.

The most common adverse events of grade 3 or higher included neutropenia, anemia, and a decreased white-cell count.

Diarrhea was highlighted by the investigators as the second most common adverse event, occurring in 62% of the patients overall (all grades). The incidence of grade 2 diarrhea was 14%, and the incidence of diarrhea of at least grade 3 was 8%.

No peripheral neuropathy of grade 3 or higher was reported.

"Importantly, the drug did not cause neuropathy, the numbness and tingling that can be quite painful and limiting for patients," Kalinsky said. "It is promising to have an active treatment that does not have neuropathy as a side effect," he added.

On-treatment death occurred in four patients (4%) within 30 days of the last dose. All such deaths were attributed to disease progression by the treating investigator.

Serious adverse events were reported in 35 patients (32%); the most common (>2% incidence) were febrile neutropenia (7%), vomiting (6%), nausea (4%), diarrhea (3%), and dyspnea (3%).

The study authors summarize that sacituzumab govitecan has a better side effect profile (and efficacy) than irinotecan (multiple brands), possibly because of its ability to more precisely deliver a cytotoxic drug, SN-38, to tumor cells.

In addition, the cytotoxic activity of SN-38 (delivered via sacituzumab govitecan) is much greater than that of irinotecan, add the authors, citing laboratory research.

Immunotherapy in TNBC

Sacituzumab govitecan becomes the second new agent to recently show promise in the treatment of metastatic TNBC.

In October 2018, investigators from the IMpassion130 trial reported that progression-free survival was 7.2 months for patients with metastatic disease who received the immunotherapy drug atezolizumab (Tecentriq, Genentech) with nab-paclitaxel vs 5.5 months for those who received placebo with nab-paclitaxel (P < .0001). Subset analyses indicated that atezolizumab may also provide an overall survival advantage.

The response rate with atezolizumab plus nab-paclitaxel was 56% in IMpassion130.

However, Kalinsky pointed out that atezolizumab plus nab-paclitaxel was used in the first-line treatment setting, whereas in the study they report, sacituzumab govitecan was tested in heavily pretreated patients.

The new drug may be a candidate to be combined with immunotherapy in the treatment of TNBC, he suggested.

In the current study, confirmed objective responses were found in patients who had received previous programmed cell death protein–1 (PD-1)–based therapy or programmed cell death–ligand-1 (PD-L1)–based therapy. This suggests a lack of cross-resistance with immune checkpoint inhibitors and the potential usefulness of combination therapy, he said.

Sacituzumab govitecan is also being studied in urothelial cancer, lung cancer, and progesterone receptor–positive breast cancer. To date, response rates have been similar to those observed in TNBC, said Kalinsky.

Immunomedics funded the study. Kalinsky reports financial ties to Immunomedics. Study authors include employees of the company. Shapiro has disclosed no relevant financial relationships.

N Engl J Med. Published online February 21, 2019. Abstract

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