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A new targeted therapy has shown activity in an aggressive type of breast cancer.
The experimental drug Sacituzumab govitecan (Immunomedics) gave a response rate of 33% in patients with metastatic triple negative breast cancer (TNBC) and pretreated intensively.
The current standard treatment for these patients is chemotherapy, which has always been associated with low response rates of between 10% and 15%.
The new data comes from a Phase 1/2 trial published online on February 21 in the New England Journal of Medicine.
TNBC, an aggressive disease associated with a relatively poor prognosis, is devoid of three cellular targets found in the most common forms of breast cancer. The authors argue that the lack of actionable mutations and molecular targets on which drugs work is one of the causes of poorer outcomes for patients with TNBC.
Sacituzumab govitecan can represent a change – he has a target.
Administered intravenously, the investigational agent is an antibody-drug conjugate in which the SN-38, an active metabolite of irinotecan (a drug used for chemotherapy), is coupled with a monoclonal antibody that targets an antigen that has high expression in TNBC and induces cancer. cell growth, explain the authors of the study.
The new study included 108 patients (median age, 56 years) who had undergone a median of three previous treatment lines. 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, benefited clinically.
Median progression-free survival was 5.5 months and overall survival was 13.0 months.
"It's not every day that we see this type of clinical activity in this aggressive subtype of breast cancer," said lead author Kevin Kalinsky, MD , in an interview with Medscape Medical News. He is a medical oncologist at the New York Presbyterian Hospital and the Columbia University Medical Center in New York.
Among the pretreated patients, standard chemotherapy lasts only 2 to 3 months, according to the authors of the study.
Kalinsky added that the new data demonstrates "impressive results", despite the fact that it is an early phase trial.
Sactizumab is one of the most promising new drugs for TNBC.
"I think this drug has the potential to change the practice because the data looks so convincing even with the relatively small number of patients participating in the trial," Kalinsky said in a statement. press.
Charles Shapiro, MD, Director of Translational Research on Breast Cancer at the Mount Sinai Tisch Institute in New York City, said that, based on this new report, "sactizumab is one of the most most promising new drugs for TNBC. "
If current results are confirmed, the agent will likely be tested in the first-line metastatic setting and perhaps also in early stage disease, commented Shapiro. Medscape Medical News.
He also pointed out that it had already been shown that the drug model of a bispecific antibody conjugate was effective against breast cancer. Trastuzumab emtansine (TDM-1) is one of these drugs that has shown efficacy in the treatment of HER2 + disease.
Target Trop-2
The new drug targets humanized antitrophoblast cell surface antigen 2 (Trop-2), which is a "transmembrane calcium signal transducer" that stimulates the growth of cancer cells, explain the authors. It has limited expression in normal tissues and is overexpressed in many epithelial cancers, including TNBC, they add.
"The strong 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 authors of the study, citing further research.
The expression Trop-2 was not measured in this study. It will be evaluated retrospectively as part of a Phase 3 randomized confirmatory trial (ASCENT), which is currently recruiting patients in North America and Europe. In this trial, sacituzumab govitecan will be compared to the choice of chemotherapy by doctors.
New treatments are needed for all patients with metastatic TNBC, as overall survival has not changed in 20 years, say the study's authors.
Low rate of discontinuation of treatment
In the study, patients received intravenous sacituzumab govitecan (10 mg / kg body weight) on days 1 and 8 of each 21-day cycle until progression of the disease or toxicity unacceptable.
The 108 participants received an average of 18.7 doses of sacituzumab govitecan, or 9.6 cycles. The median duration of exposure was 5.1 months.
Three patients stopped treatment because of adverse effects and two patients due to drug-related events.
The most common side effects were nausea, diarrhea, fatigue, neutropenia and anemia, the researchers write.
The most common adverse reactions of grade 3 or higher included neutropenia, anemia, and decreased white blood cell counts.
The researchers pointed out that diarrhea was the second most common adverse event, occurring globally in 62% of patients (all grades). The incidence of grade 2 diarrhea was 14% and the incidence of diarrhea at least grade 3 was 8%.
No peripheral neuropathy grade 3 or higher has been reported.
"Importantly, the drug did not cause neuropathy, numbness, or tingling, which can be very painful and limiting for patients," Kalinsky said. "He is promising to have an active treatment whose side effect is not neuropathy," he added.
Treatment death occurred in four patients (4%) within 30 days of the last dose. All of these deaths were attributed to the progression of the disease by the attending investigator.
Serious adverse events were reported in 35 patients (32%); the most common (incidence> 2%) were febrile neutropenia (7%), vomiting (6%), nausea (4%), diarrhea (3%) and dyspnea (3%).
The authors of the study summarize that sacituzumab govitecan has a better side effect profile (and efficacy) than irinotecan (several brands), probably because of its ability to more accurately administer a cytotoxic drug, the SN- 38, tumor cells.
In addition, the cytotoxic activity of SN-38 (administered via sacituzumab govitecan) is much greater than that of irinotecan, the authors added, citing laboratory research.
Immunotherapy in TNBC
Sacituzumab govitecan becomes the second new agent to be promising in the treatment of metastatic TNBC.
In October 2018, researchers in the IMpassion130 study reported that progression-free survival was 7.2 months for patients with metastatic disease who had received the drug Atezolizumab immunotherapy (Tecentriq, Genentech) with nab-paclitaxel vs. 5.5 months for those who received placebo with nab-paclitaxel (p <.0001). Subset analyzes indicated that atezolizumab could also provide a benefit in terms of overall survival.
The response rate with atezolizumab plus nab-paclitaxel was 56% in IMpassion130.
However, Kalinsky pointed out that atezolizumab and nab-paclitaxel were used as first-line therapy, whereas, according to the study, sacituzumab govitecan was tested in pre-treated patients.
The new drug could be a candidate to associate with immunotherapy in the treatment of TNBC, he suggested.
In the present study, confirmed objective responses were found in patients who had previously received either a programmed cell death protein (PD-1) treatment or a programmed cell death-ligand-1 (PD-L1) treatment. ). This suggests a lack of cross-resistance with immune-checkpoint inhibitors and the potential utility of combination therapy, he said.
Sacituzumab govitecan is also being studied in urothelial cancer, lung cancer and breast cancer with progesterone receptors positive. To date, response rates have been similar to those seen in TNBC, Kalinsky said.
Immunomedics funded the study. Kalinsky reports financial links with Immunomedics. The authors of the study include the employees of the company. Shapiro did not reveal any relevant financial relationship.
N Engl J Med. Posted online 21 February 2019. Summary
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