Metaplastic breast cancer (MpBC) is a rare form of triple-negative breast cancer (TNBC), accounting for fewer than 1% of all breast cancers, but it is very aggressive and responds poorly to chemotherapy. So new results with a combination of immunotherapies that resulted in significant tumor shrinkage and survival topping 2 years have led to some excitement, even though the results were seen in only 3 of 17 women who were treated.
“The impressive part is that these are very dramatic and durable responses in a cancer that is so resistant to chemotherapy,” lead investigator Sylvia Adams, MD, professor of medicine at the Perlmutter Cancer Center at New York University Langone Health, New York City, told Medscape Medical News.
With chemotherapy, median survival of women with metastatic MpBC is typically 8 months. “Anything that is durable for 2 years is unbelievably exciting,” said Adams.
There was one complete response and two partial responses with “very little tumor burden left. That gives us the hope that maybe there is a chance for cure in these three patients,” she told Medscape Medical News.
Adams presented the results as part of the virtual scientific program of the American Society of Clinical Oncology (ASCO) 2020 annual meeting.
Approached for comment, Natalie Berger, MD, assistant professor of medicine, hematology, and medical oncology, Icahn School of Medicine at Mount Sinai, New York City, was equally impressed with the results.
“Demonstrating durable responses in patients who have such an aggressive subtype of breast cancer is very exciting, hypothesis generating, and certainly warrants further investigation,” said Berger, who wasn’t involved in the study.
Aggressive Tumor Type
The results come from the Dual Anti-CTLA-4 & Anti-PD-1 Blockade in Rare Tumors (DART) trial (SWOG S1609), a phase 2, prospective, open-label, single-arm trial evaluating the combination immune checkpoint blockade with the CTLA-4 antibody ipilimumab (Yervoy, Bristol-Myers Squibb) plus the PD-1 inhibitor nivolumab (Opdivo, Bristol-Myers Squibb) in patients with rare tumors.
One cohort in this trial comprised 17 women (mean age, 60 years) with histologically confirmed MpBC, measurable disease, and ECOG performance status 0 to 2. They all received the combination immunotherapy with ipilimumab 1 mg/kg IV on day 1 and nivolumab 240 mg IV on day 1, 15, and 29 of continuous 6-week cycles.
These women had experienced disease progression following at least one line of standard systemic therapy, and there was no other approved/standard therapy available that had been shown to prolong overall survival (OS). Patients who had undergone prior anti-CTLA4 or anti-PD-1/PD-L1 treatment (but not both) were permitted for inclusion, as well as those with treated stable brain metastases.
Chance for a Cure?
The overall response rate was 12% (2 of 17 patients) per RECIST 1.1 and 18% (3 of 17) per immune-related RECIST (iRECIST), with ongoing responses at 27, 25, and 23 months, respectively.
Two or more responses among 16 patients were considered evidence that the drug combination warrants further study in this patient population.
Median follow-up among patients who are alive is 20 months. The cutoff date of data follow-up was May 7, 2020. Median progression-free survival was 2 months, and median OS was 12 months.
“The patients that progressed, unfortunately, didn’t have a long survival, which is what we see with the majority of metaplastic patients,” Adams said.
In her practice, Adams said, chemotherapy plus a PD-1 inhibitor have generated “dramatic but not durable” responses in women with MpBC. “The addition of the CTLA-4 antibody seems to make a big difference in terms of the durability and is crucial in this disease,” Adams said.
The hope is that ongoing biomarker studies will provide a signal as to who will respond to this combination. “So far, clinically, patients who respond to this combination don’t seem to be different from those that don’t respond,” Adams said.
In her comments to Medscape Medical News, Berger noted that MpBC is associated with a “poor prognosis [and that] novel treatments are needed to improve outcomes in patients with this rare tumor.
“While this study was small, it is hard to accrue a large number of patients, given the rarity of this subtype of breast cancer. These patients were all pretreated, so further investigation can consider testing this combination earlier in the disease process,” said Berger.
With regard to toxicity, 11 of the 17 patients (65%) experienced some treatment-related adverse event (AE); four (24%) had AEs of grade 3 to 5, including one fatal AE (cardiac arrest potentially related to therapy). The most common AEs were liver function test abnormalities and fatigue.
“Patients on these medications need to be closely monitored for immune-related adverse events, and patients need to report side effects very early, and we have to be very aggressive in managing them and start steroids early when needed,” Adams said.
In a recent article published in Nature Reviews Clinical Oncology, Adams and a coauthor review the published experience with immune checkpoint inhibitors in metastatic TNBC, with an emphasis on immune-related adverse events.
The study was funded by the National Cancer Institute (NCI). Bristol-Myers Squibb provided the nivolumab to support the study through a cooperative research and development agreement with NCI. Adams has served in a consulting or advisory role for Bristol-Myers Squibb, Genentech, and Merck. Berger has disclosed no relevant financial relationships.
American Society of Clinical Oncology (ASCO) 2020: Abstract 1073
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