Triple-negative breast cancer (TNBC) is a particularly aggressive form of this disease, with a poor prognosis, so there is great interest in any new treatment approach. Immunotherapy has raised hopes in TNBC, but more recently, studies have produced conflicting results.
New results show that adding a novel immune activator, Imprime PGG (Biothera), to immunotherapy with pembrolizumab (Keytruda, Merck) appears to improve the clinical benefit. The overall survival seen with the combination was twice that seen in a separate trial with pembrolizumab alone.
The new resultsduring the American Association for Cancer Research (AACR) virtual annual meeting I.
They come from the IMPRIME 1 trial, conducted in 44 women with metastatic TNBC who had anti-glucan antibodies.
“These were patients who had had prior chemotherapy and had extensive disease, including the majority with visceral disease and even liver metastasis,” said investigator Steven O’Day, MD, from the John Wayne Cancer Institute in Santa Monica, California.
All patients were treated with the combination. “We see encouraging clinical benefit evidence across all of our clinical measurements: response, durable response, and median and overall survival compared to historical single-agent [anti] PD-1 in a similar metastatic triple-negative breast cancer population,” he said.
At a median follow-up of 22.5 months, median overall survival with the combination among the 44 patients treated was 16.4 months.
In contrast, in the Keynote-086 trial of pembrolizumab monotherapy in patients with TNBC, median overall survival was 9 months, O’Day said.
He emphasized, however, that the IMPRIME 1 trial was not designed or powered to directly compare the combination therapy with pembrolizumab monotherapy.
Clinical benefit with the combination was particularly pronounced for patients who were so-called TNBC “converters” — that is, they originally had estrogen receptor (ER)-positive tumors that had progressed on endocrine therapy and, prior to starting treatment with Imprime PGG and pembrolizumab, they had biopsy results confirming TNBC, O’Day said.
The overall response rate (ORR) for all 44 patients included in the efficacy analysis was 15.9%. But among the 12 patients whose disease converted from ER-positive to TNBC after endocrine therapy, six had a response, for an ORR of 50% and a median overall survival of 17.1 months.
“It is not clear whether hormone resistance may have led to the increased responses versus secondary triple-negative status, but it is of great interest to us,” O’Day said.
Why This Special Benefit?
Invited discussant Ben Ho Park, MD, PhD, from Vanderbilt University Medical Center in Nashville, Tennessee, commented that the finding of special benefit among TNBC converters raises the question of biomarkers to determine which patients might most benefit from the combination.
“We already know that anti-beta-glucan antibodies were required to be actually eligible for this study, but is it that, in combination with immune activation, or prior ER-positive disease?” he said. “What about the role of PD-L1 staining? Can we actually combine all this data to come up with some sort of predictive score for whether or not a patient is more or less likely to respond, and more or less likely to have toxicities?”
Imprime PGG is a novel beta-glucan isolated from the cell walls of saccharomyces yeast that binds to endogenous anti-beta-glucan antibodies to form an immune complex.
The immune complex, which is the active drug, binds to a receptor known as dectin-1 to activate innate immunity and reprogram the immunosuppressive tumor microenvironment, enhance antigen presentation, and trigger T-cell activation to improve the efficacy of immune checkpoint inhibitor therapy, O’Day explained.
The complex has been administered to date to approximately 600 healthy volunteers and patients. In these studies, it was administered intravenously at doses of 2 mg/kg to 6 mg/kg weekly as monotherapy or in combination with anti-angiogenic antibodies or tumor-targeting antibodies, with or without chemotherapy.
Studies in volunteers showed that the complex activated innate immunity. Patients have tolerated it well, with no significant safety signals in either monotherapy or combination, with grade 1 or 2 infusion-related reactions being the most common adverse events to date, O’Day reported.
Imprime 1 was a single-arm phase 2 trial enrolling 44 women with TNBC who had received at least one prior line of treatment, but not with an immune checkpoint inhibitor. They were all required to have anti-beta-glucan antibody levels of at least 20 mcg/mL.
All patients received the combination, which comprised Imprime PGG 4 mg/kg weekly plus pembrolizumab 200 mg IV every 3 weeks.
Twenty one patients were under age 50 years, and 23 were 50 years old and older. Seventeen patients were premenopausal, and 27 were postmenopausal. In all, 15 patients had more than three prior lines of therapy for metastatic disease, 30 had visceral disease, and 12 had liver metastases; only four had metastases confined to lymph nodes.
As noted above, median overall survival for all patients was 16.4 months. The ORR was 15.9%, and the disease control rate (a combination of complete and partial responses plus stable disease) was 25%. The median progression-free survival was 2.7 months (vs 2 months in Keynote-086).
In all, 39 of the 44 patients had treatment-related adverse events, with the most common being nausea, back pain, chills, fatigue, diarrhea, arthralgia, and headache. Four patients had grade 3 or 4 events, which included an infusion-related reaction, hyperglycemia, pericarditis, and pancreatitis.
Infusion-related reactions were seen in 27 patients, but only one of these reactions was grade 3 or 4.
The most common immune-mediated events were grade 1 or 2 thyroid dysfunction, which is commonly seen with PD-1 inhibitors, and there were single low-grade events of pancreatitis, pneumonitis, and pericarditis “most likely related to PD-1 inhibitor therapy,” O’Day said.
Translational data showed that innate and adaptive immunity in peripheral blood correlates with clinical benefit, with longer overall survival among patients with either monocyte activation (P = .0045) or T-cell activation (P = .012) compared with patients without activation of those components.
Taken together, the findings suggest that larger controlled studies of the combination are warranted, O’Day said.
The study was sponsored by Biothera and Merck. O’Day disclosed advisory board activities and research funding from both companies and others, and consulting for Biothera. Park disclosed royalties and consulting activities from several companies, not including the Imprime 1 sponsors.
This article first appeared on.