Proof of concept for TNBC pembrolizumab plus innate immune activator
medwireNews: Phase 2 trial results suggest “promising clinical benefit” for the combination of pembrolizumab and a novel innate immune activator in patients with previously treated metastatic triple-negative breast cancer (TNBC), the IMPRIME 1 investigators say.
The findings were reported at the 2020 AACR Virtual Annual Meeting I by Steven O’Day, from the John Wayne Cancer Institute in Santa Monica, California, USA.
He explained that Imprime PGG is a novel immune complex, formed from a novel beta glucan that binds to endogenous anti-beta glucan antibodies (ABA). This complex acts as an active drug, binding the Dectin-1 receptor and co-receptors, reprogramming the tumor environment, activating antigen-presenting cells, and increasing tumor-specific T cell activation and infiltration, the presenter said.
Imprime PGG was given intravenously at a 4 mg/kg weekly dose alongside pembrolizumab 200 mg every 3 weeks to 44 TNBC patients with a poor prognosis who had received at least one prior line of treatment other than immune checkpoint inhibitor therapy, and had an ABA level of at least 20 µg/mL.
Approximately half (47.7%) of the patients were younger than 50 years old, 61.4% were postmenopausal, and all had an ECOG performance status of 0 or 1. The majority (56.8%) of patients had fewer than three sites of metastases but just 9.1% had only lymph node metastases; 68.2% had visceral disease and 27.3% liver metastases.
The objective response rate of patients given combination therapy was 15.9% and a further 38.6% achieved stable disease, with 25.0% of patients achieving disease control for at least 24 weeks. This compared with historical pembrolizumab monotherapy rates from the KEYNOTE-086 trial of 5.3%, 20.0%, and 7.6%, respectively.
After a median of 22.5 months of follow-up, the median progression-free survival and overall survival (OS) durations were a respective 2.7 and 16.4 months for patients given pembrolizumab plus Imprime PGG.
This compared with historical durations of 2.0 and 9.0 months for pembrolizumab alone, the researcher said.
He reported that the combination regimen was “well tolerated” with grade 3–4 toxicity reported in 9.0% of patients, including infusion-related and immune-mediated events at this severity in 2.3% and 4.5%, respectively, with the latter consisting of one case of pericarditis and another of pancreatitis.
O’Day highlighted a subgroup of special interest in the study – 12 women whose breast cancer had converted to TNBC status after receiving endocrine therapy, such as tamoxifen or aromatase inhibitors, and CDK4/6 inhibitors.
He said there was a “particularly pronounced clinical benefit” in this subgroup, with 50% achieving an objective response and 33% stable disease. This translated to a 6-month disease control rate of 50% and a median duration of OS of 17.1 months. These findings point to a cohort that “deserves further evaluation,” said O’Day.
The presenter also showed translational research confirming that the combination regimen achieved activation of both innate and adaptive immunity.
Specifically, peripheral blood samples from 43 patients indicated that those who achieved an increase in CD86 monocyte expression had significantly better median OS than patients who did not (22.1 vs 11.1 months, hazard ratio [HR]=0.310), as did those who achieved T cell activation compared with their counterparts who did not (22.1 vs 11.9 months, HR=0.334).
Furthermore, paired liver metastasis biopsy slides from four patients demonstrated “robust” myeloid and T cell activation and infiltration after combination therapy, including increased infiltration of PD-L1-positive myeloid cells, said O’Day.
Describing the IMPRIME 1 study as having “encouraging clinical benefit evident across all clinical measures,” the investigator concluded: “Larger controlled studies are warranted and we look forward to exploring this combination further in TNBC.”
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