Novel Innate Immune Activator Boosts PD-1 Inhibition Responses in mTNBC

The addition of the novel innate immune activator, Imprime PGG, to checkpoint inhibition with pembrolizumab showed pronounced clinical benefit in patients with previously treated metastatic triple-negative breast cancer.

Steven J. O'Day, MD

The addition of the novel innate immune activator, Imprime PGG (Imprime), to checkpoint inhibition with pembrolizumab (Keytruda) showed pronounced clinical benefit in patients with previously treated metastatic triple-negative breast cancer (mTNBC), according to findings from the phase II IMPRIME 1 trial presented during the virtual 2020 American Association for Cancer Research Annual Meeting.1

Outcomes with the combination regimen were significantly improved over with the use of immune checkpoint inhibition monotherapy in patients with mTNBC.

“We see encouraging clinical benefit evident across all of our clinical measurements: response, durable response, and median overall survival compared to historical [outcomes with] single-agent PD-1 [inhibition] in a similar metastatic triple-negative breast cancer population,” said Steven J. O’Day, MD, the executive director of the John Wayne Cancer Institute and Cancer Clinic and director of Providence Los Angeles Regional Research. O’Day is also a professor of medical oncology, director of Immuno-Oncology, and director of Clinical Research at the John Wayne Cancer Institute at Providence Saint John’s Health Center.

Imprime PGG is a novel beta glucan agonist that binds endogenous anti-beta glucan antibodies (ABA) to form an immune complex, which then binds to the dectin-1 receptor and its co-receptors. This Imprime immune complex activates the innate immune system to reprogram the immunosuppressive tumor microenvironment, activate antigen-presenting cells, and increase tumor-specific T-cell activation and infiltration.

Innate immunity had been demonstrated in prior studies that evaluated Imprime. This immune activator was also found to be well tolerated as both monotherapy and in combination regimens.

IMPRIME 1 is a phase II, single-arm trial that evaluated the combination of Imprime and pembrolizumab in patients with metastatic TNBC as per College of American Pathologists/American Society of Clinical Oncology (CAP/ASCO) guidelines, meaning patients showed less than 1% hormone receptor staining. Additionally, participants had received at least 1 prior line of chemotherapy and had not been exposed to prior immune checkpoint inhibition. Patients were also required to have an ABA level of at least 20 mcg/mL, which O’Day explained accounts for about 40% of patients with TNBC.

In the study, patients were treated with 4 mg/kg of Imprime PGG intravenously weekly plus 200 mg of pembrolizumab on day 1 of each 3-week cycle.

The primary end point was objective response rate (ORR) and secondary end points included safety, overall survival (OS), disease control rate (DCR), and progression-free survival (PFS). The investigators also looked to signals of innate and adaptive immune activation in tumor and peripheral blood.

Forty-four patients were included in the study; just over half of the women (52.3%) were older than 50 years and 61.4% were postmenopausal at baseline. About one-third (34.1%) of patients had received more than 3 prior lines of therapy after recurrent or metastatic diagnosis. Liver and lymph node metastases were present in 27.3% and 90.9% of patients, respectively; visceral disease was also seen in 68.2% of patients at baseline.

The ORR was 15.9% (CI, 7.9%-29.4%) and stable disease (SD) was seen in 38.6% (95% CI, 25.7%-53.4%). The DCR, consisting of complete and partial responses and SD lasting at least 24 weeks, was 25.0% (95% CI, 14.6%-39.4%). About 40% of patients had SD, whereas 40.9% had progressive disease.

After a median follow-up of 22.5 months (range, 1.6-34.3), the median PFS was 2.7 months (95% CI, 1.35-4.04) and the median OS was 16.4 months (95% CI, 11.1-19.2).

As a comparator, O’Day pointed to findings from the KEYNOTE-086 trial (NCT0244700)—the largest, single-arm study of PD-1 checkpoint blockade in patients with advanced TNBC. In this trial, 170 patients who had failed prior chemotherapy received pembrolizumab monotherapy.2

Efficacy was limited in this study, O’Day said, with a single-digit ORR (5.3%) and DCR (7.6%). The median PFS was 2.0 months and the median OS was 9.0 months.

In IMPRIME 1, adverse events (AEs) of any grade were seen in 88.6% of patients, with the most common toxicities being nausea, back pain, chills, fatigue, diarrhea, arthralgias, and headache. Grade 3/4 events of infusion-related reaction, hyperglycemia, pericarditis, and pancreatitis were seen in 9% of patients. There were no treatment-related deaths on the study.

Infusion-related reactions were reported in 61.4%, which included back pain, urticaria, pruritus, and infusion-related reaction not otherwise specified. Immune-mediated events, observed in 18.2% of patients, were most frequently thyroid events, but single events of pancreatitis, pneumonitis, and pericarditis were also observed.

One subgroup of special interest from the study involved 12 patients who originally had hormone receptor—positive disease but converted to TNBC after endocrine therapy. All of these patients met the ASCO guidelines for TNBC at enrollment with a new biopsy; had previously received treatment with tamoxifen, an aromatase inhibitor, and/or a CDK4/6 inhibitor; and were treated with more than 1 line of chemotherapy in the metastatic setting.

In this subgroup, the ORR was 50% and the SD rate was 33%; at 6 months, the DCR was 50%. The median OS was 17.1 months.

“These patients did remarkably well,” O’Day said. “Clearly an interesting subgroup within this 44-patient cohort that deserves further evaluation.”

“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 commented further.

Translational data showed activation of both innate and adaptive immunity. Analyses of serial peripheral blood samples showed increased monocyte counts and CD86 expression, as well as enhanced T-cell activation.

Patients who had activated monocytes in the blood, in terms of CD86 expression, had a higher median OS than those who did not (22.1 vs 11.1 months; HR, 0.310; 95% CI, 0.138-0.696; P = .0045). Those that had T-cell activation markers in the blood had a median OS of 22.1 months compared with 11.9 months in those without (HR, 0.334; 95% CI, 0.142-0.785; P = .012).

O’Day concluded that larger, controlled trials are warranted to investigate the combination further.

References

  1. O’Day SJ, Borges VF, Chmielowski B, et al. IMPRIME 1 (NCT02981303): A novel phase 2 study in second-line +, metastatic triple negative breast cancer patients shows promising clinical benefit for the combination of the immune checkpoint inhibitor, pembrolizumab (pembro), with the novel innate immune activator, Imprime PGG. Presented at: 2020 AACR Virtual Annual Meeting; April 27-28, 2020. Abstract CT073.
  2. Adams S, Schmid P, Rugo HS, et al. Pembrolizumab monotherapy for previously treated metastatic triple-negative breast cancer: cohort A of the phase II KEYNOTE-086 study. Ann Oncol. 2019;30(3):397-404.

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