Novel immuno-oncology combination demonstrates activity in metastatic triple-negative breast cancer
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The combination of pembrolizumab and Imprime PGG demonstrated promising clinical activity as second-line or later treatment for metastatic triple-negative breast cancer, according to phase 2 study results presented at the virtual American Association for Cancer Research Annual Meeting.
“These were patients who had prior chemotherapy and extensive disease, including the majority with visceral disease and even liver metastases,” Steven J. O’Day, MD, executive director of John Wayne Cancer Institute at Providence St. John’s Health Center, said during a presentation. “We see encouraging evidence of benefit across all of our clinical measurements — response, durable response and median OS — compared with historical single-agent PD-1 [therapy] in a similar metastatic triple-negative breast cancer population.”
Researchers observed a particularly pronounced clinical benefit in a subgroup of patients who initially were diagnosed with ER-positive/PR-positive disease but progressed on endocrine therapy and — prior to treatment in this study — had biopsies that confirmed conversion to triple-negative breast cancer.
“The efficacy in this group was significant and should be followed with further studies,” O’Day said. “It is not clear whether hormone resistance may have led to the increased responses vs. secondary triple-negative status, but it is of great interest to us.”
Immune checkpoint inhibitor monotherapy has demonstrated limited benefit for patients with metastatic triple-negative breast cancer, particularly when administered beyond the first-line setting.
The KEYNOTE-086 study evaluated immune checkpoint inhibitor monotherapy with the anti-PD-1 monoclonal antibody pembrolizumab (Keytruda, Merck) for patients with metastatic triple-negative breast cancer. Researchers reported a 5.3% overall response rate, a 7.6% disease control rate at 24 weeks, median PFS of 2 months and median OS of 9 months.
In the open-label, two-stage IMPRIME1 trial, O’Day and colleagues evaluated the combination of pembrolizumab and the novel innate immune activator Imprime PGG (Biothera Pharmaceuticals) for second-line or later treatment of metastatic triple-negative breast cancer.
Imprime PGG is a systemically delivered dectin receptor agonist that activates the immune system to reprogram the immunosuppressive tumor microenvironment, activate antigen-presenting cells and stimulate antigen-specific T-cell activation, according to study background.
Preclinical models showed Imprime PGG significantly improved the efficacy of immune checkpoint inhibitor therapy.
The IMPRIME1 trial included 44 patients, the majority of whom were aged older than 50 years (52.3%) and were postmenopausal (61.4%). All patients had ECOG performance status of 0 (47.7%) or 1 (52.3%). About one-third (34.1%) had received more than three lines of therapy after recurrent or metastatic disease, 68.2% had visceral disease and 27.3% had liver metastases.
Imprime PGG-mediated activation of innate immune cells requires anti-beta glucan antibodies (ABA), so enrollment was restricted to patients who had sufficient ABA immunoglobulin G ( 20 mcg/mL).
Patients received Imprime PGG dosed at 4 mg/kg via IV on days 1, 8 and 15 of each 3-week cycle, plus pembrolizumab dosed at 200 mg on day 1 of each cycle.
Patients underwent CT scans at baseline and every 6 weeks thereafter until disease progression.
ORR served as the primary endpoint. Secondary endpoints included safety, OS, disease control rate and PFS.
Researchers reported an ORR of 15.9% (95% CI, 7.9-29.4). More than one-third (38.6%; 95% CI, 25.7-53.4) of patients achieved stable disease and 40.9% (95% CI, 27.7-55.6) had progressive disease.
One-quarter of patients (25%; 95% CI, 14.6-39.4) achieved disease control, defined as complete response, partial response or stable disease for at least 24 weeks.
Median follow-up was 22.5 months (range, 1.6-34.3).
O’Day and colleagues reported median PFS of 2.7 months and median OS of 16.4 months. More than half (57.6%; 95% CI, 42.4-72.8) of patients survived 12 months, and 36.7% (95% CI, 21.3-52.1) survived at least 18 months.
Investigators observed pronounced clinical benefit with the combination among a subgroup of 12 patients originally diagnosed with ER-positive/PR-positive disease who underwent prior treatment with endocrine therapy and later converted to triple-negative disease.
These patients had all received prior treatment with tamoxifen, aromatase inhibitors or CDK 4/6 inhibitors, and all had received at least one line of chemotherapy after development of metastatic disease.
In this group, six (50%) achieved response to the combination, four (33%) achieved stable disease and six (50%) achieved disease control for 6 months. Median OS in this group was 17.1 months.
Overall, 39 patients (88.6%) experienced any-grade treatment-related adverse events, the most common of which were nausea, back pain, chills, fatigue, diarrhea, arthralgias and headache; 61.4% experienced infusion-related reactions, the majority of which were grade 1 or grade 2. Eight patients (18.2%) experienced immune-mediated events, the most common of which was thyroid dysfunction.
Four patients (9%) experienced grade 3/grade 4 treatment-related adverse events. They included infusion-related reaction, hyperglycemia, pericarditis and pancreatitis.
“The combination regimen was well-tolerated, and there were no unexpected safety observations,” O’Day said. “There were mild to moderate infusion reactions, and there were no treatment-related deaths.”
Translational studies showed activation of innate and adaptive immunity through both blood and paired tissue samples obtained both before and on treatment.
“Larger controlled clinical trials are warranted, and we look forward to exploring this combination further in metastatic triple-negative breast cancer,” O’Day said. – by Mark Leiser
Reference:
O’Day SJ, et al. Abstract CT073. Presented at: AACR Annual Meeting; April 27-28, 2020 (virtual meeting).
Disclosures: O’Day reports financial relationships with Biothera Pharmaceuticals and Merck. Please see the abstract for all other researchers’ relevant financial disclosures.
Perspective
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Yuan Yuan, MD, PhD
This is a single-arm study that combined a novel dectin receptor agonist — Imprime PGG, which activates the innate immune system — and the immune checkpoint inhibitor pembrolizumab for patients with metastatic triple-negative breast cancer. Compared with historical data of a 5.6% response rate with single-agent pembrolizumab, the combination showed an ORR of 15.9% and OS of 16.4 months. The combination appears to be well-tolerated, with 2.3% of patients experiencing grade 3/grade 4 infusional reactions and 4.5% experiencing grade 3/grade 4 immune-related adverse events.
These findings represent the ongoing effort of immune checkpoint inhibitor combinations, which aims to target an immune-suppressive tumor microenvironment to improve the efficacy of immune checkpoint inhibitors.
The potential encouraging clinical benefit will need to be further confirmed with a larger controlled study. It’s also noted that 12 of 44 patients had a phenotype shift from hormone receptor-positive disease to triple-negative breast cancer, and the ORR was 50% in this subgroup. The underlying etiology remains to be explored.
In this study, patients were required to be immune checkpoint inhibitor naive and have a detectable anti-beta glucan antibody (ABA) level of at least 20 mcg/mL. Patients were not selected for PD-L1. It’s estimated that approximately 20% of patients with breast cancer have an ABA level of at least 20 mcg/mL, which may limit the broad application of this combination in metastatic triple-negative breast cancer. The landscape of metastatic triple-negative breast cancer has shifted from when the immune checkpoint inhibitor atezolizumab (Tecentriq, Genentech) plus nab-paclitaxel (Abraxane, Celgene) was FDA approved as first-line therapy for those with metastatic disease. Whether the combination of immune checkpoint inhibitors plus Imprime PGG will be active as a second-line therapy after immune checkpoint inhibitor exposure remains a research question. I am very interested to see whether this combination would have benefit if evaluated in trials as adjuvant treatment or even as first-line treatment for metastatic disease.
Perspective
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Ben Ho Park, MD, PhD
Immunotherapy is approved for first-line treatment of metastatic triple-negative breast cancer. The approval of atezolizumab (Tecentriq, Genentech) and nab-paclitaxel (Abraxane, Celgene) was based on a seminal study — IMpassion130 — published in The New England Journal of Medicine. In the subgroup of patients with PD-L1-positive tumors, you could see a nice splaying of the curves between the group that received atezolizumab and nab-paclitaxel and those who received placebo plus nab-paclitaxel.
Prior studies of immune checkpoint inhibitors for metastatic breast cancer were not as encouraging, and this really begs the question: How do we turn cold tumors — those that are not responsive to immune checkpoint inhibitors — hot? That has been the focus of many studies and also of the IMPRIME1 study.
The data are very impressive. This is in a second- or later-line setting and it is uncontrolled, and there are always caveats with comparing studies, but the median OS of 16.4 months is very impressive for an already-treated population. More interesting were some of the correlative signs and how we might be able to use them for predictive biomarkers.
Not everyone is going to respond to these therapies and they can have increased toxicities, so finding biomarkers is very important to make sure we optimally choose our patients.
It appears activation of both innate and adaptive immunity using peripheral blood and following monocyte activation or T-cell activation or both is a strong predictor of response to this particular therapy. However, this leaves us with a lot of unanswered, hypothesis-generating questions that can be addressed in future studies. Chief among them is why do the so-called converters — those with ER-positive disease that converts to ER-negative — seem to have a much higher response to this combined therapy?
That leads to the second question: What are the best predictive markers for this drug? Anti-beta-glucan antibodies were a requirement to be eligible for this study, but is it that in combination with immune activation? What about the role of PD-L1 staining? Can we combine all of these data to come up with some sort of predictive score for whether a patient is more likely to respond, or more likely to have toxicities?
Are patients who convert from ER-positive to ER-negative disease more likely to have anti-beta-glucan antibodies? Maybe there is a self-selection process in those patients who switch. The reasons for that at this point would be purely conjecture, but they are questions that I think can be answered. And then how do we — or should we — fit this into first-line therapy of patients with triple-negative breast cancer with nab-paclitaxel?
These are questions to think about in terms of how we can use this information for translational benefit.
Reference:
Schmid P, et al. N Engl J Med. 2018;doi:10.1056/NEJMoa1809615.
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