Anti-CD73 antibody agent appears safe, shows promise in advanced cancers
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NATIONAL HARBOR, Md. — An investigational anti-CD73 antibody appeared safe and demonstrated promising antitumor activity among patients with advanced cancers, according to phase 1/1b trial data presented at Society for Immunotherapy of Cancer Annual Meeting.
Preliminary results of the dose escalation/dose expansion study showed no dose-limiting toxicities of CPI-006 (Corvus Pharmaceuticals) — a humanized, immunoglobulin G1 Fc gamma receptor binding-deficient anti-CD73 adenosine production inhibitor — with tumor regression seen in nearly half of evaluable patients
CPI-006 induces immunomodulatory activity that activates lymphocytes and effects T-cell and B-cell trafficking, in addition to increasing the expression of antigens CD86 and HLA-DR on cells.
“CPI-006 is an anti-CD73 antibody that has powerful immunomodulatory effects,” Jason Luke, MD, FACP, associate professor of medicine at University of Pittsburgh School of Medicine and director of the Cancer Immunotherapeutics Center within UPMC Hillman Cancer Center, said in a press release.
“Our B-cell receptor studies demonstrated selective clonal expansion to antigens, suggesting that CPI-006 may be eliciting an anticancer immune response,” he added. “To-date, this has been supported in patients, some of whom have observed tumor regression when treated with monotherapy or in combination with ciforadenant (CPI-444, Corvus Pharmaceuticals).”
Luke and colleagues presented data on 24 patients treated with CPI-006 as monotherapy and 16 patients who received CPI-006 plus ciforadenant, an investigational small-molecule immune checkpoint inhibitor of the adenosine A2A receptor.
All patients experienced disease progression following a median four previous standard therapies for advanced cancers, including colorectal cancer (n = 12), renal cell carcinoma (n = 6), pancreatic cancer (n = 6), prostate cancer (n = 6), head and neck squamous cell carcinoma (n = 5), non-small cell lung cancer (n = 3), bladder cancer (n = 1) and sarcoma (n = 1).
Investigators administered CPI-006 monotherapy at one of six dose levels ranging from 1 mg/kg to 24 mg/kg IV every 21 days. The combination therapy group received 1 mg/kg to 18 mg/kg doses of CPI-006 via IV plus a fixed 100 mg twice-daily dose of ciforadenant.
No dose-limiting toxicities occurred. Three patients experienced grade 1 infusion reactions, which were mitigated with premedication. Other grade 1 or grade 2 adverse events included nausea and fatigue. One patient experienced grade 3 anemia, and one patient had grade 3 to grade 4 diarrhea.
Tumor regression occurred in four of nine patients who were able to undergo evaluation after receiving CPI-006 at 6 mg/kg or greater, including tumor reductions of 18.2% in one of two patients with metastatic castration-resistant prostate cancer, 7% and 21.3% in two of five patients with renal cell carcinoma, and 5.8% in one of two patients with NSCLC.
Researchers observed peripheral blood mononuclear cell CD73 occupancy by CPI-006 for at least 21 days among patients who received doses of 6 mg/kg or higher (n = 12), as well as blockade of CD73 enzyme activity in tumors at a CPI-006 dose of 12 mg/kg.
CPI-006 penetration and complete occupancy of CD73 in tumors occurred at a dose of 18 mg/kg, which researchers chose as the dose for further expansion of the study.
Researchers noted a reduction in circulating CD73-positive B cells (median, 64%) at 0.5 hours in the blood of all 11 evaluable patients who were treated at or greater than the occupancy dose. Partial recovery was experienced by day 21.
Returning B cells demonstrated upregulated HLA-DR, with the proportion of memory B cells expanded (median +40% in CD27-positive, immunoglobulin D-negative); researchers observed no change in serum immunoglobulin levels.
Circulating T cells, natural killer cells and monocytes, which were reduced at 0.5 hours, recovered by 24 hours. Memory CD4 T-cell levels in blood increased more than 20% in five of 10 patients tested, with three patients showing a reduction in their tumors.
An analysis of the B-cell receptor repertoire showed treatment induced the generation and expansion of new B-cell clones in the blood of two of three patients in the study, including one of the patients with renal cell carcinoma who responded to therapy. – by Drew Amorosi
Reference:
Luke J, et al. Abstract O40. Presented at: Society for Immunotherapy of Cancer Annual Meeting; Nov. 7-10, 2019; National Harbor, Md.
Disclosures : HemOnc Today could not confirm the researchers’ relevant financial disclosures at the time of reporting.
Perspective
Back to TopRandy Sweis, MD
Luke and colleagues reported a novel approach to immunotherapy targeting CD73, both as monotherapy (CPI-006) and in combination with ciforadenant, an adenosine-A2A receptor antagonist. CD73 is a unique cell surface enzyme encoded by the NT5E gene. It converts adenosine monophosphate to adenosine, which can bind to the A2A receptor and suppress the antitumor immune response.
It is important to note that CPI-006 also has adenosine-independent effects mimicking an agonist ligand. The drug leads to B-cell differentiation, isotype switching and antibody secretion in vitro. Luke and colleagues investigated CPI-006 in a phase 1 dose-escalation study design. In the study, 24 patients received CPI-006 monotherapy and 16 received combination CPI-006 and ciforadenant.
As expected for a phase 1 study, the population was heavily pretreated, with a median four previous therapies. Grade 3 or grade 4 treatment-related adverse events occurred among four patients (17%) who received monotherapy. Interestingly, a lower percentage of patients (12.5%; n = 2) had grade 3 or grade 4 treatment-related adverse events with combination therapy. These events included anemia, lymphopenia, colitis, diarrhea, liver enzyme elevation and hyponatremia. Researchers noted grade 1 or grade 2 infusion-related reactions in three patients who did not require corticosteroid therapy, but who were managed with interruption, acetaminophen or diphenhydramine.
An analysis of peripheral B cells indicated that target occupancy was maximized at doses above 12 mg/kg, whereas tissue occupancy indicated saturation at 18 mg/kg. Researchers observed increases in peripheral B and T cells, but, importantly, the only B-cell changes were CD73 expression-dependent. Tumor regression occurred among four of eight patients at the occupancy dose, although no formal partial responses were achieved per RECIST version 1.1 criteria. The largest tumor regressions occurred in renal cell carcinoma refractory to a tyrosine kinase inhibitor and ipilimumab (Yervoy, Bristol Myers Squibb) plus nivolumab (Opdivo, Bristol-Myers Squibb), and in metastatic castration-resistant prostate cancer treated with multiple androgen targeted therapies and docetaxel chemotherapy.
This study presents interesting preliminary safety and activity data for CPI-006, both as monotherapy and in combination with ciforadenant. Ongoing questions remain and include: Is the dose correct? The expansion dose was selected on biological occupancy, but responses were observed at 24 mg.
In addition, given that the therapy was very well-tolerated, could there be an opportunity to further escalate the dose? The pharmacodynamic effects on B cells were significant and appear to be saturated at 18 mg/kg.
Also, how did CD73 expression overlay with responses observed in this expansion cohort? Could it also be used to select patients for combination therapy outside the selected tumor types? The CD73-adenosine A2A combination appears to have promising activity given tumor regressions observed in a phase 1 study, but further data from the expansion study will be eagerly awaited.
University of Chicago Medicine
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