Combining AM0010 and Pembrolizumab Produced Antitumor Activity in Patients With Advanced Solid Tumors
A multibasket phase Ib study evaluating the clinical activity, tolerability, and antitumor activity of the cytokine-based immunotherapy AM0010 alone or in combination with the immune checkpoint inhibitor pembrolizumab (Keytruda) has found that in monotherapy, objective responses to AM0010 were observed in patients with uveal melanoma, cutaneous T-cell lymphoma, and in some patients with renal cell carcinoma. The combination therapy provided durable tumor responses in some patients with renal cell carcinoma and non–small cell lung cancer (NSCLC). In addition, the regimen was well tolerated.
The study by Naing et al (abstract 16-A-389-IMM) was presented at the International Cancer Immunotherapy Conference: Translating Science Into Science in New York City on September 25–28, 2016. The conference was cosponsored by the Cancer Research Institute, the Association for Cancer Immunotherapy (CIMT), the European Academy of Tumor Immunology, and the American Association for Cancer Research.
Study Methodology
The researchers enrolled 19 patients with advanced melanoma, renal cell carcinoma, or NSCLC to a cohort in which patients received one of two doses of AM0010 daily and 2 mg/kg body weight pembrolizumab every 3 weeks.
Study Findings
The investigators found both tolerability and antitumor activity of AM0010 alone or in combination with pembrolizumab. In monotherapy, objective responses were observed in patients with uveal melanoma, cutaneous T-cell lymphoma, and in 4 of 15 patients with renal cell carcinoma. Patients with advanced melanoma, renal cell carcinoma, or NSCLC were also treated with AM0010 (daily subcutaneously) in combination with anti–PD-1 (programmed cell death protein 1) immune checkpoint blockade.
Tumor responses were monitored following immune-related response criteria. Immune responses were measured by analysis of serum cytokines, activation of blood-derived T cells, peripheral T-cell clonality, and immunohistochemistry of tumor-infiltrating CD8 T cells.
In 19 patients, AM0010 at 10 μg/kg (n = 13) or 20 μg/kg (n = 6) in combination with pembrolizumab (2 mg/kg) was well tolerated (observation period, 10–15 months). Treatment-related adverse events occurred in the frequency and severity expected from pembrolizumab monotherapy.
The combination of AM0010 with pembrolizumab achieved objective responses (partial and complete responses) in four of eight patients with renal cell carcinoma, two of five patients with NSCLC, and two of six patients with melanoma. Two additional patients with melanoma had tumor increase followed by decrease (pseudoprogression).
Independent of the combination with either chemotherapy or anti–PD-1, AM0010 increased Th1 cytokines (interleukin 18 [IL-18], interferon gamma [IFN-γ], IL-7) in a dose-dependent fashion. FasL and lymphotoxin beta—products of cytotoxic T cells—were also increased in the serum of AM0010-treated patients. In contrast, mediators of chronic inflammation, such as IL-23 and IL-17 and the immune-suppressive cytokine transforming growth factor beta (TGF-β), were reduced in the serum. AM0010 increased the number and proliferation of PD-1–positive activated CD8 T cells while decreasing the proliferation of FoxP3-positive regulatory T cells (Tregs) and TGF-β in the blood.
AM0010 induced de novo oligoclonal expansion of T-cell clones in the blood of patients without affecting total lymphocyte counts. This clonal expansion appeared to be enhanced and accelerated in patients treated with an AM0010/anti–PD-1 combination but was also seen in patients who received an AM0010/chemotherapy combination. AM0010 also increased the number of tumor-infiltrating phospho-STAT3-positive CD8 T cells in tumors and the number of granzyme-positive PD-1–positive CD8-positive T cells in tumor biopsies of treated patients.
Combinations of Immune Therapies May Lead to More Durable Responses
“In this clinical trial, we found that the two immunotherapies were well tolerated, without overlapping toxicity or severe autoimmunity, while providing strong antitumor responses,” said Aung Naing, MD, Associate Professor in the Department of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center and lead author of the study, in a statement. “In addition, we detected new, expanding T-cell clones in the blood of all patients who received AM0010. Many of those T-cell clones were not detectable before treatment. This is reminiscent of tumor-specific vaccination.”
This study was funded by ARMO BioSciences, Inc. Dr. Naing received travel reimbursement for professional conference presentations of studies relevant to ARMO-developed therapies.
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