STING Agonist Plus Atezolizumab Could Expand Immunotherapy Benefit to Nonresponsive Advanced Solid Tumors

In an effort to expand the benefit of immunotherapy to nonresponders or those who have relapsed, the novel STING agonist SB 11285 is being evaluated as a monotherapy and in combination with atezolizumab (Tecentriq) in patients with advanced solid tumors in a phase 1/1b dose-escalation trial, according to a virtual presentation during the 2020 Annual SITC meeting.¹

“We want to highlight that an intravenous STING agonist is a novel treatment approach for the treatment of patients with cancer,” Jason J Luke, MD, FACP, director of the Cancer Immunotherapeutics Center at UPMC Hillman Cancer Center and University of Pittsburgh, said during a poster presentation spotlighting the trial in progress. “SB 11285, when administered with atezolizumab, has the potential to overcome and expand the population of patients benefitting from immunotherapy.”

Preclinical models have shown that SB 11285 in combination with an anti–CTLA-4 or anti–PD-1 agent substantially enhanced local tumor shrinkage and survival, which suggests potential synergy with concomitant STING activation.

"In vivo, antitumor activity has been observed with monotherapy, as well as the combination with anti–PD-1 and anti–PD-L1 [agents] in a broad range of tumor types, including CT26, B16, MC38, and 4T1,” noted Luke.

For example, the intravenous dose of the experimental agent was found to result in responsive tumor growth inhibition in a CT26 colon cancer model and B16 melanoma model. Additionally, SB 11285 demonstrated synergistic activity when used in combination with an anti–PD-1 agent in a MC38 colon cancer model. The STING agonist has also been found to have inhibited tumor metastasis when explored in a 4T1 breast cancer model.

Although immunotherapy agents have transformed the treatment of patients with cancer, many still do not respond to these agents or they relapse on treatment; this underscores a need for new therapies, said Luke. Investigators have hypothesized that STING agonists can potentially serve as an option for these patients, as the activation of the STING pathway in immune cells within the tumor microenvironment and cancer cells could lead to the induction of innate and adaptive immunity, resulting in the activation of cytotoxic T cells and natural killer cells; this could translate into deep antitumor responses, according to Luke.

“[There is] a need for improved treatments,” Luke said. “STING and agonists of this pathway have been a high priority in the preclinical space as a potential modality to overcome immunotherapy resistance.”

SB 11285 is a novel agonist of the STING pathway that has been developed to activate tumor-resident antigen presenting cells and to bring CD8-positive cells to the tumor. The agent has been found to cause the induction of cytokines consistent with the engagement of the STING target; it is also known to induce cell death via STING-mediated apoptosis. The agent has demonstrated durable and complete tumor regression in the majority of animals tested; it induces immune memory and abscopal effect when administered intravenously, intraperitoneally, and intratumorally.

"SB 11285 activates STING, leading to increases in type 1 interferon, induction, and recruitment of CD8-positive T cells into the tumor microenvironment, and systemic delivery of this agent enables targeting of a wide range of tumor types,” Luke said.

Investigators believe that the systemic administration of this agent may additionally help with facilitating the trafficking of these newly activated CD8-positive CAR T cells from the periphery into the tumor site.

This first in human, open-label, multicenter dose-escalation study is focused on identifying dose-limiting toxicities, the maximum-tolerated dose, and the recommended phase 2 dose of the agonist. The dose-escalation portion of the study is utilizing a 3+3 dose escalation design to evaluate the safety of both SB 11285 monotherapy and in combination with atezolizumab. Investigators hope to enroll 15-30 patients to the monotherapy cohort and 9-18 patients to the combination cohort.

The combination dose-escalation portion of the trial will not begin until the second dose level for the monotherapy is determined to be safe by the Safety Review Committee, noted Luke. The study will examine the combination in 3 expansion cohorts, those who have: melanoma (n = 21), head and neck (n = 21), and tumors that aren't in either of the 2 prior cohorts or tumors that are relapsed/refractory to anti–PD-1/PD-L1 agents (n = 20).

Patients enrolled on the study will receive treatment over a 28-day dosing cycle for a total of 12 cycles until unacceptable toxicity or progressive disease.

To be eligible for enrollment, patients must be 18 years of age and older and have been diagnosed with locally advanced or metastatic or unresectable solid tumors in both parts of the study; they had to meet additional tumor-specific criteria in the expansion cohorts of melanoma and head and neck. Patients also had to have an ECOG performance status of 0 or 1 with an estimated life expectancy of 3 months or more and measurable disease via RECIST v1.1 criteria. Patients also needed to have intact hematologic and organ function.

“Exclusion criteria include active autoimmune disease, prolonged QTc, ongoing infection requiring antibodies or chronic viral infection, clinically significant disease that would generally exclude a patient from a phase 1 study, and a prior checkpoint inhibitor within 28 days,” said Luke.

While part 1 of the study will be focused on evaluating the maximum-tolerated dose, the recommended phase 2 dose, along with the safety and tolerability of the SB 11285 monotherapy and combination regimen, part 2 will examine the preliminary antitumor activity of both approaches in addition to further evaluating safety.

Key secondary objectives for both the dose escalation and dose expansion cohorts include characterizing whole blood pharmacokinetics, as well as evaluating other measures of clinical benefit, including overall response rate, duration of response, progression-free survival by RECIST criteria, and overall survival. Exploratory objectives in both cohorts include evaluating pharmacodynamics and assessing the biologic effects of SB 11285, as demonstrated by changes in immune cells, immune cell markers, serum cytokines, and gene expression patterns.

“Overall, our study is ongoing [and] we're in the midst of dose escalation,” Luke concluded. “The treatment has been, generally speaking, well tolerated so far. Other data are not available yet for disclosure.”

References

Luke JL, Janku F, Olszanski AJ, et al. A phase 1a/1b dose-escalation study of intravenously administer SB 11285 alone and in combination with atezolizumab in patients with advanced solid tumors. Poster presented at: SITC 2020; November 9-14, 2020; Virtual. Accessed November 12, 2020. Abstract 367.