The investigational therapy cavrotolimod (AST-008), in combination with the PD-1 inhibitor Keytruda (pembrolizumab), was safe and well-tolerated, and showed signs of efficacy in people with advanced solid tumors who failed prior PD-1 blockade therapy, according to the interim results of a Phase 1b/2 clinical trial.
Based on these findings from the Phase 1b stage, the trial will continue in Phase 2 to investigate cavrotolimod plus Keytruda in people with advanced Merkel cell carcinoma (MCC), and with Libtayo (cemiplimab) for those with advanced cutaneous squamous cell carcinoma (CSCC), Exicure, the potential treatment’s developer, announced in a press release.
Data were presented in the poster, “Safety and preliminary efficacy of intratumoral cavrotolimod (AST-008), a spherical nucleic acid TLR9 agonist, in combination with pembrolizumab in patients with advanced solid tumors,” at the Society for Immunotherapy of Cancer (SITC) 35th Anniversary Annual Meeting.
PD-1 inhibitors, like Keytruda and Libtayo, are antibodies designed to target the PD-1 receptor on immune cells, and block its binding with the PD-L1 ligand on tumor cells. This interaction is often used by cancer cells to evade immune attacks, thus targeting the PD-1 protein helps the immune system to identify and kill the cancer.
But not all patients respond to PD-1 blockers, which can lead to disease progression.
Cavrotolimod is designed to activate a potent anti-tumor immune response, to enhance the effectiveness of anti-PD-1 immune checkpoint inhibitors.
The ongoing, open-label Phase 1b/2 study (NCT03684785) is evaluating the safety, tolerability, and preliminary efficacy of cavrotolimod in combination with PD-1 inhibitors in about 130 adults with advanced solid tumors.
Its Phase 1b portion examined increasing doses of cavrotolimod (2, 4, 8, 16, and 32 mg) injected directly into the tumor (intratumoral) in combination with Keytruda, developed by Merck (known as MSD outside the U.S. and Canada). A total of 20 patients were enrolled across all dose levels.
Cavrotolimod was given once a week for eight weeks, then once every three weeks. Patients received two doses of cavrotolimod alone before adding Keytruda, administered intravenously (into-the-vein) once every three weeks.
This part of the study included patients with advanced solid tumors, including MCC, CSCC, advanced melanoma, head and neck squamous cell carcinoma, and leiomyosarcoma. Enrollment required two or more evaluable lesions, in which one lesion remained untreated to assess therapy effect.
Tumor biopsies were taken before cavrotolimod treatment (baseline), after cavrotolimod alone, and then after the combination therapy.
Safety analysis revealed no dose-limiting toxicities, potentially life-threatening toxicities, or treatment-related serious adverse events. The most common were injection site reactions and flu-like symptoms. Except for one case with severe agitation and another with severe injection site reaction, all treatment-related adverse events were mild or moderate.
At the time of the analysis, four (two melanoma and two MCC) of the 19 evaluable patients (21%) in the Phase 1 part responded to treatment, including one complete response and three partial responses.
Responses were ongoing, with all four responders living without signs of disease worsening for more than six months, and two for more than 16 months. Researchers noted that non-injected tumors also shrank after treatment.
Notably, 33% of patients receiving the highest dose of cavrotolimod (32 mg) responded to the combination treatment, which led the researchers to select this dose for the trial’s Phase 2 portion.
Phase 2 will include patients who failed prior anti-PD-1 therapies, and will examine cavrotolimod with Keytruda for people with advanced MCC, and with Libtayo (developed by Regeneron Pharmaceuticals) for advanced CSCC.
Phase 2 will also include an exploratory group to evaluate cavrotolimod plus Keytruda in refractory patients with the other advanced solid tumors. The trial may still be recruiting people at sites across the U.S.; information is available here.
“[Intratumoral] administration of cavrotolimod appears to be safe and well-tolerated in combination with [Keytruda],” the researchers concluded. “Durable responses have occurred in patients previously experiencing progressive disease on PD-1 blockade.”