SOT101 With or Without Keytruda Shows Promise, Safety in Treating Advanced Solid Tumors

When given as a single-agent or in combination with the immunotherapy drug Keytruda (pembrolizumab), SOT101 had promising results and a favorable side effect profile for patients with advanced solid tumors, according to findings from the phase 1 AURELIO-03 clinical trial.

“Encouraging efficacy signals were observed for the monotherapy and the combination even checkpoint inhibitor–relapsed tumors,” lead study author, Elena Garralda, head, Early Drug Development Unit, Vall Hebron Institute of Oncology, said in a presentation of the data at the 2022 ASCO Annual Meeting.

SOT101 and anti–PD-1 therapy, like Keytruda, have worked well together in tumor mouse models causing a protective memory response.

The phase 1 study evaluated the safety, tolerability, pharmacokinetics, pharmacodynamics and early efficacy of step-up doses of subcutaneous SOT101 on days 1, 2, 8 and 9 in patients with advanced and metastatic solid tumors as a single agent (30 patients; part A) and in combination with 200 mg of intravenous Keytruda every three weeks until disease progression or unacceptable toxicity (21 patients; part B). In part A, patients were allowed to crossover to the combination arm following disease progression.

To be eligible for enrollment, patients also had to have an ECOG performance status of 0 or 1, indicating that their disease or treatment has caused minimal — if any — impairments in their ability to perform daily activities. Patients also had to have measurable disease, adequate organ function and no prior treatment with IL-2 or IL-15 like agonists. Prior treatment with checkpoint inhibitors was permitted.

The data cut-off was Jan. 26, 2022.

In part A, patients received SOT101 monotherapy at a dose of 0.25 to 15 μg/kg. In part B, patients received SOT101 in combination with pembrolizumab at a dose of 1.5 to 12 μg/kg.

The median number of prior lines of therapy was three (range, 1-9) in part A and two (range, 1-6) in part B. In part A, 19 (63.3%) patients had received a prior checkpoint inhibitor, of whom nine (30 %) were refractory and five (16.7%) had relapsed. In part B, 12 patients (57.1%) had received a prior checkpoint inhibitor to which nine (42.9%) patients relapsed and one (4.8%) was refractory.

The most common side effects were short lived, and included fever, chills, lymphopenia (decrease in white blood cells called lymphocytes), anemia, transaminase elevation and vomiting. Most side effects were grade 2 or lower. No treatment-related death was reported.

The recommended phase 2 dose of SOT101 as a single agent and in combination with Keytruda was determined to be 12 μg/kg. In part A, the clinical benefit rate was 38% (13 patients) with doses ranging from 6 to 12 μg/kg.

A partial response (decrease in disease) was confirmed in one patient with checkpoint inhibitor–refractory, skin squamous cell carcinoma; the partial response duration was 46 days, and the patient was on treatment for 154 days. ­Four patients, all of whom had received a prior checkpoint inhibitor had stable disease (range, 33-183 days).

The final median duration on treatment was 84 days (range, 43-183), and the median duration of clinical benefit was 190 days.

In part B, the observed clinical benefit rate across all SOT101 doses was 63%. A complete response (CR) was confirmed in 1 patient with checkpoint inhibitor–naïve mesothelioma starting at the first tumor assessment, and the patient is ongoing in cycle 5. Three patients, two of whom had received a prior checkpoint inhibitor had a partial response (range, 51-232 days). Two of the patients are in ongoing partial response, and one patient discontinued treatment while still in partial response.

Five patients, three of whom had received a prior checkpoint inhibitor had stable disease (range, 92-340 days); two patients have ongoing stable disease. The three patients who had received a prior checkpoint inhibitor had an stable disease range of 41 to 340 days; one patient remains in ongoing stable disease. The preliminary median duration on the combination therapy was 113 days (range, 7-429), and the preliminary median duration of clinical benefit was 131 days.

Additionally, the pharmacokinetic profile, which tells how a drug moves throughout the body, for SOT101 was similar for the monotherapy and combination regimen. Notably, SOT101 promoted proliferation of target immune cells without T regulatory cell proliferation in line with the anticipated mechanism of action.

Furthermore, all patients with best clinical response of partial response or at least two instances of SD with SOT101 treatment showed increased tumor infiltrating lymphocyte density in tumors after treatment.

Increased immune cell density was also seen in the tumor tissue of patients with PR or confirmed SD with combination.

“This preliminary efficacy of the recommended phase 2 dose is currently being evaluated in expansion cohorts in skin squamous cell carcinoma, melanoma, and renal cell cancer. These encouraging efficacy signals in this heavily pretreated population will be further evaluated in the AURELIO-04 study,” Garralda concluded.

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