Clinical Activity Reported in Patients With Advanced Solid Tumors Treated With SOT101 Plus Pembrolizumab


Results of the phase 2 AURELIO-03 trial show SOT101 plus PD-1 inhibition induced responses in patients with advanced solid tumors.

Clinical benefit and acceptable safety were observed in patients with solid tumors who were treated with the combination of the interleukin (IL)–2/IL-15 Rβγ superagonist SOT101 plus pembrolizumab (Keytruda), according to interim data presented at the American Association for Cancer Research (AACR) 2022 Annual Meeting.

Investigators of the dose-escalation phase 2 AURELIO-03 trial (NCT05256381) observed complete response (CR) in 1 patient, partial response (PR) in 4 patients, and confirmed stable disease (SD) of at least 50 weeks in 5 patients with this combination. Twelve out of 16 patients with at least 1 tumor assessment experienced clinical benefit, including those who were relapsed/refractory to immune checkpoint blockade (ICB).

“SOT101 is a fusion protein containing IL-15 and the Sushi+ domain of IL-15Rα. It mimics a high-affinity binding of IL-15 trans-presented to its βγ receptor at the synapse. Therefore, it doesn’t require dendritic cells to trans-present IL-15,” Stéphane Champiat, MD, PhD, assistant professor in the drug development department of Gustave Roussy Cancer Campus, said in his presentation.

“Compared [with] IL-2, it actually does not activate [regulatory T cells] due to the fact the IL-15 does not bind to IL-2Rα. Therefore, SOT101 may have a better efficacy over [other] IL-2/IL-15 compounds because of a strong and well-balanced induction of both innate and adaptive immunity by activating T cells or NK [natural killer] cells.”

The primary end points of the open-label, single-arm, multicenter AURELIO-03 study were safety, tolerability, recommended phase 2 dose (RP2D), preliminary efficacy, pharmacokinetics, and pharmacodynamics. SOT101 was given subcutaneously on days 1, 2, 8, and 9 in combination with pembrolizumab at 200 mg intravenously every 3 weeks until disease progression or unacceptable toxicity. Standard 3+3 escalation was used, with 3 patients receiving 1.5 μg/kg of SOT101, 3 receiving 3.0 μg/kg, 7 receiving 6.0 μg/kg, 3 receiving 9.0 μg/kg, and 5 receiving 12.0 μg/kg.

The maximum tolerated dose of SOT101 was not reached, so the RP2D was determined to be 12 μg/kg. The investigators concluded there was no additive toxicity because the adverse events (AEs) seen with the combination were comparable to the toxicity profile of SOT101 and pembrolizumab used as monotherapy.

Safety data available for 21 patients at 5 dose levels of SOT101 ranging from 1.5 to 12 μg/kg demonstrated tolerability for the combination. Most AEs were grade 2 or lower, with the most common being pyrexia, chills, and vomiting. Grade 3/4 treatment-emergent AEs included lymphopenia in 7 patients, alanine aminotransferase/aspartate aminotransferase (ALT/AST) and pyrexia in 2 patients each, and neutropenia, anemia, and cytokine release syndrome (CRS) in 1 patient each.

One patient had dose-limiting toxicity [DLT] of grade 2 CRS, with grade 2 hypotension and fever, while receiving 6 μg/kg of SOT101 after the first administration. However, this resolved after 6 days, and the patient continued on 3 μg/kg. No other DLTs were observed at higher dose levels. Due to grade 3 ALT/AST, 1 patient on 1.5 μg/kg discontinued study treatment, and the AE resolved within 12 days after discontinuation. There were no incidence of treatment-related death or vascular leak syndrome.

At the data cutoff of February 3, 2022, there was 1 confirmed CR in a patient with mesothelioma at a dose level of 9 μg/kg of SOT101. Among multiple dose levels, there were 3 confirmed PRs and 1 unconfirmed in patients with medullary thyroid gland cancer not pre-treated with ICB, ICB-refractory skin squamous cell carcinoma (SCC), and ICB-relapsed skin melanoma and melanoma of the cervix. SD was confirmed in 5 patients, and unconfirmed in 2 others, with anal SCC, gastric cancer, cervix adenocarcinoma, liver cancer, and colorectal cancer across dose levels. The longest duration of response was over 40 weeks.

The adult patients on this trial had to be refractory or intolerant to existing therapies and needed to have confirmed metastatic or unresectable solid tumors. They needed adequate renal, hepatic, and hematological function and an ECOG performance status of 0 or 1.

In the 21 patients evaluated for toxicity, the median age was 62 years, and 11 patients were female. Fourteen had an ECOG performance status of 0. They had a median of 2 prior lines of therapy, although 10 patients had 3 or more lines before entering this study. Eleven patients had prior ICB treatment. The most common disease types on the trial were colorectal cancer in 3 patients, melanoma in 3, gastric cancer in 2, anal SCC in 2, and mesothelioma in 2.

For this trial, investigators looked at 2 case studies. The first was a 49-year-old woman with anal SCC who was ICB-refractory and had SD for 52 weeks. This patient was diagnosed in August 2019 and received 5-fluorouracil, leucovorin, oxaliplatin in the first line, retifanlimab in the second line, and SOT101 at 1.5 μg/kg with pembrolizumab as third-line therapy.

“There was a dramatic increase of CD8+ infiltrate and PD-L1 expression and it triggered an infiltration of NK cells. So it suggests that SOT101 in combination with pembrolizumab can induce an increase in immune cell infiltration in ICB-refractory tumors,” Champiat explained.

In the second case study, a 74-year-old woman with skin SCC had a best response of PR. She was initially diagnosed in 2016, had 22 surgeries, and received cemiplimab [Libtayo] for 4 cycles before developing primary resistance. In the AURELIO-03 trial, she was given 6 μg/kg of SOT101. After 4 cycles, this patient had a PR in her target lesions and fluctuating new lesions were appearing and disappearing, for significant clinical response. The patient has had over 50 weeks of treatment and is still receiving therapy.

Champiat concluded that based on the encouraging efficacy signals observed in these heavily pretreated patients, SOT101 plus pembrolizumab will be investigated in the AURELIO-04 trial (NCT05256381). This will be an open-label, single-arm, multicenter phase 2 trial in patients with advanced or refractory solid tumors to further evaluate efficacy and safety.


Champiat S, Marabelle A, Galvao V, et al. SOT101, an IL-2/IL-15 Rβγ superagonist, in combination with pembrolizumab in patients with advanced solid tumors: Interim safety and efficacy results from the AURELIO-03 dose escalation trial. Presented at: American Association for Cancer Research Annual Meeting 2022; April 8-13, 2022; New Orleans, LA. Abstract CT040.

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