Sotigalimab Plus Pembrolizumab Elicits Broad Immune Activity in Metastatic Melanoma

The combination of the CD40 agonist antibody sotigalimab and pembrolizumab demonstrated a favorable safety profile and led to immunologic changes that correlated with clinical response in patients with unresectable stage III or IV metastatic melanoma.

Salah-Eddine Bentebibel, PhD

Salah-Eddine Bentebibel, PhD

The combination of the CD40 agonist antibody sotigalimab (APX005M) and pembrolizumab (Keytruda) demonstrated a favorable safety profile and led to immunologic changes that correlated with clinical response in patients with unresectable stage III or IV metastatic melanoma, according to findings from a phase 1/2 trial (NCT02706353) presented during the 2022 AACR Annual Meeting.

Further, investigators identified broad immune activity in both local and distant lesions through biomarker analysis.

In addition to evaluating the safety of sotigalimab, investigators determined the maximum tolerated dose, the recommended phase 2 dose (RP2D), and objective response rate (ORR).

Among the total evaluable patients (n = 30), the ORR was 50% and was comprised of complete (17%) and partial responses (33%). Seventeen percent reported stable disease and 33% reported disease progression. The disease control rate was 67% and the response rate at the RP2D was 55%, said Bentebibel. Responses were also seen across PD-L1 and lactate dehydrogenase (LDH) levels.

By the data cutoff of December 30, 2021, 30 patients had been enrolled, said lead author Salah-Eddine Bentebibel, PhD. In the phase 1 portion of the study, 14 patients who were immune checkpoint inhibitor–naïve received an initial dose of intratumoral sotigalimab (0.1 mg) and intravenous pembrolizumab (2.0 mg/kg). This was followed by 4 increasing doses of sotigalimab at 0.5 mg, 1.0 mg, 3.0 mg, and 10 mg. Pembrolizumab was administered at 2.0 mg/kg across the escalation.

At the conclusion of phase 1, it was determined that the RP2D should be sotigalimab at 10 mg and pembrolizumab at 2 mg/kg. The phase 2 portion of the study is underway and will seek to enroll approximately 20 patients.

Investigators had hypothesized that sotigalimab could harness the CD40 pathway and activate innate and adaptive immunity. This is especially important because “many patients do not respond to [checkpoint inhibitor] therapy or develop resistance after initial tumor regressions, and new combinations are needed to improve the benefit risk profiles,” Bentebibel, an instructor in the Department of Melanoma Medical Oncology–Research at The University of Texas MD Anderson Cancer Center in Houston, Texas, said during the presentation of the data.

The majority of patients were male (n = 26; 87%) and were a median age of 65 years (range, 32-81). ECOG performance status was either 0 (57%) or 1 (43%). Fifty-seven percent had stage IV disease and 54% were BRAF negative. Most patients (47%) had low LDH levels but 30% had very high LDH levels. PD-L1 status was unknown or negative in 37% of patients, respectively, and 8 patients (27%) were PD-L1 positive.

Biomarker analysis was conducted using blood and tumor samples obtained from local and distant lesions at baseline and at 24 hours post sotigalimab. Upregulation of genes and CD40 activation were noted by the investigators. “We saw robust upregulation of genes associated with antigen-presenting cells [APCs] and also engagement of MAP kinase and nuclear factor ĸB, a regulator of innate immunity,” Bentebibel said. In addition to the early time points of upregulated APCs, the investigators also reported T-cell response at later time points. “So [taken] together, these data suggest that sotigalimab engages the CD40 pathway,” Bentebibel said.

Further immune activity observed included an increase in macrophage, T cells, CD8+ T, and cytotoxic gene signatures in responding patients and the combination resulted in an increase in T-cell infiltration and clonality in local and distant lesions.

Regarding safety, investigators reported zero study discontinuations or death due to treatment-related adverse events (TRAEs). The most common TRAEs were injection-site reactions and 6 patients (20%) reported grade 3 immune-related AEs. Zero dose-limiting toxicities were observed for any dose level of sotigalimab.

Investigators concluded that the combination of sotigalimab and pembrolizumab showed encouraging antitumor activity and that the combination could induce immune activity in both local and distant lesions.


  1. Bentebibel S-E, Johnson D, Amariae R, et al. Intratumoral CD40 agonist sotigalimab with pembrolizumab induces broad innate and adaptive immune activation in local and distant tumors in metastatic melanoma. Presented at: American Association for Cancer Research Annual Meeting; April 8-13, 2022; New Orleans, LA. Abstract CT039. Abstract CT039.
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