Sotigalimab/Pembrolizumab Combo Continues to Show Clinical Activity in Frontline Melanoma

Salah-Eddine Bentebibel, PhD

The combination of sotigalimab (APX005M) and pembrolizumab (Keytruda) showed encouraging antitumor activity and was well tolerated in the frontline setting of patients with metastatic melanoma, according to updated phase 1/2 findings presented during the 2022 SITC Annual Meeting.¹

Sotigalimab is defined as a humanized IgG1 monoclonal antibody against human CD40.

As of October 28, 2022, the overall response rate (ORR) by RECIST 1.1 criteria among 32 patients on the study (NCT02706353) was 47%, which consisted of a 16% complete response rate and a 31% partial response rate; the stable disease rate was 22% and 31% of patients had progressive disease. The disease control rate was 69%.

The ORR at the recommended phase 2 dose (RP2D) of 10 mg sotigalimab was 50%.

“[The combination] showed oncologic activity, and from our biomarker analysis we demonstrated that the combination of sotigalimab with pembrolizumab can induce broad innate and adaptive immune activation in both local and distant lesions,” lead study author Salah-Eddine Bentebibel, PhD, of the Department of Melanoma Medical Oncology, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center (MD Anderson), said in a presentation.

“Biomarker analysis demonstrates that the combination of sotigalimab with pembrolizumab can induce broad innate and adaptive immune activation in both local and distant lesions.”

Intratumoral immunotherapy operates on the principal of using the tumor as its own vaccine; local intratumoral injection of immunostimulatory agents is designed to trigger tumor-specific immunity. This leads to distant effects of systemic antitumor immunity against non-injected tumor sites.

Although immune checkpoint inhibitors are an important modality for the treatment of patients with metastatic melanoma, physicians need new combinations to improve benefit-risk profiles. Adi Diab, MD, the study’s principal investigator and an associate professor in the Department of Melanoma Medical Oncology at MD Anderson, explained that many patients are unresponsive to immune checkpoint inhibitors or develop resistance after initial tumor regression.

“Results from the ongoing Phase 2 trial of intratumoral sotigalimab and the PD-1 inhibitor pembrolizumab showed a promising ORR including responses achieved in PD-L1–negative tumors,” he said in a news release.² “Moreover, this encouraging anti-tumor activity correlated with treatment-induced immunologic changes, such as activated myeloid dendritic cells and macrophages, which support the mechanism of action and differentiated activity of sotigalimab—ultimately leading to inflammatory immune responses in the local injected tumor as well as distant non-injected lesions.”

In the phase 1/2 dose-escalation/dose-expansion study, investigators assessed the safety and tolerability of sotigalimab plus pembrolizumab in the frontline setting of patients with metastatic melanoma. The primary end point was maximum-tolerated dose and RP2D; additional outcome measures were ORR by RECIST 1.1 criteria and biomarker assessment in blood and tumor samples.

To be eligible for enrollment, patients had histologically or cytologically confirmed cutaneous or mucosal stage III/IV melanoma that was measurable and unresectable. Patients had to have an ECOG performance status of 0 or 1, adequate organ function, and fresh biopsy and archival tissue.

The phase 1 dose-escalation portion (n = 14) included checkpoint inhibitor–naïve patients who received intravenous pembrolizumab at 2 mg/kg plus sotigalimab at 0.1 mg, followed by increasing doses of sotigalimab at 0.5 mg, 1 mg, 3 mg, and 10 mg. Sotigalimab was given every 3 weeks for a total of 4 injections.

The RP2D was sotigalimab was at 10 mg, which was used in the phase 2 portion (n = 18).

In the total population of 32 patients, 84% were male, the median age was 64.5 years (range, 32-81), and 44% of patients had an ECOG performance status of 1. Thirty-four percent of patients had BRAF-positive disease, lactate dehydrogenase (LDH) levels at baseline were below the upper limit of normal in half of patients, and 25% of patients had PD-L1­–positive disease. Fifty-three percent of patients had stage IV M1a or M1b disease, 22% had stage MI1c disease, and 25% had stage III disease.

Additional findings showed that clinical responses were reported in both PD-L1–negative tumors and patients with elevated LDH.

Safety data demonstrated that the combination is well tolerated, Bentebibel said, adding that there were no study discontinuations or deaths due to treatment-related adverse events (TRAEs). The most common TRAEs were injection-site reactions, and 18% of patients (n = 6) had grade 3 immune-related adverse events. No dose-limiting toxicities were reported at any of the dose levels, and no dose-limiting toxicities were needed.

Through NanoString gene expression, investigators noted that sotigalimab engaged CD40 activation, macrophage activation, and up-regulation of genes that was associated with antigen-presenting cells. Additionally, it was found that pre-existing interferon-gamma mediated immune activation in baseline tumor tissue did not correlate with response to the combination regimen.

Bentebibel also pointed out that patients who did respond to pembrolizumab plus sotigalimab appeared to have high pre-existing CD11c⁺ myeloid cells and CD11c⁺DC-LAMP⁺ DC cells. Furthermore, the combination also activates the DC and increases macrophage signature in both local and distant tumors.

Finally, patients who responded to treatment experienced an on-treatment increase in CD8⁺ T, cytotoxic, and Th1 scores in the tumor, as well as an increase in CD8⁺ T-cell proliferation. Bentebibel also noted that, through T-cell receptor sequencing in tumor samples, the combination can lead to an increase in T-cell infiltration and clonality, as well a new clone expansion shared between local and distal lesions.

Data from a phase 2 trial (NCT03123783) presented during the 2021 SITC Annual Meeting showed that the combination of sotigalimab plus the PD-1 inhibitor nivolumab (Opdivo) elicited durable responses with a reasonable safety profile in patients with melanoma who were refractory to anti–PD-1 therapy.³ The ORR was 15.2% (95% CI, 6.2%-29.3%) among 33 evaluable patients; this included a partial response (PR) rate of 15.2% and a stable disease rate of 33.3%.

References

1. Bentebibel S-E. Intatumoral sotigalimab with pembrolizumab activates antigen-presenting cells and induces local and distant anti-tumor responses in first-line metastatic melanoma: results of a phase I/II study. Presented at: 2022 SITC Annual Meeting; November 8-12, 2022; Boston, MA. Abstract 782.
2. Apexigen announces new data from a phase 1/2 trial evaluating its CD40 antibody, sotigalimab, in combination with pembrolizumab in patients with first-line metastatic melanoma at the SITC 2022 Annual Meeting. News release. November 11, 2022. Accessed November 16, 2022. https://bit.ly/3EBf2H7
3. Weiss SA, Sznol M, Shaheen M, et al. Phase II of CD40 agonistic antibody sotigalimab (APX005M) in combination with nivolumab in subjects with metastatic melanoma with confirmed disease progression on anti-PD-1 therapy. J Immunother Cancer. 2021;9. doi:10.1136/jitc-2021-SITC2021.389