E212: Treatment with anti-Semaphorin4D To Modulate Response of Pancreatic Adenocarcinoma to Immunotherapy

Pancreatic adenocarcinoma (PDAC) is a leading cause of cancer-related mortality with poor prognosis despite maximal therapy and is unresponsive to immune checkpoint blockade (ICB). In PDAC, Semaphorin 4D (SEMA4D) expression is prognostic in patients who have undergone surgical resection and correlates with tumor infiltration of activated CD8+ T-cells. Additionally, preclinical mouse models of PDAC suggest that antibody-mediated SEMA4D blockade promotes tumoral infiltration and activation of CD8+T cells and sensitizes PDAC to ICB, with improved overall survival with standard of care chemotherapy and ICB in combination with SEMA4D blocking antibody. Thus, we hypothesized that pepinemab (humanized antiSEMA4D antibody) may improve clinical outcomes in PDAC by sensitizing tumors to ICB.

Methods:

We designed a phase Ib/II single-arm clinical trial to evaluate the safety, tolerability, and efficacy of pepinemab with anti-PD-L1 (avelumab) in patients with chemotherapy-refractory PDAC (NCT05102721). Phase 1 follows a dose de-escalation schema and targets a dose-limiting toxicity rate of 30% or less. Expansion to phase 2 occurs after enrollment of 16 subjects if 2 or more subjects demonstrate response. Treatment response is assessed via RECIST 1.1 criteria with surveillance CT prior to enrollment and after 8 weeks of treatment. Baseline and on-treatment tumor biopsies are performed to analyze changes in immune, stromal, and genomic profiles to elucidate mechanisms of treatment response and failure. Patient reported outcomes are incorporated (FACT-Hep and FAACT subdomains) to assess disease-specific symptoms.

Results:

A total of 8 patients have been enrolled to date. One subject withdrew prior to completing the evaluable period (8 weeks of treatment) and five subjects terminated treatment due to disease progression. Two subjects continue to receive combination treatment pending evaluation of tumor response. Baseline and on-treatment biopsies have been obtained and stored for correlative analysis from 4 of 4 evaluable subjects. No treatment-related toxicities have been encountered.

Conclusions:

Combining pepinemab with avelumab appears to be safe and tolerable to date. Five patients demonstrated disease progression, though 1 of these 5 demonstrated mixed response with some lesions showing radiologic partial and even complete response. Overall treatment response, survival data, and correlative science will be forthcoming.