Pancreatic ductal adenocarcinoma (PDAC) remains a highly aggressive malignancy with limited treatment options. Recent advancements in bispecific antibodies and immune checkpoint inhibitors present promising therapeutic strategies to enhance treatment outcomes. This article reviews key findings from the latest research on monoclonal antibodies, bispecific antibodies, and novel immune modulators in PDAC therapy, as presented by Dr. Eileen M. O'Reilly at the ASCO GI conference.Monoclonal Antibodies in PDAC
Monoclonal antibodies targeting key oncogenic pathways have shown potential in PDAC treatment. Late-stage trials combining monoclonal antibodies with chemotherapy have demonstrated varied efficacy. In the GLEAN Phase II trial, Zolbetuximab targeting Claudin 18.2 combined with Gemcitabine and Nab-Paclitaxel showed an overall survival (OS) improvement from 10.5 months to 15.0 months (HR ~0.7). Mitazalimab, a CD40 agonist, when combined with mFOLFIRINOX, demonstrated a response rate (RR) of 40%, median duration of response (DoR) of 12.5 months, median progression-free survival (mPFS) of 7.7 months, and median overall survival (mOS) of 14.3 months.
Bispecific Antibodies in PDAC
Bispecific antibodies represent an innovative approach by targeting two different antigens, enhancing immune system activation, and improving tumor specificity. Zenocutuzumab, a bispecific antibody targeting HER2 and HER3, was particularly effective in NRG1 fusion-positive PDAC. In a cohort of 33 patients, it achieved an objective response rate (ORR) of 42% (39% partial response, 3% complete response), tumor reduction of 82%, and a median duration of response of 9.1 months. FDA approval is expected by December 2024.
IBI389, which targets CD3 and Claudin 18.2, demonstrated promising results in Phase I advanced PDAC (N=72). The recommended Phase II dose (RP2D) was 600 µg/kg. In patients with IHC 2/3+ ≥10% (N=27), the response rate was 29.6%, while in those with IHC 2/3+ ≥40% (N=18), the response rate reached 38.9%.
PT886, a bispecific antibody targeting CD47 and Claudin 18.2, is in Phase I/II trials for locally advanced (LA) and metastatic PDAC, as well as esophagogastric cancers. It has received fast-track orphan drug designation for PDAC in 2024.
IMM2510, targeting PD-L1 and VEGF, demonstrated anti-tumor activity in a Phase I dose-escalation trial (RP2D: 20 mg/kg). In NSCLC squamous and thymic carcinoma patients, three partial responses (PRs) were observed.
Challenges and Resistance Mechanisms
Despite their potential, bispecific antibodies face several challenges. Loss of target antigen expression, MHC-1 loss impairing interferon-gamma signaling, anti-drug antibodies neutralizing bispecific Abs, and toxicity concerns all contribute to limiting their effectiveness.
Novel Immune Checkpoint Inhibitors
Immune checkpoint inhibitors have had limited success in PDAC due to the immunosuppressive tumor microenvironment. However, novel strategies are emerging. Botensilimab, a humanized anti-CTLA-4 IgG1 antibody, enhances the immunologic synapse and T cell priming while depleting regulatory T cells. When combined with balstilimab (PD-1 inhibitor) in MSS CRC 2L/3L patients, a Phase I trial (N=70) showed a response rate of 23%, while a Phase II neoadjuvant rectal trial (NEST-1; N=12) observed six pathological responses and two complete pathological responses (pCRs).
In a FOLFIRINOX-pretreated second-line setting, Gemcitabine/Nab-Paclitaxel + Botensilimab (150 mg) achieved an anti-tumor response in 5 out of 7 patients with liver metastases (2 partial responses, 2 stable disease cases).
Conclusion
The integration of bispecific antibodies and novel immune checkpoint inhibitors marks a significant advancement in PDAC therapy. Clinical trials are providing promising data on improved survival rates and response rates. Zenocutuzumab, IBI389, PT886, and IMM2510 show encouraging efficacy in targeted PDAC populations. While challenges remain, ongoing research into optimizing patient selection, overcoming resistance mechanisms, and refining combination strategies may revolutionize PDAC treatment in the near future.
