A combination of toripalimab, gemcitabine, and nab-paclitaxel (GnP) has shown promising results in patients with advanced pancreatic ductal adenocarcinoma (PDAC), according to a recent phase Ib/II study. The research, published in Nature, highlights the potential of this regimen in improving outcomes for a cancer with limited treatment options.
The study enrolled 72 eligible patients who received at least one cycle of toripalimab in combination with the GnP regimen. At the cut-off date of April 30, 2024, the median follow-up duration was 9.25 months. The primary objective was to evaluate the efficacy and safety of the combination therapy.
Treatment Efficacy
The intent-to-treat (ITT) population (n = 72) was assessed for treatment efficacy. The study reported that 1 patient (1.4%) achieved a complete response (CR), and 23 patients (31.9%) experienced a partial response (PR). Stable disease (SD) was observed in 41 patients (56.9%), while progressive disease (PD) was seen in only 7 patients (9.7%).
The objective response rate (ORR) was 33.3% (24/72), and the disease control rate (DCR) was 90.3% (65/72). The median progression-free survival (PFS) was 5.6 months (95%CI: 4.9–6.8 months), with a 6-month PFS rate of 48.6%. The median overall survival (OS) was 8.9 months (95%CI: 7.3–11.0 months), and the 1-year OS rate was 31.9%. The median duration of response (DoR) was 6.2 months (95%CI: 4.3–9.2 months).
Safety Profile
All patients (n = 72) experienced treatment-related adverse events (TRAEs). The most common TRAEs included anemia (91.7%), hypoproteinemia (77.8%), elevated aspartate aminotransferase (69.4%), and elevated alanine transaminase (66.7%). Grade 3/4 TRAEs occurred in 38 (52.8%) patients, with neutropenia (15.3%) and anemia (13.9%) being the most frequent.
Immune-related adverse events (irAEs) were mainly grade 1/2, with hypothyroidism (58.3%) and rash (36.1%) being the most common. Five cases developed grade 3 irAEs, leading to the discontinuation of toripalimab in these instances. No grade 4 irAEs or treatment-related deaths were observed.
Biomarker Analysis
Next-generation sequencing (NGS) analysis revealed that the most frequent mutations were in KRAS (86%), TP53 (71%), CDKN2A (32%), and SMAD4 (18%). However, these mutations were not significantly correlated with ORR, PFS, or OS.
PD-L1 status was determined in 56 cases, with 42.9% having a PD-L1 CPS ≥ 1 and 28.6% having a CPS ≥ 5. Patients with higher PD-L1 expression (TPS ≥ 5% or CPS ≥ 5) had an ORR of 56.3%, compared to 25.0% in those with lower PD-L1 expression (P = 0.03). However, higher PD-L1 expression did not significantly improve PFS or OS.
Baseline serum IL-8 levels were significantly lower in the response group (P = 0.0035) and in patients who achieved the median OS (≥ 8.9 months). Higher baseline levels of IL-8 predicted worse OS, suggesting its potential as a predictive biomarker.
Tumor Microenvironment Analysis
Cyclic multiplexed Tyramide Signal Amplification (CmTSA) analysis was used to profile 17 proteins in FFPE tissue sections. The analysis identified 16 cell types and their proliferating status, including PD-L1+ tumor cells, PD-L1− tumor cells, lymphoid cells, myeloid cells, and mesenchymal cells.
Spatial clustering analysis identified 10 immune niches (INs) within the TME. IN-3, characterized by a high proportion of fibroblasts, was associated with non-responders. Conversely, IN-8, composed of CTL, M1 macrophages, DCs, and Th, was closely associated with responders.
Further analysis revealed that DCs in responders frequently interacted with CTL, Th, and M1 macrophages, while in non-responders, DCs were more commonly associated with neutrophils, monocytes, and M1 macrophages. This suggests that DCs act as a key intermediary in the IN-8 of responders, facilitating interactions within the DC-CTL-Th-M1 cluster.
Clinical Implications
The study suggests that toripalimab in combination with GnP shows promise in treating advanced PDAC. The identification of IN-8 as a potential predictor for immunotherapy response and the role of DCs in mediating immune interactions highlight potential avenues for optimizing treatment strategies. The finding that baseline serum IL-8 levels could serve as a predictive biomarker warrants further investigation.
These results provide valuable insights into the complex interplay between the tumor microenvironment and treatment response in PDAC, potentially paving the way for more personalized and effective therapies.
