Paul Eliezer Oberstein

Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal malignancy and has long been regarded as a therapeutic “drug graveyard,” with modest gains from cytotoxic combination chemotherapy and numerous novel agents failing to show benefit in clinical trials. The quest to directly target RAS has moved from concept to reality with the Food and Drug Administration (FDA) approval of daraxonrasib (Rasonque) for adults with metastatic PDAC who have received at least one prior systemic therapy or are not candidates for multiagent systemic therapy. In this review, we discuss a wave of clinical trials that are poised to change this narrative and usher in the era of RAS-targeted therapy. Given the flood of compounds and combinations, we focus on therapies that have advanced to phase III clinical trials. Collectively, these studies demonstrate how RAS-targeted therapies are poised to transform the PDAC treatment landscape. The current generation of trials will determine whether these emerging strategies can translate into durable survival gains and turn PDAC from a “drug graveyard” into a drug haven for novel therapies.

Supplemental Figure 3: Presence of canakinumab does not interfere with the ability to detect IL-1b in patient serum. Baseline serum from three randomly selected patients with pancreatic ductal adenocarcinoma was evaluated by cytokine bead array for IL-1b. For each patient sample, canakinumab was spiked in at the indicated concentrations. Note that measured IL-1b values were consistent across all samples from the same patient, regardless of the presence of canakinumab.

Supplemental Figure 6. Cell populations identified by transcriptional profiling from tumor biopsies. (A) UMAP of all cells in the dataset, colored by cluster. (B-C) Relative expression of representative genes of the six major compartments across the full dataset. (D) Relative expression of IL1B, IL1R1, PDCD1, PDCDLG1, and PDCDLG2 across the full dataset. (E) The percent of each myeloid cluster that is found in each of the samples, separated into baseline and treated subgroups (Wilcoxon rank-sum test).

Supplemental Figure 7: Macrophage subtypes are unaffected by treatment in patients in SR-1. (A) Baseline and on-treatment biopsies from patients (n = 6 paired samples) in the SR-1 trial were analyzed by multiplex immunofluorescence using the indicated antibodies. Representative image of the macrophage panel is shown. (B) Densities of total macrophages (CD68+ or CD163+ cells). (C) Densities of M1 polarized macrophages (CD86+IRF5+). (D) Densities of M2 polarized macrophages (CD206+CD163+).

Supplemental Figure 2: Pharmacokinetics of canakinumab. Serum levels of canakinumab were measured in patients on SR-1 at the indicated time points.

Supplemental Figure 1: Progression-free survival for SR-1, an open-label multicenter phase Ib study evaluating gemcitabine, n(ab)-paclitaxel, canakinumab and spartalizumab in advanced pancreatic ductal adenocarcinoma. A) PFS for the 10 patients in SR-1 is shown. B) OS for the 10 patients in SR-1 is shown. C) PFS for the 11 patients in the GnP cohort is shown.

Supplemental Table 2: Patient sample information and types of experimental data collected from each patient.

Supplemental Table 3: Serum samples from baseline and on-treatment time points from patients in SR-1, the standard of care cohort, and healthy people who donated blood 28 days apart were analyzed by cytokine bead array. Significance was determined by Wilcoxon matched-pairs signed rank test.

Supplemental Table 1: Selected Adverse Events reported in ≥5 subjects (any grade) or ≥3 subjects for Grade 3 from patients in SR-1. Select immune-related adverse events are also shown.