Randomized Phase III Study of FOLFOX Alone or With Pegilodecakin as Second-Line Therapy in Patients With Metastatic Pancreatic Cancer That Progressed After Gemcitabine (SEQUOIA)

Abstract

Purpose: SEQUOIA compared efficacy and safety of adding pegilodecakin (PEG), a pegylated recombinant human interleukin (IL)-10, with folinic acid, fluorouracil, and oxaliplatin (FOLFOX) in patients following progression on first-line gemcitabine-containing therapy with metastatic pancreatic ductal adenocarcinoma (PDAC).

Patients and methods: SEQUOIA, a randomized, global phase III study, compared FOLFOX with PEG + FOLFOX as second line in gemcitabine-refractory PDAC. Patients were randomly assigned 1:1 (PEG + FOLFOX:FOLFOX) and stratified by prior gemcitabine and region. Eligible patients had only one prior gemcitabine-containing treatment. Primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), response evaluation per Response Evaluation Criteria in Solid Tumor (RECIST) 1.1, and safety. Exploratory analyses included biomarkers related to immune activation.

Results: Between March 1, 2017, and September 9, 2019, 567 patients were randomly assigned PEG + FOLFOX (n = 283) or FOLFOX (n = 284). Most (94.7%) patients received prior gemcitabine plus nab paclitaxel. OS was similar comparing PEG + FOLFOX versus FOLFOX (median: 5.8 v 6.3 months; hazard ratio = 1.045; 95% CI, 0.863 to 1.265). Also, PFS (median 2.1 v 2.1 months; hazard ratio = 0.981; 95% CI, 0.808 to 1.190) and objective response rate (4.6% v 5.6%) were similar between the treatment arms. Most common (≥ 35%) treatment-emergent adverse events in PEG + FOLFOX versus FOLFOX were thrombocytopenia (55% v 20%), anemia (40% v 16%), fatigue (61% v 45%), neutropenia (39% v 28%), abdominal pain (37% v 29%), nausea (45% v 41%), neuropathy (37% v 38%), and decreased appetite (35% v 31%). Exploratory analyses revealed increases in total IL-18, interferon (IFN)-γ, and granzyme B and decreases in transforming growth factor (TGF)-β with the addition of PEG.

Conclusion: PEG added to FOLFOX did not improve efficacy in advanced gemcitabine-refractory PDAC. Safety findings were consistent as previously observed from PEG with chemotherapy; toxicity was manageable and tolerable. Exploratory pharmacodynamic results were consistent with immunostimulatory signals of the IL-10R pathway.

Trial registration: ClinicalTrials.gov NCT02923921.

Figures

FIG 1.

CONSORT diagram. This profile of the SEQUOIA trial depicts the schema of the trial including random assignment and patient disposition. Thirty-six of 40 patients who received maintenance therapy had received 12 cycles of FOLFOX treatment (all components or partial components). The remaining four patients received 5, 9, 10, and 11 cycles of FOLFOX treatment, respectively. AE, adverse event; FOLFOX, folinic acid, fluorouracil, and oxaliplatin; PD, progressive disease.

FIG 2.

OS and PFS. (A) Kaplan-Meier plot compares OS in the ITT population between patients who received FOLFOX and patients who were provided FOLFOX with PEG. (B) Kaplan-Meier plot compares progression-free survival between patients who received FOLFOX and patients who were provided FOLFOX with PEG. FOLFOX, folinic acid, fluorouracil, and oxaliplatin; ITT, intent-to-treat; OS, overall survival; PEG, pegilodecakin; PFS, progression-free survival.

FIG 3.

Prespecified subgroup analysis for OS. The forest plot depicts the different stratification factors used for OS subgroup analyses. CA 19-9, carbohydrate antigen 19-9; ECOG, Eastern Cooperative Oncology Group; FOLFOX, folinic acid, fluorouracil, and oxaliplatin; OS, overall survival; ULN, upper limit of normal.

FIG 4.

Cytokine expression. The boxplots depict the level of expression of the given cytokine at baseline, cycle 1 day 13 (C1D13), cycle 2 day 13 (C2D13), and cycle 4 day 13 (C4D13) for the control arm, FOLFOX, in gray and the experimental arm, PEG + FOLFOX, in red. Dots represent an individual patient sample, and the median is plotted for each category as the horizontal line on the bar and is listed below the figure. Circulating levels of granzyme B (A), IFNγ (B), IL-18 (C), and TGFβ (D) are shown. FOLFOX, folinic acid, fluorouracil, and oxaliplatin; IFN, interferon; IL, interleukin; PEG, pegilodecakin; TGF, transforming growth factor.

FIG A1.

Kaplan Meier plot demonstrates no significant association between survival probability and pegilodecakin concentration (A) or exposure at steady state (B). FOLFOX, folinic acid, fluorouracil, and oxaliplatin; PEG, pegilodecakin.

FIG A2.

Kaplan-Meier plots of overall survival (A) and progression-free survival (B) for ITT population and Cytokine TR populations. ITT, intention to treat; OS, overall survival; PEG, pegilodecakin; PFS, progression-free survival; TR, translational research.

FIG A3.

Fold change in IL-18 expression is depicted for 214 patients in relationship to OS (A) and PFS (B). FOLFOX, folinic acid, fluorouracil, and oxaliplatin; IL, interleukin; OS, overall survival; PEG, pegilodecakin; PFS, progression-free survival.

FIG A4.

Baseline IL-18 expression is plotted for 294 patients in relationship to OS (A) and PFS (B). FOLFOX, folinic acid, fluorouracil, and oxaliplatin; IL, interleukin; OS, overall survival; PEG, pegilodecakin; PFS, progression-free survival.

FIG A5.

The level of Cmin was analyzed in relationship to newly-detectable T-cell clonal receptor clones in patients treated with pegilodecakin + FOLFOX (N = 36) or FOLFOX (N = 10) at cycle 2 day 13. Dose of 0.4 mg is indicated by circles and 0.8 mg is indicated by triangles. Cmin, pegilodecakin concentration; FOLFOX, folinic acid, fluorouracil, and oxaliplatin.

FIG A6.

The number of copies of the T-cell receptor amino acid sequence was evaluated in order to assess the number of copies of that T-cell clone in a given patient. The frequency of each amino acid sequence was compared between samples on treatment, end of treatment, and baseline. Clones were considered newly-detectable if not detected at baseline, but detected after treatment initiation. (A) The newly-detectable T-cell clones in patient samples were analyzed at baseline, C2D13, C4D13, and EOT comparing between the control arm (FOLFOX) and the experimental arm (PEG + FOLFOX). Wilcoxon tests were used for each group of data. (B) Newly-detectable T-cell clones were assessed in relationship to best clinical response of PR (blue), SD (red), or PD (green). One patient on both treatment arms was NE (orange). Wilcoxon test of SD versus PD patients in the experimental arm; no comparisons were statistically significant. The experimental arm (PEG + FOLFOX; red) and the control arm (FOLFOX; blue) were split into two groups by level of newly-detectable clone counts (“high” [solid line] and “low” [dashed line] in respect to the median) and plotted in relationship to progression-free survival (C) and overall survival (D) at C2D13. C2D13, cycle 2 day 13; C4D13, cycle 4 day 13; EOT, end of treatment; FOLFOX, folinic acid, fluorouracil, and oxaliplatin; NE, not evaluable; PD, progressive disease; PEG, pegilodecakin; PR, partial response; SD, stable disease.