In the phase III SEQUOIA trial reported in the Journal of Clinical Oncology, J. Randolph Hecht, MD, and colleagues found that the addition of pegilodecakin—a pegylated recombinant human interleukin (IL)-10—to FOLFOX (leucovorin, fluorouracil [5-FU], and oxaliplatin) did not improve overall survival as a second-line treatment for patients with metastatic pancreatic ductal carcinoma whose disease progressed after treatment with gemcitabine.

Study Details

In the trial, 567 patients from sites in Asia, Europe, and North America who experienced disease progression after one gemcitabine-containing regimen (gemcitabine plus nab-paclitaxel in 95%) were randomly assigned between March 2017 and September 2019 to receive pegilodecakin/FOLFOX (n = 283) or FOLFOX alone (n = 284).

J. Randolph Hecht, MD

Pegilodecakin was given subcutaneously at two fixed doses (0.4 mg in patients weighing ≤ 80 kg, 0.8 mg in those weighing > 80 kg) on days 1 to 5 and 8 to 12, with FOLFOX initiated on day 1 of 14-day cycles for up to 12 cycles or progressive disease; patients were permitted to continue maintenance pegilodecakin therapy at a higher dose after FOLFOX discontinuation in the absence of disease progression. Patients in the FOLFOX group received treatment initiated on day 1 of 14-day cycles for up to 12 cycles or progressive disease. The primary endpoint was overall survival.

Overall Survival

Median follow-up was 15.0 months in the pegilodecakin/FOLFOX group and 14.5 months in the FOLFOX group at data cutoff in September 2019. Median overall survival was 5.78 months in the pegilodecakin/FOLFOX group vs 6.28 months in the FOLFOX group (hazard ratio [HR] = 1.045, 95% confidence interval [CI] = 0.863–1.265, P = .6565), with estimated 1-year rates of 14.7% vs 19.1%. Results in patient subgroups were consistent with those in the overall analysis.

Objective response rates were 4.6% vs 5.6%, with no complete responses being observed.

Median progression-free survival was 2.14 months vs 2.1 months (HR = 0.981, 95% CI = 0.808–1.190, P = .8144). Postprogression therapy was received by 36% vs 42% of patients, with the most commonly used treatments being 5-FU (22% vs 27%) and irinotecan (23% vs 24%).

Exploratory pharmacodynamic analyses showed increases in total interleukin (IL)-18, interferon-γ, and granzyme B, and decreases in transforming growth factor–β with the addition of pegilodecakin—factors consistent with immunostimulatory signals of the IL-10R pathway.

Adverse Events

Grade ≥ 3 adverse events occurred in 88.3% vs 66.9% of patients, with those occurring more frequently in the pegilodecakin/FOLFOX group including thrombocytopenia (25.2% vs 3.6%), anemia (16.2% vs 4.0%), neutropenia (29.5% vs 22.7%), and fatigue (17.6% vs 10.8%). Serious adverse events occurred in 43.2% vs 36.7%, with those occurring more frequently in the pegilodecakin/FOLFOX group being pyrexia (4.7% vs 2.8%), abdominal pain (4.3% vs 2.0%), and sepsis (3.6% vs 1.6%).

The investigators concluded, “Pegilodecakin added to FOLFOX did not improve efficacy in advanced gemcitabine-refractory pancreatic ductal adenocarcinoma. Safety findings were consistent as previously observed from pegilodecakin with chemotherapy; toxicity was manageable and tolerable. Exploratory pharmacodynamic results were consistent with immunostimulatory signals of the IL-10R pathway.”

Dr. Hecht, of the David Geffen School of Medicine at UCLA, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by Eli Lilly and Company. For full disclosures of the study authors, visit ascopubs.org.