AM0010 Plus FOLFOX Shows Promise in Metastatic Pancreatic Cancer

Joel Randolph Hecht, MD

Combination therapy with AM0010, a PEGylated human interleukein (IL)-10, plus fluorouracil (5-FU), leucovorin, and oxaliplatin (FOLFOX) demonstrated improved immunologic parameters, promising safety findings, and encouraging clinical activity compared with single-agent AM0010 and historic treatment with FOLFOX alone in the second line and beyond in patients with metastatic pancreatic ductal adenocarcinoma (PDAC), according to results reported during the 2017 World Congress on Gastrointestinal Cancer.

The objective response rate (ORR) was 15.8% in patients with PDAC treated with AM0010 plus FOLFOX, which included 2 patients (11%) who achieved a complete response (CR) compared with no responses in patients on AM0010 monotherapy. The disease control rate (DCR) in the respective cohorts was 78.9% versus 53%, median progression-free survival was 3.5 versus 1.7 months, and the median overall survival (OS) was 10.2 versus 3.8 months. The median follow-up with the combination was 11.0 months (range, 5.8-16.3).

Comparatively, the DCR with FOLFOX alone in patients with PDAC was cited as 34%.

The 1-year OS rate was 47% in patients treated with AM0010 and FOLFOX compared to a 1-year OS of 22% in patients receiving AM0010 monotherapy.

“Pancreatic cancer has just become the third leading cause of cancer death in the United States,” said lead author Joel Randolph Hecht, MD, professor of clinical medicine, David Geffen School of Medicine, University of California, Los Angeles (UCLA), and director, UCLA Gastrointestinal Oncology Program. “The benefit of adding nal-irinotecan or oxaliplatin to 5-FU in second-line therapy for PDAC is relatively small. In addition, PDAC has been refractory to immune therapies; clearly, new treatment approaches are needed.”

IL-10 at low concentrations is anti-inflammatory, but at high concentrations IL-10 stimulates the proliferation and cytotoxicity of tumor infiltrating CD8-positive T cells, leading to both a systemic and intratumoral increase of effector T cells, according to Hecht.

“AM0010 has demonstrated single-agent activity in renal cell carcinoma and 22.5% of salvage PDAC patients achieved 1-year survival with AM0010 monotherapy,” said Hecht. Since oxaliplatin has demonstrated the ability to induce immunogenic tumor cell death, Hecht and colleagues considered pairing AM0010 with an oxaliplatin-containing regimen.

The investigators conducted this phase Ib trial comparing AM0010 at 20 μg/kg monotherapy in patients with advanced pancreatic cancer to 5 mg/kg of AM0010 plus FOLFOX in 25 patients, with 19 patients evaluable for tumor response, and 21 for OS in the combination arm. The majority of patients were male and had a median age of 62 and 66 years in the respective cohorts.

Although the patients had been heavily pretreated and had received up to 6 lines of prior treatment, patients receiving prior immune checkpoint inhibitors were ineligible. Patients with autoimmune disease could be enrolled, excepting those with Guillain-Barré syndrome or neuro-inflammatory disease. Tumor responses were measured according to immune-related response criteria.

Patients receiving AM0010 plus FOLFOX showed a sharp reduction in CA19-9 levels; 75% of 12 patients with evaluable CA19-9 showed a reduction. Patients on AM0010 monotherapy also showed a reduction; of 12 patients with evaluable CA19-9, 66.7% of patients showed reduced levels.

“The success and the durability of immunotherapy in immune sensitive indications is thought to depend on the activation and expansion of intratumoral, tumor specific cytotoxic CD8-positive T cells which are very low in the majority of cases of PDAC,” Hecht explained.

AM0010 and FOLFOX had an acceptable tolerability profile and the treatment was tolerated on continuous dosing without autoimmune adverse events (AEs). Grade 3/4 AEs included anemia, which occurred in 40% of patients, and thrombocytopenia in 52%. Both were reversible and resolved within 2 or 3 days off the dosing schedule. “AM0010 plus FOLFOX also led to increased Th1 and Th2 cytokines in the serum and a reduction of the immune suppressive molecule TGFb as well as Th17 cytokines,” noted Hecht.

“These encouraging results support the ongoing phase III pivotal study of FOLFOX with and without AM0010 as second-line in patients with pancreatic adenocarcinoma,” he commented.

Hecht JR, Naing A, Falchook G, et al. Immunologic and objective tumor responses to PEGylated human IL-10 (AM0010) with 5-FU/LV and oxaliplatin (FOLFOX) in metastatic pancreatic adenocarcinoma (PDAC). Ann Oncol. 2017;28(suppl 3). doi: 10.1093/annonc/mdx262.003.

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Combination AM0010/FOLFOX induced expansion of T-cell clones; furthermore, the level of pretreatment intratumoral T cells were found to correlate with OS (P = .012).