Therapeutic options for second line metastatic pancreatic ductal adenocarcinoma (PDAC) are limited with FOLFOX or FOLFIRI having mOS of 5-6 months. PDAC has low tumor mutational burden and tumor infiltrating CD8+ T cells are rare, which may explain why immune-oncology approaches to date have been less than promising. Pegilodecakin (AM0010) is a pegylated recombinant human interleukin-10 that stimulates activation, survival and clonal expansion of intra-tumoral, tumor antigen specific CD8+ T cells. Pegilodecakin also up-regulates IFNγ and the expression of MHC, which enables tumor antigen presentation in neoplasias of low mutational burden and promotes immunosurveillance by expanding effector memory T cells (Mumm et al. 2010, 2011). Finally, pegilodecakin reduces tumor inflammatory processes such as angiogenesis and and metastatic dissemination (Oft 2017), the off-target auto-immune side effects of immunotherapy and the inflammatory-related side effects of some chemotherapies, including FOLFOX-induced peripheral neuropathy (Krukowski JNeurosci 2016).
In a 353 patient phase 1/1b dose escalation and expansion study conducted in the US from 2013 to 2017, 21 heavily pretreated metastatic PDAC subjects received pegilodecakin in combination with FOLFOX. Responses were assessed by irRC. CD8 T cell activity was determined by IHC and TCR clonality in the blood.
|Pegilodecakin||N||Prior Therapies||ORR||CR||DCR||mPFS||mOS||One- Year||Two- Year|
|Regimen||E (ITT)2||Median (Range)||(%)||(%)||(%)||(mos)||(mos)3||OS (%)||OS (%)|
|Plus FOLFOX1||19 (21)||2 (1-5)||15.8||10.5||73.7||2.6||10.2||42.9||28.6|
Pegilodecakin 5.0 µg/kg + FOLFOX;2
E (evaluable - baseline tumor assessment + >1 post-baseline assessments, and no major protocol deviations); ITT (intent to treat); All treated/safety population: n = 25; 25 pts were treated with pegilodecakin (5 ug/kg) in combination with FOLFOX. 21 out of 25 pts progressed on prior gemcitabine containing regimen and did not receive prior platinum containing therapy.3
Subjects with OS > 8 mos had 75-250 CD8+ T cells/mm2 in the retreatment tumor and had a clonal expansion of new T cell clones in the blood. Data cut on 05.01.18; Median follow-up 26.4 months (22.0-32.0 months).
Grade 3/4 TrAEs included thromobocytopenia (56%), anemia (44%), neutropenia (36%), leukopenia (12%) and fatigue (12%). Grade 1/2 neuropathy was observed in 16% of patients but no grade 3/4 neuropathy.
Pegilodecakin in combination with FOLFOX is well-tolerated in patients with metastatic PDAC, and has a reduced incidence of FOLFOX related neuropathy. Immune activation and overall survival are encouraging in this advanced PDAC population.
Clinical trial identification
Legal entity responsible for the study
A. Hung, M. Oft, J. Leveque: Employee: ARMO BioSciences. All other authors have declared no conflicts of interest.