Responses in NSCLC to agents targeting the PD-1/PD-L1 axis are correlated with PD-L1 expression by immunohistochemistry (IHC), tumor mutational burden (TMB), interferon associated mRNA Expression Profile (GEP) and the absence of liver metastases. 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.
In a 353 patient phase 1/1b dose escalation and expansion study, 34 pretreated NSCLC subjects received pegilodecakin with pembrolizumab or nivolumab. Responses were assessed by irRC. PD-L1 was tested with the 22C3 IHC assay, TMB by whole exome sequencing and pre-treatment GEP by Nanostring.
Pegilodecakin when added to anti-PD-1 therapy in advanced NSCLC patients was associated with response rates and durability of benefit greater than has been seen with anti-PD-1 alone. Responses were seen in settings in which anti-PD-1 therapy has demonstrated limited benefit, such as absent PD-L1 expression, low TMB and/or the presence of liver metastasis. These preliminary findings support further studies of pegilodecakin with anti-PD-1 therapies.Table: 1144P
|Regimen||E (ITT)10||Median (Range)||%||%||mos||mos||All Grades (%)||Grades 3 & 4 (%)|
|Plus Pembrolizumab2||5 (5)||2 (0-5)||40.0||100||11.0||32.2|
|Plus Nivolumab3||22 (29)||2 (0-5)||41.0||82.0||7.4||NR|
|Pooled Plus Anti-PD-14||27 (34)||2 (0-5)||41.0||85.0||8.9||NR||14.7||5.9|
10-20µg/kg QD SC;2
2mg/kg, q3wk IV;3
3mg/kg, q2wk IV;4
pembrolizumab and nivolumab cohorts combined;5
TMB High (tumor mutational burden high) >243 mut/exome;9
TMB Low (tumor mutational burden low) <243 mut/exome;10
E (evaluable - baseline tumor assessment + >1 post-baseline assessments, and no major protocol deviations); ITT (intent to treat);11
irAE - Immune-Related Adverse Events (e.g. pneumonitis, adrenal insufficiency, thyroiditis, hypothyroiditis, hypophysitis, mucositis/stomatis, colitis, hepatitis, cholangitis, polyarthritis, myasthenia gravis, optic neuritis); Data cut on 05.01.18; Median follow-up for pembrolizumab cohort 37.3 months (35.9-39.1 months); Median follow-up for nivolumab cohort 23.2 months (9.1-32.0 months)
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.