The information contained in this letter may not completely match the current local labeling for PEMETREXED. Please see local labeling approved in your country. If you require the local labeling, please request it through your Sales Representative.

The KEYNOTE-189 trial demonstrated that the addition of pembrolizumab, a PD-1 antibody, to pemetrexed/platinum chemotherapy resulted in a significantly longer OS and PFS than pemetrexed/platinum chemotherapy alone in patients with untreated, metastatic nonsquamous NSCLC without EGFR or ALK mutations.1 These results are consistent with a positive interaction between these therapeutics.2

Pemetrexed inhibits enzymes in the folate pathway and disrupts cellular processes that are required for cell division. Rapidly dividing cancer cells are the favored targets of pemetrexed.3

The folate pathway is a component of the one-carbon metabolism that plays a critical role during T cell activation. Antifolate treatment like pemetrexed could thus interfere with the one-carbon metabolism and have a detrimental effect on effector T cells in the tumor microenvironment.4,5

Preclinical studies were completed to better understand the effects of pemetrexed on tumor immune microenvironment. The following key questions were evaluated using MC38 or Colon26 murine tumor models.

• Does pemetrexed have immune modulating properties?
• Does pemetrexed induce ICD leading to an immune response against tumors?
• Why and how does pemetrexed work with immunotherapy?2,3

In MC38 syngeneic mouse tumors, pemetrexed monotherapy

• increased frequency of tumor-infiltrating lymphocytes, and
• increased expression of genes associated with the enrichment of
  • macrophages
  • dendritic cells/NK cells
  • T helper cells, and
  • interferon signaling.2
    

Pemetrexed monotherapy showed more differentially expressed genes compared to therapies with paclitaxel, cisplatin or carboplatin monotherapy, and pemetrexed or paclitaxel in combination with carboplatin.2,6

The combination of pemetrexed and anti-PD-L1 improved the antitumor efficacy in MC38 and Colon26 syngeneic mouse tumor models.2 Pathway analysis of gene expression in Colon26 tumors revealed that the combinatorial effect of pemetrexed and anti-PD-L1 was associated with a pronounced inflamed/immune activation phenotype characterized by

• improved antigen presentation
• enhanced T cell signaling and cytokine signaling, and
• engagement of CD4+ T cell-mediated immunity.2

These changes correlated with an upregulation of MHC-I and MHC-II on monocytes, macrophages, and of MHC-II on tumor cells, suggesting increased immune priming. Supporting this, blockade of T cell priming in lymph nodes after initiation of combination therapy resulted in a loss of combination efficacy.2

In both MC38 and Colon26 tumor cells, treatment with pemetrexed induced a robust release of HMGB1 and calreticulin indicative of immunogenic cell death.2

Pemetrexed slightly reduced proliferation of primary human T cells, and led to T cell-intrinsic effects as evidenced by

• enhanced mitochondrial respiratory capacity,
• enhanced oxidative respiration, and
• increased expression of
  • cell surface molecules, and
  • immune-related genes.2

Murine T cells primed in the presence of pemetrexed displayed improved antigen specific in vitro cytotoxic activity.2

ALK = anaplastic lymphoma kinase 

CD4 = cluster of differentiation 4

EGFR = epidermal growth factor receptor

HMGB1 = high mobility group box 1 protein

ICD = immunogenic cell death

IFN-γ = Interferon gamma

IL2 = interleukin 2

MHC = major histocompatibility complex

mTOR = mammalian target of rapamycin

NK cells = Natural Killer cells

NSCLC = non-small cell lung cancer

OS = overall survival

PD-1 = programmed death-1

PD-L1 = programmed death-ligand 1

PFS = progression-free survival

p70S6K = ribosomal protein S6 kinase

STAT = signal transducer and activator of transcription