New PDL1 Inhibitors for Non-small Cell Lung Cancer: Focus on Pembrolizumab

Abstract: The advent of immune-checkpoint inhibitors during the past decade represents a major advancement in the treatment of non-small cell lung cancer (NSCLC) with personalized treatment. Platinum-based chemotherapy has reached its efficacy threshold, with its use remaining limited by its toxicity. For NSCLC, inhibitors of the PD1 protein and its ligand PDL1 show promising clinical activity and induce durable responses in patients with advanced disease. The US Food and Drug Administration has approved pembrolizumab for treatment-naïve metastatic NSCLC with ≥50% of tumor cells expressing PDL1 and for metastatic NSCLC with ≥1% PDL1 expression after progression following first-line platinum-based doublet chemotherapy. In 2017, it also authorized the first-line combination of pembrolizumab and carboplatin–pemetrexed chemotherapy without selection based on PDL1 expression, but European health authorities are still waiting for the results of a Phase III trial. In this review, the clinical results of published and ongoing studies evaluating pembrolizumab for advanced NSCLC are analyzed and the potential role of PDL1 as a factor predictive of overall responses addressed.

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Keywords: pembrolizumab, immune-checkpoint inhibitor, NSCLC, PDL1 

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INTRODUCTION

Lung cancer is a major public health problem, with an estimated 1.8 million new cases worldwide in 2012, representing 12.9% of new cancers and 19.4% of cancer-attributable deaths.^1,2 Non-small cell lung cancer (NSCLC) represents 85% of lung cancer.^1,3 NSCLC prognosis is mediocre, with 5-year overall survival (OS) <15%, and until recently, therapeutic options beyond first-line treatment remained limited for patients.^4–7

In the early 2000s, the management of NSCLC patients was based on a combination of platinum and third-generation chemotherapy (pemetrexed, gemcitabine, and paclitaxel), with OS lasting about 12 months. The arrival of targeted therapies has transformed management for some patients (~15%), but the majority of patients cannot benefit from these treatments. The addition of bevacizumab to chemotherapy and maintenance strategies has resulted in a life gain of a few weeks for eligible patients. Despite these therapeutic advances, most patients with advanced or metastatic NSCLC received the same chemotherapy in 2015 as in 2005. Results of several recent studies initially revealed the potential of second-line immune-checkpoint inhibitors (ICIs) for these patients and even as first-line therapy.^8–13 Herein, we review clinical trial results and try to discern where pembrolizumab (Keytruda; Merck, Kenilworth, NJ, USA) fits best in the management of metastatic NSCLC.

IMMUNE CHECKPOINTS IN CANCER

The immune system has long been considered a key actor in the surveillance and rejection of malignant tumors.^14–16 Cancer cells generally have genetic and/or epigenetic alterations that can lead to the synthesis of neoantigens recognizable as “nonself” by the host’s immune system. However, its responses can be limited by numerous immunosuppression mechanisms that render antitumor immunity ineffective.¹⁵ Diverse mechanisms have been described in the literature, notably negative regulation of antigen presentation; autoimmunization, which is T-lymphocyte recognition of specific tumor antigens that leads to the proliferation of clones deprived of immunodominant antigens; induction of self-tolerance, meaning that T lymphocytes are unable to kill tumor cells expressing the antigen; and finally, positive regulation of the immune control points (checkpoints) in the peritumoral microenvironment.^17,18

ICIs are intended to block immune-system control points, with the goal of inducing the proliferation of immune cells and their activation against cancer cells. One of these checkpoints is the axis of the PD1 protein and its ligand PDL1.¹⁷ PD1 is expressed at the surface of activated T cells, B lymphocytes, and natural killer cells.¹⁹ The interaction of PD1 with one of its two ligands, PDL1 or PDL2, engenders perturbed intracellular signaling and negative regulations of effector T-cell functions.^20,21 PDL2 is expressed mainly on antigen-presenting cells, and PDL1 can be expressed on diverse cell types, including T lymphocytes, and epithelial and endothelial cells. PDL1 can also be expressed by tumor cells and other cells in the local tumor environment.^17,22,23

PD1 is strongly expressed on the surface of activated T lymphocytes in response to inflammation or infection. Tumor cells can escape the immunoresponse via regulated PDL1 expression.¹⁷ When PD1 is bound to its ligand PDL1, the resulting complex blocks the immunoresponse by inhibiting the cytotoxic T-lymphocyte response. ICIs interrupt that, inhibiting T-cell signaling, thereby reactivating the antitumor actions of specific cytotoxic T cells.^17,24,25 NSCLC cells frequently express PDL1, with up to 68% of tumors being PDL1+ according to the literature.^9,26