Immunotherapy with antibodies to prevent the binding of PD-1 ligand to its receptors, PD-L1 or

PD-L2, can prevent an innate cytotoxic T-cell response against tumor by inhibiting kinases that
are involved in T-cell activation. Immunotherapy with anti-PD-L1 or anti-PD-1 antibodies
unleashes the innate immune system to react to the tumor growth (Yu, H. 2016). FDA approval
of immune checkpoint inhibitors has changed patient’s treatment paradigms. Majority of NSCLC
patients fail to respond to checkpoint inhibitors and block inhibitory T-cell signaling. PD-1 is a
transmembrane immunoregulatory molecule for the negative regulation of T cell activation and
peripheral tolerance. PD-L1 on tumor cells, which occurs during oncogenic processes in a state
of chronic antigen presentation.

The FDA granted approval to pembrolizumab in combination with platinum-based chemotherapy

in first-line NSCLC (non-squamous histology), irrespective of PD-L1 expression, based on
results from the KN-021 trial. PD-L1 expression was assessed using the Dako 28-8 assay. This
phase II study, which capitalizes on the immunological effects of chemotherapy to improve the
efficacy of immunotherapy, show 55% improvements for patients treated with combination
therapy compared to chemotherapy alone. There was a suggestion of higher proportion of
responses in patients with a TPS of ≥50%, but sample sizes were too small for significance. In
comparison to the KN-024 trial, the phase III CM 026 trial evaluating the efficacy of first-line
nivolumab in stage IV/recurrent NSCLC with PD-L1 positive tumors shows 95% benefit in
patients with a PD-L1 expression level of ≥5% (Mathew,2017). Similarly, IDO enzyme is
producing the immunosuppressive environment and shows promising result in responding to the
checkpoint blockade. But unfortunately, in advanced stages IDO combined with anti PD-L1 drug
embrolizumab didn’t show promising results in Lung cancer (Mancuso,2015).

With KN-024, patients with PD-L1 levels ≥50%, representing approximately 25% of NSCLC
patients. PD-L1 testing, using the Dako 22C3 assay, is most useful. For treatment-naïve, non-
squamous patients with lower PD-L1 levels, the results of KN-021 provide alternative approach
to first-line chemotherapy alone. Negative PD-L1 score may help decision-making with other
immunotherapy combinations. Furthermore, phase III ANVIL and PEARLS trials seek to
evaluate nivolumab and pembrolizumab, respectively, as adjuvant therapy for patients with
resected stage IB to IIIA NSCLC (Mathew, 2017).

Efforts are ongoing to clarify the role of anti-PD-1/PD-L1 therapy outside of NSCLC.
Refrences

Yu, H., Boyle, T. A., Zhou, C., Rimm, D. L., & Hirsch, F. R. (2016). PD-L1 expression in lung cancer. Journal of
Thoracic Oncology, 11(7), 964-975.

Mathew, M., Safyan, R. A., & Shu, C. A. (2017). PD-L1 as a biomarker in NSCLC: challenges and future
directions. Annals of translational medicine, 5(18).

Mancuso, R., Hernis, A., Agostini, S., Rovaris, M., Caputo, D., Fuchs, D., & Clerici, M. (2015). Indoleamine
2, 3 dioxygenase (IDO) expression and activity in relapsing-remitting multiple sclerosis. PLoS One, 10(6),
e0130715.