Abstract
Programmed death-1 (PD-1) immune checkpoint inhibitors are novel immuno-oncology agents being developed for the treatment of advanced non-small cell lung cancer (NSCLC) and other cancers. Clinical trial data have shown promising antitumor activity in patients with NSCLC, and approval of PD-1 immune checkpoint inhibitors in lung cancer is expected soon. Immune checkpoint inhibitors that target the PD-1 and CTLA-4 pathways are furthest along in clinical development. Unlike chemotherapy or targeted agents which act directly on the tumor to stop proliferation or induce tumor cell death, immuno-oncology agents are designed to stimulate a patient’s own immune system to eliminate tumors. When PD-1 on a T cell binds to one of its ligands, PD-L1 or PD-L2, T-cell activation is inhibited, suppressing T-cell attack. Tumors can express PD-L1 as a mechanism to avoid antitumor T-cell immune responses. PD-1 immune checkpoint inhibitors are designed to prevent PD-1 pathway mediated suppression of T-cell activity and restore antitumor immune responses. Initial phase 1 data with immune checkpoint inhibitors against PD-1 or PD-L1 have shown response rates in patients with advanced or metastatic NSCLC of 10–23% (across agents), and 1- and 2-year survival rates of 42% and 24% (nivolumab). Responses with nivolumab were seen across a broad array of NSCLC patient populations, regardless of histology or mutational status, and including heavily pretreated and older patients. The incidence of grade ≥3 adverse events (AEs) in trials of PD-1 immune checkpoint inhibitors ranged from 10–14%. The most commonly-reported AE with PD-1 agents is fatigue. As a result of their mechanism of action of stimulating immune responses, immune checkpoint inhibitors may be associated with select AEs with immunologic etiologies. Practitioners must thoroughly assess baseline AEs and be vigilant for select treatment emergent immunologic AEs which require prompt diagnosis and management. These include skin and gastrointestinal AEs (typically mild), and endocrine, hepatic, renal, and respiratory AEs, including pneumonitis. Most select AEs in clinical trials of nivolumab were effectively managed with treatment interruption and/or corticosteroid or other immunosuppressive agents. Endocrinopathies may require permanent hormone replacement therapy. A specialist consult (gastroenterologist, pulmonologist, endocrinologist) may be required in some cases. Infusion-related AEs with immune checkpoint inhibitors were uncommon in initial trials with NSCLC patients (≤5% all grades; ≤1% grade 3–4). A good understanding of the clinical profile of PD-1 pathway inhibitors will be instrumental in helping advanced practitioners manage patients who will receive these treatments in the near future.
