Immunotherapy in Advanced NSCLC 
The targeted therapies described above have significantly changed the outlook for those patients with identifiable mutations. However, nearly 70% of patients with advanced NSCLC do not have driver genetic mutations, and immune checkpoint inhibitors are the mainstay of treatment for these patients [80]. These inhibitors target either programmed cell death protein 1 (PD-1) or programmed cell death ligand 1 (PD-L1).PD-1 is a transmembrane protein that is expressed on T cells, B cells and Natural Killer cells and inhibits PD-L1 when it binds [81]. As PD-L1 is expressed on many tumor cells, the interaction of PD-1 and PD-L1 can be exploited in cancer treatment [80]. The PD-1 inhibitors pembrolizumab and nivolumab[80]and the PD-L1 inhibitors atezolizumab, avelumab, and durvalumab[80] can be used alone or in combination with chemotherapy based on individual patient factors, and have been shown to improve OS in patients with advanced NSCLC.
In patients with NSCLC who have not received chemotherapy, treatment decisions are based on the amount of PD-L1 expression. If PD-L1 expression is high (50% or greater), pembrolizumab can be used as monotherapy if patients do not have rapidly progressing disease.This is based on the KEYNOTE-024 trial of 305 patients with high PD-L1 expression who were assigned pembrolizumab monotherapy versus platinum-doublet therapy [82]. The results of this study showed prolonged PFS (10.3 versus 6 months) and higher ORR (45% versus 28%) in the pembrolizumab group compared to chemotherapy [82]. The pembrolizumab group also had a lower number of severe adverse events [82]. An update on KEYNOTE-024 presented 3 years later showed a median OS with pembrolizumab of 30.0 months (95% CI, 18.3-NR) versus 14.2 months (95% CI, 9.8-19.0) with chemotherapy (HR, 0.63; 95% CI, 0.47-0.86) [83].No studies have been performed to directly compare pembrolizumab monotherapy versus chemotherapy plus pembrolizumab in patients without rapidly progressing disease. For patients with high PD-L1 expression and rapidly progressing disease, pembrolizumab with chemotherapy is recommended based on a meta-analysis of five studies with either pemborlizumab monotherapy or pemborlizumab in combination with chemotherapy[84]. Again, no randomized controlled trials have directly studied pembrolizumab monotherapy versus pembrolizumabplus chemotherapy in this patient group.
If PD-L1 expression is less than 50% and patients are treatment-naive, pembrolizumab with chemotherapy is the first line treatment option for both squamous and nonsquamous NSCLC. There have been two large randomized control trials comparing chemotherapy with and without pembrolizumab in patients with nonsquamous NSCLC, the KEYNOTE-021 and KEYNOTE-189 trials[85,86].KEYNOTE-021 randomized 123 patients to chemotherapy with and without pembrolizumab. The group with pembrolizumab had higher ORR (55% versus 29%) and PFS (13 versus 6 months) [85].KEYNOTE-189 studied 616 patients with nonsquamous NSCLC. These patients either received chemotherapy alone or with pembrolizumab, and patients receiving chemotherapy alone hadpembrolizumab added with disease progression. Pembrolizumabtreatment resulted in an improved PFS of 8.8 versus 4.9 months. There was also improved 12-month OS in the pembrolizumabpluschemotherapy versus chemotherapy alone (69% versus 49%)[86]. A similar study was performed in patients with squamous NSCLC, KEYNOTE-407, where 559 patients were randomized to either chemotherapy with pembrolizumab or chemotherapy with placebo. The addition of pembrolizumabagainresulted in improved OS and PFS[87].
The anti-PD-L1 antibodyatezolizumab may provide an alternative therapy to pembrolizumab and chemotherapy, and has been investigated in combination with chemotherapy in patients with nonsquamous NSCLC. The IMpower 150 trial assigned 1202 patients with advanced NSCLC to three groups: chemotherapy with atezolizumab, chemotherapy with atezolizumab plus bevacizumab, or chemotherapy with bevacizumab. Those receiving chemotherapy with atezolizumab plus bevacizumab had better PFS and OS (19.2 versus 14.7 months in the chemotherapy/bevacizumab group)[88]. The IMpower 130 and IMpower 132 trials also demonstrated improved OS and PFS with the addition of atezolizumab to chemotherapy in patients with nonsquamous NSCL. [89,90]. The addition of atezolizumab has also been studied in squamous NSCLC but did not demonstrate any OS benefit, so is not recommended for these patients [91].
Immunoglobulin G4 monoclonal antagonist antibodies such as nivolumabcan also play a role in the treatment of NSCLC. Cytotoxic T-lymphocyte antigen-4 (CTLA-4) is a negative regulator of T cell activation and is implicated in immune surveillance of cancer [92].Ipilimumab is a monoclonal antibody directed against CTLA-4 that can be used in combination with nivolumab as an alternative to pembrolizumab and chemotherapy in patients with low PD-L1 expression [92].Nivolumab was studied as monotherapy in the CheckMate 026 trial of 541 patients with advanced, untreated PD-L1 positive tumors but did not result in prolonged PFS or OS[93],while the combination of nivolumab and ipilimumab used in the CheckMate 227 trial has shown improved OS compared to chemotherapy (17.1 versus 13.9 months) [94].The combination of nivolumab plus ipilimumab has also been shown to be beneficial in patients with high PD-L1 expression, though pembrolizumab remains the preferred treatment.
In another study presented at ASCO 2020, data from CheckMate9LA, a phase III trial evaluating nivolumab plus low-dose ipilimumab combined with chemotherapy showed superior OS compared to chemotherapy alone in the first line NSCLC treatment. Nivolumab plus ipilimumab combined with 2 cycles of platinum-doublet chemotherapy demonstrated superior OS versus chemotherapy alone (HR, 0.69; 96.71% CI, 0.55-0.87; p=0.0006), regardless of PD-L1 expression or tumor histology [95].
Although immunotherapy has been shown to impart a statistically significant survival benefit and drastically changed the current treatment of NSCLC, the survival difference is generally months over that achieved with conventional therapy. Therefore, it is imperative to discuss all of the risks and benefits of immunotherapy with a patient in order to best suit that individual’s goals of care. Table 4 lists the ongoing clinical trials of immunotherapy in advanced NSCLC. Completion of these trials will potentially result in better treatment options for the future.