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.