REVIEW ARTICLE

Immunotherapy
for non-small cell
lung cancer
Sam Vafadar, MSPAS, PA-C

© CI PHOTOS / SHUTTERSTOCK
ABBSTRACT
Im
mmunotherapy is a new genre of treatment for paati t ents
witth advanced cancer. Initially approved for use in meta-
static
atic melanoma, immunotherapy has found a signifi
significcant
can
a t
place in treating non-small cell lung cancer (NSCLC).
Clinical trials using several combinations of immunotherapy
immunology and the current clinical uses of immuno-
are underway to help to determine the best treatment for
specific patient groups. This article reviews approved uses of
therapy in NSCLC, as well as potential future directions.
immunotherapy for NSCLC, immune-related toxicities, and
explores the future direction of this treatment. THE IMMUNE SYSTEM
Keywords: non-small cell lung cancer, immunotherapy, Researchers once thought that stimulating the immune
nivolumab, pembrolizumab, atezolizumab, durvalumab system to induce tumor regression was futile. However,
we now know that tumors with the highest mutational
burden, such as melanoma and lung cancer, are the can-

L
ung cancer is the second most common cancer and cer types most likely to respond positively to immuno-
the top cause of cancer-related deaths in both men therapies such as cancer vaccines and immune checkpoint
and women in the United States, claiming more inhibitors.3 In one phase III study conducted in Cuba,
lives than breast, prostate, and colon cancers combined.1 researchers studied the immunogenic effects of vaccina-
The American Cancer Society (ACS) projects that in 2019, tion against endogenous epidermal growth factor (EGF)
nearly 229,000 people will be diagnosed with lung cancer to the EGF receptor.4 However, cancer vaccines historically
and nearly 143,000 deaths will be related to lung cancer.1 have not induced significant responses in most people
Significant advances in chemotherapeutics, radiation because of the immunosuppressive nature of the tumor
therapy, and surgical techniques have led to notable microenvironment.5
improvements in progression-free and overall survival, The human immune system consists of the innate (cel-
but overall survival remains dismal. Of the three types lular) immune system and the adaptive (humoral) immune
of lung cancer–non-small cell lung cancer (NSCLC), small system. The innate immune system recognizes antigens
cell lung cancer, and lung carcinoid tumors–NSCLC is when a patient is exposed to infection, activating antigen-
the most common. Adenocarcinoma is the most common presenting cells such as dendritic cells, natural killer
subtype of NSCLC and squamous cell carcinoma is the cells, and circulating macrophages. T and B cells make
second most common subtype.2 up the humoral aspects of immunity, in that they secrete
Immunotherapy, a new treatment aimed at harnessing proteins (antibodies) that have various stimulatory and
immune system pathways, has fewer toxicities and better inhibitory properties. The purpose of inhibiting, or
outcomes compared with traditional chemotherapeutic dampening, the immune response is to resolve the pro-
approaches. This article describes the concept of tumor inflammatory state caused by illness. Were it not for the
built-in inhibition of our immune system, we would be
Sam Vafadar practices thoracic oncology at Moffitt Cancer Center in chronically inflamed.
Tampa, Fla. The author has disclosed no potential conflicts of interest,
However, our greatest defense can become our greatest
financial or otherwise.
foe. Cancer cells exploit the built-in inhibitory mecha-
DOI:10.1097/01.JAA.0000569792.99069.e6 nisms. Cancer sacrifices many clonal cells, leaving behind
Copyright © 2019 American Academy of PAs immune-resistant cells that develop the ability to upreg-

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Copyright © 2019 American Academy of Physician Assistants

REVIEW ARTICLE

PD-1 inhibitors, and the latter two agents target the ligand
Key points PD-L1. Durvalumab is FDA-approved to reduce the risk
Immunotherapy, initially approved for use in metastatic of cancer progression and improve overall survival after
melanoma, has found a significant place in treating definitive treatment with chemotherapy and radiation in
NSCLC. patients with inoperable stage III NSCLC.7 To date, dur-
Immunotherapy has fewer toxicities and better outcomes valumab is the only lung cancer immunotherapy with this
compared with traditional chemotherapy. specific indication.
Four drugs have been approved for treating NSCLC: For most patients with advanced disease without a
nivolumab, pembrolizumab, atezolizumab, and specific driver mutation such as epidermal growth factor
durvalumab. receptor (EGFR) mutations, anaplastic lymphoma kinase
Clinical trials using several different combinations of (ALK) fusion variants, or c-ROS oncogene 1 (ROS1)
immunotherapy are underway to help determine which rearrangements, first-line therapy consists of a platinum-
combinations are best in specific patient groups. based two- or three-drug chemotherapy doublet delivered
IV for four to six cycles, with CT or positron emission
tomography (PET) imaging assessments every two to
ulate inhibitory receptors and dampen the immune three treatment cycles. For people with specific driver
response.5 mutations, first consider oral agents such as osimertinib,
Two major pathways of immune activation are of erlotinib, or afatinib for EGFR-positive lung cancer, and
great importance in the context of metastatic NSCLC: alectinib or crizotinib for ALK-positive lung cancer.
the programmed cell death (PD-1) and cytotoxic T-lym- Unfortunately, most people experience cancer progres-
phocyte-associated protein 4 (CTLA-4) pathways. sion, necessitating further therapy when appropriate.
CTLA-4 upregulation and binding to B7, which com- Most of the indications for immunotherapy are for
petes with the CD28 receptor on T cells, leads to inhi- subsequent IV treatment.
bition of the immune response. Between 51% and 87% Nivolumab is a human IgG4 monoclonal antibody that
of NSCLC tumors express CTLA-4, and immuno- targets the PD-1 receptor on immune system cells.6,8
therapies targeting this pathway are under investigation.6 Approved in 2015, it was the first immunotherapy agent
The programmed cell
death (PD-1 and PD-L1)
pathways are the most TABLE 1. FDA-approved immunotherapies for NSCLC8-15,17,35-37
well-studied pathways in Mechanism PD-L1 level
NSCLC. The PD-1 recep- Agent Line of therapy Notes
of action required?
tor is a protein expressed Also FDA-approved
on the surfaces of CD4 Nivolumab
PD-1 in third-line treat-
(Bristol-Myers Second No
and CD8 T cells, B cells, Squibb)
inhibitor ment for small cell
lung cancer
and natural killer cells.
The exploitation of this • First, in patients with 50% or
more positive PD-L1
pathway is the mecha- • First, in patients with
nism by which NSCLC adenocarcinoma receiving Yes, in both
tumors evade immune carboplatin and pemetrexed lines, except Used in PD-L1-
detection. Addressing this Pembrolizumab • First, in patients with squamous PD-1 for first-line positive mesothe-
(Merck, Inc.) NSCLC receiving carboplatin inhibitor combination lioma as second-line
inhibitory exploitation is and either paclitaxel or with chemo- therapy
a logical approach in the nab-paclitaxel therapy
treatment of NSCLC. • Second, in patients after initial
platinum chemotherapy and if
PD-L1 > 1%
FDA-APPROVED CHECK-
POINT INHIBITORS • First, in patients with non-
Also FDA-approved
squamous NSCLC receiving
As of February 2018, the Atezolizumab carboplatin, paclitaxel, and PD-L1
as first-line treatment
FDA had approved four No with carboplatin and
(Genentech) bevacizumab inhibitor
etoposide for small
checkpoint inhibitors for • Second, in patients after initial
cell lung cancer
treating advanced lung platinum chemotherapy
cancer (stage IIIB or IV): As consolidation therapy for up
to 1 year for patients with un-
nivolumab, pembroli- Durvalumab PD-L1 Pneumonitis
resectable stage III NSCLC only, No
zumab, atezolizumab, and (AstraZeneca)
after definitive chemotherapy and
inhibitor incidence up to 34%
durvalumab (Table 1). The radiation
former two agents are

38 www.JAAPA.com Volume 32 • Number 9 • September 2019

Copyright © 2019 American Academy of Physician Assistants

 Immunotherapy for non-small cell lung cancer

for treating advanced squamous cell-type NSCLC, and chemotherapy; two clinical trials demonstrated supe-
was approved after a phase III trial (CheckMate-017) rior overall survival.16 The large phase III OAK clinical
demonstrated superior overall survival (9.2 months com- trial randomized patients (N = 1,225) to receive either
pared with 6 months; hazard ratio for overall survival docetaxel chemotherapy or atezolizumab immunother-
[OS] = 0.59) and a 41% risk reduction of death compared apy.16 Patients in the investigational arm had an overall
with docetaxel chemotherapy. The drug’s indications were survival of 16.3 months compared with 6.2 months in
expanded to include adenocarcinoma-type NSCLC after the standard arm (hazard ratio 0.73; 95% confidence
another phase III study (CheckMate-057) demonstrated interval: 0.62-0.87; P = .0003). Similarly, the phase II
superior overall survival (12.2 months compared with poplar study demonstrated superior efficacy (atezoli-
9.4 months; hazard ratio for OS = 0.73).9,10 Nivolumab zumab, OS = 14.3 months; docetaxel, OS = 7.2 months;
is administered IV at a dose of 240 mg once over 30 hazard ratio 0.73; 95% confidence interval: 0.53-0.99;
minutes every 2 weeks until progression or unacceptable P = .04).4 Atezolizumab is administered IV at a dose
toxicity.8 of 1,200 mg once over 60 minutes every 3 weeks until
Pembrolizumab is a humanized IgG4 monoclonal anti- progression or unacceptable toxicity.15
body that targets the PD-1 receptor.11 It was approved in Durvalumab is a human IgG1 monoclonal antibody
2016 as initial therapy for PD-L1 positive metastatic that blocks PD-L1. This is the most recent immuno-
NSCLC, and was the first immunotherapy approved for therapy agent to gain FDA approval for the treatment
the initial treatment of advanced lung cancer. The drug of NSCLC but is indicated specifically for the treatment
provided patients with an alternative to traditional che- of unresectable stage III NSCLC following completion
motherapy if their lung tumors tested with more than of chemotherapy and radiation to reduce the risk of
50% positivity on an FDA-approved test for PD-L1 status. progressive disease.17 This is a unique indication and
In addition to the first-line approval, the FDA also stands alone as the only immunotherapy approved in
approved pembrolizumab for patients whose tumor a non-stage IV setting.7 An interim analysis by Antonia
expressed greater than 1% positivity for PD-L1, on or and colleagues demonstrated that durvalumab benefited
patients with stage III lung cancer compared with pla-
cebo following definitive chemotherapy and radiation
A patient’s bacterial flora treatment.18 The results were based on a 2:1 randomized
placebo-controlled phase 3 clinical trial (pacific) in
may modulate response to which progression-free survival was significantly longer
in the durvalumab group (hazard ratio 0.52; P < .001).18
cancer immunotherapy. Adverse reactions of any grade or cause were similar
in both investigational and control groups. 18 Dur-
after progression on first-line platinum chemotherapy.12 valumab is administered IV at a dose of 10 mg/kg over
The drug’s indications were later expanded to first-line 60 minutes every 2 weeks until progression or unac-
use for adenocarcinoma-type NSCLC in combination with ceptable toxicity.17
carboplatin and pemetrexed.13 This approval was based
on findings from a randomized phase I/II clinical trial IMMUNE-MEDIATED ADVERSE REACTIONS
(KEYNOTE-021) that compared carboplatin and peme- PD-1 and P-L1 inhibitors share common adverse reac-
trexed chemotherapy with or without pembrolizumab. tions based on their common mechanisms of action.
Both treatment arms received four cycles of carboplatin Immune-related adverse reactions, most commonly
and pemetrexed followed by maintenance chemotherapy cutaneous and gastrointestinal (GI) manifestations, are
at the investigator’s discretion. Pembrolizumab was con- a possibility when patients with NSCLC are exposed to
tinued in the investigational arm for up to 2 years in a immunotherapy.19 Patients also can develop a macular,
maintenance fashion. Randomization was stratified accord- erythematous rash covering various areas of the body,
ing to PD-L1 status.11 The group receiving carboplatin with or without pruritus. Management of cutaneous
and pemetrexed with pembrolizumab saw an improvement manifestations consists of topical corticosteroid prepara-
in both progression-free survival (hazard ratio, 0.53; 95% tions, antihistamines, or a short course of oral cortico-
confidence interval, 0.31, 0.91, P = .0205) and overall steroids.20 Hydroxyzine also may be used to manage itch,
response rate (ORR).13 Pembrolizumab is administered which can also widely vary in severity. Gabapentin is
IV at a dose of 200 mg once over 30 minutes every 3 weeks another, lesser-known option in the treatment of refrac-
until progression or unacceptable toxicity.11,14 tory pruritus.
Atezolizumab is a humanized IgG1 monoclonal anti- GI immune-related adverse reactions include bloody
body that targets the PD-L1 ligand and B7.1 recep- stool, diarrhea, abdominal cramping, and fever. Early
tor.15 It was approved in 2016 for treating metastatic recognition of bowel changes in a patient undergoing
NSCLC after initial treatment with platinum-based immunotherapy can be lifesaving. Establishing a patient’s

JAAPA Journal of the American Academy of PAs www.JAAPA.com 39

Copyright © 2019 American Academy of Physician Assistants

REVIEW ARTICLE

baseline characteristics regarding bowel habits is helpful. COMBINATION STRATEGIES

Management of GI adverse reactions may include loper- The National Comprehensive Cancer Network (NCCN)
amide, atropine, and high-dose corticosteroids. Obtain recommends enrolling patients with NSCLC in clinical
stool cultures to rule out infectious causes of diarrhea, such trials as the best management strategy.25 When appropri-
as Clostridium difficile. ate, patients healthy enough to participate in clinical
Pulmonary immune-related adverse reactions include trials have an opportunity to use novel agents in the
pneumonitis, which can present as hypoxia, dyspnea, chest treatment and management of their disease, sparing
pain, fever, and, especially, a new or worsened cough. FDA-approved immunotherapies for a later time if
Pneumonitis rates typically are higher with combination necessary. An exhaustive review of available clinical
PD-1/CTLA-4.19 This can be a life-threatening complication trials using combination immunotherapy approaches
and prompt management with high-dose IV and oral cor- exceeds the scope of this article. What follows is an
ticosteroids, supplemental oxygen, and supportive manage- abbreviated discussion on experiences with immuno-
ment is essential. therapy approaches in a combination manner. Clinical
The immune-stimulating activity of the checkpoint trials are ongoing to evaluate the efficacy of these
inhibitors can cause virtually any endocrinopathy. Depend- approaches.
ing on the severity of the endocrinopathy, immunotherapy Radiation therapy as a combination treatment with
may need to be withheld or permanently discontinued. immunotherapy is getting renewed interest because of
Laboratory panels including complete blood cell count the relatively non-overlapping toxicity profiles of radia-
with differential and a complete metabolic panel can be tion and immunotherapy and the “abscopal effect”
helpful in identifying early signs of immune-mediated (systemic response after exposure to radiotherapy). Sev-
hepatitis, pancreatitis, and nephritis. Changes in vital signs eral mechanisms of immune modulation from radiation
and electrolytes, especially BP and sodium, can be early therapy have been proposed and may result in upregula-
indicators of immune-related adrenal insufficiency or, less tion of certain cell-surface receptors or secretion of
commonly, hypophysitis (pan-hypopituitary syndrome). specific cytokines.26
If the latter is suspected, an MRI with attention to the Vorinostat is one example of a novel agent being stud-
pituitary gland is essential. ied in combination with checkpoint inhibition. This drug
is approved for treating cutaneous manifestations of T
GUT MICROBIOME cell lymphoma.27 Vorinostat is a pan-histone deacetylase
The gut microbiome may have a role as a potential inhibitor that has immune system-dependent antineo-
modulator of cancer immunotherapy. Studies indicate plastic activity.28 The OX-40 costimulatory molecule also
that both the overall diversity and the presence of specific may play a role in its modulation and is being investigated
bacterial flora in a patient may modulate response to as another target for the treatment of metastatic lung
cancer immunotherapy.21,22 Conversely, exposure to cer- cancer.6
tain antibiotics may impair progression-free survival in A logical approach for combination therapy is with the
patients undergoing immunotherapy.23 tyrosine kinase inhibitors (TKIs) indicated for EGF recep-
Thompson and colleagues performed a retrospective tor- or ALK-related lung cancers. Lung cancers with these
review of patients with lung cancer who were treated with mutations typically are nonimmunogenic. The drivers of
immunotherapy (PD-1 inhibitors) and had antibiotic these tumor cells are due to activating mutations. The
exposure within a certain time frame.24 They found that CheckMate-057 study that led to the approval of nivolumab
patients who had antibiotic exposure had inferior progres- in 2015 concluded that there was no benefit for patients
sion-free survival.24 with EGF receptor-related lung cancers.29 This sheds further
Gopalakrishnam and colleagues looked at the differ- light on the fact that these driver mutation-related cancers
ences in gut flora between responders and nonresponders have less mutational load.30
to immunotherapy in a subset of melanoma patients.21 Another approach uses chimeric antigen receptor T cell
They found that a difference in composition of gut flora technology and T cell receptor technology. These immu-
may be associated with a level of response to immuno- notherapies fall under the category of adoptive cell therapy,
therapy. which is being evaluated in several different solid tumor
These studies highlight the possibility that the gut types, including NSCLC.31 Genetic engineering of compo-
microbiome may modulate responses to immunotherapy. nents of immune system cells has been a reality for decades.
The researchers’ results warrant further investigation Adoptive cell therapy involves explanting host immune
with clinical trials involving the gut microbiome across cells and then reinfusing them after genetic reengineering.
cancer types, especially in the context of immunotherapy This method of immunotherapy offers greater specificity
exposure. This also raises questions about whether for the target disease. Manipulation of T cells in combina-
probiotics or prebiotics could augment immunotherapy tion with checkpoint inhibition represents a viable, prom-
strategies. ising area of investigation.32 In patients with metastatic

40 www.JAAPA.com Volume 32 • Number 9 • September 2019

Copyright © 2019 American Academy of Physician Assistants

 Immunotherapy for non-small cell lung cancer

melanoma, response rates of up to 50% were seen with cell lung cancer with progression on or after platinum-based
combination adoptive cell therapy and tumor-infiltrating chemotherapy. Oncologist. 2016;21(5):634-642.
lymphocytes.33 10. US Food and Drug Administration. Modification of the dosage
regimen for nivolumab. www.fda.gov/drugs/resources-informa-
tion-approved-drugs/modification-dosage-regimen-nivolumab.
CONCLUSION Accessed May 28, 2019.
Treatment for patients with NSCLC has undergone sig- 11. Merck & Co., Inc. Pembrolizumab prescribing information.
nificant change with the approvals of nivolumab, pem- www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_
brolizumab, atezolizumab, and durvalumab. Overall, pi.pdf. Accessed April 22, 2019.
these PD-1- and PD-L1-directed checkpoint inhibitors 12. US Food and Drug Administration. Pembrolizumab (Keytruda)
checkpoint inhibitor. www.fda.gov/Drugs/InformationOnDrugs/
have led to lasting responses and survival benefits.34 What ApprovedDrugs/ucm526430.htm. Accessed April 22, 2019.
once was considered a nonimmunogenic malignancy is
13. US Food and Drug Administration. Pembrolizumab (Keytruda).
now well-understood as a disease with great potential in www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/
responding to immunotherapy. PD-L1 is an imperfect, ucm558048.htm. Accessed April 22, 2019.
dynamic biomarker used as a surrogate marker for 14. Pai-Scherf L, Blumenthal GM, Li H, et al. FDA approval sum-
response to immunotherapy. Researchers continue to mary: pembrolizumab for treatment of metastatic non-small
cell lung cancer: first-line therapy and beyond. Oncologist.
investigate the complicated tumor microenvironment for 2017;22(11):1392-1399.
better predictors. Although immunotherapy has led to
15. Genentech, Inc. Tecentriq prescribing information. www.gene.com/
great improvements in survival, management of disease, download/pdf/tecentriq_prescribing.pdf. Accessed April 22, 2019.
tolerability, and its potential to replace chemotherapy,
16. Rittmeyer A, Barlesi F, Waterkamp D, et al. Atezolizumab versus
several questions remain about further personalizing docetaxel in patients with previously treated non-small-cell lung
immunotherapy for patients with cancer. Who would cancer (OAK): a phase 3, open-label, multicentre randomised
benefit most from immunotherapy? Why do certain controlled trial. Lancet. 2017;389(10066):255-265.
patients have durable remissions and others do not? Can 17. AstraZeneca Pharmaceuticals LP. Imfinzi prescribing informa-
tion. www.azpicentral.com/imfinzi/imfinzi.pdf. Accessed April
responses to immunotherapy be primed using chemo- 22, 2019.
therapy and/or radiation? The answers to these questions
18. Antonia SJ, Villegas A, Daniel D, et al. Durvalumab after
help tailor these treatments to the patient, and the poten- chemoradiotherapy in stage III non-small-cell lung cancer. N
tial for NSCLC to be cured or managed as a chronic Engl J Med. 2017;377(20):1919-1929.
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