Introduction ?

Lung cancer has become a common cancer type around the world. 1One of the risk factors of ?lung cancer is cigarette smoking, and the risk increases both for smokers and second-hand ?smokers. 1,2?
The risk for lung cancer can also be associated with a family history of lung cancer. Different ?treatments for lung cancers are currently being tested clinically 3 .One of the treatments is ?immunotherapy in Non-Small Cell Lung Cancer (NSCLC)4. The management of ?immunotherapy differs from other treatments such as chemotherapy and radiotherapy5. In ?immunotherapy, the disease is treated by trying to reactivate a person’s immune system natural ?response to uncommon cells6. Every treatment has advantages and disadvantages, like an ?improved survival rate of patients and cost effectiveness. Concerning the use of ?immunotherapy 3 7, healthcare professionals are still in doubt whether this relatively new ?treatment modality will be successful in treating lung cancer8. Therefore, this thesis aims to ?track the development of the use of immune-therapy in treating lung cancer disease.?

?1. Gridelli C, Rossi A, Maione P, et al. The Role of Maintenance Treatment in Advanced Non-Small Cell Lung ?Cancer: Reality or Early Second Line. Clin Lung Cancer. November2010; Vol 11, 6: 374 – 382.?
?2. Gabrilovich, D. I. (2007). Combination of chemotherapy and immunotherapy for cancer: a paradigm ?revisited. The lancet oncology, 8(1), 2-3.?
?3. Nowak, A. K., Robinson, B. W., ; Lake, R. A. (2003). Synergy between chemotherapy and ?immunotherapy in the treatment of established murine solid tumors. Cancer research, 63(15), 4490-4496.?
?4. Finley RS. Lung cancer: detection, prevention and therapeutics. American Pharmacy. 1989, NS29(11):39-??46?
?5. Tucker ZC, Laguna BA, Moon E, Singhal S. Adjuvant immunotherapy for non-small cell lung cancer. Cancer ?Treatment Reviews. 2012, 38(6):650-661.?
?6. Lissoni, P., Meregalli, S., Fossati, V., Paolorossi, F., Barni, S., Tancini, G., ; Frigerio, F. (1994). A ?randomized study of immunotherapy with low-dose subcutaneous interleukin-2 plus melatonin vs ?chemotherapy with cisplatin and etoposide as first-line therapy for advanced non-small cell lung ?cancer. Tumori, 80(6), 464-467.?
?7. Ohnuma, T., ; Holland, J. F. (1977). Nutritional consequences of cancer chemotherapy and ?immunotherapy. Cancer research, 37(7 Part 2), 2395-2406.?
?8. Terrry, W. D., ; Windhorst, D. (Eds.). (1978). Immunotherapy of cancer: Present status of trials in ?man (Vol. 6). Raven Press.?
?9. Lake, R. A., ; Robinson, B. W. (2005). Immunotherapy and chemotherapy—a practical ?partnership. Nature Reviews Cancer, 5(5), 397-405.?
?10. Frazier, J. L., Han, J. E., Lim, M., ; Olivi, A. (2010). Immunotherapy combined with chemotherapy in the ?treatment of tumors. Neurosurgery Clinics of North America, 21(1), 187-194.?
?11. Leprieur, E. G., Dumenil, C., Julie, C., Giraud, V., Dumoulin, J., Labrune, S., ; Chinet, T. (2017). ?Immunotherapy revolutionises non-small-cell lung cancer therapy: Results, perspectives and new ?challenges. European Journal of Cancer, 78, 16-23.?

Objectives ?
Treating cancer, especially lung cancer, is still an ongoing challenge. Although ?there are ?different options of treatment, the success of this treatment still depends on ?the patient itself. ?Comorbidities present at the time of diagnosis of progressive ?disease might limit the ?treatment modalities due to the toxicity profile of the ?experimental drugs.?
This systematic review aims to evaluate the changing landscape the management of Non-?small lung cancer patients looking at clinical characteristics of the disease discussing novel ?approaches and different combinations used through the recently published clinical trials.?
Background and Introduction ?
Globally, lung cancer is the largest contributor to new cancer diagnoses and to death from ?cancer.20, 21. Lung cancer has a key influence on the worldwide burden of disease. It ?triggered the death of almost 1.5 million individuals, which makes lung cancer the major cause ?of cancer-related mortality in males (24%) and the second leading cause in females (14%) ?worldwide 2, 3. ?
Most of cases are of the non-small-cell subtype NSCLC, which comprises approximately 80%-??85 of all lung cancers. 4?

Non-Small Cell Lung Cancer subtypes

NSCLC has three main subtypes: squamous cell carcinoma, large-cell carcinoma and ?adenocarcinoma, the latter accounting for the majority (40%) of NSCLC cases, while 25–30% ?of NSCLC being squamous histology type, Unlike nonsquamous NSCLC, squamous NSCLC ?seldom wharves epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase ??(ALK) mutations for which there are directed targeted therapies 15, 6. ?
One study in Poland of 20,567 lung cancer cases found that squamous cell carcinoma ?was ?most common among male never smokers and current smokers 64. ?
An analysis of 437976 Korean men from which 1357 new lung cancer cases were detected ??found that adenocarcinoma was the most common histological type amid never ?smokers, ?previous smokers, and current smokers 65.?

Data of Lung cancer incidence for women versus men over decades

Population-based statistics on lung cancer incidence or mortality rates among people who ??never smoked are available for women in the U.S. during the 1930s and for women in ?other ?countries during time periods when few women smoked. In disparity, regular smoking was ?infrequent among women in the U.S. before World ?War II. National data on death and ?provincial statistics on lung cancer incidence ?accumulated during the 1930s principally echo ?the background rates among women who ?never smoked actively 58. ?
Vital statistics data for women aged 40-69 years in the U.S. in 1935-1940 show that ?female ?lung cancer death rates before the dawn of female smoking were similar to ?those of women ?of the same age who have conveyed no history of active smoking in ?cohort studies carried ?out since 1960 23, 59-62 ?
The absolute rates are 20-25 times more for the male current than never smokers, ?and 10-12 ?times higher for female current smokers than never smokers 63.?
Because of the change in lung cancer incidence in women, recent figures show that lung ?cancer death rates decreased in women for the first time, more than a decade after ?decreases in men 4.?
The lag in the decline of lung cancer rates in women compared with men has been ?attributed to the fact that cigarette smoking in women peaked two decades later than in ?men 66. ?
For women, lung cancer was the fourth most commonly diagnosed cancer and the second ?leading cause of cancer death 20.?
Lung cancer surpassed breast cancer as the leading cause of cancer deaths in women in the ?late 1980s, and now almost twice as many women die of lung cancer than breast cancer 67. ?
The lung cancer death rate in women is beginning to plateau, with an annual increase of ??0.2% in 2005.104 Lung cancer death rates for women fell for the first time in four decades ?amid continued declines in the overall cancer death rate.4 There has been a drop of 2.5% in ?lung cancer deaths among men and a 0.9% decline in lung cancer deaths in women 68. ?
The American Cancer Society Cancer Prevention Study II, which followed 1 to 2 million ?subjects between 1982 and 1988, reported an overall risk for lung cancer in women smokers ?of 11.94, compared with an overall risk of 22.36 in male smokers, after considering the ?intensity of smoking 69. ?
A Canadian case-control study of male-female differences in lung cancer covering the period ??1981 to 1985 showed that with a history of 40 pack-years of cigarette smoking relative to ?lifelong nonsmoking, the OR for women developing lung cancer was 27.9 versus 9.6 in men. ?
In both these studies, the increase in lung cancer risk held for all major histologic types 70. ?
A routine but crucial part of diagnosing lung cancer is to assess the stage of disease to hand-?pick the suitable treatment and to evaluate prognosis. Hence, newly diagnosed lung cancer ?patients undertake numerous diagnostic procedures to determine the extent of disease, like ?contrast-enhanced chest computed tomography, fluorodeoxyglucose-positron emission ?tomography scan and minimally invasive endosonography 7, 8.?
A central dogma in the treatment of metastatic NSCLC is that treatment is palliative, and the ?key ?treatment objective is an improvement in quality of life (QOL); consequently, a ?concentration to limit toxicity is of principal ?importance. But, treatment with ICIs can ?occasionally be associated with durable remissions 9.?
Lung cancer had conventionally been well-thought-out as nonimmunogenic, and numerous ?efforts to modulate the immune system to treat lung cancer by nonspecific agents such as ?interleukin-2 (IL-2), interferon, and Bacillus Calmette–Guerin were ineffective. Efforts to ?unleash the immune system by means of several vaccines were also unsuccessful 10.?
Recent better therapeutic strategies like the commencement of the immune cascade is a ?multifaceted, multistep process 11-13. ?
Multiple agents inhibiting the PD-1/PD-L1 pathway have been approved for use as second-line ?agents in non-small cell lung cancer (NSCLC) and some of them got approved as frontline ?treatment in NSCLC patients, with some label restriction to some patients with high PD-L1 ?expression 14-16.?

Descriptive Epidemiology ?

Races and Age risk
Age Lung cancer risk rises with age in both ?smokers and never smokers. The age-standardized ?death rate from lung cancer was roughly 40% higher ?among African American than white ?women who reported never smoking , ?but a statistically significant racial difference was not ?seen for never smoking women ?; there were insufficient data to measure the risk in black ?men 71. ?
Patients older than 80 years constitute 14% of all patients with lung cancer in the United ?States but account for almost a quarter of all lung cancer deaths 76, 77. ?

Genetic Factors ?
There is a genetic component to the pathogenesis of lung cancer, whether it relates to host ?susceptibility to lung cancer, with or without exposure to cigarette smoke to the ?development of certain types of lung cancer, or to an individual’s responsiveness to biologic ?therapies 73, 74.?
Smokers with history of early commencement of lung cancer in their first degree relatives ?have increased risk for lung cancer with growing older in age than smokers lacking such a ?family history 75.?
High incidence of HPV DNA in lung cancer has been reported in Asian cohorts, especially in ?nonsmokers; alternatively, studies in Western Europe failed to show an etiologic role of HPV ?in lung cancer 85-87.?

Correlation between NSCLC and smoking
Overwhelmingly, the major risk factor for lung cancer is cigarette smoking with a relative risk ?of 20 to 25 and an attributable risk of 85% to 90% 93.?
A little more than half of the lung cancers prompted by factors other than active ?smoking ?occur in never smokers 20, 21. lung cancers that happen in never smokers ?differs from ?those that are diagnosed in smokers in their molecular profile and responsiveness to the ??targeted therapies. Primary factors meticulously knotted to lung cancer in never smokers ?embrace exposure to ?known and suspected carcinogens including radon, second-hand ?tobacco smoke, and ?other indoor air pollutants 22. ?
In five researches, investigators explored indoor contact to smoke from wood, straw, ?and ?further solid fuel and lung cancer risk amongst never smoking women 22. ?
A European cohort showed similar association of solid fuel use for heating and cooking with ?lung cancer risk; OR of lung cancer in lifetime users of solid fuel was 1.80; switching to ?nonsolid fuels resulted in lowered risk. It has been suggested that the lung cancer that arise ?from wood smoke may behave differently from lung cancer due to tobacco smoke 52.?

Lung Cancer Occurrence in Never Smokers ?
Nonsmokers inhale a mixture of side stream smoke and exhaled mainstream smoke ?that is ?mostly denoted to as secondhand smoke 23. ?
Roughly 10 – 15% of all lung ?cancers arise in never smokers, making lung cancer in never ?smokers one of the ?principal causes of cancer-related mortality 24, 25 ?
The excessive and extended use of tobacco was an imperative influence in the initiation of ?lung cancer, putting in consideration that lung cancer in a nonsmoker was infrequent; and ?there could be a lag period of 10 years or more between cessation of smoking and the ?clinical onset of carcinoma 26. ?
Although more than 80% of lung cancers occur in persons with tobacco exposure, fewer than ??20% of smokers develop lung cancer 27.?
There is relative risk of 2.1 for lung cancer compared with nonsmokers, with men who ?smoked 5 or more cigars a day having the greatest risk 28. ?
The increased risk for lung cancer for the reason that pipe smoking is comparable to cigar ?smoking 29, 30. ?
Also, active pipe smoking was associated with a relative risk for lung cancer of 5.0.48 Cigar ?and pipe smokers have a larger risk for lung cancer than lifelong nonsmokers or ex-smokers ??31.?
The overall global statistics estimation is that 15% of lung cancers in men and up to 53% in ?women are not attributable to smoking, with never smokers accounting for 25% of all lung ?cancer cases globally 32.?
If lung cancer in never smokers were considered unconnectedly, it would rank as the seventh ?most common cause of cancer death globally before cervical, pancreatic, and prostate cancer ??33. ?
Regarding the demographics between smokers and nonsmokers, the best statistical analysis ?was done in North America since the fifties. ?
In the United States, one study valued that 19% of lung cancer in women and 9% of lung ?cancer in men arises in never smokers 34. ?
A series following 12,000 patients with lung cancer in California found a dramatic increase in ?broncho-alveolar carcinoma in never smokers from 19% during 1995 to 1999 to 26% during ??1999 to 2003 35.?
The percentage of other types of lung cancer in never smokers also increased from 8.6% to ??9.4%. Another study in the United States found a small but statistically significant increase in ?the mortality rate in women with non- smoking associated lung cancers from 12.3% in the ?years 1959 to 1972 to 14.7% in the years 1982 to 2000 41. A corresponding increase did not ?occur in men 36. ?
A population-based case-control study in Canada instituted that job-related exposures, ?history of lung disease, and family history of early commencement cancer were important ?risk factors for lung cancer amongst never smokers 37. ?
An amplified risk of lung cancer has been steadily shown amongst ?never smoking women ?exposed to indoor biomass smoke and cooking vapors. Less reliable outcomes were found ?for different types of oils used for cooking and ?exposure to smoke from coal and risk of lung ?cancer among never smokers 53. ?
With little exceptions, these researches established the increased risk of lung cancer among ?asbestos occupationally exposed never smokers compared to unexposed non-smokers ?evaluation groups. Although the accurate nature of the interaction between asbestos and ?tobacco smoking ?in lung carcinogenesis is still a topic to argument, the indication of a ?carcinogenic effect ?of asbestos independent from smoking is very robust 54. ?
over-all, the conclusions on occupational risk factors in never smokers are corresponding to ?those in ?smokers, although the measure of the scale of the smoking interaction is ?complexed ?by the insignificant number of cases of lung cancer amongst never smokers ?involved in most ?studies 22.?
Pooled data from 8 such studies in the United States from 1981 to 1991 found the relative ?risk for lung cancer in nonsmokers living with smokers to be 1.23.213 ETS consists of both ?mainstream smoke and side stream smoke 92.?

Secondhand smoking
Strong evidence from multiple sources supports the causal association of second hand ??smoke exposure in lung cancer in never smokers 57.?
In 1981 published reports from Asia (Japan) and Europe (Greece) ?showed larger lung cancer ?risk in never smoking wives whose husbands are cigarette ?smokers 39, 40. ?
Additional causal implication of involuntary smoking with lung cancer ascends biological ??likelihood from the existence of carcinogens in side stream smoke and the absence of a ??documented threshold dose for respiratory carcinogens in active smokers 37, 41-43. ?
Epidemiologists have verified the association between lung cancer and involuntary ?smoking ?using case-control and cohort designs have steadily found that Secondhand smoking ?contact ?is connected with lung cancer risk in never smokers 44. ?
other pooled investigation of large-scale studies to evaluate the risk of lung cancer of never ??smokers exposed to spouse and workplace sources of Secondhand smoking found an ?additional risk of ??23% from exposure to spousal smoking and 27% from exposure to ?workplace sources ?of Secondhand smoking45. ?
? In view of substitutions to a causal association, confounding has also been ?proposed as ?causative to the linking of Secondhand smoking with lung cancer 45. ?
exposure to Secondhand smoking intensifies the risk of cancer based on the ?features of side ?stream and mainstream smoke, the absorption of tobacco ?smoke materials during ?involuntary smoking, and the nature of dose response ?relationships for carcinogenesis 46. ?
The National Research Council and the U.S. Surgeon General also concluded that ?involuntary ?smoking increases the incidence of lung cancer in never smokers 47, 48. ?
The best estimation for the excess risk of lung cancer in never smokers ?married to smokers ?was 25%. The 1986 report of the Surgeon General considered ?involuntary smoking as a ?reason of lung cancer in never smokers 48. ?
A cohort study of 516 white miners who have never smoked cigarettes, pipes, or ?cigars from ?the Colorado Plateau cohort showed 14 lung cancer deaths with only 1.1 ?expected, based on ?comparison to the never smokers in a cohort study of U.S. ?troupers 50. ?
Another analysis of 2,798 never smoking miners in the cohorts quantified the risk ?per ?working-level month as approximately three times as high in never smokers as in ?smokers, ?consistently with the sub-multiplicative interaction among smoking and ?radon found with ?examination of the full data set 51. ?
In Japan, China, and Mexico, there were additional Three investigations, conducted , found ?an increased risk in lung ?cancer among never smoking women exposed to smoke formed ?while cooking with ?several biomass fuels 52. ?
Another case control study following 2400 families relatives of 316 never smokers patients ?with lung cancer cases uncovered a 25% excess risk for cancer in first-degree relatives of lung ?cancer cases 38. ?
The analysis found a meaningfully amplified risk of lung cancer in never ?smoking women ?married to smoking men; for the studies conducted in the United ?States, the projected ?relative risk was 1.19 49. ?
A summary analysis of a large number of epidemiologic studies on the risk for lung cancer in ?nonsmokers found an excess risk for lung cancer of 24% in nonsmokers who lived with a ?smoker 91. ?

The correlation between other Diseases, smoking and Lung cancer

Grippingly, one study that examined lung cancer risk among smokers and never ?smokers ?with tuberculosis found that female never smokers with tuberculosis had ?approximately an ??8-fold increase in lung cancer risk, while there was no association ?among female smokers ??56. ?
Indoor air pollution, including combustion of coal or solid fuels for cooking or heating ?in ?poorly ventilated spaces, has been clearly associated with increased risk of lung ?cancer in ?never smokers, and may be a particularly important factor contributing to ?the high incidence ?of lung cancer in never smokers in the East Asia. Additional exposures associated with lung ?cancer in never smokers in multiple studies ?include asbestos, which has known carcinogenic ?synergy with Viral infections. 55.viruses including HPV and HIV have been implicated in lung ?cancer risk in ?studies that included both never smokers and ever smokers. Currently, studies ?testing lung cancer specimens for HPV have yielded mixed results, and such variability of the ?frequency of HPV-positive lung cancer may be due to genetic susceptibility; methodologic ?approaches to detect HPV, such as those that involve the use of polymerase chain reaction; ?in situ hybridization and immunohistochemistry; and environmental and high-risk behavior ?variables Similar to the concerns related to the evidence for various viruses as causes of lung ?cancer further investigations are needed to solidify the evidence for a causal role of ?Chlamydia in lung cancer 27.?
Although smoking is a key risk factor for lung cancer in HIV-infected patients, several other ?factors may contribute to the higher incidence of lung cancer 90. ?

Common limitations found in many of the epidemiologic studies reviewed included a ?failure ?to clearly stratify analyses by smoking status, failure to quantify exposure to ?second hand ?smoke and other risk factors, and variable definitions of the terms non-?smoker and never ?smoker 22 55.?
More recent studies after adjusting for pack-years of smoking and other relevant covariates ?in a female cohort, showed that there was evidence for inverse associations of BMI and lung ?cancer risk in current and former smokers; whereas in never smokers, BMI was positively ?associated with lung cancer 78. ?
Some nonmalignant diseases have been associated with an increased risk for lung cancer, ?the strongest association being with Chronic obstructive pulmonary disease (COPD). Tobacco ?smoking is the primary cause of both lung cancer and Chronic obstructive pulmonary disease ??(COPD). A study of women never smokers with lung cancer showed a statistically significant ?association between the presence of airflow obstruction and the development of lung cancer ??79.?
Lung cancer was the most common cause of death, accounting for 38% of all deaths and lung ?cancer deaths exceeded deaths from cardiovascular disease by nearly 50%. More recent ?studies in large cohorts have shown that Chronic obstructive pulmonary disease (COPD) is ?significantly associated with an increased risk for lung cancer, especially in men 80, 81. ?
Because Chronic obstructive pulmonary disease (COPD) affects an estimated 40% to 70% of ?patients with lung cancer, a coexisting disease of lung cancer and Chronic obstructive ?pulmonary disease (COPD) likely reflects a common smoking exposure. A recent study ?evaluated 602 patients with lung cancer and found that 50% of them had prebronchodilator ?pulmonary function test results consistent with a diagnosis of Chronic obstructive ?pulmonary disease (COPD) with Global Initiative for Chronic Obstructive Lung Disease stage 2 ?and higher, independent of age, gender, and smoking history, with an OR of 11.6 82. ?
The prevalence of Chronic obstructive pulmonary disease (COPD) in newly diagnosed lung ?cancer was 6-fold greater than matched smokers, suggesting that Chronic obstructive ?pulmonary disease (COPD) itself is an important independent risk factor with potential ?relationship to the pathogenesis of lung cancer 82. ?
? A large retrospective study of patients with Chronic obstructive pulmonary disease (COPD) ?patients found that the risk for lung cancer was lower among patients who took high-dose ?inhaled corticosteroids compared with patients taking lower doses or none 83.?
? These results suggest that inhaled corticosteroids may have a chemo preventive role in lung ?cancer among patients with Chronic obstructive pulmonary disease (COPD). A study tested ?whether ?1antitrypsin deficiency carriers have a higher risk for lung cancer, after adjusting ?for the effects of tobacco smoke exposure and Chronic obstructive pulmonary disease ??(COPD). Using a multiple logistic regression analysis, they found a significantly increased lung ?cancer risk among ?1-antitrypsin deficiency carriers from two parallel case-control cohorts ??84, 85.?

A study from Taiwan showed an increased risk for lung cancer in tuberculosis patients with ?hazard ratio of 3.3 after adjusting for confounding factors, such as Chronic obstructive ?pulmonary disease (COPD) and smoking-related cancers other than lung cancer 88, 89.?

Reducing the incidence of lung cancer

A study described spontaneous smoking cessation before lung cancer diagnosis and ?challenged the widely believed notion that cessation was due to disease symptoms but ?instead spontaneous smoking cessation represent a presenting symptom of lung cancer itself ??94. ?
A randomized, double-blind, placebo-controlled trial was designed to determine whether ?daily supplementation of ?-tocopherol, ?-carotene, or both could reduce the incidence of ?cancers, including lung cancer, it was called The Alpha-Tocopherol, Beta Carotene Cancer ?Prevention Study 95. ?
A large prospective study displayed no relation between total intake of fruits and vegetables ?with lung cancer risk. The study did show that higher ingestion of several botanic groups, ?such as Convolvulaceae, rosacea, and umbelliferae, was significantly inversely associated ?with lung cancer risk in men and in former smokers 96.?
Chemoprevention has been used with some success in breast cancer, prostate cancer, and ?colon cancer; however, no agents have been validated as effective chemoprevention for lung ?cancer 97. ?
Omenn GS. Chemoprevention of lung cancer is evidenced to be difficult and unsatisfying, ?demanding new tactics and modalities 98.?
Early diagnosis of lung cancer is imperative because the 5-year survival rate for treated stage ?I lung cancer is substantially better than for stages II to IV. The issue of benefit related to ?lung cancer screening is being actively revisited. As promising as the National Lung Screening ?Trial results are, official guidelines on CT scan for lung cancer screening are not available ?pending careful evaluation of the new data to determine who should or should not consider ?undergo screen for early lung cancer detection 27.?

Cancer ?Prevention Studies I and II on Lung Cancer mortality ?

Comprehensive death data was published regarding lung cancer mortality rates amongst ?never ?smokers enrolled in two large American Cancer Society cohorts, the Cancer ?Prevention ?Studies I and II, which were initiated in the late 1950s and early 1980s, ?respectively, to ?characterize the risks of smoking. Scientists have followed their vital status through the ?present and have published ?thorough information on age-, sex-, and race-specific lung ?cancer death rates in never ?smokers for the entire 12-year follow-up of Cancer ?Prevention ?Studies ?-I and 18-year follow-up of Cancer ?Prevention Studies ?-II 71.?
These modeling studies did not contemplate the large and progressive upsurge in ?lung ?cancer risk associated with cigarette smoking that took place as the median ?duration of ?smoking has increased over time in the population 72.?
The greatest indication on time trends of lung cancer in never smokers ?originates from ?Cancer ?Prevention Studies ?-I and Cancer ?Prevention Studies ?-II. At least for the time period ?covered by these two ?studies, lung cancer mortality does not appear to be increasing in ?never smokers 22. ?

Nivolumab, a fully human IgG4 monoclonal antagonist monoclonal antibody to PD-1, was ?the first targeted drug agent in this category (anti-PD-1) to obtain U.S. Food and Drug ?Administration approval in the treatment ?of pretreated NSCLC. The drug demonstrated ?improved overall survival (OS) compared to docetaxel in patients with squamous and ?nonsquamous cell histologies progressing on platinum doublet chemotherapy in large Phase ?III trials 148, 149. ?
Results from a phase I clinical trial of BMS-936558 or ?Nivolumab in 296 patients with ?advanced cancers including NSCLC were published in ??2012. The cumulative response rate was ??18% among NSCLC patients; 65% of responses ?lasted one year or more 148-150. ?
The first trial, CheckMate 017 trial (NCT01642004), included 272 patients with previously ?treated advanced squamous were higher with nivolumab compared to chemotherapy. ?CheckMate 057 trial (NCT01673867) included 582 patients with previously NSCLC randomized ?to nivolumab (3 mg/kg intravenously every 2 weeks) or docetaxel (75 mg/m2 intravenously ?every 3 weeks) 149. ?
The primary endpoint was OS which was achieved with a median OS (mOS) of 9.2 months in ?the nivolumab arm compared to 6 months in the control arm. One-year survival rate was ??42% with nivolumab versus 24% with docetaxel. Other endpoints including objective ?response rate (ORR) and duration of response treated advanced nonsquamous NSCLC who ?had progressed on platinum-based chemotherapy or targeted therapy 148.?
Patients were randomized 1:1 to nivolumab or docetaxel. This study also achieved its ?primary endpoint of OS with a mOS for nivolumab of 12.2 months compared to 9.4 months ?in the chemotherapy arm. One-year survival rate was 51% with nivolumab compared to 39% ?with chemotherapy and the 18-month survival rate was 39% and 23%, respectively. ?
the ORR was significantly higher for nivolumab (19%) versus chemotherapy (12%) and the ?median DoR (mDoR) was 17 and 6 months, respectively. ?
Based on these studies, nivolumab was granted approval by the FDA for previously treated ?NSCLC of both squamous and nonsquamous histologies. ?

In a huge open-label randomized Phase III trial for Stage IV NSCLC patients, Nivolumab was ?evaluated against standard platinum-doublet chemotherapy in chemotherapy-naïve ?patients, the study was known as CheckMate 026 (NCT02041533) 208.?
on the other hand, the Phase III Checkmate 026 trial comparing another anti-PD-1 antibody, ?nivolumab, against doublet chemotherapy in NSCLC patients with >1% PD-L1 expression, ?failed to meet its endpoint. In the redefined subset of 423 patients with >5% PL1 expression ??209?
nivolumab did not improve PFS (4.2 vs 5.9 months; HR: 1.15; 95% CI: 0.91–1.45; p = 0.25) or ?OS (14.4 vs 13.2 months; HR: 1.02; 95% CI: 0.80–1.30). Furthermore, patients with increasing ?PD-L1 expression, even those with ?50% PD-L1 expression, did not appear to have greater ?benefit with nivolumab therapy over chemotherapy in a post-hoc analysis 208, 209.?

The phase II, single arm CheckMate 063 trial enrolled 117 patients with advanced, ?refractory ?squamous NSCLC between November 2012 and July 2013 150.?
CheckMate 057, a randomized, open-label, international, phase III study evaluated ?the ?efficacy and safety of nivolumab compared with docetaxel in 272 patients with ?advanced ?squamous NSCLC with disease progression during or after first-line ?chemotherapy 149.?
The phase III CheckMate 017 trial enrolled 292 patients with stage IIIB/IV non-?squamous ?NSCLC who progressed during or after first-line chemotherapy. Based on these results, in ?March 2015, nivolumab was approved by the FDA for ?patients with previously treated ?advanced or metastatic NSCLC. Of note, in the ?CheckMate studies, PD-L1 biomarker analyses ?were incorporated into the study ?design; however, these assessments were performed ?retrospectively and did not ?factor in study eligibility. ?
Patients received nivolumab with concurrent chemotherapy every 3 weeks for four ?cycles ?followed by nivolumab alone until progression or unacceptable toxicity. A total of 148 ?patients with advanced NSCLC received nivolumab and ipilimumab ?across 4 dose cohorts. ?Subsequently, KEYNOTE-010, a randomized, multi-national, phase II/III study ?compared ?pembrolizumab with docetaxel in 1,034 patients with pretreated advanced ?NSCLC expressing ?PD-L1 ?1%. Patients were randomized to receive pembrolizumab ??2 mg/kg, pembrolizumab 10 ?mg/kg, or docetaxel 75 mg/m2 every 3 weeks 143.?