Role of Anti-PD-1 / PD-L1 Immunotherapy in Lung Cancer

Special Issues, June 2015, Volume 1, Issue 1

In recent years, immunotherapy has taken the spotlight as a promising treatment modality, evolving with our increased understanding of the complex relationship between cancer cells and the immune system.

Lung cancer is very common, and patients with advanced-stage and metastatic lung cancer in particular have poor prognoses and greatly reduced quality of life. The main approaches to battling lung cancer have included surgical intervention, chemotherapy, radiation therapy (RT), and certain targeted therapies, but current options may be insufficient for many patients. In recent years, immunotherapy has taken the spotlight as a promising treatment modality, evolving with our increased understanding of the complex relationship between cancer cells and the immune system. The discovery of immune checkpoint proteins and a clearer picture of their role in cancer cell evasion has allowed for specific mobilization of the immune system in new ways. Treatment with monoclonal antibodies (mAbs) that block the inhibitory signals produced by the programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway is changing the overall cancer treatment paradigm. This supplement will review the current treatment paradigm for lung cancer and discuss emerging anti—PD-L1 immunotherapies and their clinical data in lung cancer.

Lung Cancer

Epidemiology

Lung cancer is one of the most common types of cancer worldwide1 and is the leading cause of cancer death in the United States.1,2 Cancers of the lung and bronchus account for 60.1 new cases of cancer and 48.4 deaths per 100,000 people in the United States each year, based on SEER data from 2007 to 2011. The risk of developing some form of lung or bronchus cancer over the course of a lifetime is about 6.8%, according to 2009-2011 SEER data.3 An estimated 224,210 new cases of lung and bronchus cancer were expected to be diagnosed in 2014, which would account for about 13% of all cancer diagnoses and lead to 159,260 deaths (27.2% of all cancer deaths).3,4 Between 2004 and 2010, the estimated 5-year survival rate of patients with lung cancer was 16.8%. The peak incidence of new cases of lung cancer occurs in patients aged 65 to 74 years, and the median age at diagnosis is 70 years. Men are more likely to develop and die of lung cancer than women.3

Risk Factors

The single most important risk factor for the development of lung cancer is smoking tobacco,2 which is estimated to be responsible for approximately 85% to 90% of all cases of lung cancer.2,5 Smoking increases the risk of developing lung cancer 10- to 20-fold, with the risk further increasing based on both the quantity of cigarettes smoked and the number of years spent smoking.2,6 Secondhand exposure to tobacco smoke also increases the relative risk.2,5

Smoking in combination with exposure to certain occupational or environmental factors compounds the risk of developing lung cancer. In particular, exposure to asbestos (which occurs in automobile shops, shipyards, mines, and textile and cement plants, as well as in construction and insulation workplaces) is thought to combine with smoking to exert a synergistic effect on the risk of lung cancer.2,5,6 Smokers with asbestos exposure have an approximately 50-fold relative risk of lung cancer compared with unexposed nonsmokers.5

Environmental contaminants such as radon, radiation, and air pollution may also increase risk.4 The US Environmental Protection Agency cites radon as the main cause of lung cancer in nonsmokers.7 In addition, lung cancer may occur after exposure to known carcinogens, such as heavy metals (eg, arsenic, beryllium, cadmium, nickel), oxidizing agents (eg, hexavalent chromium), polycyclic aromatic hydrocarbons, and bischloromethyl ether.2,5,6 Occupations associated with increased risk due to chemical exposure include paving, roofing, painting, chimney sweeping, and the manufacture of rubber products.4

Risk is nearly doubled in individuals belonging to families with prior lung cancer,6 potentially due to shared exposure to tobacco smoke and/or environmental carcinogens, or to shared genetic susceptibility (implicated in those who develop the disease at a young age).4,5 Patients with first-degree relatives who have received a lung cancer diagnosis are at 2 to 6 times the risk of patients whose first-degree relatives have not developed lung cancer, even after adjusting for tobacco use.5

Pathophysiology

The World Health Organization (WHO) divides lung cancer into 2 major classes that have different prognoses and are treated with different strategies2: non-small cell lung cancer (NSCLC), which accounts for the majority (85%) of all lung cancers, and small cell lung cancer (SCLC) (Table 1).2,4-6,8,9 Additionally, there are other neuroendocrine tumors of the lung that are not classified as either NSCLC or SCLC, such as carcinoid and atypical carcinoid tumors.6

NSCLC can be either non-squamous cell carcinoma (including adenocarcinoma and large cell carcinoma) or squamous cell (epidermoid) carcinoma. Each subtype of NSCLC reflects the type of tissue from which the tumor originated.2 Adenocarcinoma is the most common type of lung cancer in North America and the most frequently occurring type in nonsmokers.2,6 Usually found in the periphery of the lung, this cancer starts in mucus-secreting cells.6,8 Adenocarcinoma can also occur centrally, multifocally, or in an entire lobe. Tissue sections may have different cell patterns, which may be characterized as acinar (glandular), papillary, lepidic (bronchioloalveolar), micropapillary, solid, or mucinous. About 80% of adenocarcinomas demonstrate 2 or more of these different patterns.6

Large cell carcinoma can appear in any part of the lung, but usually occurs peripherally.6,8 Large cell carcinomas may appear under microscopic examination as sheets of relatively large malignant cells and lack the features of small cell carcinomas. In addition, large cell carcinomas are often identified with associated necrosis. On cytologic preparations, cells may be arranged in syncytial groups that lack squamous, glandular, or papillary characteristics. In addition, some large cell carcinomas may be classified as neuroendocrine tumors (large cell neuroendocrine carcinomas).6

Table 1. Summary of Lung Cancer Types2,4-6,8,9

NSCLC indicates non-small cell lung cancer; SCLC, small cell lung cancer.

Squamous cell (epidermoid) carcinoma starts in squamous cells and tends to occur centrally in the lungs near a bronchus.8 Histopathologically, these cells show keratinization and/or intercellular bridges. The most common pattern is one of infiltrating nests of malignant squamous cells with central necrosis, often resulting in cavitation. Important variants (eg, papillary, basaloid) have also been described.6 SCLC is less common, accounting for approximately 14% of lung cancers, but more aggressive than NSCLC, growing and spreading quickly after starting bronchially, in the portion of the lung located near the center of the chest.4,5,9 Subtypes include small cell carcinoma,also known as oat cell cancer, and combined small cell carcinoma, which includes components of both SCLC and NSCLC subtypes, most commonly squamous cell carcinoma, adenocarcinoma, and large cell carcinoma.6,9 Small cell carcinoma cells are typically small and round, oval, or spindle-shaped with prominent nuclear molding, scant cytoplasm, and finely granular (“salt-and-pepper”) chromatin without prominent nucleoli.6,10 Small cell carcinoma is categorized as a poorly differentiated neuroendocrine tumor. Cells may form patterns characteristic of neuroendocrine tumors, such as rosettes and trabeculae. Combined small cell carcinoma includes characteristics of small cell carcinoma with traits of any of the NSCLC subtypes.6

Screening

Patients with NSCLC or SCLC typically present with cough, dyspnea, chest pain, and weight loss.6 Those with SCLC may also present with neurologic and/or endocrine paraneoplastic syndromes and symptoms, including proximal leg weakness, encephalomyelitis, sensory neuropathy, Cushing syndrome, and syndrome of inappropriate antidiuretic hormone secretion.5,6,10 However, some patients, especially those with slow-growing tumors, are asymptomatic.6 Risk assessment, including a patient’s history of smoking and exposure to radon or asbestos, and symptom assessment (if symptoms are present) may help guide the decision of whether or not to screen for lung cancer.11

Lung cancer screening aims to detect disease at a stage when it is not causing symptoms and when treatment will be most successful. The detection of early-stage disease may present an opportunity for decreasing mortality rates and improving quality of life.11 According to a study conducted by the International Early Lung Cancer Action Program, patients diagnosed as a result of an annual computed tomography (CT) screening have an overall 10-year lung cancer—specific survival rate of 80% regardless of tumor stage or the type of treatment they receive. Further, the lung cancer–specific 10-year survival rate among patients with screen-detected early-stage lung cancer who underwent surgical resection within 1 month after diagnosis was 92%.12

The National Comprehensive Cancer Network (NCCN) recommends that lung cancer screening with spiral (helical) low-dose CT (LDCT) should be part of a program of care.11 Candidates for LDCT include patients at high risk for developing lung cancer, particularly patients with an extensive (≥30 pack-year) smoking history.2 The effectiveness of LDCT has been evaluated in patients at high risk for lung cancer. In the National Lung Screening Trial, LDCT screening to detect lung cancer among smokers was shown to reduce the rate of lung cancer mortality by 20% compared with chest radiography.13

Diagnosis

The NCCN recommends that the diagnostic strategy for lung cancer be decided in a multidisciplinary setting and individualized for each patient.2 Diagnostic workup in patients with signs of lung cancer on LDCT may include biopsy or minimally invasive tests. The type of biopsy performed should be individualized based on the risks associated with the biopsy procedure, size and location of the tumor, and other patient-specific factors (eg, comorbidities). 2,5 In general, a diagnosis of central lesions (eg, squamous cell carcinomas or small cell carcinomas) may be accomplished most readily with bronchoscopic examination, whereas diagnosis of peripheral lesions (eg, adenocarcinomas or large cell carcinomas) may require more invasive strategies, such as biopsy or transthoracic fineneedle aspiration.6 Diagnostic accuracy in distinguishing between NSCLC and SCLC is excellent; however, immunohistochemistry (IHC) may be required to differentiate between subtypes of NSCLC.2,6

IHC staining in lung cancer can test for keratin immunoreactivity, epithelial membrane antigen, thyroid transcription factor-1 (TTF-1), chromogranin A, neuron-specific enolase (NSE), neural cell adhesion molecule (NCAM), and synaptophysin.2,10 These markers are indicative of specific subtypes. For example, IHC staining for TTF-1 helps identify adenocarcinoma, while markers of squamous cell carcinoma such as high-molecular-weight cytokeratins (eg, CK5/6, p63) may aid in establishing a diagnosis.6

Predictive and Prognostic Biomarkers

After diagnosis, the detection of genetic abnormalities or biomarkers may predict therapeutic efficacy and/or the prognosis.2 Genetic tests in lung cancer commonly look for mutations in the KRAS gene (occurring in approximately 25% of adenocarcinomas in North America) and the epidermal growth factor receptor (EGFR) gene (occurring in approximately 20% of lung cancers), as well as ALK gene rearrangements (occurring in 2% to 7% of patients with NSCLC).2,6 The NCCN strongly recommends testing patients with NSCLC for sensitizing EGFR mutations and ALK gene rearrangements so they may receive the appropriate targeted therapy as part of their treatment plan (eg, erlotinib, afatinib, crizotinib, and ceritinib). In addition, KRAS detection may be performed to determine prognosis, as these mutations are associated with poor survival and may predict lack of benefit from certain treatments (eg, EGFR inhibitors). Lung cancer may also possess driver mutations and gene rearrangements such as HER2 (ERBB2) or BRAF mutations, ROS1 or RET rearrangements, or MET amplification. The NCCN also recommends testing for these genetic abnormalities with multiplex/next-generation sequencing to ensure that patients receive the most appropriate treatment, including treatment in clinical trials of agents targeting these mutations.2

Staging

Importantly, all diagnosed lung cancer patients should be clinically staged, because stage at presentation also helps determine treatment and prognosis.5,6 Noninvasive imaging techniques aid in staging tumors by revealing the burden of disease, including the tumor burden outside the lung. While the sensitivity and accuracy of a chest x-ray are limited, a chest CT scan should be performed in all patients with known or suspected NSCLC because it provides greater anatomic detail necessary for staging. Whole-body positron emission tomography (PET) scanning may also be performed to provide functional information on metabolic activity, and it provides improved sensitivity and specificity versus chest CT in staging mediastinal tumors. In general, magnetic resonance imaging does not play a major role in NSCLC staging but can be useful in selected circumstances.6

Using information gathered from imaging studies, staging of tumors may be accomplished with the tumor, node, metastasis (TNM) staging system established by the 7th edition of the AJCC Cancer Staging Manual published by the American Joint Committee on Cancer (AJCC) (shown in Table 2).14 Pathologic staging with TNM uses both clinical staging information (noninvasive and including medical history, physical examination, and imaging) and other invasive staging procedures (eg, thoracotomy and mediastinoscopy).2 The primary tumor classification takes into account whether the tumor is in the lobar bronchus or more distal airways; involvement of the visceral pleura; involvement of the main bronchus; presence and extension of atelectasis or obstructive pneumonitis; involvement of the mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, or carina; and presence/location of satellite tumor nodules. Involvement of regional (eg, hilar, mediastinal) lymph nodes may be determined with the aid of the International Association for the Study of Lung Cancer (IASLC) lymph node map. The system also delineates the presence (including location, such as to a contralateral lobe or to extrathoracic organs) or absence of lung cancer metastases.14

SCLC is staged using a combined approach that incorporates the AJCC TNM staging system and the older Veterans Administration system for SCLC. In this approach, SCLC is classified as limited-stage disease, defined as stage I to III disease that can be safely treated with RT, or extensivestage disease, defined as stage IV (metastatic disease) or T3-4 because of multiple lung nodules or tumor/nodal volume that is too large to be safely treated with RT.10

It is also important to note that adenocarcinoma has a specific, separate staging system.15 This classification of adenocarcinoma was revised in 2011 by the IASLC, American Thoracic Society, and European Respiratory Society, using a special subsystem in order of invasiveness, from least invasive to most invasive: adenocarcinoma in situ, minimally invasive adenocarcinoma, invasive adenocarcinoma, and invasive adenocarcinoma variants. The former term for adenocarcinoma, bronchioloalveolar carcinoma, is no longer used.2,15 Taken together, pathologic evaluation (including genetic mutational status) and accurate staging are important to consider when determining the course of treatment for lung cancer.6

Treatment Options

Treatment varies depending on many factors, including the subtype of lung cancer, the patient’s performance status, and the stage of the lung cancer lesion.2,5 Regardless of the approach, all smokers with lung cancer should quit. When appropriate, medications that promote smoking cessation should be prescribed. Current treatment options include surgery, RT, chemotherapy, and (in NSCLC, but not yet in SCLC) targeted therapies, and the NCCN strongly recommends enrollment in a clinical trial.2,10 This section will describe the various treatment options for NSCLC and SCLC recommended by the NCCN.

Non-Small Cell Lung Cancer

Surgery

For stage I or II NSCLC, surgical removal of the tumor provides the best chance of cure. Prior to surgery, the overall treatment plan should be determined, necessary imaging studies performed, and a comprehensive medical evaluation conducted. The surgical procedure chosen depends on the disease extent and the patient’s cardiopulmonary reserve. In general, resection (including wedge resection) is preferred over ablation, and systematic lymph node sampling is appropriate during resection. In patients with stage III NSCLC, the use of surgical techniques depends on resectability of the tumor as well as the number and size of nodes. According to the NCCN, surgery may be an appropriate option for certain patients with N2 disease, particularly those who have responded to earlier induction chemotherapy.2 These patients should not be denied surgical intervention, as patients with stage IIIA N2 disease who have had a prior response to chemotherapy have demonstrated 5-year survival rates of approximately 30%. Because long-term survival or cure is a possible outcome in these patients, surgical treatment in patients with up to 2 nodes and stage III disease is an important consideration. 2,16,17

Radiation Therapy

In patients with NSCLC that can be surgically removed, RT may be appropriate as adjuvant therapy, provided patients have no contraindications for surgery. In addition, RT may be used as local treatment and/or as palliative therapy in patients with NSCLC for whom surgery is not an option. In patients with stage I or II unresectable or otherwise medically inoperable NSCLC, stereotactic ablative radiotherapy (SABR), also known as stereotactic body RT, may be an appropriate option. SABR may also be used as palliative therapy in patients with limited lung metastases. This technique uses RT administered at a very high dose for a short course of therapy administered in a targeted manner. Definitive RT is an alternative to SABR for patients with stage I or II disease who do not have involved nodes and refuse surgery or are unable to have surgery.2

Table 2. AJCC TNM Staging System for Lung Cancer14

AJCC indicates American Joint Committee on Cancer; TNM, tumor, node, metastasis.

Republished with permission of the American Joint Committee on Cancer from Edge S, Byrd DR, Compton CC, et al. AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer; 2010. Permission conveyed through Copyright Clearance Center, Inc.

RT, often administered in combination with chemotherapy (chemoradiation), is recommended for patients with stage II to III disease who cannot undergo surgery. In stage IV lung cancer with extensive metastases, RT may be part of a palliative treatment regimen for primary or distant sites.2

Radiofrequency ablation (RFA) may be another option for node-negative patients who either refuse surgery or cannot tolerate surgery because of poor performance status, significant cardiovascular risk, poor pulmonary function, and/or comorbidities. Patients with an isolated peripheral lesion less than 3 cm are considered optimal candidates for RFA. Even in patients who have received previous RT, RFA may be used as a part of treatment and palliation.2 A clinical study evaluating RFA in 33 patients with NSCLC yielded overall survival (OS) of 70% (95% CI, 51%-83%) at 1 year and 48% (95% CI, 30%-65%) at 2 years.18

Brain metastases affect approximately 30% to 50% of patients with NSCLC. Whole-brain RT and stereotactic radiosurgery (SRS) may be used to treat patients with brain metastases. The NCCN recommends surgery followed by whole-brain RT for select patients (those with good performance status) with a single brain metastasis. Patients with a single brain metastasis who cannot tolerate or who refuse surgery may be treated with SRS with or without whole-brain RT. Ultimately, treatment for patients with brain metastases should be individualized based on multidisciplinary discussion.2

Chemotherapy

Chemotherapy agents commonly used to treat NSCLC include platinating agents (eg, cisplatin, carboplatin), taxanes (eg, paclitaxel, albumin-bound paclitaxel, docetaxel), vinca alkaloids (eg, vinorelbine, vinblastine), and other agents such as etoposide, pemetrexed, and gemcitabine.2 Trials have identified a survival benefit with chemotherapy in patients with resectable NSCLC using chemotherapy either before or after surgical tumor removal.19,20 However, in the setting of unresectable stage III disease, chemoradiation is recommended, and concurrent treatment in these patients has been shown to be superior to sequential therapy.2,21,22 Patients with stage IV disease may derive a palliative benefit from chemotherapy, particularly platinum-based agents, in the form of improved quality of life and survival,2,23 and platinum-based chemotherapy is the standard of care for patients with stage IV NSCLC who have good performance status. For patients with advanced disease and poor performance status, the NCCN recommends either monotherapy or a platinum-based combination regimen. Common platinum-based regimens used to treat NSCLC include carboplatin/paclitaxel, cisplatin/paclitaxel, cisplatin/vinorelbine, gemcitabine/cisplatin, cisplatin/ pemetrexed, and docetaxel/cisplatin. In the United States, the most frequently used first-line regimens for non-squamous NSCLC include cisplatin (or carboplatin)/ pemetrexed, and carboplatin/paclitaxel with or without bevacizumab (Avastin). For patients with squamous cell carcinoma, gemcitabine/cisplatin is generally used.2

Targeted Therapy

Molecular targeted therapy is a strategy for cancer that relies on exploiting the pathways and mutations that enable tumors to grow and progress. Because of the specificity of targeted therapy, the therapeutic window should be improved, because these agents affect tumor cells while sparing healthy cells.6 Targeted therapies used in the treatment of advanced NSCLC include bevacizumab, erlotinib, afatinib, crizotinib, and ceritinib.2

Bevacizumab, an mAb that blocks vascular endothelial growth factor (VEGF), is indicated for non-squamous NSCLC with carboplatin and paclitaxel as first-line treatment of unresectable, locally advanced, recurrent, or metastatic disease.2,24 The NCCN recommends bevacizumab in combination with chemotherapy as one treatment option for patients with non-squamous NSCLC and good performance status whose tumors do not contain mutations of the EGFR or ALK genes.2

Patients with EGFR substitution mutations or deletions confirmed by genetic testing may be treated with erlotinib, an oral tyrosine kinase inhibitor (TKI).2,25 Compared with chemotherapy, TKIs may improve quality of life and progression-free survival (PFS) in patients with EGFR mutations.26 Erlotinib was approved for first-line use in patients with metastatic EGFR-mutated NSCLC and for the treatment of locally advanced or metastatic NSCLC after failure of at least 1 prior chemotherapy regimen25 after it demonstrated efficacy and safety both as first-line therapy and second-line or subsequent therapy in phase 3 clinical trials.27,28 The NCCN recommends erlotinib as first-line therapy regardless of performance status in patients with advanced, recurrent, or metastatic non-squamous NSCLC tumors that have EGFR mutations. According to the NCCN, switching patients from chemotherapy to erlotinib therapy is an appropriate option when EGFR mutations are detected during chemotherapy.2

Afatinib, crizotinib, and ceritinib are other TKIs used to treat NSCLC.2 Afatinib is approved for first-line treatment of patients with metastatic NSCLC who have sensitizing EGFR mutations.29 It is also recommended for second-line treatment of patients who have progressed after first-line chemotherapy, but it is not yet approved for this use.2 Crizotinib is an option for patients with metastatic NSCLC who test positive for ALK gene rearrangements.30 Crizotinib may result in significantly greater reductions (P < .001) in pain, dyspnea, and cough than conventional nontargeted chemotherapy, and it may be effective as secondline therapy in patients with ALK rearrangements, compared with chemotherapy.31 Patients with ALK-positive metastatic NSCLC who progress or become intolerant to crizotinib may instead be treated with ceritinib.32 In addition, cetuximab (Erbitux), an EGFR antagonist approved for treatment of squamous cell carcinoma of the head and neck and colorectal cancer (CRC), has shown a survival benefit in NSCLC in combination with chemotherapy, although it is not approved for this indication.33,34 For patients with advanced NSCLC without EGFR mutations or ALK rearrangements, regardless of histology, cetuximab/ cisplatin/vinorelbine combination therapy is an option. However, benefits of this regimen are slight, it is difficult administer, and tolerability may be poor.2,34

Small Cell Lung Cancer

Surgical resection is an option in only 2% to 5% of patients with resectable, limited-stage SCLC in whom biopsy has confirmed that mediastinal lymph nodes are not involved. If resection is performed, the NCCN recommends lobectomy; segmental or wedge resections are not considered appropriate for patients with SCLC. If complete tumor removal is successful, treatment with chemotherapy or chemoradiation as adjuvant therapy is recommended.10

Chemotherapy is essential to the treatment of all patients with SCLC because of this cancer type’s propensity for growing rapidly and spreading to distant sites.5,10 Both single-agent and combination chemotherapy regimens have demonstrated activity in SCLC, but combination chemotherapy has been the foundation of SCLC treatment for more than 3 decades.6 The most frequently used initial combination regimen is etoposide/cisplatin (EP), which demonstrated significant improvements in survival rates (P = .001) of patients with both limited-stage and extensive-stage SCLC.10,35 Patients with limited-stage disease (approximately 30%-40% of SCLC patients)5 and good performance status should be treated by EP with concurrent thoracic RT. Concurrent chemoradiation is preferable to sequential therapy because it achieves numerically higher complete response rates (P = .07) than sequential chemotherapy followed by RT in patients with limitedstage SCLC.10,36 RT should start with the first or second cycle. The optimal dose and schedule of RT have not been established, but a twice-daily radiotherapy regimen (45 Gy administered over 3 weeks) is superior to a once-daily regimen (45 Gy administered over 5 weeks) in terms of overall 5-year survival.10,37 EP plus concurrent thoracic RT is the treatment of choice in the United States for patients with limited-stage disease because it can achieve an overall response rate (ORR) of up to 97% (vs 92% with sequential therapy).5,10,36

Extensive-stage SCLC is usually treated with chemotherapy alone, although RT may be used in select patients for its palliative benefits.10 Either EP or etoposide/platinating agent (cisplatin or carboplatin) regimens may be used in extensive-stage SCLC.5,10 Combination chemotherapy alone can achieve response rates between 50% and 70% in extensive-stage disease.38,39 Unfortunately, the 2-year survival rate is less than 5%.35 Thus, many treatment regimens and chemotherapeutic agents have been evaluated in an effort to improve survival.10 Among these is the addition of a third agent to standard 2-drug regimens. This approach has yet to show a significant survival advantage or sufficient tolerability.10,40,41

In patients with extensive disease along with brain metastases, which occur in more than 50% of patients with SCLC, chemotherapy is an option either before or after whole-brain RT, depending in part on the patient’s neurologic symptoms. To reduce the risk of developing brain metastases, some patients may choose to undergo prophylactic cranial irradiation (PCI). The NCCN recommends PCI for patients who have experienced a complete or partial response to therapy and have limited- or extensivestage disease. PCI is also recommended for all patients who have had a complete brain tumor resection.10

SCLC is generally very responsive to initial treatment, but tumors in most patients will subsequently regrow and will be more resistant to chemotherapy.10 Later-line chemotherapy, which typically consists of single-agent chemotherapy, may be used with a palliative intent.10,42 The NCCN recommends administering subsequent chemotherapy until best response (plus 2 additional cycles), disease progression, or the development of unacceptable toxicity. The likelihood of response depends on the length of time between initial chemotherapeutic treatment and relapse.10

Overall, management of SCLC has changed little in the past decade, with chemotherapy remaining the mainstay of treatment.5 Currently, the NCCN does not recommend the use of bevacizumab in patients with SCLC,10 and other targeted therapy drugs are not approved for use in SCLC.

Emerging Therapies: Anti—PD-1/PD-L1 Immunotherapy

Evolution of Immunotherapy

Immunotherapy has been employed as a method of cancer treatment for over a century, starting with William Coley, who first observed spontaneous remission in cancer patients after infection with a mixture of killed infectious agents (dubbed Coley’s toxins).43 In the years that followed, understanding of the dynamic and complex relationship between the immune system and cancer continued to increase, leading to the concept of immunotherapy.6

Strategies of immunotherapy are diverse, including immunostimulatory mAbs and cancer vaccines, but the ultimate goal is to enable the patient’s immune system to recognize and kill cancer cells.6,44-47 Immunotherapies may be passive, which use immune system components to target cancer cells without initiating the patient’s immune system, or active, which trigger a patient’s endogenous immune response. Initial immunotherapies in cancer were passive agents that target various cancerassociated proteins or pathways of inflammation (eg, HER2/neu, EGFR, VEGF, CD20, CD52, CD33, interleukin [IL]-2 [Proleukin], interferon [IFN]-α).44 Later, mAbs that exert a number of passive and active effects on the immune system to fight a variety of cancers changed the immunotherapy landscape.48 Cancer vaccines, in particular sipuleucel-T (Provenge), an active cellular immunotherapy, have also demonstrated efficacy and led to significant improvement in OS for men with metastatic castrationresistant prostate cancer (CRPC).49 Today, we further define immunotherapies as treatments that harness the immune system to establish targeted responses, and researchers continue to improve and expand the repertoire of cancer immunotherapies.47

Our improved understanding of the immune system and cancer has revealed the ability of cancer cells to escape the anticancer effects of the immune system as well as exert multiple direct and indirect immunosuppressive effects. Cancer cells have several mechanisms of evading immune system response. Some tumors release paracrine mediators (eg, adenosine, transforming growth factor β [TGF-β], VEGF-A) that may function in the suppression of dendritic cells (DCs), indirectly inhibiting T-cell penetration into the tumor bed or directly suppressing activation of effector T cells. Other mediators secreted by tumors (eg, CCL2, CXCL12) can promote the immunosuppressive cell recruitment and function. Cancer cells may also escape the recognition of T cells by downregulating expression of surface major histocompatibility complex class I antigens. On the other hand, some cancer cells upregulate certain surface ligands, such as those that mediate T-cell anergy or otherwise inhibit T cells.44

An increased understanding of the various evasion mechanisms has led to the development of a new set of anticancer immunotherapies intended to abolish the mechanisms by which cancer cells avoid immune detection.

Some immunotherapies in development for NSCLC include allogeneic cancer vaccines targeting mucin 1 (MUC1), melanoma antigen encoding gene A3 (MAGEA3), and CIMAvax epidermal growth factor (EGF), as well as belagenpumatucel-L (BGPT-L), which is an autologous cellular therapy against TGF-β2.50 Other immunotherapies unleash suppressed immune responses by modulating immune “checkpoints,” or interactions of T cells and either antigen-presenting cells (APCs) (eg, DCs, macrophages) or tumor cells, thereby preventing cancer from evading immune-mediated destruction. These drugs are referred to as immune checkpoint inhibitors. Currently, immune checkpoint inhibitors target cytotoxic T-lymphocyte antigen-4 (CTLA-4) and the PD-1/PD-L1 pathway.51

CTLA-4 inhibitors were among the first immune checkpoint inhibitors available for cancer treatment.51 CTLA-4 is a regulatory molecule recruited to the plasma membrane after T-cell activation. Once in the membrane, CTLA-4 binds to the B7 family of accessory molecules expressed by APCs.44 Ipilimumab (Yervoy) is an anti-CTLA-4 mAb that blocks the interaction of CTLA-4 with its ligands. It has been shown to augment activation and proliferation of T cells.52 Approved by the US Food and Drug Administration (FDA) in 2011, it is indicated for the treatment of unresectable or metastatic melanoma after demonstrating improved OS compared with a peptide vaccine.52,53 Ipilimumab is currently being investigated in a phase III trial in patients with squamous NSCLC.54 However, with the ascendance of other immune checkpoint inhibitors that target PD-1/PD-L1, CLTA-4-directed immune checkpoint inhibitors are no longer considered the best immunotherapy candidates for NSCLC.51

PD-1/PD-L1

An increased understanding of PD-1 and its ligands has led to the development of anti-PD-1/PD-L1 immunotherapy; use of these agents has recently gained momentum in NSCLC, with several currently being evaluated in clinical trials.55 The PD-1 receptor (also known as CD279) is expressed on the surface of activated T cells and binds to its ligands PD-L1 (also known as B7-H1 or CD274) and PD-L2 (also known as B7-DC or CD273). The predominant ligand PD-L1 can be expressed by a variety of cells, including T cells, B cells, DCs, macrophages, and cancer cells, while PD-L2 is largely found on APCs but rarely on cancer cells.47 In T cells, when PD-1 binds to its ligands, an inhibitory signal is transmitted into the T cell, leading to reduced cytokine production and suppression of proliferation.56,57 PD-L1 is also known to bind to the B7-1 (CD80) receptor found on T cells; this interaction likewise produces an inhibitory signal, causing reduced cytokine production and decreased proliferation.58

The PD-1 pathway is an attractive therapeutic target in cancer because cancer cells exploit this pathway to create an immunosuppressive environment. They often increase activation of inhibitory pathways, production of inhibitory substances, and suppression of stimulatory pathways, which together allow the cancer cells to evade destruction by the immune system.46,47,58 Tumor-infiltrating T cells from patients with NSCLC have shown dramatically increased expression of PD-1 compared with T cells in healthy control patients.59 Further, cancer cells, including NSCLC cells, upregulate PD-L1 expression, which is enhanced in part by proinflammatory cytokines in the tumor microenvironment.57,60 Overexpressed PD-L1 on cancer cells binds to highly expressed PD-1 on tumor-infiltrating T cells, which produces inhibitory signals inside the T cells. These signals lead to the dysfunction of the tumorinfiltrating T cells; such T cells in NSCLC patients have exhibited a reduced capacity to produce cytokines, as well as poor proliferation.59,61,62 In short, high levels of PD-L1 on tumor cells ensure interaction with abundant PD-1 on attacking T cells, allowing cancer cells to inactivate the T cells and thus avoid destruction.61,62

Therefore, researchers have focused on developing agents that block the PD-1/PD-L1 interaction. Blocking the PD-1/PD-L1 pathway (with anti-PD-L1 mAb) in patients with NSCLC has been shown to reverse T-cell dysfunction, resulting in increased cytokine production and T-cell proliferation.59 Several important anti-PD-1/PD-L1 mAbs currently being investigated in both solid and hematologic cancers, including NSCLC, are pembrolizumab, nivolumab, and MPDL3280A.55

Evidence also suggests the promise of anti-PD-L1 drugs as part of combination therapy in lung cancer. Targeted agents and immunotherapy can have complementary roles in cancer treatment; consequently, combinatorial therapy may prove synergistic in certain cases.48 For example, there may be an advantage of combination therapy in NSCLC patients with abnormalities in the EGFR, KRAS, or ALK genes. To determine whether NSCLCs driven by oncogenes express PD-1/PD-L1 similarly to other NSCLCs and may thus may respond to combination therapy, investigators analyzed 125 patients with NSCLC. Patients had EGFR mutation (n = 56), KRAS mutation (n = 29), and ALK rearrangement (n = 10). A control group of patients (n = 30) had wild-type expression of EGFR, KRAS, and ALK. They found that patients harboring KRAS mutations had higher levels of PD-1 expression compared with the KRAS wild-type population, and presence of EGFR mutations or ALK rearrangements were associated with increased PD-L1 protein levels.63 These patients may be ideal candidates for combination therapy that utilizes both targeted agents and PD-1/PD-L1 immunotherapy.

Targeted agents are not the only option for combination with immunotherapy. Investigators also hypothesize that a combination of epigenetic therapies and immune checkpoint inhibitors is potentially synergistic in NSCLC because azacytidine (an epigenetic agent that promotes hypomethylation) upregulates transcription of PD-L1 in NSCLC cells.64

Patient Selection for PD-1/PD-L1 Immunotherapy

With the knowledge that anti—PD-1/PD-L1 immunotherapies may be effective in lung cancer, it becomes important to predict which patients might respond better to this type of treatment. PD-L1 expression has been characterized in specific subsets of NSCLC and patients with NSCLC. Investigators performed IHC analysis of 164 patients with NSCLC to assess levels of PD-L1 on the surface of cells via flow cytometry. They determined that PD-L1 levels were generally higher in women than in men, in neversmokers than in smokers, and in adenocarcinomas than in squamous cell carcinomas (which also corresponded to the subsets of patients more likely to harbor EGFR mutations).65 Another study found that expression of PD-1 on NSCLC cells was associated with current smoking, KRAS mutations, EGFR mutations, and adenocarcinomas.63 It is possible that these subsets of patients with higher levels of PD-1/PD-L1 will respond better to PD-1/PD-L1 checkpoint inhibitors.

Further, T-cell response against a transcription factor called sex determining region Y (SRY)-box 2 (SOX2) may be associated with response to anti—PD-1 immunotherapy in NSCLC. The detection of SOX2-specific T cells is another potential strategy to identify lung cancer patients who are more likely to benefit from treatment with anti–PD-1 mAbs.66

Finally, PD-1 and PD-L1 may also carry prognostic significance in lung cancer. Indeed, PD-L1 expression is known to correlate with poor prognosis in other cancers, such as melanoma.45 In lung cancer, a multivariate analysis demonstrated that PD-L1-positive lung cancer cells were related to a poor prognosis,60 and an investigation assessing single-nucleotide polymorphisms (SNPs) in 583 surgically excised NSCLC samples analyzed the relationship between abnormal promoter regions in DNA encoding PD-1 and prognosis. A specific SNP of the PD-1 promoter region (—606 GG) was associated with significantly poorer survival (P = .0183) compared with 2 other SNPs of the PD-1 promoter region (—606 AA and –606 GA).67

Select Anti—PD-1/PD-L1 Immunotherapies for Lung Cancer

The anti-PD-L1 immunotherapies MPDL3280A, nivolumab, and pembrolizumab have shown promise for NSCLC in early studies. Several clinical trials are under way to further evaluate the safety and efficacy of these immune checkpoint inhibitors in lung cancer.

MPDL3280A (Genentech/Roche)

MPDL3280A is a human mAb that targets PD-L1, thereby preventing its binding to its receptors (PD-1 and B7-1)68 and restoring antitumor T-cell activity and proliferation. It also can improve T-cell priming.58 MPDL3280A contains an engineered fragment crystallizable (Fc) domain designed to optimize efficacy and safety.68 In theory, this structure will allow inhibition of the PD-1/PD-L1 pathway while minimizing the antibody-dependent cellular cytotoxicity-mediated depletion of activated T cells that is required for an effective antitumor immune response.47

MPDL3280A has demonstrated efficacy and safety in lung cancer in several clinical trials. In a phase I expansion study, investigators assessed the effects of MPDL3280A in patients with squamous or non-squamous NSCLC at a range of doses (1-20 mg/kg) for up to 1 year of treatment. Of the 53 patients evaluable in early 2013, the median age was 61 years; the majority had a good performance status (Eastern Cooperative Oncology Group 0 to 1); and most had undergone prior surgery (89%), RT (55%), or systemic therapy (98%). Grade 3 and 4 adverse events (AEs) occurred in 34% of the patients and included pericardial effusion (6%), dehydration (4%), dyspnea (4%), and fatigue (4%) but did not include any cases of grade 3 to 5 pneumonitis or diarrhea. ORR in 37 evaluable NSCLC patients who enrolled before July 1, 2012, was 24% (9/37), and 24-week PFS was 48%. Further, patients with PD-L1- positive tumors had an ORR of 100% (4/4), and none of these 4 patients experienced progressive disease (PD). Patients with PD-L1-negative tumors had an ORR of 15% (4/26) and a PD rate of 58% (15/26). Thus, PD-L1 tumor status was shown to correlate with response to MPDL3280A.68 While the phase I study is ongoing, it has been concluded that treatment with MPDL3280A is tolerable and provides rapid and durable responses.68,69 Phase Ib trials are currently evaluating the combinations of MPDL3280A with vemurafenib (Zelboraf) in treatment-naïve metastatic melanoma70 and MPDL3280A with bevacizumab in advanced solid tumors, including NSCLC.71

A phase II study (FIR) of MPDL3280A in patients with PD-L1-positive locally advanced or metastatic NSCLC is ongoing,72 and a second phase II study (BIRCH) in metastatic NSCLC is currently recruiting participants.73 Both trials are multicenter, single-arm studies that will evaluate the efficacy and safety of MPDL3280A therapy in lung cancer patients, who will receive intravenous (IV) treatment once every 3 weeks until disease progression.72,73

Also ongoing is a multicenter, open-label, randomized phase II trial (POPLAR) comparing MPDL3280A with docetaxel in patients with advanced or metastatic NSCLC who have failed platinum-based chemotherapy.74 Finally, a phase III trial (OAK) is currently enrolling patients with locally advanced or metastatic NSCLC. This multicenter, open-label, randomized, controlled study will also compare MPDL3280A with docetaxel in patients with NSCLC after failure with platinum-based chemotherapy.75

Nivolumab (BMS-936558) (Bristol-Myers Squibb)

Nivolumab was the first PD-1/PD-L1 immune checkpoint inhibitor to enter clinical testing. It is a fully human immunoglobulin G4 (IgG4) mAb targeted against PD-1 on activated T and B cells. Blocking PD-1 prevents these activated lymphocytes from undergoing anergy, or immunologic inactivation. In this way, PD-1 blockers help maintain antitumor immunologic activity.59,76 Pharmacokinetic studies of nivolumab included single ascending dose and multiple ascending dose studies in patients with advanced solid malignancies. Investigators reported that the half-life of nivolumab is 17 to 25 days (consistent with that of endogenous IgG4), mean volume of distribution ranged from 83 to 113 mL/kg, and mean clearance ranged from 0.13 to 0.19 mL/h/kg.76

Nivolumab has been studied extensively in patients with NSCLC and other tumors. A phase I study evaluated the activity, pharmacokinetics, and safety of nivolumab in refractory solid tumors. A total of 39 patients with advanced metastatic NSCLC (n = 6), melanoma (n = 10), CRC (n = 14), CRPC (n = 8), or renal cell carcinoma (RCC) (n = 1) received the nivolumab therapy at several dosage levels. Median age was 62 years, and all patients in this study had progressive treatment-refractory disease. One patient with NSCLC (and another with melanoma) experienced lesional regression or regression of the primary tumor, but had progression at other tumor sites. Pharmacokinetic findings included a 12- to 20-day half-life and 72% mean plateau occupancy (range, 59%-81%) of PD-1 on T cells that appeared to be dose-independent. Investigators also found preliminary evidence that the level of PD-1 expression on tumor cells correlates with response. In terms of safety, nivolumab was well tolerated to the maximum planned dose of 10 mg/kg. The most common grade 2 and greater AEs were decreased CD4-positive T-cell counts (35.9%), lymphopenia (25.6%), fatigue (15.4%), and musculoskeletal events (15.4%). No grade 3 or 4 immunerelated AEs occurred in the 28 days after the first dose of nivolumab.77

Additional studies further demonstrated the acceptable safety profile of nivolumab in NSCLC and other cancers. In a study of the activity and safety of nivolumab in 240 patients with several types of tumors (melanoma [n = 95], RCC [n = 33], CRC [n = 19], CRPC [n = 17], NSCLC [n = 75], or unknown cancer type [n = 1]) who received nivolumab for a median of 15 weeks, grade 3 and 4 AEs occurred in 13% of patients and included pneumonitis, hypophysitis, hepatitis, colitis, and thyroiditis; there were 2 deaths due to pulmonary toxicity. This study also found PD-L1 expression to be potentially predictive of response because 50% (16/29) of patients with PD-L1-positive tumors achieved OR compared with no patients with tumors lacking PD-L1. Also, durable activity was recorded in patients with advanced melanoma, RCC, or NSCLC.78

Safety data and initial OS for NSCLC patients from another phase I study of nivolumab in advanced solid tumors46 were reported. Patients with at least 1 prior chemotherapy regimen received nivolumab (1 to 10 mg/kg IV every 2 weeks) for at least 12 cycles (4 doses/8-week cycle) or until discontinuation criteria were met.79 In 127 evaluable patients, long-term drug-related AEs included decreased appetite (9%), anemia (8%), diarrhea (7%), nausea (7%), and pruritus (7%). The most common grade 3 or 4 AEs (2% each) were fatigue, pneumonitis, and elevated levels of aspartate aminotransferase (AST).79 Median OS across all dose cohorts was 9.2 months for patients with squamous NSCLC and 9.6 months for non-squamous NSCLC. Median OS was not reached at the time the report was published in patients receiving the 3 mg/kg dose (the dose that will be evaluated in phase III trials) for patients with either histology. Sustained OS was observed, with 44% of patients with squamous NSCLC alive at both 1 and 2 years, and 41% and 17% of patients with non-squamous NSCLC alive at 1 and 2 years, respectively.79

In a third study evaluating IV nivolumab for a median of 11 weeks in 162 patients (melanoma [n = 53], RCC [n = 17], CRC [n = 18], ovarian cancer [n = 17], pancreatic cancer [n = 7], or NSCLC [n = 50]), common AEs (occurring in ≥5% of patients) included fatigue, diarrhea, infusion reaction, arthralgia, rash, and pruritus. The incidence of grade 3 and 4 AEs was 8.6% and included hypothyroidism, hepatitis, sarcoidosis, endophthalmitis, and myasthenia gravis. No patients died because of drug treatment. Clinical activity was observed in melanoma, RCC, and NSCLC.

Of 16 patients experiencing objective response, 7 patients experienced objective responses lasting 1 year or more.80 The phase I CheckMate-012 study evaluated several different nivolumab-containing combinations in patients with NSCLC. One part of the study evaluated the efficacy and safety of nivolumab in combination with gemcitabine, cisplatin, pemetrexed, carboplatin, and/or paclitaxel in patients with stage IIIB or IV NSCLC who failed at least 1 prior chemotherapy regimen. Patients were randomized to receive either nivolumab/gemcitabine/cisplatin, nivolumab/pemetrexed/cisplatin, or nivolumab/carboplatin/ paclitaxel. Investigators administered deescalating doses to assess dose-limiting toxicities (DLTs) in the initial 6 weeks of therapy. Grade 3 and 4 AEs included pneumonitis, rash, nephritis, and colitis and occurred in roughly half (49% [21/43]) of patients across all 3 arms of the study. No DLTs were seen with 10 mg/kg nivolumab combined with platinum-based doublet chemotherapy.81 A year later, an updated analysis reported AEs and DLTs after maintenance therapy. Again, nearly half (45% [25/56]) of patients across all arms experienced grade 3 or 4 AEs, including pneumonitis, fatigue, and acute renal failure. ORR after more than 10 months of follow-up ranged from 33% to 50%, and 1-year OS rates ranged from 59% to 87%.82 CheckMate-012 also evaluated nivolumab plus ipilimumab combination therapy in 46 NSCLC patients. Treatment-related AEs were reported in 85% of patients (39/46; grade 3 and 4 in 48% [22/46] of patients), 16 of whom discontinued due to AEs. Three patients died because of drug-related AEs (respiratory failure, bronchopulmonary hemorrhage, or toxic epidermal necrolysis). ORR was 22% and SD was achieved by 33% of patients.83 Thus, ipilimumab and nivolumab combination therapy is a feasible treatment option for advanced NSCLC.

As previously mentioned, combinations of targeted therapy and immunotherapy may be beneficial in cancer patients. CheckMate-012 further investigated the combination of erlotinib and nivolumab. The interim results suggest that this combination may provide durable clinical benefit and an acceptable safety profile. Objective response occurred in 19% of patients (4/21). After 24 weeks, investigators found that 47% of patients met criteria for PFS. Treatment-related grade 3 or 4 AEs (19% [4/21]) were increased AST (10% [2/21]) or alanine aminotransferase (ALT) (5% [1/21]), and weight decrease and diarrhea (5% [1/21] each). Two patients discontinued due to treatmentrelated AEs (grade 3 AST increase, grade 2 nephritis). No pneumonitis was observed.84

Other nivolumab combination studies are planned. These include the combination of ipilimumab and nivolumab (for various cancers, including SCLC),85 the combination of the anti-CTLA-4 mAb tremelimumab and nivolumab (for solid tumors, including NSCLC),86 and the combination of an anti-killer cell immunoglobulin-like receptor (KIR) mAb (lirilumab) and nivolumab (for solid tumors, including NSCLC).87

Several phase II trials of nivolumab monotherapy in lung cancer are also under way. CheckMate-063 is a phase II trial of nivolumab in patients with advanced or metastatic squamous cell NSCLC who have failed at least 2 prior chemotherapy regimens.88 Another phase II trial is evaluating nivolumab in resectable NSCLC to determine whether nivolumab therapy is safe and feasible in the preoperative setting.89 A third phase II study is investigating the efficacy and safety of nivolumab in patients with stage IIIB/IV or recurrent NSCLC unsuited to radical RT and resistant to platinum-based chemotherapy.90

Phase III trials are also investigating the utility of nivolumab in lung cancer. An open-label, randomized, phase III trial (CheckMate-026) is recruiting to show whether nivolumab will improve PFS in subjects with stage IV or recurrent PD-L1-positive NSCLC when compared with the investigators’ choice of chemotherapy.

This trial will assess the clinical activity of first-line nivolumab monotherapy in treatment-naïve patients.91,92 CheckMate-153 is a phase III safety trial set to estimate the incidence and characterize the outcome of select highgrade AEs. Patients include those who have advanced or metastatic NSCLC who have progressed during or after receiving at least 1 prior systemic regimen.93 In Check- Mate-017, an open-label, phase III trial of 264 patients with advanced or metastatic squamous cell carcinoma who have failed platinum-based chemotherapy, patients are randomized in a 1:1 ratio to receive either nivolumab every 2 weeks or docetaxel every 3 weeks until disease progression or unacceptable toxicity. Investigators will evaluate objective response, OS, PFS, and benefits stratified by PD-L1 expression in cancer tissue.94,95 Similarly, the phase III study CheckMate-057 is comparing the OS of nivolumab and docetaxel in patients with metastatic or recurrent non-squamous NSCLC. A total of 574 previously treated patients will receive nivolumab or docetaxel in a 1:1 ratio until disease progression or unacceptable toxicity. OS, ORR, PFS, disease-related symptom progression, and benefits stratified by PD-L1 expression in cancer tissue will be assessed.96,97

Pembrolizumab (Keytruda) (Merck)

Pembrolizumab is a humanized IgG4 mAb that targets the PD-1 receptor.98 Pembrolizumab was approved by the FDA in 2014 for the treatment of patients with unresectable or metastatic melanoma and disease progression after previous treatment with certain other drugs (ipilimumab and BRAF inhibitors).99 The drug was approved for this indication through the FDA’s accelerated approval program because of the tumor response rate (26% ORR) and durability of response (88% of responses ongoing at a median follow-up of 8 months) in advanced melanoma patients in the phase I KEYNOTE-001 study.99,100

Pembrolizumab has also shown promise in early trials in NSCLC. An open-label, dose-escalation, phase I clinical trial investigated pembrolizumab in patients with refractory advanced solid tumors (including 3 patients with NSCLC). Cohorts of 3 to 6 patients were treated with escalating IV doses of 1, 3, and 10 mg/kg and evaluated by radiographic assessment. Pembrolizumab was well tolerated without DLT across tested dose levels, and evidence of antitumor activity was observed.98 In an ongoing phase I/II multicenter, open-label study of pembrolizumab in patients with NSCLC, nearly half of patients (43%) experienced grade 1 to 2 treatment-related AEs, none of which led to drug discontinuation. Preliminary results showed 3 cases of partial response out of 13 patients in the trial. The study will be expanded to include more than 300 patients with NSCLC and is ongoing but not currently recruiting participants.101,102

Several phase I studies of pembrolizumab are also ongoing. KEYNOTE-001 is investigating pembrolizumab as initial therapy in patients with locally advanced or metastatic NSCLC. Preliminary data indicate an ORR (confirmed and unconfirmed) of 36%. About 52% of patients experienced a drug-related AE (usually grade 1 or 2 in severity), most commonly fatigue (14%), pruritus (8%), dermatitis acneiform (6%), diarrhea (6%), or dyspnea (6%). There was a single serious drug-related AE (grade 3 pericardial effusion). Based on these data, pembrolizumab appears to be generally well tolerated, and provides antitumor activity in a first-line setting in patients with locally advanced or metastatic NSCLC.103,104 KEYNOTE-025, another phase I study in patients with advanced NSCLC, aims to evaluate the safety and efficacy of pembrolizumab in PD-L1-positive tumors. The investigators hypothesize that pembrolizumab will result in a clinically meaningful ORR in this trial.105

Phase II and III studies in lung cancer are also under way. The activity of pembrolizumab in NSCLC or melanoma patients with untreated brain metastases is being studied in a phase II trial (NCT02085070) currently recruiting participants.106 Additionally, a randomized phase II/III study (KEYNOTE-010) is comparing 2 doses of pembrolizumab therapy with docetaxel in NSCLC patients who progressed after platinum-based chemotherapy. To date, 50 patients have enrolled, and the study is still recruiting. OS, PFS, and AEs will be reported.107,108 Finally, 2 phase III trials (KEYNOTE-024 and -042) are evaluating the efficacy and safety of pembrolizumab compared with platinum-based chemotherapies in the treatment of patients with PD-L1- positive advanced or metastatic NSCLC.109,110

Pembrolizumab is also being evaluated in combination with other agents. Studies include a phase I/II study (KEYNOTE-021) that aims to determine the safety, tolerability, and efficacy of pembrolizumab in combination with chemotherapy or immunotherapy in participants with unresectable or metastatic NSCLC.111 KEYNOTE-037 is a phase I/II study of the combination of pembrolizumab and INCB024360 (an oral inhibitor of indoleamine 2,3-dioxygenase). The second phase of this study will include only patients with advanced NSCLC and will be randomized, double-blind, and placebo-controlled.112 In addition, investigators are enrolling for a phase lb open-label study of the combination of tremelimumab and pembrolizumab in advanced NSCLC.113 This dose escalation and expansion study will evaluate the safety, pharmacodynamics, and preliminary activity of this combination in immunotherapy- naïve and -pretreated cohorts. In 3 patients (follow- up of 8-10 weeks), related AEs included a grade 2 asymptomatic elevated amylase. No grade 3/4 AEs or DLTs were reported. Thus, the safety profile supports continued dose escalation. Pharmacokinetic and pharmacodynamic data are being analyzed.114

Conclusion

Patients with lung cancer, especially those with advanced or metastatic NSCLC, may suffer from poor prognosis and greatly reduced quality of life. Traditional treatment approaches, such as surgery, RT, chemotherapy, and targeted therapies, may be insufficient in many cases. A clearer picture of the complex interplay between cancer and the immune system has paved the way for immunotherapy drugs. Several clinical trials demonstrate the promise of immunotherapy in the battle against lung cancer, particularly NSCLC. Targeting immune checkpoint proteins and activating important components of the immune system can be a safe and effective method of treating solid tumors, including lung cancer. Thus, immune checkpoint inhibitors are challenging current cancer treatment paradigms. PD-1/PD-L1 inhibitors in particular (namely MPDL3280A, nivolumab, and pembrolizumab) have demonstrated safety and efficacy in lung cancer both as monotherapies and as part of a combination regimen in a variety of circumstances (ie, treatment-naïve, previously treated, relapsed, and refractory disease). Ongoing trials will likely determine the most effective therapeutic regimens, including combination regimens of targeted therapies and PD-1/PD-L1 inhibitors that provide the benefits of each type of therapy. Importantly, immunotherapies that block the PD-1/PD-L1 pathways have demonstrated favorable safety profiles in clinical trials. Novel approaches to lung cancer treatment such as the PD-1/PD-L1 blockade continue to push the immunotherapy landscape and cancer treatment paradigm, resulting in potential new options for patients.

References

  1. Cancer fact sheet. World Health Organization website. http:// www.who.int/mediacentre/factsheets/fs297/en/. Accessed December 10, 2014.
  2. NCCN clinical practice guidelines in oncology (NCCN Guidelines): non-small cell lung cancer (version 4.2015). National Comprehensive Cancer Network website. http://www.nccn.org/professionals/ physician_gls/pdf/nscl.pdf. Accessed February 17, 2014.
  3. SEER stat fact sheets: lung and bronchus cancer. National Cancer Institute website. http://seer.cancer.gov/statfacts/html/lungb .html. Accessed December 14, 2014.
  4. Cancer facts & figures 2014. American Cancer Society website. http://www.cancer.org/acs/groups/content/@research/ documents/webcontent/acspc-042151.pdf. Accessed December 10, 2014.
  5. Ettinger DS. Chapter 197: Lung cancer and other pulmonary neoplasms. In: Goldman’s Cecil Medicine. 24th ed. Philadelphia, PA: Elsevier Saunders; 2012.
  6. Horn L, Eisenberg R, Gius D, et al. Cancer of the lung: non-small cell lung cancer and small cell lung cancer. In: Abeloff’s Clinical Oncology. 5th ed. Philadelphia, PA: Elsevier Saunders; 2014.
  7. Radon: health risks. Environmental Protection Agency website. http://www.epa.gov/radon/healthrisks.html. Accessed January 2, 2015.
  8. Lung cancer (non-small cell). American Cancer Society website. http://www.cancer.org/acs/groups/cid/documents/ webcontent/003115-pdf.pdf. Accessed January 2, 2015.
  9. American Cancer Society. Lung cancer (small cell). American Cancer Society website. http://www.cancer.org/acs/groups/ cid/documents/webcontent/003116-pdf.pdf. Accessed January 2, 2015.
  10. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology (NCCN Guidelines): small cell lung cancer (version 1.2015). http://www.nccn.org/professionals/ physician_gls/pdf/sclc.pdf. Accessed January 2, 2015.
  11. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology (NCCN Guidelines): lung cancer screening (version 1.2015). http://www.nccn.org/professionals/physician_ gls/pdf/lung_screening.pdf. Accessed January 4, 2015.
  12. Henschke CI, Yankelevitz DF, Libby DM, et al; International Early Lung Cancer Action Program Investigators. Survival of patients with stage I lung cancer detected on CT screening. N Engl J Med. 2006;355(17):1763-1771.
  13. Aberle DR, Adams AM, Berg CD, et al; National Lung Screening Trial Research Team. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med. 2011;365(5): 395-409.
  14. Edge S, Byrd DR, Compton CC, et al. AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer; 2010.
  15. Travis WD, Brambilla E, Noguchi M, et al. International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society international multidisciplinary classification of lung adenocarcinoma. J Thorac Oncol. 2011;6(2):244-285.
  16. Decaluwé H, De Leyn P, Vansteenkiste J, et al. Surgical multimodality treatment for baseline resectable stage IIIA-N2 nonsmall cell lung cancer: degree of mediastinal lymph node involvement and impact on survival. Eur J Cardiothorac Surg. 2009;36(3):433-439.
  17. Stefani A, Alifano M, Bobbio A, et al. Which patients should be operated on after induction chemotherapy for N2 non-small cell lung cancer? analysis of a 7-year experience in 175 patients. J Thorac Cardiovasc Surg. 2010;140(2):356-363.
  18. Lencioni R, Crocetti L, Cioni R, et al. Response to radiofrequency ablation of pulmonary tumours: a prospective, intention-to-treat, multicentre clinical trial (the RAPTURE study). Lancet Oncol. 2008; 9(7):621-628.
  19. Arriagada R, Bergman B, Dunant A, et al. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med. 2004;350(4):351-360.
  20. Song WA, Zhou NK, Wang W, et al. Survival benefit of neoadjuvant chemotherapy in non-small cell lung cancer: an updated metaanalysis of 13 randomized control trials. J Thorac Oncol. 2010; 5(4):510-516.
  21. Curran WJ Jr, Paulus R, Langer CJ, et al. Sequential vs concurrent chemoradiation for stage III non-small cell lung cancer: randomized phase III trial RTOG 9410. J Natl Cancer Inst. 2011;103(19): 1452-1460.
  22. Aupérin A, Le Péchoux C, Rolland E, et al. Meta-analysis of concomitant versus sequential radiochemotherapy in locally advanced non-small-cell lung cancer. J Clin Oncol. 2010;28(13): 2181-2190.
  23. Temel JS, Greer JA, Muzikansky A, et al. Early palliative care for patients with metastatic non-small-cell lung cancer. N Engl J Med. 2010;363(8):733-742.
  24. Avastin (bevacizumab) solution for intravenous infusion [package insert]. South San Francisco, CA: Genentech Inc; 2014.
  25. Tarceva (erlotinib) tablets for oral use [package insert]. South San Francisco, CA: Genentech Inc; 2014.
  26. Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatinpaclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361 (10):947-957.
  27. Rosell R, Carcereny E, Gervais R, et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012;13(3):239-246.
  28. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med. 2005;353(2):123-132.
  29. Gilotrif (afatinib) tablets, for oral use [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals Inc; 2014.
  30. Xalkori (crizotinib) capsules, oral [package insert]. New York, NY: Pfizer Inc; 2014.
  31. Shaw AT, Kim DW, Nakagawa K, et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med. 2013;368(25):2385-2394.
  32. Zykadia (ceritinib) capsules for oral use [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2014.
  33. Erbitux (cetuximab) injection, for intravenous infusion [package insert]. Princeton, NJ: Bristol-Myers Squibb; 2013.
  34. Pirker R, Pereira JR, Szczesna A, et al. Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial. Lancet. 2009;373(9674):1525-1531.
  35. Sundstrøm S, Bremnes RM, Kaasa S, et al. Cisplatin and etoposide regimen is superior to cyclophosphamide, epirubicin, and vincristine regimen in small-cell lung cancer: results from a randomized phase III trial with 5 years’ follow-up. J Clin Oncol. 2002;20(24):4665-4672.
  36. Takada M, Fukuoka M, Kawahara M, et al. Phase III study of concurrent versus sequential thoracic radiotherapy in combination with cisplatin and etoposide for limited-stage smallcell lung cancer: results of the Japan Clinical Oncology Group Study 9104. J Clin Oncol. 2002;20(14):3054-3060.
  37. Turrisi AT 3rd, Kim K, Blum R, et al. Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide. N Engl J Med. 1999;340(4):265-271.
  38. Lara PN Jr, Natale R, Crowley J, et al. Phase III trial of irinotecan/ cisplatin compared with etoposide/cisplatin in extensive-stage small-cell lung cancer: clinical and pharmacogenomic results from SWOG S0124. J Clin Oncol. 2009;27(15):2530-2535.
  39. Owonikoko TK, Aisner J, Wang XV, et al. E5501: phase II study of topotecan sequenced with etoposide/cisplatin, and irinotecan/ cisplatin sequenced with etoposide for extensive-stage small-cell lung cancer. Cancer Chemother Pharmacol. 2014;73(1):171-180.
  40. Niell HB, Herndon JE 2nd, Miller AA, et al. Randomized phase III intergroup trial of etoposide and cisplatin with or without paclitaxel and granulocyte colony-stimulating factor in patients with extensive-stage small-cell lung cancer: Cancer and Leukemia Group B Trial 9732. J Clin Oncol. 2005;23(16):3752-3759.
  41. Loehrer PJ Sr, Ansari R, Gonin R, et al. Cisplatin plus etoposide with and without ifosfamide in extensive small-cell lung cancer: a Hoosier Oncology Group study. J Clin Oncol. 1995;13(10): 2594-2599.
  42. Sevinc A, Kalender ME, Altinbas M, et al. Irinotecan as a secondline monotherapy for small cell lung cancer. Asian Pac J Cancer Prev. 2011;12(4):1055-1059.
  43. Coley WB. The treatment of inoperable sarcoma with the mixed toxins of erysipelas and bacillus prodigiosus: immediate and final results in one hundred and forty cases. JAMA. 1898;XXXI(9): 456-465.
  44. Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature. 2011;480(7378):480-489.
  45. Hino R, Kabashima K, Kato Y, et al. Tumor cell expression of programmed cell death-1 ligand 1 is a prognostic factor for malignant melanoma. Cancer. 2010;116(7):1757-1766.
  46. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366(26):2443-2454.
  47. Chen DS, Irving BA, Hodi FS. Molecular pathways: next-generation immunotherapy--inhibiting programmed death-ligand 1 and programmed death-1. Clin Cancer Res. 2012;18(24):6580-6587.
  48. Vanneman M, Dranoff G. Combining immunotherapy and targeted therapies in cancer treatment. Nat Rev Cancer. 2012;12(4):237-251.
  49. Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363(5):411-422.
  50. Hall RD, Gray JE, Chiappori AA. Beyond the standard of care: a review of novel immunotherapy trials for the treatment of lung cancer. Cancer Control. 2013;20(1):22-31.
  51. Johnson DB, Rioth MJ, Horn L. Immune checkpoint inhibitors in NSCLC. Curr Treat Options Oncol. 2014;15(4):658-669.
  52. Yervoy (ipilimumab) injection, for intravenous infusion [package insert]. Princeton, NJ: Bristol-Myers Squibb; 2013.
  53. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363(8):711-723.
  54. Trial in squamous non small cell lung cancer subjects comparing ipilimumab plus paclitaxel and carboplatin versus placebo plus paclitaxel and carboplatin. ClinicalTrials.gov website. https:// clinicaltrials.gov/ct2/show/NCT01285609. Accessed January 6, 2015.
  55. Gettinger S, Herbst RS. B7-H1/PD-1 blockade therapy in nonsmall cell lung cancer: current status and future direction. Cancer J. 2014;20(4):281-289.
  56. Carter L, Fouser LA, Jussif J, et al. PD-1:PD-L inhibitory pathway affects both CD4(+) and CD8(+) T cells and is overcome by IL-2. Eur J Immunol. 2002;32(3):634-643.
  57. Freeman GJ, Long AJ, Iwai Y, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med. 2000;192(7):1027-1034.
  58. Butte MJ, Keir ME, Phamduy TB, Sharpe AH, Freeman GJ. Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses. Immunity. 2007;27(1):111-122.
  59. Zhang Y, Huang S, Gong D, Qin Y, Shen Q. Programmed death-1 upregulation is correlated with dysfunction of tumor-infiltrating CD8+ T lymphocytes in human non-small cell lung cancer. Cell Mol Immunol. 2010;7(5):389-395.
  60. Mu CY, Huang JA, Chen Y, Chen C, Zhang XG. High expression of PD-L1 in lung cancer may contribute to poor prognosis and tumor cells immune escape through suppressing tumor infiltrating dendritic cells maturation. Med Oncol. 2011;28(3):682-688.
  61. Wang SF, Fouquet S, Chapon M, et al. Early T cell signalling is reversibly altered in PD-1+ T lymphocytes infiltrating human tumors. PloS One. 2011;6(3):e17621.
  62. Ahmadzadeh M, Johnson LA, Heemskerk B, et al. Tumor antigenspecific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired. Blood. 2009;114(8):1537-1544.
  63. D’Incecco A, Andreozzi M, Ludovini V, et al. PD-1 and PD-L1 expression in molecularly selected non-small-cell lung cancer patients. Br J Cancer. 2015;112(1):95-102.
  64. Wrangle J, Wang W, Koch A, et al. Alterations of immune response of non-small cell lung cancer with azacytidine. Oncotarget. 2013; 4(11):2067-2079.
  65. Azuma K, Ota K, Kawahara A, et al. Association of PD-L1 overexpression with activating EGFR mutations in surgically resected nonsmall-cell lung cancer. Ann Oncol. 2014;25(10):1935-1940.
  66. Dhodapkar KM, Gettinger SN, Das R, Zebroski H, Dhodapkar MV. SOX2-specific adaptive immunity and response to immunotherapy in non-small cell lung cancer. Oncoimmunology. 2013; 2(7):e25205.
  67. Sasaki H, Tatemaysu T, Okuda K, et al. PD-1 gene promoter polymorphisms correlate with a poor prognosis in non-small cell lung cancer. Mol Clin Oncol. 2014;2(6):1035-1042.
  68. Spigel DR, Gettinger SN, Horn L, et al. Clinical activity, safety, and biomarkers of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC). Presented at: 2013 Annual Meeting of the American Society of Clinical Oncology; May 31-June 4, 2013; Chicago, IL. Abstract 8008.
  69. A phase 1 study of MPDL3280A (an engineered anti-PDL1 antibody) in patients with locally advanced or metastatic solid tumors. ClinicalTrials.gov website. https://clinicaltrials.gov/ct2/ show/study/NCT01375842. Accessed January 7, 2015.
  70. A phase 1b study of MPDL3280A (an engineered anti-PDL1 antibody) in combination with vemurafenib (Zelboraf) or vemurafenib plus cobimetinib in patients with previously untreated BRAFV600-mutation positive metastatic melanoma. ClinicalTrials.gov website. https://clinicaltrials.gov/ct2/show/ NCT01656642. Accessed January 7, 2015.
  71. A phase 1b study of MPDL3280A (an engineered anti-PDL1 antibody) in combination with Avastin (bevacizumab) and/or with chemotherapy in patients with locally advanced or metastatic solid tumors. ClinicalTrials.gov website. https://clinicaltrials.gov/ ct2/show/NCT01633970. Accessed January 7, 2015.
  72. A phase 2 study of MPDL3280A (an engineered anti-PDL1 antibody) in patients with PD-L1 positive locally advanced or metastatic non-small cell lung cancer-“FIR.” ClinicalTrials.gov website. https://clinicaltrials.gov/ct2/show/NCT01846416. Accessed January 8, 2015.
  73. A phase 2 study of MPDL3280A (an engineered anti-PDL1 antibody) in patients with PD-L1 positive locally advanced or metastatic non-small cell lung cancer-“BIRCH.” ClinicalTrials.gov website. https://clinicaltrials.gov/ct2/show/NCT02031458. Accessed January 7, 2015.
  74. A randomized phase 2 study of MPDL3280A (an engineered anti-PDL1 antibody) compared with docetaxel in patients with locally advanced or metastatic non-small cell lung cancer who have failed platinum therapy-“POPLAR.” ClinicalTrials.gov website. https://clinicaltrials.gov/ct2/show/NCT01903993. Accessed January 7, 2015.
  75. A randomized phase 3 study of MPDL3280A (an engineered anti-PDL1 antibody) compared with docetaxel in patients with locally advanced or metastatic non-small cell lung cancer who have failed platinum therapy-“OAK.” ClinicalTrials.gov website. https://clinicaltrials.gov/ct2/show/NCT02008227. Accessed January 7, 2015.
  76. Agrawal S, Feng Y, Kollia G, et al. Clinical pharmacokinetics (PK) of BMS936558, a fully human anti-PD-1 monoclonal antibody. Presented at: 2012 Annual Meeting of the American Society of Clinical Oncology; June 1-5, 2012; Chicago, IL. Abstract TPS2622.
  77. Brahmer JR, Drake CG, Wollner I, et al. Phase I study of singleagent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol. 2010;28(19):3167-3175.
  78. Topalian SL, Brahmer JR, Hodi FS, et al. Anti-PD-1 (BMS-936558, MDX-1106) in patients with advanced solid tumors: clinical activity, safety, and a potential biomarker for response. Presented at: 2012 Annual Meeting of the American Society of Clinical Oncology; June 1-5, 2012; Chicago, IL. Abstract CRA2509.
  79. Brahmer JR, Horn L, Antonia SJ, et al. Survival and long-term follow-up of the phase I trial of nivolumab (anti-PD-1; BMS- 936558, ONO-4538) in patients (pts) with previously treated advanced non-small cell lung cancer (NSCLC). Presented at: 2013 Annual Meeting of the American Society of Clinical Oncology; May 31-June 4, 2013; Chicago, IL. Abstract 8030.
  80. Tykodi SS, Brahmer JR, Hwu W, et al. PD-1/PD-L1 pathway as a target for cancer immunotherapy: safety and clinical activity of BMS-936559, an anti-PD-L1 antibody, in patients with solid tumors. Presented at: 2012 Annual Meeting of the American Society of Clinical Oncology; June 1-5, 2012; Chicago, IL. Abstract 2510.
  81. Rizvi NA, Antonia SJ, Chow LQM, et al. A phase I study of nivolumab (anti-PD-1; BMS-936558, ONO-4538) plus platinumbased doublet chemotherapy (PT-doublet) in chemotherapy-naive non-small cell lung cancer (NSCLC) patients (pts). Presented at: 2013 Annual Meeting of the American Society of Clinical Oncology; May 31-June 4, 2013; Chicago, IL. Abstract 8072.
  82. Antonia SJ, Brahmer JR, Gettinger SN, et al. Nivolumab (anti-PD-1; BMS-936558, ONO-4538) in combination with platinum-based doublet chemotherapy (PT-DC) in advanced non-small cell lung cancer (NSCLC). Presented at: 2014 Annual Meeting of the American Society of Clinical Oncology; May 30-June 3, 2014; Chicago, IL. Abstract 8113.
  83. Antonia SJ, Gettinger SN, Chow LQM, et al. Nivolumab (anti-PD-1; BMS-936558, ONO-4538) and ipilimumab in first-line NSCLC: interim phase I results. Presented at: 2014 Annual Meeting of the American Society of Clinical Oncology; May 30-June 3, 2014; Chicago, IL. Abstract 8023.
  84. Rizvi NA, Chow LQM, Borghaei H, et al. Safety and response with nivolumab (anti-PD-1; BMS-936558, ONO-4538) plus erlotinib in patients (pts) with epidermal growth factor receptor mutant (EGFR MT) advanced NSCLC. Presented at: 2014 Annual Meeting of the American Society of Clinical Oncology; May 30-June 3, 2014; Chicago, IL. Abstract 8022.
  85. Callahan MK, Bendell JC, Chan E, et al. Phase I/II, open-label study of nivolumab (anti-PD-1; BMS-936558, ONO-4538) as monotherapy or combined with ipilimumab in advanced or metastatic solid tumors. Presented at: 2014 Annual Meeting of the American Society of Clinical Oncology; May 30-June 3, 2014; Chicago, IL. Abstract TPS3114.
  86. Callahan MK, Ott PA, Odunsi K, et al. A phase 1 study to evaluate the safety and tolerability of MEDI4736, an anti-PD-L1 antibody, in combination with tremelimumab in patients with advanced solid tumors. Presented at: 2014 Annual Meeting of the American Society of Clinical Oncology; May 30-June 3, 2014; Chicago, IL. Abstract TPS3120.
  87. Segal NH, Hodi FS, Sanborn RE, et al. A phase I dose escalation and cohort expansion study of lirilumab (anti-KIR; BMS-986015) in combination with nivolumab (anti-PD-1; BMS-936558, ONO- 4538) in advanced solid tumors. Presented at: 2014 Annual Meeting of the American Society of Clinical Oncology; May 30- June 3, 2014; Chicago, IL. Abstract TPS3115.
  88. Study of nivolumab (BMS-936558) in subjects with advanced or metastatic squamous cell non-small cell lung cancer who have received at least two prior systemic regimens (CheckMate 063). ClinicalTrials.gov website. https://clinicaltrials.gov/ct2/show/ NCT01721759. Accessed January 7, 2015.
  89. Neoadjuvant anti-PD-1, nivolumab in resectable NSCLC (NA_00092076). ClinicalTrials.gov website. https://clinicaltrials .gov/ct2/show/NCT02259621. Accessed January 7, 2015.
  90. ONO-4538 study in patients with advanced non-small cell lung cancer. ClinicalTrials.gov website. https://clinicaltrials.gov/ct2/ show/NCT02175017. Accessed January 7, 2015.
  91. Carbone DP, Socinski MA, Chen AC, et al. A phase III, randomized, open-label trial of nivolumab (anti-PD-1; BMS-936558, ONO- 4538) versus investigator’s choice chemotherapy (ICC) as first-line therapy for stage IV or recurrent PDL1+ non-small cell lung cancer (NSCLC). Presented at: 2014 Annual Meeting of the American Society of Clinical Oncology; May 30-June 3, 2014; Chicago, IL. Abstract TPS8128.
  92. An open-label, randomized, phase 3 trial of nivolumab versus investigator’s choice chemotherapy as first-line therapy for stage IV or recurrent PD-L1+ non-small cell lung cancer (CheckMate 026). ClinicalTrials.gov website. https://clinicaltrials.gov/ct2/ show/NCT02041533. Accessed January 7, 2015.
  93. A safety trial of nivolumab (BMS-936558) in subjects with advanced or metastatic non-small cell lung cancer who have progressed during or after receiving at least one prior systemic regimen (CheckMate 153). ClinicalTrials.gov website. https://clinicaltrials.gov/ct2/show/ NCT02066636. Accessed January 7, 2015.
  94. Borghaei H, Lynch TJ, Rizvi NA, et al. A phase III comparative study of nivolumab (anti-PD-1; BMS-936558, ONO-4538) versus docetaxel in patients with previously treated advanced or metastatic squamous cell non-small cell lung cancer (NSCLC). Presented at: 2013 Annual Meeting of the American Society of Clinical Oncology; May 31-June 4, 2013; Chicago, IL. Abstract TPS8122.
  95. Study of BMS-936558 (nivolumab) compared to docetaxel in previously treated advanced or metastatic squamous cell nonsmall cell lung cancer (NSCLC) (CheckMate 017). ClinicalTrials .gov website. https://clinicaltrials.gov/show/NCT01642004. Accessed January 7, 2015.
  96. Gettinger SN, Brahmer JR, Rizvi NA, et al. A phase III comparative study of nivolumab (anti-PD-1; BMS-936558, ONO-4538) versus docetaxel in patients (pts) with previously treated advanced/ metastatic nonsquamous non-small cell lung cancer (NSCLC). Presented at: 2013 Annual Meeting of the American Society of Clinical Oncology; May 31-June 4, 2013; Chicago, IL. Abstract TPS8121.
  97. Study of BMS-936558 (nivolumab) compared to docetaxel in previously treated metastatic non-squamous NSCLC (CheckMate 057). ClinicalTrials.gov website. https://clinicaltrials.gov/show/ NCT01673867. Accessed January 7, 2015.
  98. Patnaik A, Kang SP, Tolcher AW, et al. Phase I study of MK-3475 (anti-PD-1 monoclonal antibody) in patients with advanced solid tumors. Presented at: 2012 Annual Meeting of the American Society of Clinical Oncology; June 1-5, 2012; Chicago, IL. Abstract 2512.
  99. Keytruda (pembrolizumab) for injection, for intravenous use [package insert]. Whitehouse Station, NJ: Merck & Co, Inc; 2015.
  100. Robert C, Ribas A, Wolchok JD, et al. Anti-programmed-deathreceptor- 1 treatment with pembrolizumab in ipilimumabrefractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet. 2014;384(9948):1109-1117.
  101. Brahmer JR, Rizvi NA, Lutzky J, et al. Clinical activity and biomarkers of MEDI4736, an anti-PD-L1 antibody, in patients with NSCLC. Presented at: 2014 Annual Meeting of the American Society of Clinical Oncology; May 30-June 3, 2014; Chicago, IL. Abstract 8021.
  102. A phase 1/2 study to evaluate MEDI4736. ClinicalTrials.gov website. https://clinicaltrials.gov/show/NCT01693562. Accessed January 7, 2015.
  103. Study of pembrolizumab (MK-3475) in participants with progressive locally advanced or metastatic carcinoma, melanoma, or non-small cell lung carcinoma (P07990/MK-3475-001/ KEYNOTE-001). ClinicalTrials.gov website. https://clinicaltrials .gov/ct2/show/NCT01295827. Accessed January 7, 2015.
  104. Rizvi NA, Garon EB, Patnaik A, et al. Safety and clinical activity of MK-3475 as initial therapy in patients with advanced non-small cell lung cancer (NSCLC). Presented at: 2014 Annual Meeting of the American Society of Clinical Oncology; May 30-June 3, 2014; Chicago, IL. Abstract 8007.
  105. Study of pembrolizumab (MK-3475) in participants with advanced non-small cell lung cancer (MK-3475-025/KEYNOTE-025). ClinicalTrials.gov website. https://clinicaltrials.gov/ct2/show/ NCT02007070. Accessed January 7, 2015.
  106. MK-3475 in melanoma and NSCLC patients with brain metastases. ClinicalTrials.gov website. https://clinicaltrials.gov/ ct2/show/NCT02085070. Accessed January 7, 2015.
  107. Study of two doses of MK-3475 (pembrolizumab) versus docetaxel in previously-treated participants with non-small cell lung cancer (MK-3475-010/KEYNOTE-010). ClinicalTrials.gov website. https://clinicaltrials.gov/ct2/show/NCT01905657. Accessed January 7, 2015.
  108. Herbst RS, Gurpide A, Surmont V, et al. A phase II/III randomized trial of two doses of MK-3475 versus docetaxel in previously treated subjects with non-small cell lung cancer. Presented at: 2014 Annual Meeting of the American Society of Clinical Oncology; May 30-June 3, 2014; Chicago, IL. Abstract TPS8124.
  109. Study of pembrolizumab (MK-3475) compared to platinum-based chemotherapies in participants with metastatic non-small cell lung cancer (MK-3475-024/KEYNOTE-024). ClinicalTrials.gov website. https://clinicaltrials.gov/ct2/show/NCT02142738. Accessed January 7, 2015.
  110. Study of MK-3475 (pembrolizumab) versus platinum-based chemotherapy for participants with PD-L1-positive advanced or metastatic non-small cell lung cancer (MK-3475-042/ KEYNOTE-042). ClinicalTrials.gov website. https://clinicaltrials .gov/ct2/show/NCT02220894. Accessed January 7, 2015.
  111. A study of pembrolizumab (MK-3475) in combination with chemotherapy or immunotherapy in participants with lung cancer (MK-3475-021/KEYNOTE-021). ClinicalTrials.gov website. https://clinicaltrials.gov/ct2/show/NCT02039674. Accessed January 7, 2015.
  112. A phase 1/2 study exploring the safety, tolerability, and efficacy of MK-3475 in combination with INCB024360 in subjects with selected solid tumors and advanced NSCLC (INCB 24360-202 / MK-3475-037 / KEYNOTE-037). ClinicalTrials.gov website. https://clinicaltrials.gov/ct2/show/NCT02178722. Accessed January 7, 2015.
  113. A phase 1b study of MEDI4736 in combination with tremelimumab in subjects with advanced non-small cell lung cancer (D4190C00006). ClinicalTrials.gov website. https:// clinicaltrials.gov/show/NCT02000947. Accessed January 7, 2015.
  114. Pinder MC, Rizvi NA, Goldberg SB, et al. A phase 1b open-label study to evaluate the safety and tolerability of MEDI4736, an anti- PD-L1 antibody, in combination with tremelimumab in subjects with advanced non-small cell lung cancer. Presented at: 2014 Annual Meeting of the American Society of Clinical Oncology; May 30-June 3, 2014; Chicago, IL. Abstract e19137.