Evolving Paradigms in Squamous NSCLC: Introduction

This article is part I of a series. View parts II and III:Evolving Paradigms in Squamous NSCLC> >

Lung cancer is the leading cause of cancer-related mortality worldwide, with approximately 1.6 million deaths annually.¹Estimates by the American Cancer Society for 2015 project 221,200 new diagnoses in the United States and 58,040 lung cancer-related deaths.²The current 5-year overall survival (OS) rate in the US is 16.8%; however, relative survival rates differ with stage at diagnosis, ranging from 54% with local disease to 26.5% to 4% for patients with regional and distant stage disease, respectively.^2,3Approximately two-thirds of lung cancers are diagnosed at advanced stages. More than 85% of lung cancer cases are classified as non—small cell lung cancer (NSCLC), which encompasses nonsquamous subtypes, including adenocarcinoma and large cell carcinoma, and squamous cell (epidermoid) carcinoma (SCC) of the lung; these represent distinct entities differing in pathophysiology, mutational profile, and response to treatment.⁴Adenocarcinomas are the most common NSCLC subtype diagnosed in the United States, and they are also the most frequent subtype of lung cancer found among nonsmokers. Squamous cell carcinoma, the NSCLC subtype most strongly associated with smoking, makes up 20% to 30% of NSCLC, with approximately 85,000 new cases in the United States annually and more than 400,000 worldwide.^4,5

Although therapy of early-stage SCC is similar to other histologic subtypes of NSCLC, therapeutic options for advanced-stage SCC have remained much more limited than those for adenocarcinoma. In the latter, the discovery and therapeutic exploitation of recurrent mutations in oncogenic driver genes have yielded a large armamentarium of targeted agents, which are selected based on genomic screening for genetic alterations that predict response to treatment.³In contrast, specific genetic alterations are largely absent from SCC, such that most targeted agents being investigated for advanced NSCLC are not active.³Other agents, such as the antiangiogenic agent bevacizumab, indicated for the first-line treatment of nonsquamous tumors, were not clinically developed for SCC because of safety concerns after incidences of fatal hemoptysis in early trials.^3,6

Platinum-doublet chemotherapy remains the standard of care in first-line treatment of SCC. With the approval of nanoparticle bound (nab)-paclitaxel plus carboplatin for the treatment of untreated locally advanced or metastatic NSCLC, a regimen with particular activity in SCC has become available. Weekly nab-paclitaxel plus carboplatin improved the overall response rate (ORR) to treatment compared with solvent-based (sb)-paclitaxel plus carboplatin, with the highest increase in ORR among patients with squamous histology.⁷

Approximately 25% of patients with NSCLC show disease progression during or after the initial cycle of chemotherapy.³Treatment options for advanced SCC after failure of first-line platinum-based doublet chemotherapy were recently expanded with the approval of two new therapeutic regimens suitable for the subsequent-line treatment of platinum-resistant SCC—the immune checkpoint inhibitor, nivolumab, specifically for advanced SCC, and the antivascular endothelial growth factor receptor-2 (VEGFR-2) antibody ramucirumab, in combination with docetaxel for metastatic NSCLC of all histologies.³Based on clinical activity and durable responses, the clinical investigation of immunotherapeutic and targeted treatment approaches for SCC is ongoing with the anticipation that therapeutic options may be expanded in all lines of therapy.

Risk factors, epidemiology, and prevention

Exposure to tobacco smoke through active smoking or from second-hand smoke is the main risk factor for lung cancer and accounts for 85% to 90% of lung cancer-related deaths.⁸Tobacco smoke contains multiple classes of carcinogens, such as polycyclic aromatic hydrocarbons, tobacco-specific nitrosamines, and aldehydes; these induce metaplasia and subsequent tumorigenesis primarily through the formation of DNA adducts that cause mutations.^9,10Other risk factors include diseases such as chronic obstructive pulmonary disease, family history of lung cancer, and exposure to carcinogens such as asbestos, radon, arsenic, diesel fumes, and silica, among others.8 Of all NSCLC subtypes, SCC is most strongly associated with cigarette smoking and almost exclusively present in current or former heavy smokers.^11-13

With changes in smoking habits, the prevalence of NSCLC subtypes has shifted in past decades. SCC, which was the most common histologic subtype of lung cancers in the past, accounting for approximately half of lung cancers in males in 1970, has decreased to about 30% to 40%, whereas the prevalence of adenocarcinomas has increased to about 50%.^4,14These changes correlate with decreased smoking rates and changes in cigarette design, including lower tar and nicotine content, which may promote more frequent smoking and deeper inhalation, such that tobacco carcinogens become deposited further into the lung periphery.^11,12

Lung cancer risk is proportional to cigarette smoke exposure, measured as pack-years of smoking history. Outcomes of the randomized National Lung Screening Trial among 53,454 current or former heavy smokers demonstrated that in high-risk individuals, defined as current or former smokers 55 to 80 years of age who have a 30 pack-year smoking history and smoke or have quit within the past 15 years, lung cancer screening using low-dose computed tomography (CT) decreased the mortality rate from lung cancer by 20%.¹⁵Therefore, guidelines released by multiple organizations, including the American College of Chest Physicians, US Preventive Services Task Force, and National Comprehensive Cancer Network (NCCN), among others, strongly recommend lung cancer screening using low-dose CT for high-risk current and former smokers.^8,16,17Continued smoking after cancer diagnosis has been associated with second primary cancers, treatment complications, and decreased survival,¹⁸and evidence also suggests that it may increase risk of cancer recurrence, poor treatment response, and toxicity of treatment.¹⁹Smoking cessation should therefore be encouraged, particularly in patients with cancer and can be supported with nicotine replacement, bupropion sustained release, and varenicline.¹⁹

Molecular pathogenesis and characteristics of SCC

Figure 1. NSCLC subtypes by histology and mutations with potential therapeutic utility.

Adapted from Chan et al.²³

Analyses of genetic mutations in NSCLC subtypes by gene expression profiling, single nucleotide polymorphism (SNP) arrays, and focused DNA sequencing have revealed that SCC and adenocarcinomas exhibit distinct and largely nonoverlapping mutational profiles, consistent with the lack of response of SCC to targeted agents successfully used for the treatment of adenocarcinomas.^20-22Frequent recurrent genetic alterations in lung adenocarcinoma include epidermal growth factor receptor (EGFR) kinase gene and fusions of the anaplastic lymphoma kinase (ALK) gene, which predict sensitivity to targeted treatment with EGFR inhibitors, gefitinib and erlotinib and the ALK inhibitor crizotinib, respectively.

Table 1. Genetic Alterations in Lung Squamous Cell Carcinoma

Adapted and expanded from Gandara⁵and Chen⁴

Such core genomic events in driver oncogenes are not prominent in SCC, which lack highly recurrent activating tyrosine kinase mutations (FIGURE 1).²³The rate and spectrum of somatic mutations in SCC are similar to small cell and other smoking-related cancers and dissimilar to adenocarcinoma of the lung.^20-22The normal lung does not contain squamous cells; therefore, squamous differentiation in SCC results from metaplasia. The presumptive carcinogenic sequence leading to SCC formation encompasses progressive changes in cell morphology upon exposure to tobacco smoke, including mucosal changes that progress from basal-cell hyperplasia through squamous metaplasia, varying degrees of squamous dysplasia, and carcinoma in situ.²⁴These changes are accompanied by sequential allelic losses at 3p, 9p21, and 17p13, causing loss ofFHIT,CDKN2A, andTP53, respectively.^20-22,25Other common genetic features of SCC include mutations in genes of the oxidative stress response, includingNFE2L2,KEAP1, andCUL3; truncating mutations ofNOTCH1, which regulates squamous cell differentiation; and amplification of chromosomal region 3q, which containsSOX2,TP63, andPIK3CA.^20-22,26,27Genetic alterations in lung SCC that may be associated with sensitivity to targeted agents include mutations in growth factor receptor genes, particularly amplification/mutation of fibroblast growth factor receptor 1 (FGFR1), which occurs in up to 20% of SCC, mutations inFGFR2,FGFR3, and discoidin domain-containing receptor 2 (DDR2),FGFRfusion genes, overexpression of ErB family members, and alternations of genes encoding factors of the PI3K/AKT/MTOR pathway (TABLE 1).^20,28-31High-levelMETamplifications, potentially conferring sensitivity to the ALK inhibitor crizotinib, have been identified in 3% of SCC.³¹Moreover, many SCC lung tumors display alterations in genes regulating cellular immunity and immune evasion, including human leukocyte antigens(HLA)-A, -B, -C,andB2M, among others.²⁰Based on these genomic changes and the generally high somatic mutation rate, which promotes increased formation tumor antigens, immunotherapy has become a main therapeutic focus in SCC.&

In contrast to adenocarcinoma, for which predictive and prognostic biomarkers includeALK,EGFR, andKRASmutations, a prognostic gene signature of SCC has not been identified.³As part of an ongoing study to identify predictive gene expression signatures in SCC, the Squamous Lung Cancer Consortium is validating existing mRNA and miRNA prognostic signatures in a test cohort of 300 patients with early-stage SCC, with follow-up for more than 3 years. Candidate signatures identified in these sets will be further assessed in validation cohorts and verified in additional large (>700) sample sets.⁴⁴

Clinical features and diagnosis of SCC

Squamous cell carcinomas are centrally located, often bulky and cavitating tumors that are characterized by squamous differentiation resembling the pseudostratified columnar epithelium lining trachea and upper airways.^4,45Symptoms of central lung tumors include cough, shortness of breath, hemoptysis, and fever secondary to atelectasis and postobstructive pneumonia.^46-48Centrally located SCC in airways of the main stem, lobar and segmental bronchi presumably arises from squamous metaplasia of tracheal basal cells (FIGURE 2).^4,49This origin is supported by commonly observed metaplasia basal cells in smokers and consistent expression of basal cell markers in SCC, including p63, SOX2, and cytokeratin 5 (CK-5). SCCs have also been increasingly found in the periphery; presumptive progenitors of SCC in the alveolar space include bronchiolar progenitor cells and bronchioalveolar stem cells.^47-48

Figure 2. Origin and molecular markers of NSCLC subtypes. SCC presumably arise from tracheal basal cells in the proximal lung, with retained expression of basal cell markers p63, SOX2 and KRT5, and may arise from bronchiolar progenitor cells and bronchioalveolar stem cells (BASCs) in the alveolar space. Adenocarcinomas typically express markers of the proximal airways, including surfactant protein C (SPC), KRT7, and thyroid transcription factor 1 (TTF1).

Adapted from Chen et al.⁴

Histologically, well-differentiated SCC is characterized by distinct diagnostic histopathologic features, including intercellular bridges, individual cell keratinization, and squamous pearl formation.^47-48Cells are often large with abundant dense cytoplasm, irregular hyperchromatic nuclei, and small nucleoli. Histologic variants according to the current World Health Organization (WHO) classification include papillary, clear cell (abundant clear cytoplasm), small cell (small cells, focal squamous differentiation), and basaloid (peripheral palisading of nuclei) subtypes; these are largely descriptive without established prognostic or clinical impact. Clinically relevant variants of SCC of the lung and other sites are basaloid and lymphoepithelioma-like subtypes, associated with aggressive disease and Epstein-Barr virus, respectively.^46,49,50

Well-differentiated SCC tumors can usually be diagnosed based on the morphology of cytology samples (effusions/aspirates/ washes) or tumor and mediastinal lymph node samples obtained by biopsy or minimally invasive techniques.^3,51The classification of tumors without clear SCC or adenocarcinoma morphology relies on additional immunohistochemical (IHC) staining for markers. Squamous cell carcinomas are usually thyroid termination factor 1 (TTF- 1) and napsin negative and p63 positive, whereas adenocarcinomas express both TTF-1 and napsin.^8,52,53A two-marker panel of TTF-1/ p63 is typically sufficient to distinguish SCC and adenocarcinomas.^54,55To increase sensitivity and specificity, particularly in small samples, IHC panels may include additional markers such as p40, an antibody that recognizes a p63 isoform specific for squamous/basal cells,⁵⁶CK-5 and -6, and 34bE-^1.52An IHC panel of TTF1, p63, CK-5 and -6 has up to 100% accuracy in distinguishing lung SCC and adenocarcinoma.⁵⁴Particularly in small samples, the distinction of pure SCC from mixed adenosquamous tumors containing SCC and adenocarcinoma components may be challenging but is therapeutically relevant because the latter, which constitute 0.4% to 4% of NSCLC, frequently harborEGFRmutations andALKrearrangements and may respond to targeted agents.^51,56Molecular profiling, a standard approach required for treatment selection for nonsquamous NSCLC based on the presence of sensitizingEGFRmutations,ALKrearrangements, orKRASmutations, can additionally refine the diagnosis. This approach is particularly pertinent to small samples with potentially unsampled adenocarcinoma components, with the presence ofKRASmutation suggesting predominantly adenocarcinoma subtype.ALKrearrangements or sensitizingEGFRmutations can be present in tumors of mixed or squamous cell histology.^56,57Therefore, testing for these two mutations should be performed for tumors with squamous cell histology from patients who have never smoked, or in cases of mixed histology or small biopsy specimens.^3,58Testing forEGFRandALKis also recommended in metastatic disease with squamous histology.³EGFR,KRAS, andALKgenetic alterations do not usually overlap.⁵⁹

Current treatment approaches for lung SCC

The treatment of early-stage NSCLC relies on surgery, radiotherapy, and combined modalities, including adjuvant and neoadjuvant cisplatin-based chemotherapy regimens for all histologic subtypes, while the selection of systemic therapy of recurrent and metastatic disease is guided by tumor histology and genetic profile.⁸Because SCC largely lacks recurrent mutations predicting sensitivity to targeted agents used in the first-line treatment of advanced NSCLC, the standard of care first-line treatment for patients with advanced or metastatic SCC and Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 1 is cytotoxic chemotherapy with a platinum-based doublet (FIGURE 3). For patients with ECOG PS 2, recommended first-line options include single-agent chemotherapy (vinorelbine, gemcitabine, or taxanes) or platinum-based doublet therapy (carboplatin/paclitaxel); patients with ECOG PS of 3 to 4 should receive best supportive care (BSC).³

Figure 3. NCCN treatment algorithm for SCC.³

Assessment of tumor response to first-line therapy should be evaluated with CT scans after 1 to 2 cycles and every 2 to 4 cycles thereafter.³Current guidelines do not endorse treatment beyond 4 to 6 cycles of chemotherapy; however, in the absence of disease progression, continuation or switch maintenance regimens are considered category 2B options.³For patients with disease progression during or after first-line therapy (approximately 25%), subsequent therapy is recommended. Recommended regimens are nivolumab (category 1) and ramucirumab plus docetaxel (category 2A;FIGURE 3). Other category 2A options include docetaxel, erlotinib (depending on proteomic testing results), or gemcitabine.³Therapy after second disease progression depends on previous treatment and may include any of the previously mentioned agents if not previously given.³These regimens are often associated with limited response but may be palliative.

First-line treatment for SCC

Initial therapy of advanced NSCLC should be a drug regimen that has the highest likelihood of benefit and the least toxicity.³A large proportion of patients with NSCLC are elderly, and 30% or more have a poor PS (≥2); therefore, toxicity avoidance and consideration of comorbidities need to be balanced carefully against the anticipated benefit from treatment, while avoiding undertreatment.^60-64In patients with adequate PS, doublet chemotherapy is recommended over single agents based on superior 1-year survival rates of 30% to 40%.³Available agents generally considered useful for stage IV NSCLC include platinum agents (cisplatin, carboplatin), taxanes (paclitaxel, nab-paclitaxel, docetaxel), vinorelbine, gemcitabine, and others. Current category 1 recommendations for the first-line treatment of patients with advanced and metastatic SCC are cisplatin/gemcitabine, carboplatin/paclitaxel, carboplatin/nab-paclitaxel, and cisplatin/vinorelbine.³These recommendations incorporate clinical trial evidence for differential activity of chemotherapeutic agents in patients with SCC versus those with other NSCLC histology.

After platinum doublet, one of the more recent entrants to firstline therapy includes nab-paclitaxel. Nab-paclitaxel/carboplatin is recommended as first-line therapy for patients with advanced NSCLC and good PS (0-1), based on a favorable risk-benefit profile that was demonstrated in a phase III trial and led to US Food and Drug Administration (FDA) approval for this indication.^3,7Nab-paclitaxel is a solvent-free, albumin-stabilized paclitaxel formulation designed to overcome the risk of hypersensitivity reactions and need for steroid/antihistamine premedication associated with formulations of taxanes in polyethoxylated castor oil.⁶⁵The albumin-bound formulation additionally exploits albumin receptor-mediated endothelial transport that may improve the agent&rsquo;s tumor penetration.⁶⁶In patients with advanced NSCLC (n = 1052), a weekly nab-paclitaxel/ carboplatin regimen significantly improved ORR (33% vs 25%; RR, 1.313; 95% CI, 1.082-1.593;P<.005) compared with conventionally formulated sb-paclitaxel/carboplatin every 3 weeks.⁷Furthermore, subgroup analysis of patients stratified by histology demonstrated that patients with SCC in particular (n = 450; 43%) benefited from nab-paclitaxel, with an ORR of 41% compared with 24% for the sbpaclitaxel/carboplatin regimen (RR, 1.68;P<.001; reflecting 68% improvement) (TABLE 2).^7,67No difference between treatments was observed in patients with nonsquamous histology (ORR, 26% vs 25%) or adenocarcinoma (ORR, 26% vs 27%). Patients with SCC had a nonsignificant 1-month improvement in median OS (10.7 months with nab-paclitaxel/carboplatin vs 9.5 months with sb-paclitaxel/ carboplatin; HR, 0.890; 95% CI, 0.719-1.101;P=.284).⁶⁷The weekly regimen of nab-paclitaxel/carboplatin was better tolerated than sbpaclitaxel/carboplatin and caused significantly less neurotoxicity, including sensory neuropathy (all grades, 46% vs 62%;P<.001), neutropenia, arthralgia, and myalgia (allP<.05). Time to improvement in sensory neuropathy was faster (median time to improvement from grade 3 or greater sensory neuropathy to grade 1, 38 days vs 104 days for sb-paclitaxel/carboplatin). Anemia (grade 3, 22% vs 6%, grade 4, 5% vs 1%;P<.001) and thrombocytopenia (grade 3, 13% vs 7%; grade 4, 5% vs 2%;P<.001) were observed more frequently in the nab-paclitaxel arm. In most patients, anemia was managed with a single blood transfusion, and thrombocytopenia did not increase hemorrhage rates.⁷The median cumulative taxane dose and average dose intensity were higher (18% and 26%, respectively) in patients receiving nab-paclitaxel/carboplatin compared with sb-paclitaxel/carboplatin. Such increased systemic paclitaxel levels may particularly affect SCC, which is often centrally located and close to major blood vessels; this may explain the particular activity of nab-paclitaxel in this NSCLC type.⁶⁷Nab-paclitaxel/carboplatin also improved outcomes among elderly patients (&ge;70 years of age) who had a significantly higher median OS (19.9 months vs 10.4 months on sb-paclitaxel/carboplatin;P=.009) and a higher ORR (34% vs. 24%;P= not significant).⁶⁸Toxicities were similar in patients less than 70 and 70 or more years of age. A randomized phase IV trial evaluating the long-term safety and efficacy of nab-paclitaxel/carboplatin as first-line treatment in elderly subjects (&ge;70 years old) is ongoing (NCT02151149).

Table 2. Efficacy Outcomes with Taxane-containing Regimens in Advanced Squamous NSCLC

Adapted from Socinski. NR indicates no response; PFS, progression-free survival; ORR, objective response rate; OS, overall survival; SCC, squamous cell carcinoma. Abbreviations: NR, not reported; ORR, overall response rate; OS, overall survival; PFS, progression-free survival

Other potential treatment options are being evaluated. Two agents, pemetrexed and bevacizumab, are specifically not recommended for SCC because they are considered ineffective and are contraindicated because of hemoptysis risk, respectively.^3,6A phase III study comparing three platinum-doublet combinations as firstline treatment in patients with advanced (stage IIIB or IV; mostly stage IV) NSCLC (n = 1725) found that patients with SCC (n = 473) had improved survival with cisplatin/gemcitabine compared with cisplatin/pemetrexed (10.8 months vs 9.4 months; HR, 1.23; 95% CI, 1.00-1.51; P = .05; TABLE 2).⁶⁹Inversely, patients with adenocarcinoma and large-cell carcinomas experienced better survival with cisplatin/pemetrexed (11.8 months vs 10.4 months; HR, 0.81; P =.005). Cisplatin/gemcitabine (a category 1 first-line option in SCC) is therefore considered of superior efficacy when compared with cisplatin/pemetrexed in patients with SCC; and pemetrexed is not recommended for the treatment of patients with squamous tumors.³The observed resistance of SCC to pemetrexed, a folate antimetabolite inhibiting thymidylate synthase (TS), may be associated with high expression levels of TS in SCC.⁷⁰

In general, current guidelines recommend selection of first-line platinum-doublet combinations based on avoidance of toxicity, convenience, and cost.³Additional options for the first-line treatment of patients with advanced SCC include platinum-doublet combinations considered of comparable activity in advanced NSCLC, and nonplatinum combinations such as gemcitabine/docetaxel and gemcitabine/vinorelbine, which are considered reasonable based on activity and lower toxicity (category 2A recommendations.^71-76No particular third-generation platinum doublet has been identified as being clearly superior for the treatment of advanced SCC.^3,76-78Nab-paclitaxel/carboplatin appears superior to sb-paclitaxel/carboplatin in SCC (TABLE 2) and is associated with better tolerability, shorter duration of infusion, and no requirement for premedication.^7,65,67Particular activity of taxanes in the first-line treatment of SCC was previously suggested by a retrospective subgroup analysis of a phase III trial in advanced NSCLC that revealed a significantly greater ORR among patients with SCC receiving sbpaclitaxel/carboplatin compared with gemcitabine/carboplatin (46% vs 25%,P= .02;TABLE 2).(Treat 2010) Among patients with nonsquamous tumor histology, efficacy of regimens, which also included gemcitabine/sb-paclitaxel, did not differ significantly.⁷⁹Taxane-based therapy, particularly with nab-paclitaxel, also appears to benefit elderly patients with SCC. Outcomes from a study evaluating OS with first-line chemotherapy in elderly (age &ge;65 years) Medicare beneficiaries (n = 15,318; treated 2000-2007) with advanced NSCLC suggest that patients with squamous cell histology (n = 2063) had better survival with carboplatin/paclitaxel than with carboplatin/gemcitabine (HR for death with carboplatin/gemcitabine, 1.20; 95% CI, 1.07-1.35).⁷⁹In the phase III trial comparing nab-paclitaxel/carboplatin versus sb-paclitaxel/carboplatin, more elderly patients in the nab-paclitaxel arm received second-line therapy (61% vs 50%), which improves survival over BSC or placebo.^68,80-81

Maintenance therapy

Maintenance therapy can improve progression-free survival (PFS) in subsets of patients with advanced NSCLC after completion of 4 to 6 cycles of first-line platinum-doublet therapy and stable or responding disease.^82-83Because evidence for an overall increase in OS and quality of life, or for superiority over subsequent therapy initiated at progression, remains inconclusive, maintenance therapy in NSCLC is considered an individual choice that depends on multiple factors, including patient performance and toxicities experienced during treatment, among others.³The role of maintenance therapy in SCC is therefore not well established; recommended therapeutic options without specific indication in SCC include gemcitabine as continuation maintenance therapy regardless of histology, and docetaxel and erlotinib as switch maintenance therapy; all of these are considered category 2B because the benefits are slight; close observation remains category 2A.³These recommendations are based on outcomes from a phase III trial in NSCLC, including SCC, revealing that continuation maintenance therapy with single-agent gemcitabine increased PFS to a greater extent (3.8 months) than did switch maintenance therapy with erlotinib (2.9 months) when compared with observation (1.9 months).⁸²Another phase III, randomized trial reported significant improvement in median time to progression (TTP) with gemcitabine continuation maintenance versus BSC after an initial regimen of cisplatin/gemcitabine (TTP, 6.6 months vs 5 months); approximately 40% of patients in each arm had squamous histology.^83-84A phase III trial reported that switch maintenance therapy with docetaxel given immediately after first-line therapy with gemcitabine plus carboplatin significantly increased PFS and resulted in a numerical increase in OS compared with docetaxel given at progression.⁸⁵Outcomes for the SCC subset (n = 98, 17.3%) were not separately reported. Switch maintenance with docetaxel is considered a category 2B option because many patients in the delayed arm did not receive docetaxel, and survival of actually treated patients did not differ between arms.^3,86

An ongoing phase III trial is evaluating the potential benefits of nab-paclitaxel with BSC compared to BSC alone in patients with stage IIB/IV SCC responding to first-line nab-paclitaxel plus carboplatin (NCT02027428; n = 260). A phase III trial conducted in France by the International Forum on Cancer Treatment (IFCT) will investigate switch maintenance with pemetrexed (nonsquamous NSCLC) or gemcitabine (SCC) in elderly patients (&ge;70 years) with disease control after 4 cycles of carboplatin/sbpaclitaxel (NCT01850303; n = 549).

Targeted agents for subsequent (second- and third-line) therapy

Subsequent-line treatment options for patients with metastatic SCC have recently added two targeted agents. The immunotherapeutic agent nivolumab demonstrated improved survival of pretreated patients with SCC compared with docetaxel, resulting in FDA approval for patients who have progressed on or after platinumbased chemotherapy. Nivolumab is recommended as the first choice for subsequent-line treatment of platinum-resistant SCC (category 1).³Secondly, the combination of ramucirumab/docetaxel was added as a category 2A option for metastatic platinum-resistant NSCLC irrespective of histology. Other available agents in subsequent-line treatment of SCC include erlotinib (depending on proteomic testing), docetaxel, and gemcitabine (category 2A). Clinical trial evidence exists for improved survival with nivolumab when compared with docetaxel, improved survival with ramucirumab/docetaxel compared with docetaxel alone, superiority of single-agent docetaxel to vinorelbine or ifosfamide, and superiority of erlotinib to BSC.³In patients with wild-type EGFR, docetaxel is preferred over erlotinib based on clinical trial evidence demonstrating higher efficacy of docetaxel or nonsuperiority of erlotinib in this patient subset, respectively.^3,87-88

Nivolumab is a fully human monoclonal antibody (mAb) that binds to a key receptor of an inhibitory immune checkpoint, preventing it from engaging with its ligands, resulting in improved antitumor immunity in multiple solid malignancies.⁸⁹Based on activity of nivolumab in advanced SCC observed in phase I and II trials,^90-91the randomized phase III CheckMate-017 trial was designed to compare nivolumab with docetaxel. For patients (n = 272) with previously treated SCC, nivolumab treatment provided a clear survival benefit; the median OS was 9.2 months with nivolumab and 6.0 months with docetaxel.⁹²Similarly, ORR and PFS were significantly improved (20% vs 9% with docetaxel, P = .008, and 3.5 months vs 2.8 months with docetaxel; HR for death or disease progression, 0.62; 95% CI, 0.47-0.81;P<.001, respectively). Nivolumab was associated with fewer grade 3 to 4 adverse events (AEs; 7% vs 55%) and deaths (0 vs 3) compared with docetaxel but did produce immunerelated AEs, including pneumonitis.^90-91This organ-specific immune toxicity may derive from pre-existing pulmonary inflammation in lung cancer that might be enhanced upon programmed cell death-1 (PD-1) blockade. Current recommendations therefore suggest close monitoring for immune-mediated AEs and administration of highdose corticosteroids, dose interruption, or discontinuation if pneumonitis or other severe or life-threatening immune-mediated AEs occur.³Long-term efficacy and safety data for nivolumab have become available from a phase I dose-escalating study of nivolumab in patients with advanced solid tumors, confirming continued survival benefit in patients with NSCLC, including patients with SCC.^90-93The median OS of patients with NSCLC (n = 129) and the SCC subgroup (n = 54) were 9.9 months (95% CI, 7.8-12.4) and 9.2 months (95% CI, 7.3-12.5) across doses, respectively, and 14.9 months (95% CI, 7.3- 30.3) and 9.5 months (95% CI, 5.3 to not estimable) at the approved dose of 3 mg/kg. One-, 2-, and 3-year survival rates with this dose were 56%, 42%, and 27% for all patients, and 49%, 35%, and 28% for patients with SCC.⁹⁰

Ramucirumab, a VEGFR2-targeted mAb, was recently approved for use in combination with docetaxel in patients with advanced NSCLC progressing after primary platinum-based chemotherapy, regardless of tumor histology. The phase III, randomized REVEL trial (n = 1253 patients) demonstrated modest benefits with the addition of ramucirumab to docetaxel, with increased OS (10.5 months vs 9.1 months;P= .023) and PFS (4.5 months vs 3.0 months;P<.0001). The study was not powered for subgroup analysis but found a numerical increase in OS for most subgroups, including the approximately 25% of patients with squamous histology (ramucirumab arm, n = 157; control arm, n = 171; OS 9.5 months vs 8.2 months; HR, 0.88; 95% CI, 0.69-1.13).94 Similarly, benefits in PFS, ORR (overall, 23% vs 14%;P<.001), and disease control rate (overall, 64% vs 53%;P<.0001) were consistent across tumors with different histologies. Treatment-related AEs were observed in almost all patients in the ramucirumab arm (98%) and the control arm (95%) and were manageable with appropriate dose reductions and supportive care. The most common grade 3 and 4 AEs in the ramucirumab and control arm were neutropenia (49% and 40%, respectively), febrile neutropenia (16% and 10%), fatigue (14% and 10%), leukopenia (14% and 12%), and hypertension (6% and 2%).

Superiority of erlotinib over BSC in patients with NSCLC of all histologic subtypes was shown in the phase III BR-21 trial of erlotinib versus placebo in the second-/third-line setting (erlotinib arm, 29.5%; placebo, 32.1%).⁸¹The trial found OS and PFS benefits with erlotinib for patients with SCC, including male ever-smokers with SCC (HR, 0.66;^P=.015).⁹⁵

After second disease progression, selection of therapy is guided by previous exposure and performance. If not previously exposed to the respective agent, patients with PS 0 to 2 may receive single-agent therapy, including nivolumab (category 2A), erlotinib (depending on proteomic testing results, category 2A) and docetaxel, gemcitabine, and ramucirumab plus docetaxel (all category 2B).³These regimens are often associated with limited response but can have a palliative role. Options for PS 3 to 4 include erlotinib or BSC, and for further progression, BSC. In patients with advanced or platinum-resistant SCC, participation in a clinical trial is highly recommended.³

Necitumumab was recently reviewed by members of the FDA Oncologic Drugs Advisory Committee, most of whom agreed that the drug shows promise in the first-line treatment of locally advanced or metastatic NSCLC.⁹⁵

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