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Shifting Paradigms in Non-Small Cell Lung Cancer: An Evolving Therapeutic Landscape
Jonathan Riess, MD, MS
Post Test: Non-Small Cell Lung Cancer: Clinical and Economic Considerations in Targeting Therapy Based on Molecular Profiling

Shifting Paradigms in Non-Small Cell Lung Cancer: An Evolving Therapeutic Landscape

Jonathan Riess, MD, MS
Globally, lung cancer is the leading cause of cancer-related mortality among both men and women, and while mortality associated with the disease has demonstrated relative stability over the years, evidence has suggested an increasing incidence and prevalence of the disease. Unfortunately, the diagnosis of lung cancer is often made late in the course of the disease, with almost 70% of patients presenting with locally advanced or metastatic disease at initial diagnosis. Non-small cell lung cancer (NSCLC) is the most common form of the malignancy, occurring in up to 85% of cases. There are 3 subtypes of NSCLC: squamous-cell carcinoma, adenocarcinoma, and large-cell carcinoma. Enhanced understanding of the pathophysiology of NSCLC has led to substantial improvements in diagnostic, prognostic, and therapeutic interventions for NSCLC. The discovery of targetable molecular alterations in genes, such as epidermal growth factor receptor (EGFR), has driven the evolution of targeted therapies for NSCLC and shifted treatment paradigms for the disease. This article will summarize the epidemiology and pathophysiology of NSCLC, its associated gene mutations and biomarkers, and the approach to treatment, with a focus on patients whose tumors harbor EGFRactivating mutations.

Am J Manag Care. 2013;19:S390-S397
Lung cancer is the leading cause of cancer-related mortality in the world.1 Unfortunately, the diagnosis is frequently made late in the course of lung cancer; nearly 70% of patients have locally advanced or metastatic disease at diagnosis. Among patients with lung cancer, 75% to 85% have non-small cell lung cancer (NSCLC), and 50% of those patients present with advanced metastatic disease (stage IV).1,2 Recent research has led an to expansion of the diagnostic and treatment landscape beyond cytotoxic chemotherapy to include molecularly targeted therapies that inhibit key components of cellular pathways implicated in tumor growth and progression.3 This article provides a clinical overview of NSCLC, its associated gene mutations, current targeted treatments, and predictive biomarkers, with particular focus on epidermal growth factor receptor (EGFR). The next article in the supplement explores recent recommendations on molecular profiling, the incorporation of molecular profiling into clinical practice, and the economic implications in a cost-constrained healthcare and managed care environment.

Epidemiology and Pathophysiology

Lung cancer, including both small-cell lung cancer and NSCLC, is the second most common cancer among men and women, and accounts for approximately 14% and 12% of all new cancer diagnoses in males and females, respectively. The American Cancer Society estimates that in 2013, there will be 228,190 new cases of lung cancer (118,080 in men; 110,110 in women) in the United States, with an estimated 159,480 deaths resulting from lung cancer (87,260 in men; 72,220 in women), accounting for roughly 27% of all cancer deaths.

Lung cancer is the leading cause of cancer-related death among both men and women, with more people dying from lung cancer than from colon, breast, and prostate cancers combined.4 The estimated incidence of lung cancer has increased from 169,500 in 2001 to 228,190 in 2013; however, mortality appears to remain relatively stable (157,400 in 2001 to 159,480 in 2013), which suggests that the prevalence of the disease is also increasing.1,4

Due to the high mortality rate associated with lung cancer, it is important to identify risk factors associated with its development. Risk factors for lung cancer include: (1) current or former cigarette smoking; (2) proximity to cigarette smoking (ie, passive inhalation); and (3) exposure to asbestos or radon. In men, the lifetime risk of developing lung cancer is about 1 in 13, and in women, the lifetime risk is about 1 in 16. When only smokers are considered, the risk is much higher, whereas the risk for nonsmokers is much lower.4 When looking at the types of lung cancer, NSCLC is far more prevalent than small-cell carcinoma, accounting for 75% to 85% of lung cancer cases.1,2

Once lung cancer is present, one must examine the type, because it can affect treatment decisions. Lung cancer is characterized by histology and stage.1,5 NSCLC consists of squamous-cell carcinoma (about 30% of all lung cancers), adenocarcinoma (about 30%-40% of all lung cancers), or large-cell carcinoma (about 10%-15% of all lung cancers). Small-cell carcinoma constitutes the remaining 20% to 25% and appears to have been decreasing in incidence over the last 30 years, possibly due to decreased cigarette smoking.6 Small-cell lung cancer and squamous cell carcinoma are most strongly associated with smoking and are typically found in the central part of the chest. Adenocarcinomas are associated with smoking, but are also the most common lung cancer among nonsmokers and women. This subtype of NSCLC often grows near the periphery of the lung, and is more likely to metastasize to distant sites than squamous cell carcinoma. Similarly, largecell carcinomas are also more likely to metastasize than squamous cell carcinoma. Small-cell carcinomas grow very rapidly, are very likely to be diagnosed in a metastatic state, and usually manifest centrally in the chest.1 Staging of NSCLC is determined based upon the primary tumor, lymph node involvement, and the presence or absence of distant metastases.

In addition to the traditional risk factors that one might typically associate with lung cancer, age also plays a notable role in disease development and outcomes. Lung cancer predominantly develops in older individuals, with approximately 2 out of every 3 people diagnosed with lung cancer at 65 years or older.4 Patients under the age of 45 years account for less than 2% of all cases of lung cancer. Factors that are associated with the diagnosis of lung cancer at a younger age include: (1) adenocarcinoma cancer type; (2) African American race; (3) Asian or Pacific Islander race; and (4) stage IV disease.7 Overall, roughly 50% of patients with newly diagnosed NSCLC will have metastatic disease, and the 5-year survival following a diagnosis with NSCLC is less than 20%.1,2 When compared with younger patients with the same stage of NSCLC, 5-year survival tends to be shorter among older patients.7 In general, the prognosis of a patient with NSCLC is greatly affected by the stage at which the NSCLC is diagnosed (Figure).8 Despite the very serious prognosis associated with lung cancer, much has been learned in recent years about the disease and the factors that impact treatment outcomes. Further, some individuals with earlierstage cancers are able to be cured, including the 380,000 people who have been diagnosed with lung cancer at some point but are still alive today.4

Targeted Therapies in NSCLC

There are several approaches to treating NSCLC, including surgical management for early stage and select locally advanced lung cancers, but for metastatic disease, systemic therapy is the mainstay of treatment.1,2 Systemic therapy is available in 2 general categories, standard therapy and, more recently, targeted therapy. Systemic standard therapy consists of nonselective chemotherapy which targets the cell cycle of dividing cells. Targeted therapies were designed to selectively target molecular pathways that drive, or are responsible for, cancer cells in NSCLC. Because targeted therapies are more specific to the biology of the cancer cells than standard therapies, there is potential for reduced treatment-related toxicity.

To define the place in therapy of various targeted therapies, including the tyrosine kinase inhibitors (TKIs), this article includes a representative sampling of available literature rather than an exhaustive review of all treatment options. Multiple clinical trials have shown that chemotherapy in advanced NSCLC can reduce symptoms, improve survival, and benefit patient quality of life (QOL). The mainstay of front-line systemic therapy has been platinum-doublet chemotherapy with either cisplatin or carboplatin and a partner drug (typically gemcitabine, pemetrexed, vinorelbine, or a taxane such as docetaxel or paclitaxel). Despite these advances, NSCLC is still associated with a 5-year survival rate of 15%.2

One key factor associated with driving NSCLC is angiogenesis. Angiogenesis plays an important role in lung cancer growth and spread. Due to the role of angiogenesis in feeding NSCLC, the addition of the vascular endothelial growth factor inhibitor bevacizumab to a paclitaxel-carboplatin combination therapy versus paclitaxel-carboplatin alone was assessed for the possibility of enhanced efficacy.9,10 In a phase 3 trial, the addition of bevacizumab to paclitaxelcarboplatin improved median survival in non-squamous NSCLC to 12.3 months versus 10.3 months with paclitaxelcarboplatin alone (hazard ratio [HR], 0.79; P = .003), with progression-free survival (PFS) of 6.2 months and 4.5 months (HR, 0.66; P <.001), respectively, and response rates of 35% and 15% (P <.001), respectively.10 While the use of bevacizumab is associated with several adverse effects, including rash, diarrhea, headache, and minor bleeding episodes, bevacizumab is not used in squamous lung cancers because of the increased rate of pulmonary hemorrhage, which is sometimes fatal.

Pemetrexed is another therapy that is an inhibitor of thymidylate synthase and a general anti-folate inhibitor of purine and pyrimidine synthesis. The agent has been studied extensively as a chemotherapeutic agent in NSCLC.11-13 Assessment of prognostic factors for efficacy of pemetrexed from phase 3 trials revealed enhanced efficacy in nonsquamous (ie, adenocarcinoma, large-cell carcinoma) histology relative to squamous histology. When compared with a cisplatin- gemcitabine combination therapy, cisplatin-pemetrexed demonstrated similar overall survival (10.3 months in both groups) in the overall population, which consisted of patients with stage IIIB or IV NSCLC and good performance status (Eastern Cooperative Oncology Group performance status of 0 to 1) using chemotherapy for the first time. However, in histologic subgroup analysis, improvements were noted in overall survival among the adenocarcinoma (10.9 months vs 12.6 months; P = .03) and large-cell carcinoma groups (6.7 months vs 10.4 months; P = .03), but not in the squamous cell group (10.8 months vs 9.4 months; P = .05).12 The preferential efficacy of pemetrexed in non-squamous NSCLC may be attributed to higher levels of expression of thymidylate synthase and S-phase kinase-associated protein in squamous cell lung cancers than in non-squamous lung cancers.13 Although pemetrexed was associated with lower rates of hematologic toxicity than gemcitabine, there were higher rates of nausea, dehydration, and fatigue in the premetrexed treatment group.12

Although the addition of bevacizumab and pemetrexed has improved patient outcomes, survival still remains poor, with overall survival approximately 10 to 12 months for patients with stage IIIB or IV disease. In addition, QOL is influenced by the quality of treatment and the patient’s health status, and in recent QOL studies of second-line targeted therapies, quality-adjusted life-years scores ranged from 0.46 for progressive disease with grade 3/4 toxicity to 0.712 for responding disease without grade 3/4 toxicity.14 The scale is based on a score of 0 for deceased to a score of 1 for perfect health, indicating that patients with NSCLC treated with these agents have 50% to 70% of a normal health status.15,16 Patient QOL surveys have identified that the type of treatment and the adverse effects of treatment affected patientperceived QOL, whereas gender, age, tumor stage, and survival time did not affect patient-perceived QOL.17 Given the incurable nature of advanced NSCLC, future strategies are focused on the identification and targeting of patients with NSCLC tumors that express certain oncogenes that may respond to targeted therapies.

Molecular Aberrations in NSCLC

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