Carys Davies, PharmD Candidate

About 218,000 new cases of lung cancer were reported in 2016 and more than 148,000 people died from this disease, according to the CDC.

More individuals die from lung cancer each year than from breast, colon, and prostate cancer combined.

 Cigarette smoking is the biggest risk factor for developing lung cancer, as it is responsible for 80% to 90% of lung cancer deaths.

 The 2 main types of lung cancer are non—small cell lung cancer (NSCLC) and small cell lung cancer.

 The majority of lung cancer cases are NSCLC, however, representing about 80% to 85% of cases.

 Additionally, NSCLC has 3 main subtypes: adenocarcinoma, large cell carcinoma, and squamous cell carcinoma (see Figure 14). For patients with localized NSCLC, the overall 5-year survival rate is about 60%. For regional NSCLC, the 5-year survival rate is about 33%. If the cancer has spread to distant sites of the body (metastatic lung disease), the 5-year survival rate precipitously declines to just 6%. However, with the advent of earlier interventions and newer, more effective therapies, these survival percentages are improving.

The choice of first-line agents used initially in patients with NSCLC depends on multiple factors (see Figure 14). The expression of programmed cell death ligand 1 (PD-L1) greatly influences therapy decisions.

 In patients with a low PD-L1 expression of less than 50% and no other genetic mutations, pembrolizumab, an immunotherapy agent, in combination with carboplatin and pemetrexed, are the preferred therapy options.

 In patients with a high PD-L1 expression, pembrolizumab monotherapy can be used in the absence of rapidly progressing disease. For instance, in rapidly progressive disease, pembrolizumab with chemotherapy is preferred.

First-line agents depend on a variety of genetic test results that could display certain mutations, according to the most recent National Comprehensive Cancer Network NCSLC guidelines.

Mutations are biomarkers and act as predictive and prognostic markers for therapy efficacy. For example, the firstline agents in patients with a known epidermal growth factor receptor mutation prior to starting any chemotherapy are afatinib, erlotinib, or gefitinib. Additionally, the presence or absence of PD-L1, anaplastic lymphoma kinase, B-raf proto-oncogene, and c-ros oncogene 1 are all examined to establish initial therapy.

New types of treatment options are being tested in clinical trials, which include chemoprevention and other investigational options.

Despite advances in lung cancer treatment, including biologic therapy and targeted treatment, survival rates have not dramatically improved, primarily because by the

time most patients present with symptoms, the disease has metastasized to an advanced stage. Chemoprevention involves using dietary or pharmacologic agents to prevent or slow the growth of cancer, and it is classified as either primary, secondary, or tertiary chemoprevention, depending on the target population

Although antioxidants and vitamins have not been successful as agents for primary chemoprevention, incidental observations regarding the use of inhaled corticosteroids and low-dose aspirin have shown more promising results. In a cohort study of 10,474 US veterans diagnosed with chronic obstructive lung disease and no history of lung cancer, there was a dose-dependent decrease in lung cancer associated with the use of inhaled corticosteroids.

 Additional randomized controlled trials with extended follow-up periods are warranted to further validate these findings. In a retrospective cohort study of nearly 13 million individuals in the Korean National Health Institute, low-dose aspirin (less than 100 mg) was associated with a reduced risk of lung cancer, which was even more apparent in participants 65 years and older and those diagnosed with diabetes.

Secondary and tertiary chemoprevention, such as oral iloprost and celecoxib, displayed promising results in phase II trials,

 but the end points used were not validated, and future larger trials are necessary to confirm supportive data.

Early detection confers better treatment outcomes in most malignancies and NSCLC is no exception.

Low-dose chest computed tomography screening is recommended for patients aged 55 to 77 years, who are asymptomatic smokers and former smokers who have smoked for 30 pack-years or more and either continue to smoke or have quit within the past 15 years. Asymptomatic is defined as the absence of symptoms suggesting the presence of lung cancer.

A promising alternative to chemotherapy and pembrolizumab in patients with low or unknown PD-L1 expression is the immunotherapy combination of nivolumab plus ipilimumab. In the CheckMate-227 trial, the results indicated superior survival outcomes over chemotherapy alone.

 Durvalumab and tremelimumab were also studied in a phase 3 trial, MYSTIC, versus chemotherapy alone.

Although preliminary results did not show improved outcomes, post hoc exploratory analysis displayed improved outcomes in patients with a higher tumor mutational burden.

Radiosensitizers, substances that work to enhance the effect of radiation on tumors without increasing the effect on normal tissue, are being investigated in patients with NSCLC.

 Vicenin-2, a substance that has been reported to possess a wide variety of pharmacologcal activities, has been proven effective in lowering cancer cell survival while promoting expression of proapoptotic genes, making it an effective radiosensitizing agent.

Although there have been numerous advancements in the treatment of NSCLC, early detection, public education, and smoking cessation are the most important cornerstones of preventing the disease and improving patient survival outcomes. Additional research and targeted therapy will continue to improve survival, but tobacco

avoidance and early intervention are the key areas of opportunity for combating this lethal malignancy.

Glenn Schulman, PharmD, MS, BCPS, BCACP, BCG BCIDP

, are clinical pharmacists in Pensacola, Florida.

 is a PharmD candidate at the Universityof Florida in Gainesville.

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Articles

Despite numerous treatment advances, early detection, public education, and smoking cessation are the best bets. 

Prevention is Key for Non-Small Cell Lung Cancer

An estimated 96,000 cases of melanoma were diagnosed in 2019, and 7230 deaths were attributed to this type of cancer, based on statistics from the National Cancer Institute.

The 5-year overall survival rate for melanoma is high, because 83.6% of cases are diagnosed early, at the local stage (Figure 1).

 However, this percentage drastically decreases once the cancer has metastasized (Figure 2).

Melanoma arises when melanocytes, the cells responsible for producing melanin that provides pigmentation of the skin, become cancerous and create a malignant tumor.

Advanced melanoma is classified as melanoma that has escalated beyond the point of the primary tumor in the body, according to the Skin Cancer Foundation.

This classification encompasses stage III and IV cancers, which are diagnosed by physicians based on the tumor, node, and metastasis system.

 Typically, these advanced stages of melanoma involve the tumor spreading regionally to the lymph nodes (stage III) or metastasizing to other organs (stage IV) and can be further classified within each stage based on the characteristics of the tumor(s).

There are 5 standard treatment options for melanoma: chemotherapy, immunotherapy, radiation therapy, surgery, and targeted therapy.

 Most patients will receive a combination of these treatment modalities. 

As melanoma advances in stage, the treatment approaches will usually involve systemic therapy to target cells in various locations of the body.

Targeted therapy involves BRAF and MEK inhibitors, which are personalized treatment options designed to aim for a specific defective gene in the body contributing to melanoma. BRAF is a gene that when functioning normally, regulates cell multiplication.

 Mutations affecting this gene can lead to continuous cell growth. BRAF mutations are found in about 50% of advanced melanoma cases and should be tested for in all patients with a confirmed diagnosis of advanced melanoma.

 BRAF and MEK inhibitors work by interrupting abnormal cell growth. When used alone, BRAF inhibitors are initially very effective in blocking the overproduction of cells, but then the tumor(s) typically develops resistance to the treatment. To combat this issue, an MEK inhibitor should also be administered in combination with a BRAF inhibitor to prevent the disease from advancing.

for personalized cancer treatment to be effective, the patient’s melanoma must carry the BRAF mutation targeted by these medications (Table 1).

Used in combination, BRAF and MEK inhibitors are first-line therapy when the BRAF mutation is present, according to the National Comprehensive Cancer Network guidelines for

Systemic immunotherapy is also considered first-line therapy in the treatment of patients with advanced melanoma

 because of its significant progress in treatment outcomes

 and is a continuously evolving therapeutic option at the center of ongoing research. Immunotherapy, also referred to as biological therapy, harnesses the body’s natural defenses within the immune system to fight the cancer via the use of synthetic substances acting as either proteins of the immune system or signaling molecules.

There are 4 main classifications of immunotherapy, each with diverse mechanisms of action employed to fight cancer cells (Table 2).

Over the past decade, the use of a single or combination of checkpoint inhibitors, a specific class of immunotherapy, has been at the core of numerous clinical research trials. The 2 categories of checkpoint inhibitor therapies are listed below with their specific mechanisms.

Cytotoxic T-lymphocyte antigen 4 (CTLA-4) inhibitors block the CTLA-4 proteins from protecting cancer cells being destroyed by T cells.

Programmed cell death protein 1 (PD-1) inhibitors attach to another protein, programmed death-ligand 1, to prevent PD-1 from binding and stopping T cells from killing cancer cells.

Ipilimumab is a CTLA-4 inhibitor and also inhibits nivolumab and pembrolizumab PD-1.

 All of these medications are monoclonal antibodies, created by fusing human antibody-producing cells with an immortalized cell line and designed to bind to antigens in order to exert a desired effect within the immune system.

In a randomized, controlled trial published in 2010, ipilimumab was compared alone and with glycoprotein 100 (gp100) versus gp100 alone.

 Gp100 is a well-studied cancer vaccine designed to decrease tumor growth.

 The results of this study indicated that ipilimumab, with or without gp100, led to longer overall survival in patients with metastatic melanoma compared with gp100 alone.

 The KEYNOTE-006 trial, published in 2015, then compared ipilimumab with pembrolizumab in patients with advanced melanoma. Pembrolizumab improved both progression-free survival as well as overall survival more significantly than ipilimumab and caused fewer high-grade adverse events related to toxicity.

 Later in 2015, the Check-Mate 067 trial compared nivolumab with ipilimumab alone and combined in patients with unresectable stage III or IV melanoma. The median progression-free survival for ipilimumab in combination with nivolumab was 11.5 months compared with 2.9 months with only ipilimumab only and 6.9 months for nivolumab alone.

CheckMate 067 therefore sparked interest for further research regarding combination therapy compared with monotherapy. In October 2019, the CheckMate 067 trial provided additional follow-up to the study involving ipilimumab and nivolumab. This update followed patients for a minimum of 5 years, elaborating on the 12-month follow-up from 2015. Overall 5-year survival outcomes were clearly superior in the nivolumab-containing treatment groups compared with ipilimumab alone (Figure 3).

Quality of life (QOL) was measured, and the authors concluded no deterioration in health-related QOL in both groups receiving nivolumab but did note clinically meaningful decreases in QOL for the ipilimumab group.

Survival rates for patients with advanced melanoma were quite dismal in the past. New advances in research and the use of immunotherapy have led to major breakthroughs

regarding biologics such as ipilimumab and nivolumab. Identification of the BRAF mutation is the first step in choosing appropriate therapy, and if present, targeted therapy should be used.

 Because of the significantly greater outcomes with combined immunotherapy, 

 this treatment approach should be used in patients with stage III or IV melanoma without the BRAF mutation, to optimize treatment outcomes. 

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Advances in research and immunotherapy have led to breakthroughs regarding biologics targeting melanoma.