Second-Line Therapy for Advanced NSCLC

Abstract

Most patients with lung cancer have non-small cell lung cancer (NSCLC) subtype and have advanced disease at the time of diagnosis. Improvements in both first-line and subsequent therapies are allowing longer survival and enhanced quality of life for these patients. The median overall survival observed in many second-line trials is approximately 9 months, and many patients receive further therapy after second-line therapy. The cytotoxic agents pemetrexed and docetaxel and the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) erlotinib and gefitinib are standard second-line therapies. For patients with EGFR mutation, a TKI is the favored second-line therapy if not already used in first-line therapy. For patients without the EGFR mutation, TKIs are an option, but many oncologists favor cytotoxic therapy. The inhibitor of the EML4/ALK fusion protein, crizotinib, has recently become a standard second-line treatment for patients with the gene rearrangement and has promise for patients with the ROS1 rearrangement. The Oncologist 2013;18:947-953Implications for Practice: The landscape of first-line treatment has generated challenges for clinical decisions in second-line therapy. For the patient treated with standard chemotherapy in the first line who has a treatable molecular change, this change should be targeted. More specifically, the patient with an epidermal growth factor receptor (EGFR) mutation should be treated with an EGFR tyrosine kinase inhibitor, and the patient with EML4/ALK rearrangement should be treated with crizotinib. However, these agents are increasingly being used in the first line, and most patients do not have these molecular changes. This leaves the clinician with many challenging questions regarding second-line therapy. How should the patient without treatable mutations be treated? Which clinical trials are most promising? How should the patient treated with a targeted agent in the first line be treated in the second line? This review addresses these issues, exploring the key existing data available to help guide informed clinical decisions. INTRODUCTIONLung cancer is the leading cause of cancer-related mortality in the United States and in the world [1,2]. Most patients have the non-small cell lung cancer (NSCLC) subtype and have advanced-stage disease at the time of diagnosis. The standard first-line therapy for advanced disease (defined as stage IIIB or IV) is a platinum doublet alone or with a targeted agent such as bevacizumab for four to six cycles [3]. Chemotherapy extends overall survival (OS), reduces disease-related symptoms, and improves quality of life (QoL). Historically, after completion of four to six cycles of platinum-based therapy, patients were observed, and at the time of radiographic or clinical evidence of disease progression, therapy was re-initiated. Approximately 30% of patients experience disease progression during firstline chemotherapy, and all patients with initial disease control will eventually experience disease progression and requ...

Non–Small Cell Lung Cancer, Version 5.2017, NCCN Clinical Practice Guidelines in Oncology

“…Subsequent systemic therapy regimens for patients who have disease progression during or after first-line therapy are described in the NSCLC algorithm and depend on the specific genetic alteration, the histologic subtype, and whether the patient has symptoms (see the complete version of these guidelines, available at NCCN.org). [225][226][227][228][229][230][231][232][233][234] For the 2017 update (Version 1), the NCCN panel now recommends response assessment of known sites of disease with CT (with contrast) every 6 to 12 weeks in patients receiving subsequent therapy. Note that traditional RECIST 1.1 criteria are used to assess response for most types of systemic therapy, but different response criteria may be useful for assessing response in patients receiving immunotherapy.…”

“…95,98 Nivolumab, pembrolizumab, atezolizumab, docetaxel with or without ramucirumab (category 2B for both), gemcitabine (category 2B), or pemetrexed (nonsquamous only) (category 2B) are recommended for subsequent therapy after second disease progression in patients with advanced NSCLC and PS 0 to 2 if these agents have not already been given. 226,246,251,252 …”

Epidemiological profile and prognostic factors in patients with lung cancer

“…In line with the literature, there are studies that show OS benefit using second and third lines, especially with molecularly targeted drugs. [26][27][28][29] As the laboratory variables, hemoglobin and LDH were related to survival in previous studies. 17,18 Our study did not establish this association as statistically significant; however, our sample is small compared with the literature and, also, we did not have data on all patients, and these factors may be responsible for any negative data.…”

Nintedanib: A Review of Its Use as Second-Line Treatment in Adults with Advanced Non-Small Cell Lung Cancer of Adenocarcinoma Histology

“…In patients with advanced non-small cell lung cancer (NSCLC) without driver mutations, standard first-line treatment with platinum-based doublet therapy (administered alone or with a targeted agent) extends overall survival (OS) and improves symptom control and health-related quality of life (HR-QOL) [1,2]. However, ≈30 % of patients who receive first-line chemotherapy experience disease progression and all patients who initially respond to treatment eventually develop disease progression and require subsequent treatment [2].…”