Non-small cell lung cancer (NSCLC) is a leading cause of death among cancer patients. The 5-year overall survival rate in patients with localized cancer is 55.2 %, and this decreases to 4.3 % in those with advanced disease. Since the development of platinum-based therapy two decades ago, there has been little progress in the treatment of advanced stage NSCLC. Agents like EGFR and ALK inhibitors showed efficacy in the first line treatment of NSCLC; however, their role is limited to a subset of patients who carry sensitizing mutations which are almost exclusively found in tumors with adenocarcinoma histology. No significant progress has been made in the second line treatment of NSCLC since the approval of docetaxel in 1999. This remained the standard agent in this setting until recently. The advent of checkpoint inhibitors in the treatment of non-small lung cancer, particularly the anti-PD-1 monoclonal antibodies nivolumab and pembrolizumab, has brought new hope to many patients with advanced stage disease who failed first line treatment with platinum-based, doublet chemotherapy.
Nivolumab was compared to docetaxel in two pivotal studies: checkmate 017 (nivolumab vs docetaxel in advanced stage squamous cell lung cancer) and checkmate 057 (nivolumab vs docetaxel in advanced stage non-squamous cell lung cancer). In both studies, nivolumab performed superiorly to docetaxel demonstrating higher efficacy, improved survival benefit, and a better safety profile. In checkmate 017, the hazard ratio (HR) for overall survival (OS) in patients receiving nivolumab compared to those who were allocated to docetaxel was 0.52 (95 % CI, 0.35–0.75) in 152 patients <65 years, 0.56 (95 % CI, 0.34–0.91) in 91 patients aged 65 to 75 years, and 1.85 (95 % CI, 0.76–4.51) in 29 patients aged ≥75 years.
Pembrolizumab garnered accelerated approval in NSCLC based on its performance in the phase 1b Keynote-001 study. Subsequent to this pivotal study, Keynote-010 compared pembrolizumab to docetaxel in a three-arm, phase 2/3 randomized trial. Patients were divided into three groups: 345 received pembrolizumab 2 mg/kg, 346 received pembrolizumab 10 mg/kg, and 343 received docetaxel. Pembrolizumab, at both doses, outperformed docetaxel across all study populations. The HR for OS in the pembrolizumab 2 mg/kg group was 0.71 (95 % CI, 0.58–0.88) compared to docetaxel. The median OS of this dose was 10.4 months. Pembrolizumab 10 mg/kg had a HR of 0.61 (0.49–0.75) and median OS of 12.7 months, and docetaxel had a median OS of 8.5 months. The benefit was more significant in patients with PD-L1 expression higher than 50 % in their tumor tissue. AE rates associated with pembrolizumab 2 and 10 mg/kg were 63 and 66 %, respectively, compared to 81 % with docetaxel. Pembrolizumab, at both doses, was associated with a range of autoimmune events, most frequent being hypothyroidism (8 %), pneumonitis (4–5 %), and hyperthyroidism (4–6 %).
Non-small lung cancer is predominantly found in older adults. More than 50 % of patients with this diagnosis are over 65 years old, and highest mortality rates are also seen in this age group. However, most evidence used in management of older patients with NSCLC is extrapolated from literature on younger adults due to underrepresentation of this age category in clinical trials. The patient population included in the aforementioned trials had a higher percentage of older adults (approximately 40 %) compared to what is usually seen in the literature. However, the numbers are still not representative of the actual NSCLC population. This observation is important because while many older patients with advanced NSCLC are already being treated with checkpoint inhibitors, data from the main trials are not completely supportive. Interestingly, patients aged ≥75 years had a non-significant HR for survival of 1.85 (95 % CI, 0.76–0.451) in checkmate 017, and 0.90 (95 % CI, 0.43–1.87) in checkmate 057. In Keynote-010, the HR for survival in patients ≥65 years was 0.76 (95 % CI, 0.57–1.02). While these numbers might be due to statistical reasons more than a lack of efficacy, they still put a question mark on whether these new agents are truly effective in older patients. Aging is associated with a decline in the immune function which could be associated, at least hypothetically, with decreased efficacy of immune mediated therapies. However, checkpoint inhibitors are a favorable option in the second line treatment of older adults with NSCLC due to their improved safety profile compared to chemotherapy. Ongoing trials are looking into combining checkpoint inhibitors with chemotherapy or molecularly targeted agents, use of dual checkpoint inhibition (anti-PD-1 and anti-CTLA-4), and the role of checkpoint inhibitors in the adjuvant setting.
Rawad Elias & Joshua Morales & Yasser Rehman & Humera Khurshid. Curr Oncol Rep (2016) 18: 47