What Can We Save for the First-Line Treatment of NSCLC in 2016?

Lung cancer is the leading cause of cancer-related deaths worldwide. In the United States, there were 221,200 new diagnoses and 158,400 deaths in 2015, according to the National Cancer Institute. In these last years, histologic definition has become crucial in the therapeutic algorithm of NSCLC. Today we recognize three big groups of lung cancer: non-squamous “wild type”, non-squamous with genetic mutations and squamous. For the non-squamous “wild type”, pemetrexed plus cisplatin or carboplatin is the gold standard of care with chance of pemetrexed maintenance in patients with responsive or stable disease; another option is the addition of bevacizumab to a doublet with paclitaxel/carboplatin. For the non-squamous with genetic mutations, we can take into account clinical practice of epidermal growth factor receptor (EGFR) mutations, ALK translocations and ROS-1 rearrangements: gefitinib, erlotinib and afatinib for EGFR mutations, crizotinib for ALK translocations and ROS-1 rearrangements. For squamous cell carcinoma, a doublet with platinum derivate plus gemcitabine, vinorelbine or docetaxel is the gold standard; last year, necitumumab (a new anti-EGFR monoclonal antibody) has been approved by FDA in combination with cisplatin and gemcitabine (SQUIRE trial). In these last 2 years, immunocheck-point inhibitors documented high activity as second line in squamous and non-squamous cell carcinoma. In 2015, FDA approved nivolumab (Opdivo®) as second line, regardless of PD-L1 expression, in patients with NSCLC progressed during or after platinum-based chemotherapy according to results of CheckMate 017 (squamous) and CheckMate 057 (non-squamous) [1, 2]. In the same year, pembrolizumab (Keytruda®) was approved by FDA as second line in squamous and non-squamous patients with PD-L1 expression, according to results of a large multicenter, open-label, multi-part study (keynote 010) [3]. But what news in 2016? The main results concerned immunocheck-point inhibitors. In October 24, FDA approved pembrolizumab (Keytruda®) for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 ≥ 50% as determined by an FDA approved test [4]. This is the first approval of a check-point inhibitor for the first line of lung cancer. Approval was based on results of two randomized, controlled trials that demonstrated statistically significant improvements in progression-free survival (PFS) and overall survival (OS) for patients randomized to pembrolizumab compared with chemotherapy. In the first trial of 305 patients (keynote 024) who had no prior treatment for metastatic NSCLC and PD-L1 expression greater than or equal to 50%, those who received pembrolizumab (200 mg every 3 weeks) had a significant improvement in PFS (HR: 0.50; 95% CI: 0.37 0.68; P < 0.001) with a median PFS of 10.3 months versus 6.0 months for those receiving platinum-based chemotherapy. A pre-specified interim analysis demonstrated a statistically significant improvement in OS for patients randomized to pembrolizumab as compared with chemotherapy (HR: 0.60; 95% CI: 0.41 0.89; P < 0.005). In the second three-arm trial (keynote 010, previously cited), 1,033 patients who were previously treated for metastatic NSCLC with PD-L1 expression greater than or equal to 1%, randomized to pembrolizumab 2 mg/kg every 3 weeks (HR: 0.71; 95% CI: 0.58 0.88; P < 0.001) or pembrolizumab 10 mg/kg every 3 weeks (HR: 0.61; 95% CI: 0.49 0.75; P < 0.001), had an improved OS compared with patients receiving docetaxel [3]. The median survival was 10.4 months in the pembrolizumab 2 mg/kg arm, 12.7 months in the pembrolizumab 10 mg/kg arm, and 8.5 months in the docetaxel arm. The most common side effects of treatment with pembrolizumab included decreased appetite, fatigue, nausea, dyspnea, cough, and constipation. Rare but serious adverse events included immune-mediated pneumonitis, colitis, hepatitis, endocrinopathies, and nephritis. Unlike pembrolizumab, nivolumab (Opdivo®) fails to demonstrate a benefit in PFS and OS in the same setting of patients. In Checkmate 026 trial [5], 541 patients with PD-L1 expression ≥ 5% were randomized to receive nivolumab 3 mg/kg every 2 weeks versus best chemotherapy. PFS was the main endpoint but was not met (4.2 months with nivolumab versus 5.9 months with chemotherapy; HR: 1.15; P = 0.25); OS was similar in the two arms of treatment (14.4 and 13.2 months for nivolumab and chemotherapy, respectively; HR: 1.02). Several explanations were proposed to clarify so different results in the same setting of patients. The main issue appears to be patient selection, whereas pembrolizumab trial was conducted in patients whose tumors showed at least 50% PD-L1 expression, and nivolumab trial enrolled patients with PD-L1 expression ≥ 5%. However, the same results were documented in a small subgroup of patients who had at least 50% PD-L1 expression (HR for PFS: 1.1; HR for OS: 0.90); nevertheless, the trial was not statistically powered for this analysis. Other explanations may be that OS was better than historical data in the chemotherapy arm Manuscript accepted for publication April 04, 2017