Is smoking history the truly best biomarker for immune checkpoint inhibitor treatment in advanced non-small cell lung cancer?

Immune checkpoint inhibitors have shown remarkable efficacy in patients with advanced non-small cell lung cancer (NSCLC) and have been approved for these patients. Nivolumab, pembrolizumab and atezolizumab improved outcome of patients with advanced NSCLC compared with docetaxel among patients who had been pretreated with chemotherapy.1–4 Pembrolizumab improved overall survival among chemo-naive patients with advanced NSCLC and programmed death-ligand 1 (PD-L1) expression in ≥50% of tumour cells.5 Among patients with PD-L1 levels below 50%, however, pembrolizumab as single agent did not increase progression-free survival or overall survival compared with chemotherapy.6 Nivolumab failed to improve outcome compared with platinum-based chemotherapy in patients with PD-L1 expression in ≥5%.7 Among patients with high tumour mutational burden, nivolumab combined with ipilimumab increased overall survival compared with chemotherapy.8 Combinations of first-line chemotherapy with immune checkpoint inhibitors were recently shown to improve outcome compared with chemotherapy alone.9 10 Pembrolizumab added to platinum-based chemotherapy increased progression-free survival and overall survival compared with chemotherapy in advanced NSCLC, both among patients with PD-L1 levels ≥1% and those with levels <1%.9 The addition of atezolizumab to chemotherapy plus bevacizumab also improved outcome including overall survival among patients with metastatic non-squamous cell NSCLC.10While the therapeutic advances with immune checkpoint inhibitors are clinically meaningful, these benefits are limited to a fraction of patients. Within phase III trials, response rates of immune checkpoint inhibitors were higher in the chemo-naive than pretreated patients and highest in combination with first-line chemotherapy.1–5 9 10 In patients who had been pretreated with chemotherapy, response rates with immune checkpoint inhibitors as single agents were 19%–20% for nivolumab, 29%–30% for pembrolizumab and 14% for atezolizumab, respectively.1–4 In chemo-naive patients, a response rate of 44.8% was achieved with pembrolizumab among patients with PD-L1 expression in ≥50% of tumour cells.5 When combined with platinum-based chemotherapy, the …