Pembrolizumab plus platinum-based chemotherapy for squamous non-small cell lung cancer: the new kid on the block.

Abstract

Immune checkpoint inhibitors (ICIs) and targeted therapies have revolutionised the diagnostic and treatment paradigm of advanced non-small cell lung cancer (NSCLC). However, treatment advances in squamous cell subtype have been much slower than those occurring in adenocarcinoma, mainly due to the lack of targetable oncogenic aberrations in squamous tumours. The unprecedented durable response and favourable toxicity profile observed with ICIs in advanced squamous NSCLC, represents a true therapeutic milestone in a population previously limited to cytotoxic chemotherapy (Cht). The inhibition of programmed cell death ligand 1 (PD-1/PD-L1) pathway has been extensively investigated in NSCLC and currently dominates the treatment landscape of advanced NSCLC. The first approval of ICIs came from several randomized trials conducted in platinum-treated advanced NSCLC patients (any histology) (1-4) where overall survival (OS) and toxicity profile favoured PD-1/PD-L1 inhibitors over docetaxel. Subsequently, KEYNOTE-024 (5) showed that, in advanced NSCLC patients (all histologies) with a PD-L1 tumour proportion score (TPS) ≥50%, first-line pembrolizumab achieved higher objective response rates (ORR) and longer progression-free survival (PFS) and OS when compared to standard platinum-based Cht. However, high PD-L1 expression only occurs in a third of NSCLC patients and, until recently, platinum-based Cht remained the only approved option for fit patients with a PD-L1 TPS <50%. In the phase III trial KEYNOTE-407 (6), 559 patients with treatment-naive advanced squamous NSCLC and performance status 0-1 were randomised to receive 4 cycles of carboplatin (AUC 6, 3 weekly) with either Paclitaxel (200 mg/m2, 3 weekly) or nab-paclitaxel (100 mg/m2 on day 1, 8 and 15) plus Pembrolizumab (200 mg, 3 weekly) or placebo for 35 cycles. Stratification factors were PD-L1 TPS ≥1% versus <1% assessed by 222C3 assay, type of taxane (paclitaxel versus nab-paclitaxel) and geographic region (East Asia versus rest of the world). The co-primary endpoints were PFS and OS. After a median follow-up of 7.8 months, the chemo-immunotherapy arm achieved longer PFS (4.8 vs. 6.4 months, HR 0.56; 95% CI, 0.45–0.70; P 50%). Incidence of grade ≥3 adverse events (AEs) (69.8% vs. 68.2%) and AEs leading to death (8.3% vs. 6.4%), was similar between the two arms. According to an exploratory analysis (7), the type of taxane (paclitaxel versus nab-paclitaxel) did not impact in treatment tolerance or treatment efficacy in terms of OS, PFS and ORR. Furthermore, the addition of Pembrolizumab to chemotherapy maintained or improved Health-related quality of life (HRQoL) measurements relative to baseline. There was also improved HRQoL at weeks 9 and 18 versus chemotherapy alone (8). On the basis of KEYNOTE-407, the combination of carboplatin and (nab)paclitaxel plus pembrolizumab is now approved by FDA and EMA as a first line option for advanced squamous NSCLC patients, independently on PD-L1 expression.