Pembrolizumab for the Treatment of Non–Small-Cell Lung Cancer¶
Why this mattered¶
Before this study, advanced non-small-cell lung cancer was still largely treated as a disease managed by cytotoxic chemotherapy and selected targeted therapies for tumors with driver mutations. This paper helped make immune checkpoint blockade a central therapeutic strategy in a cancer type long regarded as poorly immunogenic. In a large phase 1 cohort, pembrolizumab produced durable responses in a subset of patients, with a median response duration of 12.5 months and an acceptable toxicity profile. The key shift was not simply that some tumors shrank, but that metastatic lung cancer could be controlled for prolonged periods by releasing an antitumor immune response rather than directly poisoning dividing cells or inhibiting a single oncogenic kinase.
The study also made biomarker-directed immunotherapy practical in lung cancer. By prospectively defining and validating tumor PD-L1 expression in at least 50% of cells as a threshold associated with greater benefit, it connected a measurable tumor-immune feature to clinical decision-making. In the validation group, patients above this cutoff had a 45.2% response rate, far higher than the overall response rate of 19.4%. That result helped establish PD-L1 immunohistochemistry as a companion-style tool for selecting patients most likely to benefit from pembrolizumab, while also exposing the limitations of a single biomarker: some PD-L1-low tumors could still respond, and some PD-L1-high tumors did not.
Its broader importance lies in how it redirected the development path of lung-cancer therapy. KEYNOTE-001 supplied pivotal early evidence that led to later randomized trials of pembrolizumab in previously treated and first-line non-small-cell lung cancer, including studies that compared it with chemotherapy and combined it with chemotherapy. Those later breakthroughs transformed pembrolizumab from an experimental checkpoint inhibitor into a standard component of care across major NSCLC settings. The paper therefore stands at the transition point where immunotherapy moved from a promising concept in melanoma and renal cancer to a durable, biomarker-informed treatment paradigm for the most common cause of cancer death worldwide.
Abstract¶
BACKGROUND: We assessed the efficacy and safety of programmed cell death 1 (PD-1) inhibition with pembrolizumab in patients with advanced non-small-cell lung cancer enrolled in a phase 1 study. We also sought to define and validate an expression level of the PD-1 ligand 1 (PD-L1) that is associated with the likelihood of clinical benefit. METHODS: We assigned 495 patients receiving pembrolizumab (at a dose of either 2 mg or 10 mg per kilogram of body weight every 3 weeks or 10 mg per kilogram every 2 weeks) to either a training group (182 patients) or a validation group (313 patients). We assessed PD-L1 expression in tumor samples using immunohistochemical analysis, with results reported as the percentage of neoplastic cells with staining for membranous PD-L1 (proportion score). Response was assessed every 9 weeks by central review. RESULTS: Common side effects that were attributed to pembrolizumab were fatigue, pruritus, and decreased appetite, with no clear difference according to dose or schedule. Among all the patients, the objective response rate was 19.4%, and the median duration of response was 12.5 months. The median duration of progression-free survival was 3.7 months, and the median duration of overall survival was 12.0 months. PD-L1 expression in at least 50% of tumor cells was selected as the cutoff from the training group. Among patients with a proportion score of at least 50% in the validation group, the response rate was 45.2%. Among all the patients with a proportion score of at least 50%, median progression-free survival was 6.3 months; median overall survival was not reached. CONCLUSIONS: Pembrolizumab had an acceptable side-effect profile and showed antitumor activity in patients with advanced non-small-cell lung cancer. PD-L1 expression in at least 50% of tumor cells correlated with improved efficacy of pembrolizumab. (Funded by Merck; KEYNOTE-001 ClinicalTrials.gov number, NCT01295827.).
Related¶
- cite → PD-1 Blockade in Tumors with Mismatch-Repair Deficiency — The pembrolizumab lung cancer study links to mismatch-repair deficiency through the claim that high mutation burden can predict stronger response to PD-1 blockade.
- cite → PD-1 blockade induces responses by inhibiting adaptive immune resistance — The pembrolizumab lung cancer study builds on adaptive immune resistance as the mechanistic rationale for blocking PD-1 signaling in tumors.
- cite → Mutational landscape determines sensitivity to PD-1 blockade in non–small cell lung cancer — Both papers connect PD-1 blockade response in non-small-cell lung cancer to tumor mutational burden and neoantigen load.
- cite → Improved Survival with Ipilimumab in Patients with Metastatic Melanoma — The pembrolizumab lung cancer study cites ipilimumab as prior evidence that immune checkpoint inhibition can improve survival in cancer.
- cite → Safety and Activity of Anti–PD-L1 Antibody in Patients with Advanced Cancer — The pembrolizumab lung cancer study cites anti-PD-L1 antibody activity as clinical precedent for targeting the PD-1/PD-L1 pathway in advanced cancer.
- cite → Nivolumab versus Docetaxel in Advanced Nonsquamous Non–Small-Cell Lung Cancer — Both studies test PD-1 pathway blockade in advanced nonsquamous non-small-cell lung cancer, comparing pembrolizumab evidence with nivolumab survival results.
- cite → Signatures of mutational processes in human cancer — The pembrolizumab study uses cancer mutational signatures as context for linking smoking-associated mutations to immunotherapy sensitivity.
- cite → Nivolumab versus Docetaxel in Advanced Squamous-Cell Non–Small-Cell Lung Cancer — Both studies establish PD-1 blockade as active therapy in non-small-cell lung cancer, with nivolumab data specifically in squamous-cell disease.
- cite → Safety, Activity, and Immune Correlates of Anti–PD-1 Antibody in Cancer — The pembrolizumab lung cancer study cites early anti-PD-1 clinical data showing safety, antitumor activity, and immune correlates across cancers.
- cite → Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma — The pembrolizumab study cites combined nivolumab-ipilimumab melanoma results as broader evidence for checkpoint blockade strategies.
- cite ← Pembrolizumab plus Chemotherapy in Metastatic Non–Small-Cell Lung Cancer — The 2018 trial extends early pembrolizumab NSCLC efficacy findings by testing PD-1 blockade combined with platinum chemotherapy in metastatic disease.
- cite ← Pembrolizumab versus Chemotherapy for PD-L1–Positive Non–Small-Cell Lung Cancer — The 2016 pembrolizumab trial extends earlier NSCLC evidence by testing pembrolizumab as first-line therapy in PD-L1-positive disease.
- cite ← Nivolumab versus Docetaxel in Advanced Nonsquamous Non–Small-Cell Lung Cancer — The nivolumab lung-cancer trial links to pembrolizumab through clinical PD-1 checkpoint blockade as a therapeutic strategy in non-small-cell lung cancer.
- enables ← Improved Survival with Ipilimumab in Patients with Metastatic Melanoma — Ipilimumab's survival benefit validated immune-checkpoint blockade in cancer, enabling pembrolizumab trials targeting PD-1 in non-small-cell lung cancer.