Lancet (London, England) 2016-04-09
Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial.
Abstract
Background
Despite recent advances in the treatment of advanced non-small-cell lung cancer, there remains a need for effective treatments for progressive disease. We assessed the efficacy of pembrolizumab for patients with previously treated, PD-L1-positive, advanced non-small-cell lung cancer.
Methods
We did this randomised, open-label, phase 2/3 study at 202 academic medical centres in 24 countries. Patients with previously treated non-small-cell lung cancer with PD-L1 expression on at least 1% of tumour cells were randomly assigned (1:1:1) in blocks of six per stratum with an interactive voice-response system to receive pembrolizumab 2 mg/kg, pembrolizumab 10 mg/kg, or docetaxel 75 mg/m(2) every 3 weeks. The primary endpoints were overall survival and progression-free survival both in the total population and in patients with PD-L1 expression on at least 50% of tumour cells. We used a threshold for significance of p<0.00825 (one-sided) for the analysis of overall survival and a threshold of p<0.001 for progression-free survival. This trial is registered at ClinicalTrials.gov, number NCT01905657.
Findings
Between Aug 28, 2013, and Feb 27, 2015, we enrolled 1034 patients: 345 allocated to pembrolizumab 2 mg/kg, 346 allocated to pembrolizumab 10 mg/kg, and 343 allocated to docetaxel. By Sept 30, 2015, 521 patients had died. In the total population, median overall survival was 10.4 months with pembrolizumab 2 mg/kg, 12.7 months with pembrolizumab 10 mg/kg, and 8.5 months with docetaxel. Overall survival was significantly longer for pembrolizumab 2 mg/kg versus docetaxel (hazard ratio [HR] 0.71, 95% CI 0.58-0.88; p=0.0008) and for pembrolizumab 10 mg/kg versus docetaxel (0.61, 0.49-0.75; p<0.0001). Median progression-free survival was 3.9 months with pembrolizumab 2 mg/kg, 4.0 months with pembrolizumab 10 mg/kg, and 4.0 months with docetaxel, with no significant difference for pembrolizumab 2 mg/kg versus docetaxel (0.88, 0.74-1.05; p=0.07) or for pembrolizumab 10 mg/kg versus docetaxel (HR 0.79, 95% CI 0.66-0.94; p=0.004). Among patients with at least 50% of tumour cells expressing PD-L1, overall survival was significantly longer with pembrolizumab 2 mg/kg than with docetaxel (median 14.9 months vs 8.2 months; HR 0.54, 95% CI 0.38-0.77; p=0.0002) and with pembrolizumab 10 mg/kg than with docetaxel (17.3 months vs 8.2 months; 0.50, 0.36-0.70; p<0.0001). Likewise, for this patient population, progression-free survival was significantly longer with pembrolizumab 2 mg/kg than with docetaxel (median 5.0 months vs 4.1 months; HR 0.59, 95% CI 0.44-0.78; p=0.0001) and with pembrolizumab 10 mg/kg than with docetaxel (5.2 months vs 4.1 months; 0.59, 0.45-0.78; p<0.0001). Grade 3-5 treatment-related adverse events were less common with pembrolizumab than with docetaxel (43 [13%] of 339 patients given 2 mg/kg, 55 [16%] of 343 given 10 mg/kg, and 109 [35%] of 309 given docetaxel).
Interpretation
Pembrolizumab prolongs overall survival and has a favourable benefit-to-risk profile in patients with previously treated, PD-L1-positive, advanced non-small-cell lung cancer. These data establish pembrolizumab as a new treatment option for this population and validate the use of PD-L1 selection.
Funding
Merck & Co.
Related Questions
Would you consider using IO alone for lung cancer patients with PD-L1 <1% but who have high TMB?
The brief answer here is a resounding no. A more extended version might include a statement that this would be a case of not seeing the forest for the trees.And the tree here is the FDA approval of pembrolizumab in a tissue-agnostic fashion for patients with advanced TMB >10 mutations/Mbase- likely ...
Is there a role for retreatment with immunotherapy in patients progressing after initial treatment with immunotherapy for metastatic non small cell lung cancer and who achieve complete or partial response at two years?
The data regarding discontinuation of immunotherapy at 2 years comes mainly from melanoma studies with pembrolizumab. The data in melanoma is strong that therapy can be discontinued, and in these patients the 24-month disease free survival after discontinuation was nearly 90%. The data for NSCLC is ...
How would you treat a patient with metastatic NSCLC >50% PDL-1 positive AND an EGFR or ALK gene mutation/rearrangement in the first-line setting?
There have been multiple reports showing a positive association between EGFR activation (through mutational activation and/or signaling) and PDL1 expression (e.g. J Thorac Oncol 2015 Jun;10(6):910-23). Similarly, there are some reports of a similar association with ALK translocation (e.g. Clin Cance...
When patients with EGFR-mutant or ALK-translocated advanced NSCLC progress after all available targeted therapies, do you use chemotherapy or PD-1/PD-L1 inhibitor therapy as the next line?
In general I favor chemotherapy or a clinical trial for patients with sensitizing EGFR mutations after they have exhausted available EGFR TKI therapy. The EGFR mutated subgroups in both the nivolumab second line registration trials and the pembrolizumab second line registration trial trended toward ...