Lung cancer is the most common cause of cancer deaths in both men and women worldwide. NSCLC represents between 80% and 85% of all the diagnosed lung cancers cases and is generally diagnosed at advanced stage (1).
Programed death 1 (PD-1) is an immune checkpoint receptor expressed on activated T cells and engaged by the tumor-expressed ligands PDL1 and PDL2, which suppresses anti-tumor immunity (2). Several antibodies have been developed against PD-1 or PD-L1 achieving enthusiastic results in NSCLC. Recent randomized studies comparing second-line docetaxel with immunotherapy in advanced NSCLC have demonstrated better overall response rate, survival and quality of life with checkpoints inhibitors in both histologies (3-6). Based on these results, immunotherapy represents the new standard of care in this context.
Pembrolizumab is a monoclonal humanized IgG4 antibody against PD-1 that prevents PD-1 from engaging PD-L1 and PD-L2 (7). Data from the phase 1 Keynote-001 (8) demonstrated that patients with advanced NSCLC and a PD-L1 tumor proportion score ≥50% were more likely to response to pembrolizumab than those patients with lower PD-L1 tumor proportion score. Moreover, patients with PD-L1 expression of at least 1% of tumour cells showed major overall survival benefit with pembrolizumab compared to docetaxel for second-line treatment of advanced NSCLC, as we can conclude from phase 3 Keynote-010 (5)
Keynote-024 was recently presented at the ESMO annual meeting and published in New England Journal of Medicine in October 2016. It is the first phase III trial comparing first-line chemotherapy versus pembrolizumab in patients with strong-positive expression of PD-L1 (defined as expression in at least 50% of tumour cells) who represent 27-30% of those with advanced NSCLC. In this trial, 305 patients were randomized 1:1 to receive intravenous pembrolizumab at a fixed dose of 200 mg every 3 weeks for 35 cycles (n=154) or chemotherapy for 4 to 6 cycles of the investigator's choice (n=151) which most commonly included carboplatin plus pemetrexed (n = 67). Maintenance pemetrexed and crossover to pembrolizumab regimen were allowed in the chemotherapy arm after disease progression. Patients with EGFR- or ALK-positive tumors were excluded.
Patient characteristics were well balanced between groups except for smoking status and the incidence of brain metastases; there were more patients in the chemotherapy arm who had never smoked (12.6% versus 3.2% in the pembrolizumab arm) and there were more patients in the pembrolizumab group who had brain metastases (11.7% vs 6.6% in the chemotherapy group). However, these differences were not statistically significant. Median age of the population was 64.5 years in the pembrolizumab arm, 60% were males, and most patients had a good performance status (64% had an ECOG of 1).
Median progression-free survival (primary endpoint) was 10.3 months for the pembrolizumab group versus 6.0 months for the chemotherapy arm (HR: 0.50(CI 95%,0.37-0.69); p<0.001). Interestingly, this benefit of pembrolizumab remained consistent in all subgroups assessed (regardless of smoking status, histologic type, brain metastases at baseline or chemotherapy regimen). It is important to point out that the most common histology was non-squamous (n=249, 81.2%). In these patients, there was a 45% reduction in the risk of progression or death with immunotherapy versus chemotherapy (HR: 0.55 (CI 95%, 0.39-0.76), whereas in the squamous group the risk of disease progression or death was reduced by 45% with pembrolizumab (HR: 0.35; CI 95%,0.17-0.71).
Pembrolizumab was also associated with a prolonged overall survival (OS). The estimated 6-months OS rate was 80.2% for the experimental group and 72.4% for the control group (HR 0.60; p: 0.005). This significant improvement with the immune checkpoint inhibitor is remarkable considering that more than 40% of patients in the control arm crossed over to pembrolizumab after progression disease. At the time of the analysis, median OS had not yet been reached.
Immunotherapy was also associated with a higher overall response rate compared with chemotherapy (44.8% versus 27.8%). The duration of response was not reached in the immunotherapy arm versus 6.3 months with chemotherapy.
Pembrolizumab has shown a manageable toxicity profile. The most common treatment-related adverse events of any severity for pembrolizumab were diarrhea (14.3%), fatigue (10.4%), and pyrexia (10.4%). Less than 10% of patients receiving pembrolizumab developed grade 3/4 immune-mediated events. Toxicity led to treatment discontinuation for 7.1% of patients in the pembrolizumab arm vs 10.7% of those receiving chemotherapy.
The results of this trial confirm pembrolizumab to be superior to chemotherapy in the first-line setting for patients with advanced NSCLC whose tumors express high levels of PD-L1. Pembrolizumab is now FDA approved as first-line setting in ≥50% PD-L1 positive advanced NSCLC patients.
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- Gettinger SN, Horn L, Gandhi L, Spigel DR, Antonia SJ, Rizvi NA, et al. Overall Survival and Long-Term Safety of Nivolumab (Anti-Programmed Death 1 Antibody, BMS-936558, ONO-4538) in Patients With Previously Treated Advanced Non-Small-Cell Lung Cancer.J Clin Oncol. 2015;33(18):2004-12.
- 3.Brahmer J, Reckamp KL, Bass P, Crinó L, Eberhardt WE, Poddubskaya E, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med. 2015; 373(2):123-35.
- Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med.2015;373(2):1627-39.
- Herbst RS, Baas P, Kim DW, Felip E, Pérez-Garcia JL, Han JY, et al. Pembrolizumab versus docetaxel for pre- viously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE- 010): a randomised controlled trial. Lancet. 2016;387(10027):1540-50.
- Barlesi F, Park K, Ciardiello F, Von Pawel J, Gadgeel S, Hida T. Primary analysis from OAK, a randomized phase III study comparing atezolizumab with docetaxel in 2L/3L NSCLC. Abstract LBA44_PR. ESMO 2016.
- Chatterjee M, Turner DC, Felip E, Lena H, Capuzzo F, Horn L, et al. Systematic evaluation of pembrolizumab dosing in patients with advanced non- small-cell lung cancer. Ann Oncol 2016; 27(7):1291-8.
- Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP, et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med. 2015; 372(21):2018-28.
Will PD-L1 + CTLA-4 inhibitors or CT + immunotherapy combination improve these results in first-line of NSCLC?
Why has nivolumab failed to be superior to chemotherapy in first-line NSCLC?
The author has no actual, potential, real or apparent interest to declare. The author has no involvement that might raise the question of bias in the work reported or in the conclusions, implications, or opinions stated