Lung cancer is one of the leading causes of cancer-related deaths around the world (1, 2). Despite the development of third-generation drugs combined with platinum compounds and different maintenance therapies, the overall survival achieved by cytotoxic agents was no longer than 15 months (3, 4).
Programmed cell death 1 (PD-1) is a negative costimulatory factor expressed on the surface of T-cells. It binds to one of its ligands; PD-L1 or PD-L2 expressed on the surface of neoplastic cells and inhibits a cytotoxic T-cell response. Several antibodies were developed against PD-1 or PD-L1 achieving enthusiastic results in NSCLC (durable response in approximately 20% of the patients) (5-7). Pembrolizumab is a monoclonal humanized IgG4 antibody against the PD-1 that has shown activity in different neoplasms including NSCLC.
KeyNote-001 is a large phase I trial evaluating different doses (2 mg or 10 mg per kilogram every 2 weeks) of pembrolizumab for the treatment of different neoplasms. In 2015 Garon et. al. published the results for NSCLC (8).
Interestingly, patients could be enrolled into the study despite their histology, previous treatment or PD-L1 status. Four hundred ninety five patients were included. The objective response rate was 19.4% and the median duration of response was 12.5 months. The median progression-free survival was 3.7 months and the median overall survival was 12.0 months. Pembrolizumab has shown a manageable toxicity profile with less than 10% of grade 3 or 4 adverse events and pneumonitis incidence of less than 4% with a severity of grade 3 to 5 in half the patients (8).
The most important question is: this treatment is indicated for whom?
In the KeyNote-001 trial, PD-L1 status was assessed by IHC and after a ROC curve it was adopted the cutoff of 50% and it was different from previous trials evaluating anti PD-1 therapies, which have adopted the cutoff of 5%. Nevertheless, the difference among PD-L1 positive and PD-L1 negative neoplasms was the largest ever shown (8).
The response rate was 46.8% among PD-L1 positive patients and 12.3% among PD-L1 negative patients. This difference was significant despite the presence or absence of previous treatment. The median progression-free survival and the median overall survival were better among PD-L1 positive patients (8).
Based on this study, pembrolizumab proved activity for NSCLC despite the presence of previous treatment, however, the main limitation of this study is that it had not any control arm to be compared to pembrolizumab. Moreover, it was not designed for any specific population (previous treated or untreated; PD-L1 positive or PD-L1 negative) and all these conclusions were made based upon subgroup analysis.
- Is PD-L1 a feasible biomarker for anti PD-1 activity?
- If the above is true, what is the best cutoff value?
- Would it be reasonable to approve pembrolizumab for clinical use after the findings of the present article?
- If the above is true, which is the population that would achieve the largest benefit?
- GLOBOCAN 2012: Estimated Cancer Incidence, Mortality and Prevalence Worldwide in 2012 [Internet]. 2012. Available from: http://globocan.iarc.fr/Pages/fact_sheets_population.aspx.
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- Gerber DE, Schiller JH. Maintenance chemotherapy for advanced non-small-cell lung cancer: new life for an old idea. J Clin Oncol. 2013;31(8):1009-20.
- Leighl NB. Treatment paradigms for patients with metastatic non-small-cell lung cancer: first-, second-, and third-line. Curr Oncol. 2012;19(Suppl 1):S52-8.
- Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366(26):2443-54.
- Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366(26):2455-65.
- Rizvi NA, Mazières J, Planchard D, Stinchcombe TE, Dy GK, Antonia SJ, et al. Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial. Lancet Oncol. 2015;16(3):257-65.
- 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.
The authors have no conflict of interest to declare.
The content of this article reflects the personal opinion of the author and is not necessarily the official position of the European Society for Medical Oncology.