Immunotherapy has forever changed the management of non-small cell lung cancer (NSCLC). Its impact extends far beyond the introduction of new treatment options and improving our standard of care; immunotherapy has changed our perception of what our treatments can achieve. In particular, checkpoint inhibitors, and specifically programmed cell death protein 1 (PD-1) axis inhibitors, have provided promising results and offer the opportunity for durable, more meaningful benefit. While an improvement in median survival is certainly welcome, what captures the imaginations of patient and physician alike is a chance, albeit a modest one, of long-term survival; a goal historically beyond our reach in metastatic NSCLC.
Immunotherapy in NSCLC: monotherapy
There are three checkpoint inhibitors approved for the treatment of advanced NSCLC: PD-1 inhibitors nivolumab and pembrolizumab, and the programmed death-ligand 1 (PD-L1) inhibitor atezolizumab. In phase III trials, all three improved survival compared to second-line docetaxel [1-3], leading to their approval in NSCLC as monotherapies after platinum-doublet chemotherapy. Pembrolizumab was then approved as a first-line therapy based on KEYNOTE-024, a randomized trial comparing pembrolizumab to platinum-doublet chemotherapy . The population was enriched using high expression of PD-L1 (at least 50% using the Dako 22C3 IHC assay) as an entry criterion. In this population, pembrolizumab was associated with a higher response rate, superior progression free survival, and longer survival. Pembrolizumab was then approved as first-line monotherapy in patients with high PD-L1 expression. Unfortunately, PD-L1 testing is not always done. In the KEYNOTE-024 trial, 15% of patients screened did not have samples evaluable for PD-L1 expression .
When PD-L1 testing is performed, high PD-L1 expression is seen in only 30% of patients with NSCLC. For the remaining 70%, chemotherapy has been the standard, with immunotherapy relegated to the salvage setting. However, recently, those with non-squamous NSCLC have been given another option: a combination of chemotherapy and immunotherapy. In May 2017, the United States Food and Drug Administration (FDA) granted accelerated approval to the combination of pembrolizumab, carboplatin and pemetrexed for first line treatment of non-squamous NSCLC, irrespective of PD-L1 expression, based on the phase II KEYNOTE-021G cohort.
The accelerated approval of this treatment regimen based on limited data has prompted debate over whether this should be adopted as a standard of care. Below we outline our own personal perspectives on this new treatment strategy.
- Brahmer J, Reckamp KL, Baas P et al. Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med 2015; 373:123-135.
- Herbst RS, Baas P, Kim DW et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet 2016; 387:1540-1550.
- Rittmeyer A, Barlesi F, Waterkamp D et al. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet 2017; 389: 255-265.
- Reck M, Rodriguez-Abreu D, Robinson AG et al. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med 2016; 375: 1823-1833
- Langer CJ, Gadgeel SM, Borghaei H et al. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol 2016; 17: 1497-1508.
- Papadimitrakopoulou V, Gadgeel SM, Borghaei H et al. First-line carboplatin and pemetrexed (CP) with or without pembrolizumab (pembro) for advanced nonsquamous NSCLC: Updated results of KEYNOTE-021 cohort G. J Clin Oncol 2017; 35(Suppl 15): 9094-9094.
- Borghaei H, Langer CJ, Gadgeel S, et al. Updated results from KEYNOTE-021 cohort G: a randomized, phase 2 study of pemetrexed and carboplatin (PC) with or without pembrolizumab (pembro). Ann Oncol 2017; 28(Suppl 5):v605-v649.