Clearly, immunotherapy has come of age in multiple tumor types, as described in the main article in this publication. The question now is how to develop more personalized immunotherapy and use biomarkers to identify patients most likely to benefit from this therapy. To benefit from immunotherapy, a patient’s tumor should produce programmed-cell death ligand-1 (PD-L1), as it is PD-L1 that interacts with PD-1 to generate adaptive resistance.1 However, PD-L1 is difficult to measure because of issues with heterogeneity, various antibodies, and the dynamic nature of the marker, which is interferon-stimulated and can vary depending on when and where it is measured. Moreover, there may be other yet undiscovered, potentially targetable ligands (eg, PD-L2 and others) that may also help generate adaptive immunologic resistance.
PD-L1 is unquestionably a positive predictive marker, as a higher level of PD-L1 produces improved outcomes in progression-free survival (PFS) and overall survival.1 The issue now is that many patients who are PD-L1–negative may still have a benefit, so the significance of a negative result is questionable.2 However, in the advanced squamous non–small-cell lung cancer (NSCLC) population, the phase 3 IMpower131 trial in which patients were randomized to receive either atezolizumab, carboplatin, and paclitaxel; atezolizumab, carboplatin, and nab-paclitaxel; or carboplatin plus nab-paclitaxel, PFS benefit was enriched in all PD-L1–positive subgroups treated with atezolizumab plus chemotherapy versus chemotherapy alone, but was most pronounced in those with the highest levels of PD-L1.3 The greatest utility of PD-L1 in lung cancer has been to define a population to be studied in an untreated setting (ie, having received no prior chemotherapy). For patients with PD-L1 expression >50%, the new standard of care is to use immunotherapy in this setting, with pembrolizumab in patients with squamous-cell and non–squamous-cell disease, as demonstrated in the KEYNOTE-024 trial,1 and supported by recently reported results from the KEYNOTE-042 trial, in which there was a significantly greater overall survival benefit with pembrolizumab monotherapy compared with platinum-based chemotherapy in patients expressing PD-L1 ≥50% versus those with PD-L1 expression 1% to 49%.2 These results provided further evidence for the utility of higher levels of PD-L1 in selecting patients with NSCLC for immune checkpoint inhibitor monotherapy.
Data regarding other tumor types described in this publication are much less compelling, although PD-L1 has potential for use in melanoma to help define who should receive ipilimumab plus nivolumab versus nivolumab alone.4 Other biomarkers certainly are going to be valuable, especially measures that identify an interferon-high environment or high tumor mutational burden. Biomarkers for more specific targets will be of great importance in the near future. These may include new molecular targets, or new targets in the myeloid compartment and/or tumor microenvironment for combination therapy.5-7 The field is rapidly moving forward while helping many patients.
- 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.
- Lopes G, Wu Y, Kudaba I, et al. Pembrolizumab (pembro) versus platinum-based chemotherapy (chemo) as first-line therapy for advanced/metastatic NSCLC with a PD-L1 tumor proportion score (TPS) ≥ 1%: open-label, phase 3 KEYNOTE-042 study. Presented at: American Society of Clinical Oncology Annual Meeting; June 1-5, 2018; Chicago, IL. Abstract LBA4.
- Jotte RM, Cappuzzo F, Vynnychenko I, et al. IMpower131: primary PFS and safety analysis of a randomized phase III study of atezolizumab + carboplatin + paclitaxel or nab-paclitaxel vs carboplatin + nab-paclitaxel as 1L therapy in advanced squamous NSCLC. Presented at: American Society of Clinical Oncology Annual Meeting; June 1-5, 2018; Chicago, IL. Abstract LBA9000.
- Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373:23-34.
- 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.
- Gettinger S, Rizvi NA, Chow LQ, et al. Nivolumab monotherapy for first-line treatment of advanced non-small-cell lung cancer. J Clin Oncol. 2016;34:2980-2987.
- Herbst RS, Morgensztern D, Boshoff C. The biology and management of non-small cell lung cancer. Nature. 2018;553:446-454.