The medical management landscape for non–small cell lung cancer (NSCLC) has been changing with the rapidity of the seasons. Long gone is the day when all are treated equally. Treatment planning for lung cancer amalgamates tumor type, histologic subtyping, tumor staging, and more recently, the tumor’s molecular biomarker characteristics; specifically, oncogenic mutations in epidermal growth factor receptor (EGFR), T790M resistance mutation, anaplastic lymphoma receptor tyrosine kinase (ALK) rearrangement, ROS1 fusion, BRAF, and programmed death ligand 1 (PD-L1) expression.1-3 The advent of molecular profiling and protein expression analysis has paved the way for personalized precision treatment plans, providing access to the right treatment at the right time.
Touted as the fourth pillar in the anticancer treatment paradigm, immuno-oncology has provided a path to offer varying treatment options, revolutionizing NSCLC into a chronic disease state. The application of immune checkpoint inhibitors, whether antibodies modulating cytotoxic T-lymphocyte–associated protein 4 (CTLA-4), programmed death 1 (PD-1), or PD-L1 has been shown to restore T-cell–mediated antitumor response and is approved for the treatment of patients with advanced NSCLC.4 Treatment with immune checkpoint inhibitors targeting CTLA-4 (ipilumumab), PD-1 (nivolumab and pembrolizumab), and PD-L1 (atezolizumab and durvalumab) has altered the management and outcomes of patients with NSCLC across the continuum.2,5,6 It has become mainstay to assess PD-L1 expression prior to the initiation of systemic treatment for patients with advanced NSCLC if no actionable mutation has otherwise been identified. To receive immune checkpoint inhibitors first-line, patients must have ≥50% PD-L1 expression. PD-L1 expression was inconsequential for second-line immuno-oncology therapy plans.7
Immuno-oncology has become standard of care in the adjuvant setting following the completion of chemoradiation for unresectable stage III NSCLC. Even with the use of definitive chemoradiation, the prognosis for unresectable stage III NSCLC denotes a 5-year overall survival (OS) rate of approximately 15%.8 Patients completing concurrent platinum-based chemotherapy and radiation who have not had progression of their disease should be considered for immunotherapy. In a randomized phase 3 trial (PACIFIC), NSCLC patients were randomly assigned to receive a PD-L1 antibody, durvalumab, every 2 weeks for 1 year. By incorporating consolidation immunotherapy, patients witnessed up to 16.8 months of progression-free survival versus 5.6 months with placebo and a median time to distant metastasis or death of 23.2 months versus 14.6 months, respectively. At 18 months, patients receiving durvalumab had a longer ongoing response when compared with placebo (72.8% vs 46.8%, respectively).8,9
The introduction of immune checkpoint inhibitors has prolonged survival in patients with advanced or metastatic NSCLC. The FDA has approved nivolumab, pembrolizumab, and atezolizumab for the treatment of advanced or metastatic NSCLC based on CheckMate and KEYNOTE trials and the OAK study, respectively.
In CheckMate 017, nivolumab was compared with docetaxel in patients with advanced squamous cell carcinoma who had received prior systemic therapy. Patients receiving nivolumab had a median OS of 9.2 months versus 6.0 months by those undergoing standard of care treatment. One-year OS as well as median duration of response (DOR) was higher with nivolumab compared with docetaxel, with median OS being 42% to 24% and DOR not yet reached with nivolumab versus 8.4 months with docetaxel.6 This study led to the first FDA approval for immunotherapy in NSCLC.4 CheckMate 057 evaluated the use of nivolumab against docetaxel in patients with metastatic nonsquamous NSCLC who had progressed on or following platinum-based doublet chemotherapy. Patients receiving nivolumab had an OS of 12.2 months versus 9.4 months for those receiving docetaxel.5
For patients with advanced or metastatic NSCLC whose tumors express ≥50% PD-L1, pembrolizumab is standard of care. This is a direct result of data retrieved from KEYNOTE-001, whereby patients who progressed after being treated with platinum-based therapy received pembrolizumab. The overall response rate (ORR) for patients receiving pembrolizumab 2 mg/kg was 28% versus 40% and 41%, respectively, for those receiving pembrolizumab 10 mg/kg every 2 weeks and every 3 weeks.10
In the phase 3 randomized KEYNOTE-024 study, patients naive to systemic therapy received pembrolizumab monotherapy versus platinum-based chemotherapy. Median progression-free survival was 10.3 months with pembrolizumab versus 6.0 months with chemotherapy, with a response rate of 44.8% versus 27.8%, respectively. DOR has yet to be determined in the pembrolizumab arm versus 6.3 months in the chemotherapy.7
In the KEYNOTE-021 trial, chemotherapy-naive patients with stage IIIB or IV nonsquamous histology NSCLC without genetic aberrations were randomly assigned to pembrolizumab plus carboplatin and pemetrexed versus carboplatin/pemetrexed. The ORR was 55% versus 29%, respectively.11
The POPLAR trial was a phase 2 study comparing atezolizumab with docetaxel in patients with advanced NSCLC who had previously been treated with chemotherapy. Median OS was longer with atezolizumab compared with docetaxel, 12.6 months versus 9.7 months, respectively.12 The OAK trial further confirmed these findings, noting a median OS of 13.8 months compared with 9.6 months between atezolizumab to docetaxel, respectively.13,14
So where do we go from here? What is on the horizon? Clinical trials abound with possible answers. Currently, there are 363 studies evaluating the impact immuno-oncology may have on lung cancer care in the future. Of those, 179 are actively recruiting (www.clinicaltrials.gov). Studies currently taking place are evaluating the benefits immuno-oncology brings to resectable, early- stage disease, as well as assessing response rates when teamed with other treatment modalities—specifically radiation therapy, targeted therapy, chemotherapy, or other immunotherapies. In the adjuvant setting, trials are attempting to demonstrate an improvement in survival as well as define durable response. Some are trying to determine the optimal duration of therapy.15 To better understand immuno-oncology’s impact on clinical outcomes, patient selection for immune checkpoint inhibitors may need a more precise validated predictive biomarker beyond PD-L1 expression. Clinical trials evaluating tumor mutational burden and PD-L1 expression are ongoing.
Immuno-oncology has become the standard-of-care in the second line treatment for NSCLC patients. Recently, it has become mainstay in the first-line settings. It is difficult to determine the general impact of immuno-oncology on long-term survival. The data are still too immature to determine its overall effect on the prognosis of lung cancer. This is just the tip of the iceberg. The future of immuno-oncology holds an uncertain excitement. Will we be navigators by disease site or will we become navigators by a tumor’s biomarker?
- Alsaab HO, Sau S, Alzhrani R, et al. PD-1 and PD-L1 checkpoint signaling inhibition for cancer immunotherapy: mechanism, combinations, and clinical outcome. Front Pharmacol. 2017;23:561.
- Bernicker EH, Miller RA, Cagle PT. Biomarkers for selection of therapy for adenocarcinoma of the lung. J Oncol Pract. 2017;13:221-227.
- Langer CJ, Besse B, Gualberto A, et al. The evolving role of histology in the management of advanced non-small-cell lung cancer. J Clin Oncol. 2010;28:5311-5320.
- Somasundaram A, Burns TF. The next generation of immunotherapy: keeping lung cancer in check. J Hematol Oncol. 2017;10:87.
- Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med. 2015;373:1627-1639.
- 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.
- Reck M, Rodríguez-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.
- Antonia SJ, Villegas A, Daniel D, et al. Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N Engl J Med. 2017;377:1919-1929.
- Yeh J, Maroone KA, Forde PM. Neoadjuvant and consolidation immuno-oncology therapy in stage III non-small cell lung cancer. J Thorac Dis. 2018;10(suppl 3):S451-S459.
- Garon EB, Rizvi NA, Hui R, et al. Pembrolizumab for the treatment of non-small cell lung cancer. N Engl J Med. 2015;372:2018-2028.
- 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.
- Fehrenbacher L, Spira A, Ballinger M, et al. Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Lancet. 2016;387:1837-1846.
- Bordoni R, Ciardiello F, von Pawel J, et al. Patient reported outcomes in OAK: a phase III study of atezolizumab versus docetaxel in advanced non-small-cell lung cancer. Clin Lung Cancer. 2018;19:441-449.
- 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.
- Melero I, Berman DM, Aznar MA, et al. Evolving synergistic combinations of targeted immunotherapies to combat cancer. Nat Rev Cancer. 2015;15:457-472.