By Karen L. Reckamp, MD
When advanced NSCLC is diagnosed, the word “cure” is avoided; we focus on palliation of symptoms with prolonged survival. Unfortunately, there are more than 200,000 cases of lung cancer estimated for 2020, which will cause more deaths than breast, prostate, colorectal, and brain cancers combined.1 However, recent statistics have demonstrated an accelerated decrease in the death rate from lung cancer, resulting in the largest decline in a single year in overall cancer mortality. The reduction in death rate is likely due to improved therapy in advanced disease because lung cancer screening has had limited uptake.2 Defining lung cancer by its molecular characteristics and targeting oncogenic driver mutations has led to improved outcomes for patients.3 Furthermore, immune checkpoint inhibition results in durable responses with manageable toxicities in patients with advanced lung cancer.4-7 The population with PD-L1 expression of 50% or higher may be the group who derives the most durable benefit.8 Based on emerging longer-term follow-up data from trials of PD-1/PD-L1 and CTLA-4 immune checkpoint inhibitors as monotherapy, combination therapy, or combined with chemotherapy, a subset of patients with NSCLC may be experiencing the elusive goal of cure; in this regard, cohorts of patients with high PD-L1 expression will be explored.
Data from early, single-agent PD-1/PD-L1 inhibitor therapy trials provide the longest follow-up despite more heterogeneous patient populations. KEYNOTE-001 evaluated patients with metastatic NSCLC who were treatment naive as well as patients with prior therapy across multiple PD-L1 levels.5 Long term survival analysis in patients with PD-L1 tumor proportion score (TPS) of 50% or greater revealed 25% 5-year survival rates for those who received prior therapy and 29.6% in those who were treatment naive. Approximately 30% of patients with advanced NSCLC will have PD-L1 TPS of 50% or greater, and nearly 30% of these will survive 5 years, which marks the threshold for long-term survival in NSCLC.
When evaluating combination PD-1 inhibition with chemotherapy, follow-up is shorter but shows promising patient outcomes. KEYNOTE-024 was the first trial to demonstrate improved OS using PD-1inhibition monotherapy with pembrolizumab compared to chemotherapy.9 After more than 2 years of follow-up, the 3-year OS rate was 43.7% for pembrolizumab compared to 24.9% with chemotherapy despite more than 50% crossover in the chemotherapy arm.10 This suggests the importance of early immune checkpoint inhibition for those with high PD-L1 TPS to achieve maximum benefit. Importantly, a retrospective analysis of 187 patients who received front-line pembrolizumab implied that those with tumor PD-L1 expression of 90% or greater had significantly longer PFS and OS.8 This has not been confirmed prospectively, but it provides additional data to support the use of anti–PD-1/–PD-L1 monotherapy in patients with very high PD-L1 expression.
Combination therapy with PD-1/CTLA-4 immune checkpoint inhibition demonstrated an early OS benefit in patients with advanced melanoma.11 After 60 months of follow-up, the median survival was still not reached in patients with advanced melanoma who received ipilimumab and nivolumab, and 5-year survival rate for the combination was 52%.12 Similarly, OS was improved for patients with advanced NSCLC who received ipilimumab and nivolumab for advanced NSCLC comparted to chemotherapy in CheckMate 227.13 A more mature survival update showed a 33% 3-year OS rate for patients who received ipilimumab and nivolumab with PD-L1 expression of 1% or greater.14 Moreover, the combination of chemotherapy and PD-1/PD-L1 inhibition has resulted in prolonged OS for patients across all levels of PD-L1 expression, although long-term benefits may be more pronounced in patients with NSCLC with higher PD-L1 TPS. Updated survival data in patients who received combination chemotherapy and pembrolizumab from KEYNOTE-189 demonstrated 2-year OS rates of 45.5% in all patients and 51.9% for patients with tumors expressing PD-L1 50% or greater; a flattening of the survival curve is seen after 24 months.15 These data imply that a subset of patients with lung cancer may experience a cure. The actual number might be predicted using recent estimates of 228,820 lung cancer diagnoses in 2020 (85% with NSCLC, 57% diagnosed with distant disease, and 30% of these with PD-L1 TPS ≥ 50%).1 Extrapolating from these figures, we might anticipate nearly 10,000 people with prolonged survival if the 5 year survival rates in this cohort are 30% and more than 16,600 if those rates reach 50%. For those who achieve the OS benefit, this number is commendable and a promise that a cure may be within reach for advanced NSCLC.
- Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020;70(1):7-30.
- Jemal A, Fedewa SA. Lung Cancer Screening With Low-Dose Computed Tomography in the United States-2010 to 2015. JAMA Oncol. 2017;3(9):1278-1281.
- Soria JC, Ohe Y, Vansteenkiste J, et al. Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer. N Engl J Med. 2018;378(2):113-125.
- Garon EB, Hellmann MD, Rizvi NA, et al. Five-Year Overall Survival for Patients With Advanced NonSmall-Cell Lung Cancer Treated With Pembrolizumab: Results From the Phase I KEYNOTE-001 Study. J Clin Oncol. 2019;37(28):2518-2527.
- Garon EB, Rizvi NA, Hui R, et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med. 2015;372(21):2018-2028.
- Horn L, Mansfield AS, Szczesna A, et al. First-Line Atezolizumab plus Chemotherapy in Extensive-Stage Small-Cell Lung Cancer. N Engl J Med. 2018;379(23):2220-2229.
- Antonia SJ, Villegas A, Daniel D, et al. Overall Survival with Durvalumab after Chemoradiotherapy in Stage III NSCLC. N Engl J Med. 2018;379(24):2342-2350.
- Aguilar EJ, Ricciuti B, Gainor JF, et al. Outcomes to first-line pembrolizumab in patients with non-small-cell lung cancer and very high PD-L1 expression. Ann Oncol. 2019;30(10):1653-1659.
- 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(19):1823-1833.
- Reck M, Rodriguez-Abreu D, Robinson AG, et al. Updated Analysis of KEYNOTE-024: Pembrolizumab Versus Platinum-Based Chemotherapy for Advanced Non-Small-Cell Lung Cancer With PD-L1 Tumor Proportion Score of 50% or Greater. J Clin Oncol. 2019;37(7):537-546.
- Wolchok JD, Chiarion-Sileni V, Gonzalez R, et al. Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. N Engl J Med. 2017;377(14):1345-1356.
- Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Five-Year Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. N Engl J Med. 2019;381(16):1535-1546.
- Hellmann MD, Paz-Ares L, Bernabe Caro R, et al. Nivolumab plus Ipilimumab in Advanced Non-Small-Cell Lung Cancer. N Engl J Med. 2019;381(21):2020-2031.
- Ramalingam SS, Ciuleanu TE, Pluzanski A, et al. Nivolumab and ipilimumab versus platinum-doublet chemotherapy as first-line treatment for advanced non-small cell lung cancer: three-year update from CheckMate 227 Part 1. J Clin Oncol. 2020;38(15):9500.
- Gadgeel S, Rodriguez-Abreu D, Speranza G, et al. Updated Analysis From KEYNOTE-189: Pembrolizumab or Placebo Plus Pemetrexed and Platinum for Previously Untreated Metastatic Nonsquamous Non-Small-Cell Lung Cancer. J Clin Oncol. 2020;38(14):1505-1517.
About the Author:
Dr. Reckamp is director of medical oncology in the Department of Medicine, associate director of clinical research for the Samuel Oschin Comprehensive Cancer Institute, and medical oncology director for the Women's Guild Lung Institute at Cedars-Sinai.