Lung cancer chronification

The beginning of a new era 

James Fleck: Anticancerweb 13(01),2020

Data from the American Cancer Society reported through 2016 revealed a disappointing 19% five-year survival rate for all patients diagnosed with lung cancer, further decreasing to just 5% for those with metastatic disease. Currently, molecular discrimination of non-small cell lung cancer (NSCLC) and program-death 1 ligand (PD-L1) tumor proportion score (TPS) have been identified as prognostic and predictive factors, leading to a consistent increase in advanced NSCLC survival rate. An unprecedent 38.5 months median overall survival was recently reported for EGFR-mutated advanced lung adenocarcinoma treated with osimertinib, a third generation EGFR tyrosine kinase inhibitor (TKI), hopefully defining a new standard of care (FLAURA trial). EGFR-mutation is identified in roughly 15% of US lung adenocarcinoma, increasing up to 65% in the Asian population. Although ALK (anaplastic lymphoma kinase) translocation is observed in only 4% of US lung adenocarcinoma, it also predicts a better response. In a recent retrospective review conducted at University of Colorado Cancer Center, the use of ALK-inhibitors in the primary treatment of stage IV ALK-positive NSCLC has been associated with a median overall survival of 6.8 years. ROS-1 rearrangements and BRAF mutation have also been described as predictive factors. 

Fortunately, treatment advances have also been reported for advanced NSCLC patients who do not express driver mutations. Immune checkpoint inhibitors have been associated with an increase response rate and survival in treatment-naïve advanced NSCLC without EGFR/ALK alterations, particularly in those showing PD-L1 TPS ≥ 50%. In this selective group of patients, the use of pembrolizumab (a monoclonal antibody that binds programmed death-1 receptor, blocking its interaction with PD-L1 and PD-L2 and restoring the ability of the immune system to recognize tumor cells) has been associated to a five-year survival rate close to 30% (KEYNOTE 001). At the same time, the CHECKMATE 227 trial identified high tumor mutational burden (TMB ≥ 10 mutations/megabase) as a new predictive factor of response to the combination of nivolumab (humanized anti-PD1 IgG4 monoclonal antibody) + ipilimumab (humanized anti-CTLA-4 IgG1 monoclonal antibody). Predictive impact of TMB occurs regardless the percentage of PD-L1 expression. Despite immature data, the results indicate a potential benefit using predictive factors for a more personalized immunotherapy in non-small cell lung cancer. Additional efforts are coming from the use of new machine learning algorithms applied to the well-curated genomic data provided by The Cancer Genome Atlas in the identification of predictive markers. 



1.     Rebecca L. Siegel, Kimberly D. Miller and Ahmedin Jemal, Cancer Statistics, 2019, Ca Cancer J Clin 69:7-34, 2019

2.     S.S. Ramalingam, J. Vansteenkiste, D. Planchard, et al: Overall Survival with Osimertinib in Untreated, EGFR-Mutated Advanced NSCLC, N Engl J Med, Nov 21, 2019

3.      Pacheco, JM, Gao D, Smith D, at al: Natural History and Factors Associated with Overall Survival in Stage IV ALK-Rearranged Non-Small Cell Lung Cancer, J Thorac Oncol 14 (4): 671-700, 2019

4.     Edward B. Garon, Matthew D. Hellmann, Mayier A Rizve, et al: Five-Year Overall Survival for Patients with Advanced Non‒Small-Cell Lung Cancer Treated with Pembrolizumab: Results from the Phase I KEYNOTE-001 Study, J Clin Oncol 37:2518-2527, 2019

5.     Derrick E. Wood, James R. White, Andrew Georgiadis, et al: A machine learning approach for somatic mutation discovery, Sci Transl Med 10:457, 2018 DOI:10.1126/scitranslmed.aar7939 

6.     Photo by Tim J on Unsplash