Dr. Tan Chee Seng gives an update on the latest breakthrough in advanced non-small cell lung cancer treatments.
Based on the World Health Organization (WHO) 2018 report, lung cancer is one of the leading causes of cancer-related mortality, accounting for an estimated 1.76 million deaths worldwide.1 Each year, more people die of lung cancer than of colon, breast, and prostate cancers combined.2
Lung cancers are broadly divided into two subtypes: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). NSCLC makes up the majority of the lung cancers, consisting of about 85 per cent of cases. NSCLC cases are predominantly made up of three subtypes: adenocarcinoma (40–50%), squamous (25–30%), and large cell (10–15%). There are other rarer subtypes including adenosquamous carcinoma, sarcomatoid carcinoma and etc.
Similar to the worldwide trends, lung cancer in Singapore is the most frequent cause of cancer deaths in males and the second most common in females (see Tables 1 and 2).1 The dismal survival figures were largely related to the fact that the majority of these lung cancers were diagnosed in their advanced stages, where about 60 to 70 per cent were diagnosed at stage IV. Local figures estimated that the five-year survival rates for both males and females who were diagnosed at stage IV to be less than five per cent.
There had been several breakthroughs in the treatment of advanced NSCLC in recent years due to the discovery of several molecular subtypes that allow the use of targeted therapies. Additionally, immunotherapies had been shown to be a new treatment option for NSCLC.
NSCLC subtype – EGFR (epidermal growth factor receptor)
As researchers learn more about the pathogenesis or the abnormal growth pathways of NSCLC cells, more drugs are being developed to target these.
Targeted drugs work differently from standard chemotherapy drugs. They target specific abnormal pathway containing activated NSCLC cells unlike chemotherapy which is less specific and may harm normal cells when they kill the cancerous cells. In general, targeted therapy has lesser side effects due to the narrow pathway that is inhibited. They are currently approved for advanced lung cancer stage and newer trials are investigating their roles in early stages of NSCLC.
Epidermal growth factor receptor (EGFR) is a protein on the surface of some human cells. For reasons unknown, some of these receptors mutate and they become persistently in the "switched-on' position, resulting in uncontrolled abnormal growth. EGFR positive lung cancer refers to lung cancers that test positive for an EGFR mutation.
Somatic sensitising EGFR mutations are found in almost 50 per cent of East Asian non-smoking patients (especially female patients) and only 10 per cent of Caucasian patients.3
These sensitising EGFR mutations result in the activation of pathways, causing uncontrolled cell proliferation and survival. The deletion in exon 19 and exon 21 point mutation (L858R) are the most common mutations which together, account for 90 per cent of sensitising EGFR mutations.4,5 These mutations predict for sensitivity to EGFR tyrosine kinase inhibitors (TKIs).
In studies of untreated advanced stage NSCLC with sensitising EGFR mutations treated with EGFR TKI outcomes, the results were superior to chemotherapy in terms of efficacy and quality of life, leading to the regulatory approval of EGFR TKIs and the acceptance for use in the first line setting of EGFR mutant NSCLC.
There are currently three generations of EGFR TKIs and the most recent is osimertinib, the only approved third generation TKI at the present moment.
Osimertinib had been shown to be better than the first generation EGFR TKI in a recent pivotal phase III trial, FLAURA. The study was done on 556 patients with previously untreated, EGFR mutation–positive (exon 19 deletion or L858R) advanced NSCLC. These patients were randomised in a 1:1 ratio to receive either osimertinib or a standard first generation EGFR-TKI. Osimertinib almost doubled the median progression survival from 10 months to 19 months. There is a trend towards significant overall survival rate with osimertinib (83%) and the first generation EGFR TKI (71%) at 18 months.
Osimertinib was also found to delay brain metastases compared to the first generation EGFR TKI. Importantly, the rate of severe side effects was lower in osimertinib group compared to first generation EGFR TKI.6 This led to the FDA approval of osimertinib as one of the first line treatment options and is recommended in international guidelines.
Another new treatment approach for advanced lung cancer is immunotherapy using immune checkpoint inhibitors (ICI). Several agents have been investigated and proven to be effective in treating advanced lung cancer patients that do not have molecular mutations such as EGFR and anaplastic lymphoma receptor tyrosine kinase (ALK).
An example of an ICI is pembrolizumab. It is an anti-PD1 humanised monoclonal antibody that works by activating the immune system, specifically T lymphocytes, to detect and fight tumour cells. The 2018 Nobel Prize in Medicine was awarded to two scientists who pioneered the research work in cancer immunotherapy.7
Keynote-024 is a randomised phase III study of untreated 305 patient with metastatic NSCLC expressing high levels of PD-L1 (tumour proportion score of 50% or more). There is an increase in median overall survival (30 months vs 14.2 months) in pembrolizumab and chemotherapy respectively, despite some crossover from the control arm to pembrolizumab as subsequent therapy. Serious side effects were also significantly less frequent with pembrolizumab compared with chemotherapy (31.2% vs 53.3% respectively).8 For patients with PD-L1 level of less than 50 per cent, a combination of chemotherapy with pembrolizumab have been shown to be better option than chemotherapy alone.9
With the discovery of the different subsets of advanced NSCLC patients, it is imperative for oncologists to personalise therapies for every individual patient. This not only opens up new treatment approaches, but also improves patients’ survival and at the same time minimising any potential side effects.
These approaches are currently being studied in the early lung cancer stages and hopefully will improve the overall outcomes of all NSCLC patients in the future.
World Health Organization: Cancer Fact Sheet https://www.who.int/news-room/fact-sheets/detail/cancer (assessed 1st April 2019)
Shi Y, Au JS, Thongprasert S, et al. A prospective, molecular epidemiology study of EGFR mutations in Asian patients with advanced non-small-cell lung cancer of adenocarcinoma histology (PIONEER). Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 2014; 9(2): 154-62.
Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. The New England journal of medicine 2004; 350(21): 2129-39.
Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science (New York, NY) 2004; 304(5676): 1497-500.
Jean-Charles Soria, Yuichiro Ohe, Johan Vansteenkiste et al. Osimertinib in Untreated EGFR-Mutated Advanced Non–Small-Cell Lung Cancer. N Engl J Med 2018; 378:113-125 DOI: 10.1056/NEJMoa1713137
Reck M, Rodríguez-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 Mar 1;37(7):537-546. doi: 10.1200/JCO.18.00149. Epub 2019 Jan 8.
Leena Gandhi, Delvys Rodríguez-Abreu, Shirish Gadgeel, et al. Pembrolizumab plus Chemotherapy in Metastatic Non–Small-Cell Lung Cancer. N Engl J Med 2018; 378:2078-2092. DOI: 10.1056/NEJMoa1801005
Dr. Tan Chee Seng is a senior medical oncologist at OncoCare Cancer Centre.