A biomarker-based therapy prolongs the lifespan of non-small cell lung cancer patients
In 2022, an estimated 30,000 new lung cancer cases will be diagnosed in Canada and 24% of cancer deaths will be due to lung cancer. Lung cancer is the deadliest cancer worldwide, accounting for 1.8 million deaths in 2020.
Among the two main classes of lung cancer, non-small cell lung cancer (NSCLC) is the most common and remains the leading cause of cancer-related mortality worldwide. Reports show almost 80% of patients do not survive until 5 years after diagnosis, a rate significantly higher than the other leading cancer types.
Chemotherapy is often used as a first-line treatment for NSCLC, but it has severe side effects, and patients often develop resistance to chemotherapy agents. Lately, clinical trials assessing targeted therapies have shown a better response rate but less toxicity than chemotherapy. Targeted therapies rely on the presence of cancer cell-specific molecules called biomarkers and inhibit the biomarkers to control cancer growth. Patients with the same cancer type can have large variations among their cancerous tissues, which categorizes the patients into subgroups. Patients’ subgroups will likely respond differently to the same treatment. Thus, identifying the subgroups using biomarkers can help clinicians to tailor the best treatment for a patient.
One such biomarker in NSCLC patients is the mutation status of a protein called EGFR. ‘Activating’ mutations cause EGFR to function constantly that signal the cancer cells to grow and divide fast, unchecked. Thus, inhibiting EGFR signalling is a targeted approach in NSCLC patients. Tyrosine Kinase Inhibitors or TKIs can inhibit EGFR signalling and have shown clinical benefit in advanced-stage NSCLC patients whose tumours contain the activating mutations.
Erlotinib was approved by FDA as a second-line treatment in 2004 after clinical trials showed prolonged survival in patients whose first-line or second-line chemotherapy failed. This led to further investigations into its use as a first-line treatment. A phase III study in China, named OPTIMAL study, evaluated Erlotinib’s efficacy and safety by comparing it with the standard chemotherapy care in China. Advanced-stage NSCLC Asian patients with activating EGFR mutations who had not taken any other treatment previously were included in the study. They were randomly assigned into two treatment groups: 82 patients received Erlotinib and 72 received chemotherapy.
First, to compare the efficacy, progression-free survival was measured in both groups. This is the measure of the time from patients starting the treatment to the time until the cancer gets worse. The Erlotinib group had almost three times longer progression-free survival (median 13.1 months) than the chemotherapy group (median 4.6 months). The overall response to treatment was significantly better in the Erlotinib group. Chemotherapy patients suffered from more severe and life-threatening toxic effects. Lower toxicity led to fewer patients discontinuing treatment in the Erlotinib group (1%) than in the chemotherapy group (10%).
This overall improvement in efficacy and safety is consistent with other studies in Europe and the USA in mutation-positive patients confirming the benefit of Erlotinib irrespective of ethnic background.
Previously, Gefitinib, another EGFR inhibitor has shown similar improvement over chemotherapy in the first-line setting in randomized phase III studies. Both Erlotinib and Gefitinib conferred a significant clinical benefit over standard chemotherapy in advanced EGFR mutation-positive NSCLC patients. These findings led the OPTIMAL study authors to recommend routine EGFR mutation testing in NSCLC patients as it could help doctors in deciding the best treatment option for a patient.
Despite the successes, the median progression-free survival with targeted therapy is only above a year. Why do patients stop responding to the treatment? Could these resistant patients be treated with combination therapy?
More research is needed to increase the overall survival of NSCLC patients as we head further into the decade.
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Zhou C, Wu YL, Chen G, et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. The Lancet Oncology. 2011;12(8):735-742. doi:10.1016/S1470-2045(11)70184-X