Findings from IGNITE, a large, multinational (China, Russia, Indonesia, Taiwan, Singapore, Thailand, Australia, South Korea and Malaysia), diagnostic, non-comparative, interventional study, were presented by lead investigator Dr Baohui Han, Pulmonary Department, Shanghai Chest Hospital, Shanghai, China during the New Treatment Avenues Proffered Papers session at the European Lung Cancer Conference, 15-18 April 2015 in Geneva, Switzerland.
Enrollment was carried out in 90 centres and included 3382 patients with advanced non-small-cell lung cancer (NSCLC) of both adenocarcinoma (ADC) and non-ADC histology. Patients were chemotherapy naive, and had local and/or metastatic NSCLC that was either newly diagnosed or represented recurrent disease after resection. All patients were evaluated as ineligible for curative treatment.
The primary endpoint of IGNITE was the determination of EGFR mutation frequency by locally tested samples. Secondary endpoints included the concordance of EGFR mutation status between matched tissue/cytology and plasma, specifically circulating-free tumour-derived DNA, correlation between mutation status and demographic/disease status, treatment decisions, and EGFR testing practices.
EGFR mutation frequency varies by country, sample type, and histology
Tissue and/or cytology were evaluable in 2291 Asian and 924 Russia patients and plasma was evaluable in 1753 Asian and 941 Russian patients, within a median test turnaround of 6 and 9 days, respectively.
Among the Asian patient population the EGFR mutation frequency by tissue/cytology was 49% in ADC, 14% in non-ADC and 10% in squamous cell carcinoma, whereas in the Russian population the EGFR mutation frequency was 18% in ADC, 4% in non-ADC, and 4% in squamous cell carcinoma. The EGFR mutation frequency was lower in plasma with an overall frequency of 22% in ADC and 7% in non-ADC samples.
The most frequently observed mutation overall was Exon 19 deletion only (49% Asia Pacific, 59% Russia), followed by L858R only (42% Asia Pacific, 25% Russia), Exon 20 insertions only (2% Asia Pacific, 0% Russia), L861Q only, and G719X (both ≤1% overall).
Mutation status concordance could be determined in 2581 matched samples. EGFR mutation status concordance data for tumour vs. plasma showed that sensitivity (50% vs. 30%) and positive predictive value (93% vs. 39%) were higher in Asia Pacific vs. Russia, respectively.
EGFR mutation status was the largest driver of treatment choice in both patients with mutation-positive (50%/47% in Asia Pacific/Russia) and mutation-negative (38%/43% in Asia Pacific/Russia) NSCLC. Following EGFR mutation testing, the most common first-line treatment overall for patients with EGFR mutation-positive NSCLC was gefitinib (36%), and for patients with EGFR mutation-negative NSCLC was cisplatin (41%); however, this pattern differed between Asia Pacific and Russia. Use of tyrosine kinase inhibitors in patients with EGFR mutation-positive NSCLC varied widely within AsiaPacific, ranging from 92% in Taiwan to 0% in Thailand.
EGFR mutation frequency significantly associates with specific patient demographics and diagnoses
ADC and never-smoker status significantly associated with the mutation frequency in the overall population (both, tissue/cytology and plasma status, p < 0.0001). In the Asian versus the Russian cohort (both, p < 0.0001), greater number of metastatic organs (tissue/cytology p = 0.0909 and plasma p < 0.0001), female gender (tissue/cytology only p = 0.0075) and age 65 years or greater (plasma only; p = 0.0009) significantly associated with EGFR mutation frequency.
Immunohistochemistry analyses showed that 10% of TTF-1-negative patient samples were EGFR mutation-positive. Similarly, 44% of TTF-1-positive patient samples were EGFR mutation-positive.
Dr Wilfried Eberhardt of the West German Cancer Centre in Essen, who discussed the results, said that there is still little known about the worldwide epidemiology of EGFR mutations in lung cancer patients. Until now, several national groups have investigated the prevalence of EGFR mutations in large patient subsets. In general, EGFR mutation rate in Asian patients was considerably higher than that in non-Asians.
This study looked at the prevalence of EGFR mutations in Asia and Russia. The results of nearly 50% of EGFR mutations in patients with lung adenocarcinoma in Asia and about 20% EGFR mutated adenocarcinoma in Russia points to specific selection factors. So, these data are probably not representative for the whole population in Asia and Russia.
Data from Russia include more stage IIIA and IIIB patients that represent different patient subsets. Moving EGFR tyrosine kinase inhibitor (TKI) therapy into patient groups with early and locally advanced NSCLC may be more difficult than initially thought.
Dr Eberhardt said that only a bit more than one third of the patients received EGFR TKI in the first-line setting. These data seem realistic for the everyday practice setting.
With broader testing frequencies for EGFR mutations, epidemiological and prevalence data for EGFR mutations should become more precise.
Dr Han concluded that these data from chemotherapy-naive patients with advanced NSCLC in the ‘real world’ suggest that EGFR mutation frequency is higher in patients with ADC versus non-ADC histology. However, he cautioned that mutations in the non-ADC population were seen at a frequency that supports mutation testing for all patients.
The IGNITE study sponsor was AstraZeneca