A study presented at the 5th International Lung Cancer Conference by Professor Fred R. Hirsch showed that next-generation EGFR tyrosine kinase inhibitors (TKIs) can be of great benefit to patients with non-small cell lung cancer and should be considered as a standard second-line treatment option after the emergence of resistance to first-line therapy. Although the generation of EGFR TKIs has significantly improved remission rates and progression-free survival, resistance to therapy has inevitably emerged. For many patients (49%), resistance is due to T790M-acquired mutations. To investigate this mechanism of resistance, researchers have developed a number of next-generation TKIs that can selectively bind T790M, resulting in remission rates of nearly 60 percent with 2nd-line therapy. ”The new generation of EGFR TKIs appear to overcome the T790M mutation,” explained Professor Hirsch (Professor of Medicine and Professor of Pathology, University of Colorado Cancer Center). “Thus, this first generation of EGFR TKI resistance has once again given us new hope and encouragement after the first generation.” CO-1686 An ongoing Phase I/II trial in which 72 patients with recurrent EGFR-mutated, T790M-positive non-small cell lung cancer are treated with different doses of CO-1686, 500, 625 and 750 mg twice daily, will continue to be studied in a larger sample. The median age of the patients was 59 years, with 14 percent Asian and 75 percent female. Results from an ongoing phase I/II trial presented at the 2014 ASCO Annual Meeting showed an overall remission rate of 58% in patients with brain metastases. After 12 months of follow-up, median PFS had not been reached and the survival rate was nearly 78%. Adverse effects in the trial were few and mild, with nausea and hyperglycemia being the most common. 33% of patients had significant grade 1/2 nausea and 53% developed hyperglycemia, 22% of which were grade 3. The incidence of all grades of diarrhea was 23 percent, and only 4 percent of patients developed a significant rash. ”It’s exciting to see how the drug will develop, and there are certainly a lot of planned clinical trials. Some are ongoing and some are still being planned,” said Professor Hirch. “In the TIGER trial (Lung Cancer Next Generation EGFR Mutation Inhibitor), the study was compared to erlotinib not only in second-line treatment but also in first-line treatment. AZD9291 In a large phase I trial, 199 patients with EGFR-mutated non-small cell lung cancer were treated with five different doses (ranging from 20 to 240 mg) of AZD9291. The median age of the patients was 60 years, with 65% Asian and 32% Caucasian. Patients with stable brain metastases were not excluded from the study. The number of patients with confirmed T790M mutations was 89, with an overall remission rate of 64% (95% CI; 53% to 74%) and a disease control rate of 96%. At the time of analysis, the median duration of sustained remission had not been calculated, with the longest duration of remission being >8 months. The most common adverse reactions were mainly low-grade diarrhea (30%), rash (24%), and nausea (17%). grade 3/4 adverse reactions occurred in 16% of patients, six of whom required dose reduction. Interstitial lung disease was reported in five patients, most of whom (n=4) applied AZD9291 at a dose of 160 mg and did not die after treatment. ”The new generation of EGFR TKIs does not appear to have the same adverse effects as the first generation of EGFR TKIs, so this is a huge improvement,” Hirsch said. “Whether that’s enough for patient treatment, that’s another question. Combination dosing may find a solution.” HM61713 In a dose-escalation trial, the T790M-selective inhibitor HM61713 showed clear antitumor activity. The remission rate in mutation-positive patients was 29.2 percent and the disease control rate was 75 percent. The main adverse effects of the drug were nausea (32.2%), skin peeling (26.3%), headache (24.6%), and rash (23.7%). In addition, three patients experienced grade 3 dyspnea. ”The next generation of EGFR inhibitors has really evolved very quickly this year, and we heard results from at least three different early clinical trials at the 2014 ASCO Annual Meeting,” lung cancer expert Professor Suresh S. Ramalingam (?Emory?University Winship Cancer Institute Chief of Oncology and chief of thoracic surgery), said. The TIGER clinical trial program will continue to explore the efficacy of CO-1686 through various clinical trials. In addition, a non-blinded phase II trial has begun exploring the efficacy of 80 mg of AZD9291 in patients with T790M-positive metastatic non-small cell lung cancer that progressed after EGFR inhibitor therapy. Necitumumab In addition to TKIs, the EGFR-targeted antibody necitumumab holds promise for treating unscreened patients with squamous cell, non-small cell lung cancer, a very difficult group to treat, Hisch explained. A phase III SQUIRE trial that included 1,093 patients compared the efficacy of necitumumab + gemcitabine and cisplatin regimens with chemotherapy alone. The median overall survival was 11.5 months for patients on the regimen that included necitumumab, compared with 9.9 months for patients on chemotherapy alone (HR=0.84; P=0.012). The median progression-free survival for patients on the regimen containing necitumumab was 5.7 months, compared with 5.5 months for patients on chemotherapy alone (HR=0.85; P=0.02). The median overall remission rate for patients on the regimen containing necitumumab was 31%, compared with 29% for patients on chemotherapy alone (P=0.40). ”We don’t know the future fate of this drug, and it’s up to the regulatory system to decide that,” said Hirsch about the next step in the development of necitumumab. Detecting biomarkers for monoclonal antibodies, while difficult, is still a work in progress.