Next-Generation TKIs

Conference Correspondent - ASCO 2014 - Lung Cancer


This first day of in-depth presentations on non-small-cell lung cancer (NSCLC) kicked off with presentations on next-generation EGFR—tyrosine kinase inhibitors (TKIs) tested in patients who develop resistance to first-line EGFR inhibitor therapy due to T790M mutations (which occurs in ~40% of Asian patients and ~15% of Western patients with NSCLC and for which there are no approved treatments). In a featured presentation, AZD9291, a mutant-selective, irreversible inhibitor of EGFR that has shown activity against T790M resistance mutations while maintaining activity against wild-type EGFR, was tested in 232 patients who had documented disease progression while on continuous treatment with an approved EGFR-TKI (Janne PA, et al. ASCO 2014. Abstract 8009). The overall response rate (ORR) to AZD9291 was 64% in patients who were T790M-positive and 22% in those who were T790M-negative. No dose-limiting toxicities were reported with AZD9291, and the US Food and Drug Administration (FDA) has now granted breakthrough designation for this agent because of its promise for patients with advanced NSCLC whose disease is progressing despite optimal EGFR-TKI therapy. Preliminary data with 2 other similar agents (CO-1686 and HM61713) were also presented (Sequist LV, et al. ASCO 2014. Abstract 8010; Kim D-W, et al. ASCO 2014. Abstract 8011); these agents still require further safety and efficacy evaluation in these difficult-to-treat patients.

Representatives from the FDA presented data aimed at possibly simplifying the requirements in pivotal registration trials for targeted agents in NSCLC. In a meta-analysis of 15 clinical trials involving more than 12,500 patients, it was found that there was a strong correlation between ORR and improvements in progression free survival (PFS), the current basis for FDA drug approval in metastatic NSCLC (Blumenthal GM, et al. ASCO 2014. Abstract 8012). The presenters stopped short of embracing the notion that ORR would now be an acceptable surrogate endpoint in NSCLC clinical trials, but suggested that further work relating ORR to PFS and overall survival may open the door for such a possibility.