Fred R. Hirsch, MD, PhD
Third generation EGFR TKIs have demonstrated dramatic benefits for patients with non-small cell lung cancer (NSCLC) and should be considered as a standard second-line option following resistance to frontline therapy, according to a presentation by Fred R. Hirsch, MD, PhD, at the 5th Annual International Lung Cancer Congress.
Despite the significant improvements in response and progression-free survival (PFS) with first generation EGFR TKIs, resistance to therapy inevitably develops. For many patients (49%), resistance occurs as the result of an acquired mutation in T790M
. To address this resistance mechanism, several third generation TKIs that bind selectively to T790M are being developed, with response rates of approximately 60% in the second-line setting.
"The new generation EGFR TKIs seem to overcome the T790M
mutations," Hirsch, a professor of medicine and pathology and the associate director for international programs at the University of Colorado Cancer Center, said in an interview with OncLive
. "So that gives us a new hope and a new encouragement after resistance to first generation EGFR TKI."CO-1686
In an ongoing phase I/II study, 72 patients with recurrent EGFR
-positive NSCLC were treated with CO-1686 at various dose levels, with 500, 625, and 750 mg twice daily continuing to be investigated in an expansion cohort. The median age of patients was 59, 14% were Asian, and 75% were female.
According to results from an ongoing phase I/II trial presented at the 2014 ASCO Annual Meeting, the overall response rate (ORR) was 58% with responses observed in patients with brain metastases. The median PFS has not yet been reached, with a survival probability of approximately 78% after 12 months of follow-up.1
Adverse events in the trial were infrequent and mild, with the most common being nausea and hyperglycemia. Grade 1/2 nausea was apparent in 33% of patients, and 53% developed hyperglycemia, of which 22% was grade 3. All-grade diarrhea occurred in 23% of patients and skin rash was apparent in only 4% of patients, all grade 1.
"It will be very exciting to see how this drug will move forward; of course there are many planned clinical trials. Some are ongoing, some are planned," Hirsch said. "In the TIGER program—third generation inhibitor of mutant EGFR in lung cancer—the studies are both in the second line as well as a comparator study with erlotinib in first-line therapy."AZD9291
In a large phase I study, 199 patients with EGFR
-mutant NSCLC received treatment with AZD9291 at 5 doses ranging from 20 to 240 mg. The median age of patients was 60, 65% were Asian, and 32% were Caucasian. Patients with stable brain metastases were not excluded from the study.
In patients with confirmed T790M
resistance mutations (n = 89), the ORR was 64% (95% CI; 53%-74%) and the disease control rate was 96%. The median duration of response had not been reached at the time of the analysis, with the longest duration of response being >8 months.2
The most common adverse events were primarily low-grade diarrhea (30%), rash (24%), and nausea (17%). Grade 3/4 adverse events occurred in 16% of patients, with 6 requiring a dose reduction. There were 5 reports of interstitial lung disease, most of which occurred with a 160-mg dose of AZD9291 (n = 4) and were resolved without fatalities.
"The new generation EGFR TKIs do not seem to have the same side effects either as the first generation, so that is a huge development," Hirsch said. "Whether it is sufficient for curing patients or not, that is another question. It might be a combination of drugs that finds that solution."HM61713
In a dose escalation trial, the T790M selective inhibitor HM61713 demonstrated clear antitumor activity. The response rate in mutation-positive patients was 29.2%, with a disease control rate of 75%. The primary side effects with this agent were nausea (32.2%), skin exfoliation (26.3%), headache (24.6%), and rash (23.7%). Additionally, 3 patients experienced grade 3 dyspnea.3
"The development of third generation EGFR inhibitors has really taken off this year when we heard results of at least three different early phase clinical trials at ASCO 2014," lung cancer expert Suresh S. Ramalingam, MD, the Chief of Thoracic Oncology and director of Medical Oncology at the Winship Cancer Institute of Emory University, commented in an interview with OncLive
The TIGER clinical trial program will continue to explore treatment with CO-1686 across a variety of clinical settings. Additionally, an open-label phase II study has been initiated to explore the 80-mg dose of AZD9291 specifically in patients with T790M
-positive metastatic NSCLC following progression on a prior EGFR inhibitor.