Two studies of third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors among patients with non–small cell lung cancer (NSCLC) who had progressive disease following treatment with a first-generation EGFR tyrosine kinase inhibitor “show encouraging results,” according to an editorial accompanying the studies in The New England Journal of Medicine. The editorial was written by Ramaswamy Govindan, MD, of the Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis.
In a study of the EGFR inhibitor AZD9291 (mereletinib), the overall objective tumor response rate among 239 patients who could be evaluated was 51%. The rate was 61% among the 127 patients with centrally confirmed T790M resistance mutations vs 21% among 61 patients without centrally detectable EGFR T790M.
In a study of rociletinib, the objective response rate among 49 patients with T790M-positive disease who could be evaluated was 59% vs 29% among 17 patients with T790M-negative disease.
“Despite initial responses to EGFR tyrosine kinase inhibitors, the majority of patients will have disease progression within 1 to 2 years after treatment initiation (acquired resistance). In approximately 60% of patients, the mechanism of acquired resistance is the development of an additional EGFR mutation, EGFR T790M,” Pasi A. Jänne, MD, PhD, of the Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, and colleagues noted in their report on the AZD9291 study.
Mereletinib Study Details
AZD9291, shown in preclinical models to be effective against both EGFR tyrosine kinase inhibitor–sensitizing and T790M resistance mutations, was administered at doses of 20 to 240 mg once daily in patients with advanced lung cancer and radiologically documented disease progression after previous treatment with EGFR tyrosine kinase inhibitors. “Among 31 patients enrolled in the dose-escalation cohorts, no dose-limiting toxic effects occurred at the doses evaluated,” the investigators stated.
In addition to these patients, 222 were enrolled in expansion cohorts at 33 sites in 9 countries, including the United States. Among the total of 253 patients, 62% were Asian; 62% were women; and 96% had adenocarcinoma. All patients had at least one prior EGFR tyrosine kinase inhibitor, and 80% had received prior chemotherapy.
The median progression-free survival was 9.6 months in EGFR T790M–positive patients and 2.8 months in EGFR T790M–negative patients. The most common adverse events were diarrhea, rash, nausea, and decreased appetite.
Rociletinib (CO-1686) Study Details
The phase I/II study of rociletinib (CO-1686), shown to be active in preclinical models of EGFR-mutated NSCLC with or without T790M, enrolled 130 patients at 10 centers in the United States, France, and Australia. All patients had at least one line of EGFR tyrosine kinase inhibitor therapy, most commonly erlotinib, and the median number of prior treatments was four.
“The first 57 patients to be enrolled received the free-base form of rociletinib (150 mg once daily to 900 mg twice daily). The remaining patients received the hydrogen bromide salt form (500 mg twice daily to 1,000 mg twice daily),” the investigators explained. A maximum tolerated dose was not identified. “The only common dose-limiting adverse event was hyperglycemia,” they added.
“In an efficacy analysis that included patients who received free-base rociletinib at a dose of 900 mg twice daily or the hydrogen bromide salt form at any dose, the objective response rate among the 46 patients with T790M-positive disease who could be evaluated was 59%,” the authors stated. The disease control rate, including patients with a complete or partial response or stable disease, was 93% (43 of 46 patients). The estimated median progression-free survival at the time of analysis was 13.1 months.
The response rate among the 17 patients with T790M-negative disease who could be evaluated was 29%, and the disease control rate was 59%. The median progression-free survival was 5.6 months.
“The most common grade 3 toxic effect associated with rociletinib was hyperglycemia. Most hyperglycemia events were successfully managed with dose reduction, oral hyperglycemic therapy (most commonly metformin), or both, and no hyperglycemia events led to rociletinib discontinuation,” the researchers reported.
“Finding EGFR T790M in tumor specimens after initial therapy with first-generation EGFR tyrosine kinase inhibitors now has practical relevance,” Dr. Govindan wrote in the editorial. “In the immediate future, before the drugs are approved and widely available, these patients should be considered for ongoing clinical trials with T790M-specific EGFR tyrosine kinase inhibitors. Patients with EGFR inhibitor–resistant NSCLC whose tumor cells are activated through other oncogenes should be enrolled in appropriate clinical trials when possible.”
The AZD9291 trial was funded by AstraZeneca and is registered at ClinicalTrials.gov as NCT01802632. The rociletinib trial was funded by Clovis Oncology and is registered at ClinicalTrials.gov as NCT01526928. ■
Govindan R: N Engl J Med 372:1760-1761, 2015.
Jänne PA, et al: N Engl J Med 372:1689-1699, 2015.
Sequist LV, et al: N Engl J Med 372:1700-1709, 2015