Third-Generation EGFR TKIs Take On the T790M Mutation in NSCLC
In the April 30 issue of The New England Journal of Medicine, two articles were published describing the use of third-generation EGFR TKIs for the treatment of patients with non–small cell lung cancer (NSCLC) and EGFR-sensitizing mutations progressing under first- or second-generation TKIs.1-2 It is well-known that EGFR TKI–acquired resistance occurs in about 60% to 70% of cases and is associated with the emergence of the T790M mutation. The two compounds evaluated in the present reports are third-generation EGFR TKIs targeting this resistance mutation. Both trials were quite similar in design, with a conventional phase I part followed by an extension cohort at a predefined dose.
AZ9291, evaluated in a series of 253 patients, demonstrated an overall response rate (ORR) of 51%, including a 61% ORR in T790M-mutated NSCLC and only a 21% ORR in EGFR-mutant TKI-resistant NSCLC with no T790M mutation.1 Similarly, median progression-free survival (PFS) was 9.6 months and 2.8 months, respectively.
These results are quite impressive in these heavily pretreated patients. They show how important the identification of the resistance mechanism will be in future practice. The dose selected here for further development (80 mg once daily) was well-tolerated (as were all the doses tested in the phase I part, with no dose-limiting toxicity identified). The most frequent side effects were: diarrhea, 47% overall, increasing with dose, most often mild with only 2% grade >3; skin rash (40%, mostly grade 1 and 2); and nausea, grade 1 and 2. These impressive results will need to be confirmed in ongoing trials and mandate further development.
Rociletinib (C01686) is also a third-generation TKI targeting the T790M mutation. The present paper reports the result of an extended phase I trial in patients with EGFR-mutant NSCLC having developed resistance to first- and second-generation EGFR TKIs.2 Two different galenic forms of the drugs were tested sequentially. First, a free-base form at doses up to 900 mg twice daily, then a hydrogen bromide salt form designed to improve the pharmacokinetics at doses ranging from 500 to 1000 mg twice daily.
Rociletinib demonstrated an ORR of 59% in T790M-mutant patients and 29% in patients without the mutation. The sample size of this phase I/II study is 130 patients, but ORR is reported for only 92 patients, including 46 with the T790M mutation. The estimated PFS is presently 13.1 months for patients with the mutation and 5.6 months in those without it. In terms of tolerance, the most frequent severe side effect was hyperglycemia, with 22% grade 3, requiring dose reductions and the use of glucose-lowering drugs. Hyperglycemia might be related to a metabolite of rociletinib interfering with type 1 insulin-like growth factor receptor (IGF-1R), a potential mechanism of EGFR resistance.
Asymptomatic QTc prolongations were also reported, responding to dose decrease. Other adverse events (diarrhea, fatigue) were rare and mild (grade 1 or 2). Overall, 48% of patients required a dose reduction.
Third-generation EGFR TKIs have demonstrated activity in patients having acquired a resistant mechanism to first- and/or second-generation EGFR TKIs through the emergence of a T790M mutation. Further development will need to compare these agents against platinum-based chemotherapy in randomized trials to best define the optimal sequence of use. These data illustrate the possibility of using specific, target-oriented drugs in a specific patient population. Identification of the mechanisms of resistance will be crucial in that setting. Circulating tumor DNA could be useful in monitoring patients under treatment and help avoid re-biopsy; this approach should be evaluated prospectively in further studies. Both AZ9291 and rociletinib are active, but comparison of both is limited by the sample size of the present trials. Their pharmacokinetic properties differ as well as their tolerance profiles and ideally would require a head-to-head comparison.
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