Rociletinib Effective in T790M-Mutant NSCLC

The third-generation EGFR inhibitor rociletinib demonstrated promising responses in patients with EGFR-mutated non-small cell lung cancer with or without the acquired resistance mutation T790M.

Lecia V. Sequist, MD, MPH

The third-generation EGFR inhibitor rociletinib (CO-1686) demonstrated promising responses in patients with EGFR-mutated non-small cell lung cancer with or without the acquired resistance mutationT790M, according to findings from a phase I/II study published inThe New England Journal of Medicine.

"We found that treatment with rociletinib—an EGFR inhibitor selective for mutated EGFR, including theT790Mresistance mutation—results in sustained tumor responses in patients withEGFR-mutated NSCLC who had disease progression while taking currently available EGFR inhibitors," the authors of the study wrote.

Efficacy Seen With or Without T790M-Positivity

In the analysis, 130 patients withEGFR-mutated NSCLC who progress on prior treatment with an EGFR inhibitor received rociletinib at varying doses. The first patients enrolled were treated with an older free-base formulation of the drug (n = 74). However, remaining patients received a hydrogen bromide salt (HBr) formulation at 500 to 1000 mg twice daily (n = 56).

An analysis of efficacy was conducted on patients who received the free-base formulation of the drug at 900 mg twice daily and those who received the HBr formulation at any dose. Those who received the free-base dose of less than 900 mg (n = 38) were excluded from the analysis, as a responses was less common.

Sixty-three of the remaining 92 patients were evaluable. In these patients, the objective response rate (ORR) among those withT790M-mutation (n = 46) was 59% (95% CI, 45-73). The ORR among those without theT790Mmutation (n = 17) was 29% (95% CI, 8-51). The disease control rates were 93% and 59%, withT790Mmutations and without, respectively.

In patients who harbored aT790Malteration, the estimated median progression-free survival at the time of the analysis was 13.1 months (95% CI, 5.4-13.1).

"The response rate of 59% and prolonged disease control among someT790M-positive patients are encouraging, particularly because there are no approved therapies that specifically targetT790M, although several other molecules are in development," the researchers wrote.

Safety Profile Intriguing

A maximum tolerated dose was not achieved in the study. The only observable dose limiting toxicity appeared to be hyperglycemia, which is not normally seen with EGFR inhibition.

This adverse event was easily managed in the study with dose reductions and the administration of metformin. Hyperglycemia did not result in treatment discontinuation, with 38% of patients receiving a hypoglycemic agent to treat the condition.

"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 authors wrote.

The rash that has been commonly associated with EGFR inhibition was not observed with rociletinib. Only one patient enrolled in the study experienced any type of skin rash (grade 1 maculopapular rash). Grade 1/2 diarrhea was seen in 20% of the patients; however, more severe diarrhea was not reported in the study. Dose reductions were required for 48% of patients at the 900 mg dose.

"Rociletinib did not cause the syndrome of rash, stomatitis, and paronychia that is associated with inhibition of nonmutant EGFR, which suggests that the mutation-specific selectivity observed in preclinical testing was also present in patients," according to the researchers. "The most common grade 3 toxic effect associated with rociletinib was hyperglycemia."

Studies Ongoing

The phase II/III TIGER 1 trial is comparing rociletinib with erlotinib as first-line therapy in treatment-naïve patients withEGFRmutations who have not been screened forT790Mstatus. TIGER 2, a single-arm phase II trial, is evaluating rociletinib as second-line therapy in patients withEGFR-mutated NSCLC who areT790M-positive.

Additionally, the randomized phase III TIGER 3 trial is evaluating rociletinib versus chemotherapy in patients who have progressed on a first-line EGFR TKI and are alsoT790M-positive.

"Larger studies are ongoing, though previous results of treating NSCLCs defined by a driver mutation with corresponding tyrosine kinase inhibitors suggest that strong and early activity as we have seen with rociletinib will translate into a sustained benefit in larger populations," the authors of the study wrote.

Sequist LV, Soria J-C, Goldman JW, et al. Rociletinib in EGFR-Mutated Non—Small-Cell Lung Cancer.NEJM. 2015;372(5):1700-1709.