Third-Generation TKIs Combat EGFR T790M Treatment Resistance

AZD9291 and rociletinib both show promise for the treatment of patients with advanced lung cancer with the resistant T790M mutation

medwireNews: Patients with epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC) that has progressed during or after EGFR inhibitor therapy may benefit from a third-generation EGFR tyrosine kinase inhibitor (TKI), research suggests.

Early trial results for two such agents, AZD9291 and rociletinib, are reported in The New England Journal of Medicine, and demonstrate the drugs’ efficacy in patients whose tumours have developed theEGFRT790M mutation after treatment with a first-generation EGFR TKI.

The findings underscore the importance of molecular analysis on repeat biopsies after disease progression during EGFR TKI treatment now that detecting T790M has “practical relevance”, writes Ramaswamy Govindan, from Washington University School of Medicine in St Louis, USA, in an accompanying 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”, he recommends, noting that the two agents had lower incidences of rash and diarrhoea than first-generation EGFR TKIs. 

In the first trial reported, AZD9291, an oral irreversible EGFR TKI selective against TKI-sensitising mutations and the T790M mutation was given to 253 patients with locally advanced or metastatic NSCLC at a dose of between 20 mg and 240 mg per day for a 21-day cycle.

The objective tumour response rate for 239 assessed patients given at least one dose of AZD9291 was 51%; this increased to 61% among the 127 patients with a centrally detected EGFR T790M mutation but fell to just 21% for the 61 patients without the mutation. 

And progression-free survival was a median of 9.6 and 2.8 months in the patients with and without centrally detected EGFR T780M mutations, respectively, report Pasi Jänne, from Dana–Farber Cancer Institute in Boston, Massachusetts, USA, and co-investigators. 

A second oral mutant-selective EGFR inhibitor, rociletinib, was also assessed in a phase I–II trial by Lecia Sequist, from Massachusetts General Hospital in Boston, USA, and team.

Patients with EGFR-mutated NSCLC and disease progression during EGFR TKI therapy were given varying doses of either a free-base form of the agent (n=57) or a hydrogen bromide salt form (n=73). A maximum tolerated dose with dose-limiting toxic effects below 33% was not identified, with the main toxicity of hyperglycaemia managed with oral therapy.

The objective response rate was calculated to be 59% for the 46 patients with T790M-positive tumours who were given free-base rociletinib 900 mg twice daily or hydrogen bromide salt form at any dose, falling to 29% for the 17 patients who were negative for the mutation. 

The estimated progression-free survival at time of current analysis was 13.1 months, the researchers add, calling the sustained disease control “encouraging” in the absence of approved therapies targeting tumours with T790M mutations.

“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”, they conclude.


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