Editors' ChoiceCancer

More precision in lung cancer therapy

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Science Translational Medicine  13 May 2015:
Vol. 7, Issue 287, pp. 287ec79
DOI: 10.1126/scitranslmed.aab3977

For treatment purposes, non–small cell lung cancer (NSCLC) was essentially considered a single disease entity until the early 2000s, when it was recognized that somatic mutations in the epidermal growth factor receptor (EGFR) gene predicted clinical responsiveness to EGFR tyrosine kinase inhibitors (TKIs). Thus began the era of precision medicine in NSCLC, the most common form of lung cancer and the most common cause of cancer-related death in the United States and worldwide.

Tumor responses are observed in 60 to 70% of patients with EGFR-mutant advanced NSCLC who are treated with EGFR TKIs, a substantial improvement over conventional chemotherapy. However, resistance to pharmacologic inhibition of EGFR is almost inevitable; the majority of patients stop responding to this treatment in 1 to 2 years. Secondary mutations in the EGFR tyrosine kinase domain, specifically the EGFR T790M gatekeeper mutation, which interferes with inhibitor binding, account for 50 to 60% of acquired resistance to EGFR TKIs. The median survival is less than 2 years after the emergence of EGFR T790M. Previous efforts to specifically target T790M using “second generation” EGFR TKIs were unsuccessful because of the drugs’ inability to inhibit EGFR T790M at clinically achievable doses and their nondiscriminatory inhibition of wild-type EGFR, which was associated with skin and gastrointestinal toxic effects.

Now, two studies published in the New England Journal of Medicine offer hope for more precisely targeting EGFR T790M. AZD9291 and rociletinib (CO-1686) are orally administered, "third generation" EGFR TKIs that are selective for EGFR sensitizing mutations and the EGFR T790M resistance mutation but with minimal activity against wild-type EGFR. Both studies enrolled patients with advanced NSCLC whose disease had progressed after previous treatment with EGFR TKIs. The objective tumor response rate with AZD9291 was 61% among patients with EGFR T790M and 21% among those without EGFR T790M. The median progression-free survival (PFS) was 9.6 months and 2.8 months, respectively. The objective tumor response rate with rociletinib was 59% among patients with EGFR T790M and 29% among those without EGFR T790M. Corresponding median PFS durations were 13.1 months and 5.6 months, respectively. The incidence of toxic effects associated with inhibition of the wild-type EGFR was much smaller than observed with first-generation EGFR TKIs. Ongoing trials are comparing the efficacy of AZD9291 and rociletinib with first-generation EGFR TKIs in patients who have not yet developed EGFR T790M.

These findings represent a major therapeutic advance for patients with EGFR-mutant NSCLC. These results underscore the importance of mechanistically inspired drugs to precisely target specific mechanisms of resistance, which are elucidated by systematic study of pre- and post-treatment biopsies.

P. A. Jänne et al., AZD9291 in EGFR inhibitor–resistant non–small-cell lung cancer. N. Engl. J. Med. 372, 1689–1699 (2015). [Abstract]

L. V. Sequist et al., Rociletinib in EGFR-mutated non–small-cell lung cancer. N. Engl. J. Med. 372, 1700–1709 (2015).[Abstract]

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