Year In Review | Targeted Therapy
Progress in the management of common and rare mutations among patients with advanced NSCLC continued in 2017. Targeting oncogenic driver mutations is a core aspect of our treatment armamentarium, including such targets as ALK, EGFR, BRAF, and MEK. While these mutations are widely known, our ability to target them, and overcome potential resistances to therapy continues to evolve.
Back in January 2017, Sorio and colleagues published the first results from the phase III ASCEND-4 trial investigating the use of ceritinib in previously untreated ALK-rearranged late stage NSCLC. Patients randomized to receive the ALK inhibitor had a median PFS of 16.6 months, while patients randomized to chemotherapy had a PFS of 8.1 months, demonstrating superior efficacy.
Then in February, Mok and colleagues demonstrated that osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) able to irreversibly bind to EGFR and the notorious T790M resistance mutation, had superior efficacy and safety to a platinumpemetrexed doublet chemotherapy. Results from the phase III AURA3 trial published in the New England Journal of Medicine showed that the third-generation TKI induced a response in 71% of patients with T790M-positive advanced NSCLC, extending PFS to 10.1 months (compared with 4.4 months for patients receiving chemotherapy) while demonstrated a lower adverse event profile.
Early this year, Soria and colleagues then detailed results from the phase III FLAURA trial comparing osimertinib with standard EGFR-TKIs (gefitinib or erlotinib) for patients with previously untreated EGFR-positive NSCLC. Results in the Lancet demonstrated osimertinib had superior efficacy as a first-line treatment, extending PFS to 18.9 months (compared with 10.2 months for standard TKIs).
In August 2017, Peters and investigators published results on another ALK-inhibitor, alectinib. Results from the phase III ALEX trial comparing alectinib with crizotinib for firstline ALK-positive NSCLC showed treatment with alectinib reduced the risk of disease progression or death by 53% compared with crizotinib. Further the 12-month PFS rate was 68% for patients receiving alectinib compared with 49% for patients receiving crizotinib.
Then in September, OS results of the phase III PROFILE 1014 trial were presented at the ESMO 2017 Congress. Crizotinib previously demonstrated improved PFS compared with chemotherapy for ALK-positive NSCLC. Here, Mok and colleagues showed that when adjusting for patients who ultimately crossed treatment arms, this benefit also extended to OS.