An updated, final analysis from the phase III FLAURA study showed that compared with older EGFR inhibitors, the third-generation drug osimertinib was better tolerated and significantly improved overall survival among patients newly diagnosed with EGFR-mutant non–small cell lung cancer.

According to a final analysis of the phase III FLAURA trial, osimertinib (Tagrisso; AstraZeneca) remains a superior treatment option for patients with EGFR-mutant nonsmall cell lung cancer (NSCLC). The data were presented by Suresh Ramalingam, MD, of Emory University in Atlanta, GA, during the ESMO Congress 2019 in Barcelona, Spain, September 27October 1.

A third-generation tyrosine kinase inhibitor (TKI), osimertinib targets not only EGFR exon 19 deletions and L858R on exon 21, but also the chief resistance mutation, T790M, that emerges in response to older TKIs. As well, it is significantly more effective than earlier-generation drugs against central nervous system (CNS) metastases. Approved since 2015 as a second-line therapy for T790M-positive NSCLC, it earned a broader first-line indication in April 2018. The FDA's nod was based on previously published FLAURA data showing that of 556 patients, those randomly assigned to receive osimertinib experienced improved progression-free survival and reduced toxicity, compared with those assigned to receive gefitinib (Iressa; AstraZeneca) or erlotinib (Tarceva; Genentech).

In his update, Ramalingam reported that the median overall survival (OS) was 38.6 months and 31.8 months, respectively. “I'd like to point out that the control group's median OS is among the highest recorded for EGFR-mutant patients,” he said. “We think it can be attributed to the crossover to receive osimertinib upon progression. Even with that in play, we still saw a significant OS improvement in the study arm, which is noteworthy.”

At data cutoff, 22% of patients were still on osimertinib after more than 3 years, and the drug continued to present a favorable toxicity profile despite this prolonged exposure, Ramalingam said. As well, in both of FLAURA's arms, one third of patients were unable to receive subsequent therapy following disease progression, “mainly because most of them died,” he said. “Front-line treatment was their only shot, which is why, to me, our results clearly support using the best agent first.”

Invited discussant Pasi Jänne, MD, PhD, of Dana-Farber Cancer Institute in Boston, MA, agreed. “The concept of sequencing EGFR TKIs—starting with a prior-generation drug and saving osimertinib for later—is often talked about, but it's not optimal clinical care, in my opinion,” he said. “We aren't smart enough to figure out who will or won't develop T790M, and we may not always be able to perform the appropriate biopsy to detect this mutation.”

Targeted therapies “often do not deliver on multiple clinical end points in the context of a single trial,” Jänne added. “Looking at FLAURA, however, I'd argue that osimertinib has hit for the cycle in terms of response rate, PFS, CNS activity, and now the home run of showing improved OS” over another EGFR TKI—the first such drug to do so, as Ramalingam observed.

The future of treating this NSCLC subtype is one in which “we should be done with single-agent TKI comparisons,” said Jänne. Instead, the focus needs to shift toward building onto first-line osimertinib and better understanding acquired resistance mechanisms to this drug, including MET amplification and EGFR C797S. How to best intervene—through combination strategies, for instance, or emerging candidates such as JNJ-61186372 (Genmab/Janssen), an EGFR-cMet bispecific antibody—“will be the next area of investigation in future trials,” he said. –Alissa Poh