Sarah B. Goldberg, MD
Monotherapy with a tyrosine kinase inhibitor (TKI) is the frontline standard of care for patients with advanced EGFR-
mutant non–small cell lung cancer (NSCLC), with 3 currently approved agents: erlotinib (Tarceva), gefitinib (Iressa), and afatinib (Gilotrif). Following acquired resistance, patients who test positive for the EGFR
T790M mutation receive osimertinib (Tagrisso), while those with negative tumors undergo chemotherapy.
However, this sequence could undergo a major upheaval as a result of top-line findings from the phase III FLAURA trial, recently announced by AstraZeneca, the developer of the third-generation EGFR inhibitor osimertinib.1
In the 566-patient study, osimertinib improved progression-free survival (PFS) compared with erlotinib or gefitinib in the frontline setting for patients with EGFR-
mutant advanced NSCLC. At this point, data have not been released.
“We know that osimertinib has an improvement in PFS compared with erlotinib or gefitinib, which I don’t think is a surprise to anyone,” said Sarah B. Goldberg, MD, MPH, assistant professor of medicine (medical oncology) at the Yale School of Medicine and Yale Cancer Center in New Haven, Connecticut.
“The question is, how much of a progression-free survival benefit? It will really have to be significant enough to overcome the benefit of sequencing the 2 lines of therapy,” she said, during a presentation on sequencing EGFR inhibitors at the 18th Annual International Lung Cancer Congress®
(ILCC), hosted by Physicians’ Education Resource®
) July 27 to 29 in Huntington Beach, California. “I think we will have much more data in the next few months and maybe this will change our practice.”
Current Frontline Standards
The 3 currently approved frontline TKIs have similar efficacy but with varying toxicity profiles, with none showing superior overall survival (OS). The most recently added agent, afatinib, was compared with gefitinib in a head-to-head phase IIb study for patients with EGFR-mutant NSCLC.2
Median OS was 27.9 months with afatinib and 24.5 months with gefitinib, but this was not statistically significant (HR, 0.86; 95% CI, 0.66-1.12; P
= .258). The objective response rate (ORR) across the study was 72.5% with afatinib compared with 56% for gefitinib (P
= .0018). The median PFS was 11.0 versus 10.9 months, for afatinib and gefitinib, respectively (HR, 0.73; 95% CI, 0.57-0.95; P
Regardless of the frontline EGFR TKI selected, resistance is inevitable, primarily due to an acquired mutation in T790M. For those with this type of progression, osimertinib quickly became the standard of care, following an accelerated approval in November 2015, Goldberg noted. In March 2017, osimertinib was granted a full approval for pretreated patients with T790M-positive NSCLC, based on findings from the phase III AURA3 trial.3
In AURA3, the median PFS with osimertinib was 10.1 months compared with 4.4 months for pemetrexed plus platinum-based chemotherapy (HR, 0.30; 95% CI, 0.23-0.41; P
<.001). The ORR with osimertinib was 71% compared with 31% with chemotherapy. The median duration of response was 8.5 versus 4.2 months for osimertinib and chemotherapy, respectively. OS data were not yet available.
“Because of this trial, osimertinib is now the standard-of-care for patients. It has been approved for T790M-positive disease,” Goldberg said. “After progression, it has become standard to biopsy patients and, if T790M positive, to give osimertinib.”
Future Therapeutic Sequencing Considerations
Whether the frontline standard of care will be changed depends heavily on the magnitude of benefit seen with osimertinib. Although data from the phase III FLAURA study have not yet been released, Goldberg referenced phase I data from a 60-patient study of osimertinib in the first-line setting as a potential indicator.4
In this study, the ORR was 67% for patients assigned to 80 mg once daily osimertinib (95% CI, 47%-83%) and 87% with osimertinib at 160 mg (95% CI, 69%-96%). Across doses, the median PFS was 19.3 months with osimertinib and the 12- and 18-month PFS rates were 72% and 55%, respectively.4
“The median PFS with the other agents is about 10 to 12 months, so really this is an impressive PFS,” she said.
If the PFS benefit in this study was also seen in the phase III results, it may be sufficient to warrant switching to frontline osimertinib, Goldberg noted. “I would love to see the overall survival data from FLAURA but that’s not going to happen for a while,” she said. “That’s really what we want to know. I was not surprised at all to see that PFS was positive.”