Osimertinib improves OS in untreated, advanced NSCLC

 

Sheenu Sheela

 

Kathryn F. Mileham

The final OS analysis of FLAURA reaffirms the choice of osimertinib over other EGFR TKIs as first-line treatment for EGFR-mutated metastatic NSCLC.

After reaching the primary endpoint of PFS in the initial analysis of the FLAURA trial (18.9 months vs. 10.2 months), osimertinib was widely adopted as standard-of-care treatment for this indication. Despite the impressive PFS results, demonstrable central nervous system penetration and favorable side effect profile, many awaited the OS results to determine if osimertinib in the first line provides at least as long OS as sequential treatment with osimertinib in the second line for those with EGFR T790M acquisition as mechanism of resistance to first-line treatment. Based on these matured OS results, this is the first study demonstrating an OS benefit with an EGFR TKI in the first-line treatment of EGFR-mutated metastatic NSCLC.

The results also argue against sequencing with a first- or second-generation EGFR TKI as first-line treatment followed by osimertinib at progression. In previous studies that compared first- or second-generation EGFR TKIs with chemotherapy, OS was similar between arms, often felt to be confounded by crossover to EGFR TKI upon progression. Additionally, only 50% of patients acquire the T790M mutation at progression, limiting those eligible to receive osimertinib in next-line treatment, as proven to be effective in previous AURA studies.

FLAURA showed that even with 31% crossover allowing for osimertinib among those with T790M acquisition, the statistically significant OS benefit was maintained by those who received osimertinib first rather than in sequence. Notably, nearly 30% of patients from each arm of FLAURA received no subsequent treatment, owing to death among about 70% of these patients. This sobering statistic emphasizes the need to provide the most effective therapy first. In the setting of EGFR-mutated metastatic NSCLC, the most effective first-line treatment is proven to be osimertinib.

Prior to the FLAURA OS data maturing, multiple other clinical trials combined first- or second-generation EGFR TKIs with other agents in hopes of extending survival and overcoming resistance. These have yet to demonstrate a comparable OS benefit, tolerability and safety profile, and effective CNS penetration. New EGFR TKIs or treatment combinations must surpass what has been demonstrated with osimertinib in the first-line setting to become practically relevant. There are ongoing combination trials with osimertinib plus either ramucirumab (Cyramza, Eli Lilly; NCT02789345) or bevacizumab (Avastin, Genentech; NCT02803203, NCT02971501 and NCT 03133546).

Moving forward, based on the OS results of the FLAURA trial, osimertinib is not only the preferred standard in first-line treatment of EGFR-mutated metastatic NSCLC, but also should be the standard comparator or the combination backbone of future trials in first-line treatment of this disease.

References:

Nakagawa K, et al. Lancet Oncol. 2019;doi:10.1016/S1470-2045(19)30634-5.

Ramalingam SS, et al. N Engl J Med. 2019;doi:10.1056/NEJMoa1913662.

Saito H, et al. Lancet Oncol. 2019;doi:10.1016/S1470-2045(19)30035-X.

Soria JC, et al. N Engl J Med. 2018;doi:10.1056/NEJMoa1713137.

Sheenu Sheela, MD, FACP

Kathryn F. Mileham, MD, FACP

Levine Cancer Institute at Atrium Health

Tarek M. Mekhail, MD, MSC, FRCSI, FRCSEd

Treatment of lung cancer has changed significantly during the last 2 decades. Identification of the EGFR mutation as an oncogenic driver was perhaps the first and one of the biggest turning points in the treatment of this disease. Since then, a lot of work has gone into identifying the most effective drugs, best treatment sequence and mechanisms of acquired resistance.

Multiple studies have shown that first- and second-generation TKIs led to higher response rates and improved PFS compared with standard doublet chemotherapy. These studies all failed to show an OS advantage, except for subgroup analyses of LUX-Lung 3 and LUX-Lung 6 that showed a survival advantage for afatinib (Gilotrif, Boehringer Ingelheim) over chemotherapy among patients with EGFR exon 19 deletion (del 19). The ability of patients in the standard chemotherapy group to cross over to TKIs was thought to be the reason for failure to achieve a survival advantage. These findings led to the adoption of EGFR TKIs as first-line therapy for patients with sensitizing EGFR mutations (del 19, L858R).

Osimertinib, a third-generation selective EGFR TKI, has activity against EGFR sensitizing mutations as well as EGFR with acquired T790M resistance mutations, with the added advantage of central nervous system activity.

Ramalingam and colleagues compared osimertinib with first-generation TKIs in the FLAURA study and demonstrated not only a PFS advantage, but also an OS advantage. This is a particularly high bar to achieve, given that 48% of patients in the comparator group who received first subsequent treatment (31% of patients randomly assigned to the comparator group) received osimertinib as salvage therapy. Importantly, a 52% reduction in risk for CNS progression is further evidence of the drug’s impressive CNS activity. 

These results establish osimertinib as first-line treatment for patients with sensitizing EGFR mutations. The median survival approaching 4 years further highlights the value of identifying EGFR as a molecular target for treatment of lung cancer. 

References:

Wu YL, et al. Lancet Oncol. 2014;doi:10.1016/S1470-2045(13)70604-1.

Yang JC. Abstract LBA7500. Presented at: ASCO Annual Meeting; June 1-5, 2012; Chicago.