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MET, EGFR C797S Linked With Acquired Resistance to Frontline Osimertinib in NSCLC

Gina Columbus
Published: Friday, Oct 19, 2018

Suresh S. Ramalingam, MD
Suresh S. Ramalingam, MD
MET amplification and EGFR C797S mutations are the most commonly observed alterations associated with resistance to first-line osimertinib (Tagrisso) in patients with EGFR-mutant non–small cell lung cancer (NSCLC), according to preliminary data presented at the 2018 ESMO Congress.1

“We see a lot of similarities between what is seen in the first-line therapy [with osimertinib] and what is seen in second-line therapy, with the exception of the T790M mutation, which patients already have when they are going to osimertinib for second-line therapy,” said lead author Suresh S. Ramalingam, MD, who presented the data.

The findings were part of a paired sample analysis of the phase III FLAURA trial, which was the basis for the April 2018 FDA approval of frontline osimertinib for patients with NSCLC whose tumors harbor EGFR mutations (exon 19 deletions or exon 21 L858R substitution mutations).2

Overall results of the double-blind trial showed that osimertinib, a third-generation EGFR tyrosine kinase inhibitor (TKI), reduced the risk of progression or death by 54% versus standard TKI therapy with erlotinib (Tarceva) or gefitinib (Iressa). Moreover, the median progression-free survival was 10.2 months (95% CI, 9.6-11.1) for standard therapy and 18.9 months (95% CI, 15.2-21.4) with osimertinib (HR, 0.46; 95% CI, 0.37-0.57; P <.0001).

In FLAURA, 556 treatment-naïve patients with EGFR-positive locally advanced or metastatic NSCLC were randomly assigned to osimertinib (n = 279) or a standard TKI (erlotinib or gefitinib; n = 277). Patients with central nervous system metastases were allowed on the trial and all patients had exon 19 deletions or L858R mutations. Daily oral therapy was given with 80 mg of osimertinib, 250 mg of gefitinib, or 150 mg of erlotinib.

Previous data have shown that the most common resistance mechanisms to second-line osimertinib are EGFR C797S mutations, as well as MET and HER2 amplification, explained Ramalingam, director of medical oncology at Emory University’s Winship Cancer Institute.

For this analysis, researchers examined mechanisms of acquired resistance to osimertinib in patients who progressed while on the FLAURA trial. Paired plasma samples, which were analyzed using next-generation sequencing (NGS), were collected at baseline and following RECIST progression and/or treatment discontinuation until March 2018. NGS platforms included the Guardant360 assay or GuardantOMNI panel.

“It is important to keep in mind that nongenetic mechanisms of resistance, such as small cell lung cancer transformation and protein expression changes, are not captured in this analysis,” Ramalingam noted. “Also, amplification events may not be captured adequately in plasma analysis as they would be if we had tumor tissue to analyze.”

Paired plasma samples of patients who experienced disease progression or treatment discontinuation were analyzed in 41% (n = 113) and 57% (n = 159) of patients on the osimertinib and standard TKI arms, respectively. Those with detectable plasma EGFR mutations with exon 19 deletions and L858R mutations were evaluable—81% of whom were treated with osimertinib (n = 91/113) and 81% with standard TKI (n = 129/150).

Results showed that the most common acquired resistance mechanism to treatment with osimertinib was MET amplification in 15% (n = 14/91) and EGFR C797S mutation in 7% of patients (n = 6). Additional secondary EGFR mutations were found in another 3 patients, including L718Q + C797S (1%), L718Q + exon 20 insertions (1%), and S7681 (1%). PI3KCA mutations were found in 7% of patients; BRAF V600E mutations and KRAS (G12D/C, A146T) were each detected in 3% of patients.

Additional mechanisms of resistance were HER2 amplification (2%; HER2 mutation in 1%) and SPTBN1-ALK fusions (1%). Cell cycle gene alterations with amplification in CCND, CCNE1, and CDK4/6 in 3%, 2%, and 5%, respectively.

“Fourteen percent of patients had concurrent candidate mutations in the resistance samples. This indicates that more than 1 pathway may be turned on when patients develop acquired resistance,” said Ramalingam. “These numbers between these two are relatively small to make any strong statistical conclusions as to whether one specific mechanism is more common—with exon 19 or exon 21.”

No acquired EGFR T790M was detected in the osimertinib arm and no unexpected resistance mechanisms were observed. There were no suggestions of new mechanisms of resistance that led to aggressive disease biology, he added.

In the standard TKI therapy arm, the most common resistance mechanisms were the T790M mutation in 47% (n = 60), MET amplification in 4% (n = 5), and HER2 amplification in 2% (n = 3). Two percent of patients had both MET amplification and T790M.


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