Presence of MET, EGFR C797S Mutations Linked With Osimertinib Resistance in NSCLC

Suresh S. Ramalingam, MD

Suresh S. Ramalingam, MD

Patients withEGFR-mutant non—small cell lung cancer (NSCLC) who hadMETamplification andEGFRC797S mutations were most likely to have resistance to first-line treatment with osimertinib (Tagrisso), according to preliminary findings presented at the 2018 ESMO Congress.¹

These findings were part of a paired sample analysis of the phase III FLAURA trial, which led to the FDA approval of frontline osimertinib in April 2018 for patients with NSCLC whose tumors harborEGFRmutations (exon 19 deletions or exon 21 L858R substitution mutations).²

“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 theT790Mmutation, which patients already have when they are going to osimertinib for second-line therapy,” said lead study author Suresh S. Ramalingam, MD, who presented the data.

Overall findings from 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-na&iuml;ve patients withEGFR-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&nbsp;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 areEGFRC797S mutations, as well asMETandHER2amplification, explained Ramalingam, director of medical oncology at Emory University&rsquo;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.

&ldquo;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,&rdquo; Ramalingam noted. &ldquo;Also, amplification events may not be captured adequately in plasma analysis as they would be if we had tumor tissue to analyze.&rdquo;

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 plasmaEGFRmutations 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 wasMETamplification in 15% (n = 14/91) andEGFRC797S mutation in 7% of patients (n = 6). Additional secondaryEGFRmutations were found in another 3 patients, including L718Q + C797S (1%), L718Q + exon 20 insertions (1%), and S7681 (1%).PI3KCAmutations were found in 7% of patients;BRAFV600E mutations andKRAS(G12D/C, A146T) were each detected in 3% of patients.

Additional mechanisms of resistance wereHER2amplification (2%; HER2 mutation in 1%) andSPTBN1-ALKfusions (1%). Cell cycle gene alterations with amplification inCCND,CCNE1, andCDK4/6in 3%, 2%, and 5%, respectively.

&ldquo;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,&rdquo; said Ramalingam. &ldquo;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.&rdquo;

No acquiredEGFRT790M 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),METamplification in 4% (n = 5), andHER2amplification in 2% (n = 3). Two percent of patients had bothMETamplification and T790M.

Additionally,CCD6-RETfusion abnormalities were detected in 2%, andPI3KCAmutations were found in 3% of patients;BRAFD594N,KRASG12C, andNRASG12D were each detected in 1% of patients. This was in line with previous analyses, Ramalingam noted.

In conclusion, Ramalingam added that the frequency ofMETamplification is expected to be higher in tissue. Ongoing research, specifically the ELIOS trial (NCT03239340) will address a tissue analysis for mechanisms of resistance to first-line osimertinib.

&ldquo;While these data are very helpful in moving the field forward, we feel that definitive tissue-based testing is required to understand the full spectrum of resistance mutations and aberrations for patients treated with osimertinib,&rdquo; said Ramalingam.

References:

1. Ramalingam SS, Cheng Y, Zhou C, et al. Mechanisms of acquired resistance to first-line osimertinib: preliminary data from the phase III FLAURA study. In: Proceedings from the 2018 ESMO Congress; October 19-23, 2018; Munich, Germany. Abstract LBA50.
2. Soria JC, Ohe Y, Vansteenkiste J et al. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer.N Engl J Med. 2018;;378(2):113-125. doi: 10.1056/NEJMoa1713137.