Leading Resistance Mechanism to Osimertinib Identified as EGFR C797X, According to Real-World Analysis

Acquired EGFR C797X mutations with first- and second-line osimertinib (Tagrisso) has become to leading mechanism of resistance to the third-generation EGFR inhibitor ahead of MET amplifications, according to findings from a retrospective observational analysis presented during the 2022 World Conference on Lung Cancer by Suresh S. Ramalingam, MD.

In patients with non–small cell lung cancer (NSCLC) with EGFR mutations who received osimertinib in the first-line setting, EGFR C797X mutations were 1.25 times more common than MET amplification. In the second-line setting these mutations were 2.4 times more common than MET amplification.¹

“This real-world study improves our understanding of how resistance mutations to osimertinib emerge over time, with new insights on when EGFR C797X mutations overtake MET amplifications as the most commonly acquired resistance mechanism,” Ramalingam said in a press release.² “The analysis characterizes the increased frequency of EGFR C797X mutations as patients are treated with first-line osimertinib for longer durations, reinforcing the need for next-generation EGFR inhibitors to address C797X-driven resistance.” Ramalingam is executive director of Winship Cancer Institute of Emory University, a professor in the Department of Hematology and Medical Oncology and the Roberto C. Goizueta Distinguished Chair for Cancer Research at Emory University School of Medicine, and associate vice president for cancer at Woodruff Health Sciences Center.

Less common EGFR resistance mechanisms include EGFR L718Q, EGFR S768I, EGFR L792X, and EGFR exon 20 insertions. HER2 amplification, BRAF and KRAS mutations, and CCNE1 amplification are also known mechanisms of resistance.^1,3

Investigators leveraged data from the GuardantINFORM clinical genomic database to conduct an analysis of real-world detection rate and cooccurrence of EGFR C797X mutations. The study was a collaboration between Guardant Health, Blueprint Medicines, and Winship Cancer Institute.

The data capture included patients with NSCLC who had received cell-free DNA testing via either the Guardant360 CDx or Guardant360 assay. The total number of patients with this information was 65,273 at baseline.

Patients with activating EGFR mutations were reported as follows: EGFR L858R (n = 3817), EGFR exon 19 deletions (n = 5489), other EGFR driver detected (n = 1777), and no EGFR driver detected (n = 60,349).¹

Once treatment with osimertinib was applied to the results, 4288 patients were evaluable, and 2050 had cell-free DNA assay analysis results following treatment with osimertinib: 65.2% received osimertinib in the first-line setting (n = 1337), vs 34.8% in the second line (n = 713).

With a median follow-up of 21 months, C797X mutations were detected among 87 patients (6.5%) after first-line osimertinib. After a median follow-up of 26 months in the second-line setting, 99 patients (13.9%) had a C797X mutation.¹

Further, the results showed that following second-line osimertinib, the incidence of EGFR C797X mutations exceeded CCNE1 amplification, MET amplification, PIK3CA E545 and E542 mutations, as well as EGFR L718 and BRAF V600E mutations from 12 months.

Further, the median time to C797X detection was 16.8 months compared with 10.5 and 9.1 months for MET and CCNE1 amplification, respectively. Among those who received osimertinib in the first-line setting, the cumulative incidence of EGFR C797X was 8.0% after 5 years. MET and CCNE1 amplification were detected at rates of 6.4% and 7.9%, respectively. In the second-line setting, after 5 years the initiation the cumulative incidence of CCNE1 amplification and EGFR C797X mutations was 10.3% and 17.5%, respectively. MET amplification was detected at 7.2%.

In an analysis of patients who discontinued osimertinib with 60 days of cell-free DNA analysis (n = 600) the cumulative incidence of EGFR C797 mutations was 12.5%. This marker was used a proxy for disease progression in the analysis.

The study authors noted that the dynamics of the appearance of resistance mechanisms to osimertinib remain poorly studied. They also noted that limitations of the study include common health care claims data discrepancies including inherent to healthcare claims data missing clinical information not routinely reported, the potential for misclassification, and representativeness of the study cohort.

References

1. Ramalingam SS, Zhang N, Yu J, et al. Real-world landscape of EGFR C797X mutation as a resistance mechanism to osimertinib in NSCLC. Presented at: International Association for the Study of Lung Cancer 2022 World Conference on Lung Cancer; August 6-9, 2022; Vienna, Austria. Abstract OA03.05.
2. Guardant Health and Blueprint Medicines present real-world data identifying EGFR C797X mutation as most common resistance mechanism to osimertinib therapy at IASLC 2022 World Conference on Lung Cancer. News release. Guardant Health Inc. August 8, 2022. Accessed August 8, 2022. bit.ly/3SK0Zee
3. Leonetti A, Sharma S, Minari R, Perego P, Giovannetti E, Tiseo M. Resistance mechanisms to osimertinib in EGFR-mutated non-small cell lung cancer. Br J Cancer. 2019t;121(9):725-737. doi:10.1038/s41416-019-0573-8