Dataset Information

Erlotinib and Trametinib in Patients With EGFR-Mutant Lung Adenocarcinoma and Acquired Resistance to a Prior Tyrosine Kinase Inhibitor.

ABSTRACT: Inhibition of the MEK/ERK pathway is critical for Bcl-2-like protein 11 (BIM)-mediated epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI)-induced apoptosis, and dysregulation of this pathway may be a mechanism of acquired resistance. Therefore, MEK inhibition with trametinib and an EGFR TKI may resensitize tumors with acquired resistance. Limited targeted therapies are available after progression on EGFR TKIs, and it is in this setting that we completed a phase I/II study of erlotinib and trametinib.

Methods

Patients with metastatic EGFR-mutant lung adenocarcinoma and acquired resistance to an EGFR TKI received combination erlotinib 75 mg and trametinib 1.5 mg daily until progression or unacceptable side effects. The primary objective was objective response rate determined using RECIST version 1.1.

Results

Twenty-three patients were accrued; patients had received a median of two lines of prior TKI therapy (61% prior osimertinib), and 48% had acquired EGFR T790M. We confirmed one partial response (1/23, 4%, 95% CI, 0 to 22). The median progression-free survival was 1.8 months, and the median overall survival was 21 months. Diarrhea (87%), acneiform rash (87%), and fatigue (52%) were the most common treatment-related adverse events. Two patients who had tumor shrinkage both harbored a BRAF fusion.

Conclusion

Addition of trametinib to erlotinib in the acquired resistance setting in an unselected population is not efficacious. Future studies should focus on targeted therapies in molecularly selected populations. Acquired BRAF fusions in patients with EGFR-sensitizing mutations may be a molecular subset where EGFR and MEK combination therapy could be studied further.

SUBMITTER: Luo J

PROVIDER: S-EPMC8232136 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:IntroductionEpidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are associated with favorable response in EGFR mutant lung cancer. Acquired resistance to reversible EGFR TKIs remains a significant barrier, and acquired EGFR T790M-mutation is the major mechanism. Second-generation irreversible EGFR TKI, afatinib, had also been approved for treating EGFR mutant lung cancer patients, but the mechanism of acquired resistance to afatinib has not been well studied.ResultsForty-two patients had tissue specimens taken after acquiring resistance to afatinib. The sensitizing EGFR mutation were all consistent between pre- and post-afatinib tissues. Twenty patients (47.6%) had acquired T790M mutation. T790M rate was not different between first-generation EGFR TKI-naïve patients (50%) and first-generation EGFR TKI-treated patients (46.4%) (p = 0.827). No clinical characteristics or EGFR mutation types were associated with the development of acquired T790M. No other second-site EGFR mutations were detected. There were no small cell or squamous cell lung cancer transformation. Other genetic mutations were not identified in PIK3CA, BRAF, HER2, KRAS, NRAS, MEK1, AKT2, LKB1 and JAK2.MethodsAfatinib-prescription record of our department of pharmacy from January 2007 and December 2014 was retrieved. We investigated patients with tissue specimens available after acquiring resistance to afatinib. Enrolled patients should have partial response or durable stable disease of treatment response to afatinib. Various mechanisms of acquired resistance to first-generation EGFR TKIs were evaluated. Histology and cytology were reviewed. EGFR, PIK3CA, BRAF, HER2, KRAS, NRAS, MEK1, AKT2, LKB1 and JAK2 genetic alterations were evaluated by sequencing. Statistical analysis was performed using Chi-square test and Kaplan-Meier method.ConclusionsT790M was detected in half of the lung adenocarcinoma after acquiring resistance to afatinib. T790M is still the major acquired resistance mechanism. First-generation EGFR TKI exposure did not influence the prevalence of T790M in lung cancer acquired resistance to afatinib.