Patterns of initial and intracranial failure in metastatic EGFR-mutant non-small cell lung cancer treated with erlotinib

Abstract

Objectives Patients with metastatic EGFR-mutant (mEGFRmt) NSCLC have favorable survival when treated with erlotinib. We hypothesized that treatment failure in most patients is limited to initial sites of disease, in which case incorporating local therapy such as radiation might further delay progression. We therefore analyzed patterns and predictors of failure in a large cohort of such patients. Materials and Methods We reviewed 189 patients treated with erlotinib for mEGFRmt NSCLC. We classified first pattern of failure as involving initial sites only (ISF), new sites only (NSF), or the combination (CSF), and used competing-risks regression to identify factors associated with ISF, progression and overall survival (OS). We also separately analyzed intracranial and intrathoracic failure. Results Of 171 patients who progressed, 103 (60.2%) had ISF, 30 (17.5%) had NSF, and 38 (22.2%) had CSF. Younger age and lack of initial CNS involvement independently correlated with ISF, with a trend for higher T and N stage. Higher T and N stage was also a significant predictor of progression. Factors predicting shorter OS were female gender, weight loss, initial intracranial involvement, and ≥4 extracranial metastases. Intrathoracic progression was a component of first failure in 61%, and three-year cumulative incidence of brain metastasis was 30%. Conclusion The main pattern of progression in mEGFRmt NSCLC on erlotinib is in the initial sites of disease. Younger patients and those without brain involvement are particularly likely to develop ISF. This suggests a role for incorporating local therapy into treatment of selected patients with mEGFRmt NSCLC.

The Unique Spatial-Temporal Treatment Failure Patterns of Adjuvant Gefitinib Therapy: A Post Hoc Analysis of the ADJUVANT Trial (CTONG 1104)

“…In addition, among the 29 patients with brain metastases in the gefitinib arm, 12 relapsed after withdrawing from gefitinib therapy, and a recurrence peak occurred 5 to 10 months after gefitinib termination. This was also observed by Patel et al 27 who found that the occurrence of CNS metastasis increased sharply between 24 and 36 months in patients with EGFR mutations when treated with erlotinib. Therefore, EGFR-TKIs (such as gefitinib) may require long treatment duration to show efficacy, and adequate follow-up is required.…”

Brain Metastases in Oncogene-Addicted Non-Small Cell Lung Cancer Patients: Incidence and Treatment

“…The baseline incidence of BM in EGFR -mutant NSCLC is similar to that of other oncogenic driver mutations, ranging from 23 to 32% ( 18 – 20 ). The cumulative incidence increases over time ( 19 , 21 ), with a 2-year actuarial risk of CNS progression of approximately 15–20% when patients received standard of care EGFR TKIs ( 21 , 22 ). BM development on EGFR TKI treatment is significantly more common among patients with baseline BM (2-year cumulative incidence of 47% among patients with pre-existing BM compared to 11% among those with no prior BM; p = 0.003) and correlates with a worse outcome ( 21 , 23 , 24 ).…”

“…BM development on EGFR TKI treatment is significantly more common among patients with baseline BM (2-year cumulative incidence of 47% among patients with pre-existing BM compared to 11% among those with no prior BM; p = 0.003) and correlates with a worse outcome ( 21 , 23 , 24 ). Literature reporting the risk of cumulative incidence of brain progression according to EGFR mutation subtype is contradictory, some studies reporting higher cumulative risk among Del19- mutant tumors ( 21 ), and others among L858R -mutant tumors ( 22 , 24 ).…”

Proposing synchronous oligometastatic non–small‐cell lung cancer based on progression after first‐line systemic therapy

“…17 Patients with EGFR mutated NSCLC had prolonged PFS and OS compared with those without EGFR mutation. 33 Concurrently, a separate report has shown no significant association between the number of metastases and patterns of initial PD in patients with EGFR-mutant NSCLC, 34 suggesting that a different approach might be required to explore the pattern of initial PD in EGFR tyrosine kinase inhibitors.…”