PURPOSE: Leptomeningeal metastases (LMs) exhibit a high incidence in patients with epidermal growth factor receptor (EGFR)–mutated non–small cell lung cancer (NSCLC) post-treatment with first- or second-generation EGFR tyrosine kinase inhibitors (TKIs). This investigation evaluates the efficacy, safety, and pharmacokinetics of 80 mg once daily osimertinib in patients with LMs resistant to prior first- or second-generation EGFR TKIs. MATERIALS AND METHODS: In this phase II multicenter, open-label, single-arm study, 80 mg osimertinib was administered to patients with EGFR-mutated NSCLC who had developed LMs subsequent to treatment with prior EGFR TKIs. The primary end point was overall survival (OS), assessed alongside objective response rate by the blinded independent central review (BICR) and a pharmacokinetic analysis of plasma and cerebrospinal fluid (CSF) on the first day of cycles 3 and 6. RESULTS: A total of 73 patients diagnosed with LM were treated with osimertinib, including 64 patients evaluable for the LM efficacy set—T790M negative (n = 62) and T790M positive (n = 2). The median OS in the full-analysis set was 15.6 months (95% CI, 11.5 to 20.2). The objective response rate for LM was 51.6%, including a 15.6% complete response, and the disease control rate was 81.3% by BICR in the LM efficacy evaluable set. The median LM progression-free survival by BICR was 11.2 months (95% CI, 7.7 to 15.3), the duration of response was 12.6 months (95% CI, 7.6 to 17.7), and OS was 15.0 months (95% CI, 11.3 to 18.7). Pharmacokinetic analysis showed that the CSF to free plasma osimertinib ratio was 22%. Most safety profiles were grade 1 and 2. CONCLUSION: The study demonstrates significant intracranial efficacy and survival benefits of 80 mg once daily osimertinib in NSCLC patients with LMs. The data support considering daily 80 mg of osimertinib as a treatment option for EGFR-mutated NSCLC patients with LMs, irrespective of T790M mutation status.

BACKGROUND Epidermal growth factor receptor (EGFR) T790M mutation drives acquired drug resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs) in patients with EGFR-mutant lung cancer. However, it was reported that this mutation may exist before drug exposure. The objective of the current study was to evaluate whether the clinical outcomes are affected by the percentage of preexisting T790M mutations within a tumor. METHODS Pretreatment tissues were collected from 124 patients with advanced non-small cell lung cancer with sensitizing EGFR mutations that were detected by direct sequencing. Genotyping for EGFR T790M mutation was further performed using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Patients who were positive for the T790M mutation were divided to 2 subgroups according to T790M mutant signal frequency. RESULTS The T790M mutation was found in 31 patients (25.0%). The T790M mutation frequency at which the risk of disease progression after therapy with EGFR-TKIs begins to increase was estimated to be 3.2%. The patients with T790M-positive tumors had a shorter time to disease progression after treatment with EGFR-TKIs (median, 6.3 months vs 11.5 months; P < .001) and overall survival (median, 16.1 months vs 26.5 months; P = .065) compared with those with T790M-negative tumors. Among the T790M-positive patients, the patients with high T790M frequency (9 patients) were found to have a shorter time to disease progression (median, 2.4 months vs 6.7 months; P = .009) and overall survival (median, 9.1 months vs 18.7 months; P = .018) compared with those with low T790M frequency (22 patients). CONCLUSIONS A preexisting EGFR T790M mutation was noted in 25% of patients with EGFR-mutant lung cancer. Patients with a high T790M mutation frequency had worse clinical outcomes to EGFR-TKIs than patients with a low T790M mutation frequency. Cancer 2014;120:2090–2098. © 2014 American Cancer Society.

Background: Immune checkpoint inhibitors (ICIs) have shown significant improvements in patients with advanced non–small cell lung cancer (NSCLC). One of the major issues with ICIs is determining the optimal treatment duration.Methods: This multicenter, retrospective study analyzed clinical outcomes in patients with NSCLC who completed 2 years of ICI therapy or were treated for more than 6 months and then discontinued ICIs without disease progression at 11 medical centers in Korea between August 2017 and December 2020.Results: Ninety‐six patients who completed 2 years of ICIs were reviewed. The median durations of treatment and follow‐up were 24.0 and 33.9 months, respectively. The objective response rate (ORR) was 85.4%. The median progression‐free survival (PFS) and overall survival (OS) periods were not reached. After completion, the PFS and OS rates were 81.1% and 96.4%, respectively, at 12 months. Forty‐three patients were identified who discontinued ICIs without disease progression: 26 (60.5%) for adverse events and 17 (39.5%) for other causes. The median durations of treatment and follow‐up were 10.5 and 21.2 months, respectively. The ORR was 90.7%. The median PFS and OS periods were not reached. After discontinuation, the PFS and OS rates were 71.0% and 90.0%, respectively, at 12 months.Conclusions: A significantly high proportion of patients who completed 2 years of ICI therapy continued to experience long‐term PFS. Even if ICIs are discontinued after 6 months in patients without disease progression, they may achieve a durable response and facilitate long‐term survival.Lay Summary: The optimal treatment duration for immune checkpoint inhibitors (ICIs) remains to be determined. This study reports the long‐term outcomes of patients with non–small cell lung cancer who completed 2 years of ICI therapy or achieved a durable response after the discontinuation of ICIs without disease progression in real‐world practice. A significantly high proportion of patients who completed 2 years of ICIs continued to experience long‐term progression‐free survival. In addition, even if ICIs are discontinued after 6 months in patients without disease progression, they may achieve a durable response and facilitate long‐term survival.

To investigate a prognostic role of gross tumor volume (GTV) changes on survival outcomes following concurrent chemoradiotherapy (CCRT) in stage III non-small-cell lung cancer (NSCLC) patients. We enrolled 191 patients with stage III NSCLC from 2001 to 2009 undergoing definitive CCRT. The GTV of 157 patients was delineated at the planning CT prior to CCRT and with a follow-up CT 1 month after CCRT. We assessed the volumetric parameters of pre-treatment GTV (GTVpre) post-treatment GTV (GTVpost), and volume reduction ratio of GTV (VRR). The primary endpoint was overall survival (OS) and secondary endpoints were progression-free survival (PFS) and locoregional progression-free survival (LRPFS). The best cut-off value was defined as that which exhibited the maximum difference between the two groups. The median follow-up duration was 52.7 months in surviving patients. Median survival, 3-year OS, PFS and LRPFS rates were 25.5 months, 36.4%, 23.0%, and 45.0%, respectively. The selected cut-off values were 50 cm3 for GTVpre, 20 cm3 for GTVpost, and 50% for VRR. The smaller GTVpre and GTVpost values were associated with better OS (p < 0.001 and p = 0.015) and PFS (p = 0.001 and p = 0.004), respectively, upon univariate analysis. The higher VRR of > 50% was associated with a trend toward poorer OS (p = 0.004) and PFS (p = 0.054). Upon multivariate analysis, smaller GTVpre indicated significantly improved OS (p = 0.001), PFS (p = 0.013) and LRPFS (p = 0.002), while smaller GTVpost was marginally significant for PFS (p = 0.086). Higher VRR was associated with a trend toward poorer OS (p = 0.075). In patients with stage III NSCLC undergoing definitive CCRT, GTVpre was an independent prognostic factor of survival. Notably, improved outcome was not correlated with higher VRR after short-term follow-up with CT alone.