Background Osimertinib is a selective irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) with increased penetration across the blood brain barrier compared to previous EGFR TKIs and thus a 52% reduction in the risk of intracranial disease progression is seen when it is used as 1st line of therapy compared to gefitinib and erlotinib. It is also efficient as 2 nd line therapy for patients who developed the T790M resistance mutation following treatment with previous generation TKIs. Here, we report eleven patients who were treated by an increasing dose of osimertinib from 80 mg to 160 mg QD orally following intracranial progression in either 1 st or 2 nd line setting. Methods This is a sub-cohort analysis from a larger non-randomized, phase 2, open-label trial, evaluating the efficacy of osimertinib dose escalation from 80 to 160mg in EGFR mutated advanced NSCLC patients with intracranial progression in either 1 st (Arm A) or 2 nd line setting (Arm B for T790M+ and C for T790M-). Results Eleven patients, five in arm A, four in arm B and two in arm C were reported in this study. The mPFS of osimertinib before dose escalation was 11.4±8.9(6.6-30.7) months for arm A, 8.7±1.8(6.3-11.2) for arm B, and 14.5±7.8(6.7-22.3) for arm C. Intracranial response rate to dose-escalation was 54%(6/11) with 2/11 having intracranial stability. Median iPFS was 4.3±7.4(0.7-25.5) months; 3.8±6.4(1.8-18.9), 5.6±9.7(0.7-25.5) and 7.0±2.7(4.3-9.6) for arms A/B/C respectively. Dose escalation was well tolerated with diarrhea and paronychia as the main dose limiting symptoms. Conclusions Osimertinib 160 mg is feasible and may offer a therapeutic alternative for patients with isolated intracranial progression on osimertinib standard (80mg) dose. Further studies on CNS osimertinib pharmacokinetics are needed to test this hypothesis.

No abstract

Background Osimertinib is selective for both EGFR-TKI sensitizing and Thr790Met mutations. While intracranial activity of osimertinib is documented in larger trials, a prospective study focusing exclusively on patients with asymptomatic brain metastases has not been reported. Methods In this nonrandomized, phase II, open label, 3-arm prospective proof-of-concept pilot study, 48 patients with metastatic EGFR-mutant lung adenocarcinoma (LUAD) received osimertinib 80 mg daily. Patients were either treatment naïve (arm A=20) or previously treated with an EGFR-TKI and Thr790Met-positive (arm B=18) or negative (arm C=10). In cases of isolated intracranial progression, osimertinib dose was escalated (160 mg). The primary endpoints were intracranial objective response rate (iORR) and intracranial disease control rate (iDCR). The secondary endpoint was intracranial progression free survival (iPFS). This study is registered at Clinicaltrials.gov, NCT02736513. Results The iORR’s were 84.2%, 66.7% and 50% and the iDCR’s were 94.7%, 94.4% and 80% in arms A, B and C, respectively. The median iPFS was 11.8 months (95% CI 7.7-NA), 7.6 (95% CI 5.3-NA) and 6.3 months (95% CI 3.9-NA) in arms A, B and C, respectively. Following dose escalation, pooled iORR was 54% (arm A=5, arm B=4, arm C=2). Adverse events were similar to those in previously published literature. Conclusion Osimertinib demonstrated high efficacy on brain metastases. All trial arms displayed a significant decrease in the number and diameter of target lesions. These findings indicate that osimertinib is effective for Thr790Met-positive and negative LUAD patients with asymptomatic brain metastases. Therefore, osimertinib should be considered a viable option for EGFR-mutant patients with brain involvement regardless of their Thr790Met mutation status.

While immune checkpoint inhibitors (ICIs) have transformed standards of care and drastically improved patient prognoses in several malignant diseases, a range of immune related adverse events (irAEs) from ICIs have been observed. This case series describes the clinical course of three patients with unusual immune checkpoint-inhibitor (ICI) induced toxicities. These three patients developed carpal tunnel syndrome (CTS) while on ICI therapy. The first patient was a 79 year-old male who received neo-adjuvant chemo-immunotherapy and adjuvant immunotherapy (atezolizumab) for stage II-B lung adenocarcinoma, the second patient was a 70 year-old female who received immunotherapy only (nivolumab) for stage IV renal cell carcinoma and the third patient was a 71 year-old male who received adjuvant immunotherapy (nivolumab) for stage 2-A melanoma. The patients developed carpal tunnel syndrome with severe neuropathy as a result of therapy. All patients had complete symptomatic relief when treated with either corticosteroids or intravenous immunoglobulins for CTS.