Real-world use of osimertinib for epidermal growth factor receptor T790M-positive non-small cell lung cancer in Japan.

OBJECTIVE: Adverse drug reactions (ADRs) during real-world osimertinib use were investigated in Japan. METHODS: Patients with epidermal growth factor receptor (EGFR) T790M-positive non-small cell lung cancer treated with second-line or later oral osimertinib per the Japanese package insert (80 mg once daily) were included. Data were collected between 28 March 2016 and 31 August 2018. RESULTS: The median observation period in the safety analysis population (n = 3578) was 343.0 days. ADRs (defined as adverse events whose causality to osimertinib could not be denied by the attending physicians or manufacturer) were reported in 58.1% (2079/3578) of patients. ADRs of interstitial lung disease events were reported in 6.8% (245/3578; Grade ≥ 3, 2.9% [104/3578]) of patients, of whom 29 (11.8%) died (0.8% of patients overall). ADRs of QT interval prolonged, liver disorder and haematotoxicity were reported in 1.3% (45/3578; Grade ≥ 3, 0.1% [5/3578]), 5.9% (212/3578; Grade ≥ 3, 1.0% [35/3578]) and 11.4% (409/3578; Grade ≥ 3, 2.9% [104/3578]) of patients, respectively. In the efficacy analysis population (n = 3563), 119 (3.3%) patients had complete responses, 2373 (66.6%) had partial responses and 598 (16.8%) had stable disease. The objective response rate was 69.9%; disease control rate was 86.7%; and median progression-free survival (PFS) was 12.3 months. At 6 and 12 months, PFS rates were 77.4% (95% confidence interval [CI], 75.9-78.9) and 53.2% (95% CI, 51.3-55.1) and overall survival rates were 88.3% (95% CI, 87.2-89.4) and 75.4% (95% CI, 73.8-77.0), respectively. CONCLUSIONS: These data support the currently established benefit-risk assessment of osimertinib in this patient population.

Real-World Evaluation of Factors for Interstitial Lung Disease Incidence and Radiologic Characteristics in Patients With EGFR T790M-positive NSCLC Treated With Osimertinib in Japan.

INTRODUCTION: Using real-world Japanese postmarketing data, we characterized interstitial lung disease (ILD) development during the second- or later-line osimertinib treatment for EGFR mutation-positive NSCLC. Retrospective radiologic image evaluation of patients developing ILD was also performed. METHODS: Patients who had ILD events reported as an adverse drug reaction by their physicians and who were assessed as having developed ILD as assessed by an ILD expert committee in Japan were included. RESULTS: Among 3578 patients, 252 ILD events were reported in 245 patients (6.8%) by their attending physicians. The median (range) time to the first onset of ILD after osimertinib treatment initiation was 63.0 (5-410) days, and 29 patients with a fatal outcome were reported. The ILD expert committee assessed 231 of 3578 patients (6.5%) as having ILD. A previous history of nivolumab therapy (adjusted OR: 2.84; 95% confidence interval: 1.98-4.07) and a history or concurrence of ILD (3.51; 2.10-5.87) were identified as factors potentially associated with ILD onset during osimertinib treatment. In patients who had received a previous nivolumab treatment, the number and proportion of patients developing ILD were highest for patients who discontinued nivolumab treatment within the first month before initiating osimertinib; trends for decreasing incidence and proportion were observed, with an increasing duration between the end of nivolumab treatment and the initiation of osimertinib treatment. CONCLUSIONS: The frequency of ILD was consistent with the known osimertinib safety profile in the Japanese population. A history or concurrence of ILD and history of previous nivolumab therapy are factors potentially associated with ILD onset during osimertinib treatment.

Gastroesophageal reflux related to respiratory inhibition after crying and feeding hypoxemia in infants.

OBJECTIVE: To determine the relationships between gastroesophageal reflux (GER) and both respiratory inhibition after crying (RIAC) and feeding hypoxemia in infants. METHODS: We screened for RIAC and feeding hypoxemia among infants with a gestational age of 36 weeks or greater using pulse oximetry. We investigated the infants who showed hypoxemia with a decrease in SpO2 to less than 70% and bradycardia with a heart rate of less than 100 beats per minute caused by GER. We then evaluated the relationships between these events and both RIAC and feeding hypoxemia. RESULTS: We examined 250 infants in the present study. RIAC and feeding hypoxemia were observed in 35 (14.0%), and 30 (12.0%) infants, respectively. Ten infants showed hypoxemia and bradycardia caused by GER. These events were correlated with RIAC (p = 0.006) and feeding hypoxemia (p = 0.031). CONCLUSIONS: In the infants with RIAC and feeding hypoxemia, some show severe hypoxemia and bradycardia caused by GER. Medical staff caring for infants should note the presence of RIAC and feeding hypoxemia.

Respiratory inhibition after crying and feeding hypoxemia in infants.

OBJECTIVE: To determine the incidence, risk factors and natural history of respiratory inhibition after crying (RIAC) and feeding hypoxemia. METHODS: We screened for RIAC and feeding hypoxemia among 393 infants with a gestational age ≥ 36 weeks using pulse oximetry. Twenty-seven infants were treated in the neonatal intensive care unit. RESULTS: RIAC and feeding hypoxemia were observed in 95 (24.2%) and 124 (31.6%) infants, respectively. RIAC correlated with feeding hypoxemia (p < 0.001), grade II increased echogenicity in the ganglionic eminence (p = 0.005), dilation of the lateral ventricle (p = 0.044), threatened premature labor (p = 0.033) and twin gestation (p = 0.089). Feeding hypoxemia correlated with RIAC (p < 0.001), abnormal cranial ultrasound findings (p < 0.001), maternal smoking during pregnancy (p = 0.083), asymmetric intrauterine growth restriction (p = 0.012) and twin gestation (p = 0.067). All infants recovered from RIAC in an average of 4.5 (2.0-7.0) d. Fifteen infants recovered from feeding hypoxemia, but 10 infants needed additional assistance and monitoring by nursing until the day of discharge. The day of discharge was day 8.0 (5.0-12.4). CONCLUSIONS: RIAC and feeding hypoxemia are observed among healthy infants, and these infants experience repeated events of prolonged hypoxemia.