Phase II study of durvalumab (MEDI 4736) plus carboplatin and etoposide in elderly patients with extensive stage small cell lung cancer: Study protocol of turtle study (LOGIK 2003).

BACKGROUND: Recently, the addition of antiprogrammed cell death-ligand 1 (PD-L1) monoclonal antibodies, including durvalumab and atezolizumab to platinum-based chemotherapy, has demonstrated clinical benefits in patients with untreated advanced small cell lung cancer (SCLC). However, these clinical trials comprised small populations of elderly patients with SCLC. Therefore, the safety of anti-PD-L1 immunotherapy plus platinum and etoposide in elderly patients remains unclear. METHODS: This prospective, multicenter, single-arm study was designed to evaluate the safety and efficacy of durvalumab plus carboplatin and etoposide in untreated elderly patients (aged > 75) with extensive stage (ES) SCLC. A total of 40 patients were recruited. Patients received up to four cycles of durvalumab 1500 mg and carboplatin at a dose equivalent to an area under the curve of 5 on day 1, and etoposide 80 mg/m2 on days 1 to 3 every 3 weeks as induction treatment, followed by durvalumab maintenance treatment every 4 weeks. The primary endpoint was safety as measured by adverse events according to the Common Terminology Criteria for Adverse Events version 5.0, laboratory analyses, vital signs, and physical examination. Key secondary endpoints were objective response rate, median progression-free survival, 12-month overall survival rate, and the completion rate for four cycles of induction chemotherapy. DISCUSSION: The present study was designed to evaluate the safety of durvalumab plus carboplatin and etoposide in elderly patients with ES-SCLC.

Histologic transformation of epidermal growth factor receptor-mutated lung cancer.

PURPOSE: This study aimed to determine the incidence and clinical course of epidermal growth factor receptor (EGFR)-mutated lung cancer with histologic transformation (HT). PATIENTS AND METHODS: We conducted a multicentre, retrospective, cohort study of patients with advanced EGFR-mutated lung cancer who received EGFR-tyrosine kinase inhibitors (TKIs) between 2012 and 2019. The primary outcome was the incidence of HT. The secondary outcome was treatment efficacy in patients with HT. RESULTS: In total, 6356 patients were enrolled. In 2624 patients, the histological type was proven by rebiopsy after acquiring resistance to EGFR-TKIs. Among them, 74 patients had HT (incidence rate: 2.8% [95% confidence interval: 2.3%-3.5%]). The median progression-free survival after EGFR-TKIs and first-line therapy after confirming HT was 10.4 and 4.4 months, respectively, which was not significantly different between patients with transformation to high-grade neuroendocrine carcinoma and those with transformation to another subtype of non-small cell lung cancer. Overall survival after confirming HT was 12.2 months. Twenty-seven patients received immune checkpoint inhibitors: 6 and 21 received immune checkpoint inhibitors before and after confirming HT, respectively. No patients achieved 1-year progression-free survival. The median progression-free survival after immune checkpoint inhibitor therapy after confirming HT was 1.6 months. CONCLUSION: HT occurred in approximately 3% of EGFR-mutated patients who developed resistance to EGFR-TKIs. Cytotoxic agents are likely to be effective in patients with HT. However, the therapeutic effectiveness of immune checkpoint inhibitors was limited in these patients. Given the rarity of HT and absence of prospective trials, our findings are important to inform the treatment of these patients.

Clinical phenotypes from fatal cases of acute respiratory distress syndrome caused by pneumonia.

There have been no report of objective clinical characteristics or prognostic factors that predict fatal outcome of acute respiratory distress syndrome (ARDS) since the Berlin definition was published. The aim of this study is to identify clinically available predictors that distinguish between two phenotypes of fatal ARDS due to pneumonia. In total, 104 cases of Japanese patients with pneumonia-induced ARDS were extracted from our prospectively collected database. Fatal cases were divided into early (< 7 days after diagnosis) and late (≥ 7 days) death groups, and clinical variables and prognostic factors were statistically evaluated. Of the 50 patients who died within 180 days, 18 (36%) and 32 (64%) were in the early (median 2 days, IQR [1, 5]) and late (median 16 days, IQR [13, 29]) death groups, respectively. According to multivariate regression analyses, the APACHE II score (HR 1.25, 95%CI 1.12-1.39, p < 0.001) and the disseminated intravascular coagulation score (HR 1.54, 95%CI 1.15-2.04, p = 0.003) were independent prognostic factors for early death. In contrast, late death was associated with high-resolution computed tomography (HRCT) score indicating early fibroproliferation (HR 1.28, 95%CI 1.13-1.42, p < 0.001) as well as the disseminated intravascular coagulation score (HR 1.24, 95%CI 1.01-1.52, p = 0.039). The extent of fibroproliferation on HRCT, and the APACHE II scores along with coagulation abnormalities, should be considered for use in predictive enrichment and personalized medicine for patients with ARDS due to pneumonia.

Clinical outcomes and predictive value of programmed cell death-ligand 1 expression in response to anti-programmed cell death 1/ligand 1 antibodies in non-small cell lung cancer patients with performance status 2 or greater.

BACKGROUND: Anti-programmed cell death protein-1/ligand-1 (anti-PD-1/PD-L1) therapy is promising for patients with non-small-cell lung cancer (NSCLC); however, clinical trials have focused on patients with a performance status (PS) 0 or 1. This study aimed to evaluate the clinical outcomes and correlation between PD-L1 expression status and tumor response to anti-PD-1/PD-L1 therapy among NSCLC patients with poor PS (i.e., PS ≥ 2). METHODS: In total, 130 patients with NSCLC and PS ≥ 2 treated with anti-PD-1/PD-L1 monotherapy at 12 institutions between January 2016 and August 2019 were retrospectively reviewed. PD-L1 expression status was divided into four groups: < 1%, 1-49%, ≥ 50%, and unknown. RESULTS: The objective response rate and PS improvement rate were 23 and 21% and were higher in the PD-L1 ≥ 50% group than in other groups (P < 0.01). Median progression-free survival (PFS) was 62 days and was longer in the PD-L1 ≥ 50% group than in other groups (P = 0.03). Multivariate analyses revealed that PD-L1 expression is significantly associated with prolonged PFS (PD-L1 < 1%; reference; 1-49%, hazard ratio [HR] 0.19, 95% confidence interval [CI] 0.04-0.99, P = 0.05; ≥ 50%, HR 0.12, 95% CI 0.02-0.71, P = 0.02; unknown, HR 0.30, 95% CI 0.08-1.22, P = 0.09). CONCLUSIONS: NSCLC patients with poor PS and PD-L1 ≥ 50% are expected to benefit from anti-PD-1/PD-L1 therapy, despite a modest overall response among NSCLC patients with poor PS. Accordingly, PD-L1 expression provides useful information regarding decision-making for anti-PD-1/PD-L1 therapy even in these populations.

The effects of switching EGFR-TKI treatments for non-small cell lung cancer because of adverse events.

BACKGROUND: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are used to treat patients with non-small cell lung cancer (NSCLC) and EGFR driver mutations. Although some patients discontinued these treatments because of adverse events, it is unclear whether switching EGFR-TKI because of adverse events provides a benefit. METHODS: This retrospective study evaluated data from 22 patients with EGFR mutation-positive NSCLC who received at least two EGFR-TKIs that were switched because of adverse events (March 2011 to September 2017). Progression-free survival 2 (PFS2) was defined as the time from starting of the first EGFR-TKI treatment to disease progression during the second EGFR-TKI treatment. RESULTS: Seventeen patients received gefitinib as the first EGFR-TKI treatment, while four patients received afatinib and one patient received erlotinib. The median time to failure of the first EGFR-TKI treatment was 1.6 months. The EGFR-TKIs were switched because of hepatotoxicity (n = 16), interstitial lung disease (n = 3), and other reasons (n = 3). The median washout period was 1.1 months. Seventeen patients received erlotinib as the second EGFR-TKI treatment, while three patients received gefitinib and two patients received afatinib. The median PFS for the second EGFR-TKI treatment was 15.2 months. The median PFS2 was 17.7 months and the median overall survival was 32.8 months. CONCLUSIONS: Switching EGFR-TKIs because of adverse events provided a clinical benefit for patients with EGFR mutation-positive NSCLC. Appropriate judgment regarding switching from one EGFR-TKI to another may improve the performance status and prognosis of patients with EGFR mutation-positive NSCLC.

Comparisons between tumor burden and other prognostic factors that influence survival of patients with non-small cell lung cancer treated with immune checkpoint inhibitors.

BACKGROUND: The use of baseline tumor burden (TB) as a prognostic factor for non-small cell lung cancer (NSCLC) patients treated with immune checkpoint inhibitors (ICIs) and associations between TB and other prognostic biomarkers remain unclear. In this study, we investigated the association between TB and survival in NSCLC patients treated with ICIs in comparison with other biomarkers. METHODS: We retrospectively evaluated 83 NSCLC patients with ICIs administered between February 2016 and December 2018. TB was measured as the sum of the unidimensional diameters of up to five target lesions. RESULTS: The median observation period was 14.2 months. A total of 42 patients died during the follow-up. Univariate Cox regression analysis showed that baseline TB was associated with OS. Cox regression analysis adjusted for Eastern Cooperative Oncology Group performance status (ECOG PS) alone or with addition of programmed cell death ligand 1 expression and treatment line showed that TB was a prognostic factor for OS. Using time-dependent receiver operating characteristic curve analysis, the optimal TB cutoff for predicting OS was 12 cm, and patients were divided into a high TB group (n = 21) and a low TB group (n = 62). The low TB group achieved significantly longer OS than the high TB group (median OS: 18.5 months, [95% CI = 11.7-not reached] vs. 2.3 months [95% CI = 1.3-2.9], P < 0.001). CONCLUSION: TB is a useful, clinically measurable prognostic factor of survival in NSCLC patients treated with ICIs.

The association between tumor burden and severe immune-related adverse events in non-small cell lung cancer patients responding to immune-checkpoint inhibitor treatment.

OBJECTIVES: The use of immune checkpoint inhibitors (ICIs) for advanced non-small cell lung cancer (NSCLC) has demonstrated survival benefits, although some treatment responders (defined as patients with non-progressive disease) are forced to discontinue treatment because of severe immune-related adverse events (irAEs). An association between treatment efficacy and irAEs has been reported. However, it is unclear which treatment responders are likely to develop severe irAEs. We aimed to examine risk factors for ICI-related severe irAEs in patients with NSCLC. MATERIALS AND METHODS: Between February 2016 and October 2018, we retrospectively evaluated 42 patients with NSCLC at our institution who responded to ICI treatment. Tumor burden was measured as the sum of the unidimensional diameters of up to five target lesions, according to the Response Evaluation Criteria in Solid Tumors version 1.1. RESULTS: ICIs were discontinued in 15 of 42 treatment responders because of severe irAEs. Tumor burden was a significant independent predictor of severe irAEs (p = 0.03). The odds ratio of severe irAEs and tumor burden over 90 mm was 8.62 (95% confidence interval = 1.96-37.9, p = 0.004). CONCLUSION: A high tumor burden was a risk factor for severe irAEs in patients with NSCLC who responded to ICI treatment.

Upfront Cranial Radiotherapy Followed by Erlotinib Positively Affects Clinical Outcomes of Epidermal Growth Factor Receptor-mutant Non-small Cell Lung Cancer With Brain Metastases.

BACKGROUND/AIM: The optimal treatment strategy for epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) patients with brain metastasis (BM) has not yet been fully determined. The aim of this study was to investigate the optimal management of EGFR-mutant NSCLC patients with BM. PATIENTS AND METHODS: A multicenter retrospective study was performed on the clinical outcomes of 81 advanced/recurrent EGFR-mutant NSCLC patients with BM treated with EGFR-tyrosine kinase inhibitors (EGFR-TKIs) (gefitinib n=52 or erlotinib n=29). RESULTS: Among the 81 patients, 30 patients received upfront cranial radiotherapy (CRT) and 51 did not. The multivariate cox analyses revealed that the use of erlotinib and upfront CRT were independent predictive factors for overall survival (OS) (erlotinib: HR 0.21; 95% CI, 0.10-0.48; p<0.001; upfront CRT: HR 0.42; 95% CI, 0.20-0.88; p=0.022). CONCLUSION: Erlotinib and upfront CRT were associated with a favorable prognosis among EGFR-mutant NSCLC patients with BM. Upfront CRT followed by erlotinib may be an appropriate initial management approach for EGFR-mutant NSCLC patients with BM.

Efficacy of azithromycin in sepsis-associated acute respiratory distress syndrome: a retrospective study and propensity score analysis.

PURPOSE: Acute respiratory distress syndrome is a life-threatening form of respiratory failure without an established pharmacological treatment. Recently, macrolides have been found to be beneficial in cases of acute lung injury, but evidence is limited. MATERIALS AND METHODS: This single-centre retrospective cohort evaluation of hospitalized patients with sepsis-associated acute respiratory distress syndrome aimed to assess the impact of azithromycin on clinical outcomes by using a propensity score analysis. All data were collected prospectively as part of ongoing research on high-resolution computed tomography of acute respiratory distress syndrome. The primary outcome was 60-day mortality; the secondary outcome was the number of ventilator-free days. RESULTS: Twenty-nine of 125 patients with sepsis-associated acute respiratory distress syndrome (23.2 %) received azithromycin within 24 h after acute respiratory distress syndrome diagnosis. After adjusting for potentially confounding covariates, azithromycin use was associated with lower 60-day mortality (hazard ratio, 0.31; 95 % confidence interval, 0.11-082; P = 0.02) and a shorter time to successful discontinuation of mechanical ventilation. CONCLUSIONS: Azithromycin use was associated with decreased mortality and ventilator dependency in patients with sepsis-associated acute respiratory distress syndrome. Further well-designed prospective studies are needed.

Erlotinib plus bevacizumab as an effective treatment for leptomeningeal metastases from EGFR mutation-positive non-small cell lung cancer.

Leptomeningeal metastasis is a severe complication of non-small cell lung cancer. Its prognosis is very poor and conventional treatments have limited efficacy. However, epidermal growth factor receptor-tyrosine kinase inhibitors have exhibited high response rates in EGFR mutation-positive lung cancer patients with central nervous system metastases. It has been postulated that this could be due to the penetration of agents into the central nervous system and a high cerebrospinal fluid concentration is a key consideration in measuring treatment effect. Bevacizumab has also been used as an effective therapeutic agent in patients with central nervous system metastases. However, the efficacy of epidermal growth factor receptor-tyrosine kinase inhibitor doublet therapy for leptomeningeal metastases and the cerebrospinal fluid penetration of epidermal growth factor receptor-tyrosine kinase inhibitors have yet to be determined. Moreover, the safety of this doublet regimen in patients with a poor general condition is not known. Herein, we report on a case treated with erlotinib plus bevacizumab for leptomeningeal metastases from EGFR mutation-positive non-small cell lung cancer. The patient's performance status significantly improved and the cerebrospinal fluid penetration rate of erlotinib plus bevacizumab was equal to or greater than the past reports of erlotinib alone.