Rechallenge of afatinib for EGFR-mutated non-small cell lung cancer previously treated with osimertinib: a multicenter phase II trial protocol (REAL study).

Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of advanced non-small cell lung cancer (NSCLC) and contributed to the development of precision medicine. Osimertinib is a standard first-line (1L) treatment for EGFR-mutated NSCLC and has demonstrated superior survival benefits over previous-generation TKIs. However, resistance to osimertinib is nearly inevitable, and subsequent treatment strategies remain unmet medical needs in this setting. Afatinib, a second-generation EGFR-TKI, exhibits activity against certain uncommon EGFR mutation types in the 1L setting. There are a few case reports on the efficacy of afatinib against EGFR-dependent resistance after osimertinib treatment, although these have not been prospectively investigated. Methods: The present phase II, single-arm multicenter trial aims to verify the efficacy and safety of afatinib rechallenge after 1L osimertinib resistance. Patients (aged ≥20 years) with advanced or recurrent non-squamous NSCLC harboring drug-sensitive EGFR mutations (deletion of exon 19 or L858R) who were previously treated with 1L osimertinib and second-line chemotherapy other than TKIs are considered eligible. Undergoing next-generation sequence-based comprehensive genomic profiling is one of the key inclusion criteria. The primary endpoint is the objective response rate; the secondary endpoints are progression-free survival, overall survival, and tolerability. Thirty patients will be recruited in December 2023. Discussion: The results of this study may promote incorporating afatinib rechallenge into the treatment sequence after 1L osimertinib resistance, a setting in which concrete evidence has not been yet established. Registration: UMIN Clinical Trial Registry: UMIN000049225.

Predictive value of post-treatment C-reactive protein-to-albumin ratio in locally advanced non-small cell lung cancer patients receiving durvalumab after chemoradiotherapy.

BACKGROUNDS: The PACIFIC trial established durvalumab consolidation therapy after concurrent chemoradiotherapy (CCRT) as the standard treatment for locally advanced non-small cell lung cancer (LA-NSCLC). However, little is known about the predictive factors of durvalumab efficacy in this population. This study aimed to validate the predictive use of inflammation-related parameters in patients with LA-NSCLC treated with CCRT plus durvalumab. METHODS: We recruited 76 LA-NSCLC patients who received CCRT followed by durvalumab from 10 Japanese institutions. The neutrophil-to-lymphocyte ratio (NLR), C-reactive protein-to-albumin ratio (CAR), and prognostic nutrition index (PNI) were measured before (pre-treatment) and 2 months after (post-treatment) durvalumab induction. Cox proportional hazards analysis was used to examine prognostic factors associated with progression-free survival (PFS) after durvalumab therapy. RESULTS: The median follow-up time was 17 (range, 3.3-35.8) months. The median PFS and overall survival (OS) times were 26.1 and 33.7 months, respectively. Durvalumab was discontinued in 47 (61.8%) patients, with non-infectious pneumonitis being the most common reason. Post-treatment CAR (cutoff, 0.2) was a significant stratifying factor in survival comparison (<0.2 vs. ≥ 0.2, median PFS, not-reached vs. 9.6 months. Log-rank, p = 0.002). Multivariate analysis with a Cox proportional hazards model showed that post-treatment CAR was an independent prognostic factor for PFS (hazard ratio, 3.16, p = 0.003). CONCLUSIONS: This study suggests that post-treatment CAR has predictive value for LA-NSCLC patients treated with CCRT plus durvalumab consolidation therapy.

Current status of first-line treatment with pembrolizumab for non-small-cell lung cancer with high PD-L1 expression.

It is not clear whether pembrolizumab monotherapy (MONO) or pembrolizumab plus platinum-based chemotherapy (COMB) should be selected for patients with advanced non-small-cell lung cancer (NSCLC) exhibiting high PD-L1 expression (tumor proportion score ≥ 50%). We performed a retrospective, multicenter study of 300 patients with NSCLC exhibiting high PD-L1 expression who received MONO or COMB as first-line treatment between December 2018 and January 2020. We reviewed the medical records of all consecutive patients with no driver mutations, and assessed the patient characteristics, therapeutic regimens, treatment periods, and adverse events. In total, 166 (55%; median age: 74 years) and 134 (45%; median age: 68 years) patients received MONO and COMB, respectively. Patients were younger and had better performance status (0-1) in the COMB group (p < 0.01). With a median follow-up time of 10.6 (range: 0.1-20.6) months, the median progression-free survival was 7.1 months with MONO and 13.1 months with COMB. The objective response rate was 42.2% with MONO and 67.9% with COMB. With respect to treatment discontinuation, 36 out of 166 (21.7%) and 28 out of 134 (20.1%) patients discontinued MONO and COMB, respectively. In conclusion, COMB may be a promising option for first-line treatment for NSCLC with high PD-L1 expression and good performance status.

Blood urea nitrogen-to-serum albumin ratio and A-DROP are useful in assessing the severity of Pneumocystis pneumonia in patients without human immunodeficiency virus infection.

INTRODUCTION: There is an increasing incidence of Pneumocystis pneumonia (PcP) among individuals without human immunodeficiency virus (HIV) infection (non-HIV PcP). However, prognostic factors for patients with non-HIV PcP have not been identified. Moreover, A-DROP (for classifying the severity of community-acquired pneumonia) or the blood urea nitrogen-to-serum albumin ratio (BUN/Alb), which is reported to be a predictor of mortality of community-acquired pneumonia, has not been established as an efficient prognostic factor in patients with non-HIV PcP. In this study, we analyzed the prognostic factors for non-HIV PcP and evaluated the prognostic ability of A-DROP and the BUN/Alb ratio. METHODS: This retrospective study involved a chart review of the medical records of 102 patients diagnosed with non-HIV PcP between January 2003 and May 2019 at five medical facilities. RESULTS: Overall, 102 patients were involved in this study. The 30-day mortality rate for non-HIV PcP was 20.5% in this study population. Compared with survivors, non-survivors had significantly lower serum albumin levels and significantly higher age, corticosteroid dosage at the PcP onset, alveolar-arterial oxygen gradient, A-DROP score, lactate dehydrogenase levels, blood urea nitrogen levels, and BUN/Alb ratio. Multivariate analysis showed that a high BUN/Alb ratio at treatment initiation was significantly associated with 30-day mortality risk. The receiver operating characteristic curves showed that A-DROP score had the highest prognostic ability in estimating 30-day mortality. CONCLUSIONS: In patients with non-HIV PcP, a high BUN/Alb ratio is an independent prognostic predictor of mortality risk, and A-DROP is useful for classifying the severity.

Clinical analysis of EGFR-positive non-small cell lung cancer patients treated with first-line afatinib: A Nagano Lung Cancer Research Group.

BACKGROUND: In the LUX-Lung 3 and LUX-Lung 6 trials, afatinib improved overall survival in previously untreated patients with EGFR 19del mutated non-small cell lung cancer (NSCLC) compared to chemotherapy. The appropriate management of adverse events and dose reduction of afatinib are important for EGFR-positive NSCLC patients. We conducted a retrospective and observational study of patients treated with first-line afatinib for EGFR-positive NSCLC in Nagano prefecture, Japan, focusing on efficacy and toxicities. METHODS: We retrospectively collected the medical records of NSCLC patients initially treated with afatinib between May 2014 and March 2018. RESULTS: A total of 62 patients with a median age of 67 years and a median body surface area (BSA) of 1.57 m2 were included. The overall response rate was 87.7% and median progression-free survival (PFS) was 15.7 months. The median PFS was similar between standard initial dose (40 mg) and reduced initial doses (30 and 20 mg) (15.7 vs. 14.2 months; P = 0.978). The frequency of dose reduction and the discontinuation rate in the 40 mg daily dose group was higher in patients with BSA < 1.58 m2 (100%) compared to BSA ≥ 1.58 m2 (68.2%) (P = 0.014). The frequency of diarrhea was higher in patients with BSA < 1.58 m2 (93.5%) compared to BSA ≥ 1.58 m2 (71.0%) (P = 0.02). CONCLUSION: In real-world clinical practice, first-line afatinib was well managed and was equally as effective as in previous clinical trials of EGFR-positive NSCLC. BSA is considered a predictive marker for appropriate afatinib dose reduction.

Phase II study of cisplatin/pemetrexed combined with bevacizumab followed by pemetrexed/bevacizumab maintenance therapy in patients with EGFR-wild advanced non-squamous non-small cell lung cancer.

PURPOSE: This phase II study was performed to evaluate the efficacy and safety of cisplatin/pemetrexed combined with 15 mg/kg of bevacizumab followed by pemetrexed/bevacizumab maintenance therapy as first-line chemotherapy in advanced non-squamous non-small cell lung cancer (NSCLC) limited to epidermal growth factor receptor (EGFR)-wild type. PATIENTS AND METHODS: Fifty patients with advanced or metastatic EGFR-wild type NSCLC aged < 75 years old were enrolled in the study. The patients were treated with four cycles of cisplatin (75 mg/m2, day 1), pemetrexed (500 mg/m2, days 1), and bevacizumab (15 mg/kg, day 1), every 3 weeks, followed by pemetrexed plus bevacizumab maintenance until progression for achieving a response over stable disease after induction chemotherapy. RESULTS: Partial response and stable disease were observed in 35 (objective response rate: 70, 95% CI: 55.4-82.1%) and 9 patients, respectively, and 39 (78%) patients received pemetrexed plus bevacizumab maintenance therapy. Median progression-free survival and overall survival periods were 12.0 months (95% CI: 7.5-16.5 months) and 31.0 months (95% CI: 22.2-39.8 months), respectively. Grade 3 adverse events included neutropenia (14%), nausea (10%), anorexia (18%), and hypertension (8%). Coagulation disorder was observed in one patient, but all of these events were reversible and resulted in no treatment-related deaths. CONCLUSION: The combination of cisplatin/pemetrexed/bevacizumab followed by pemetrexed/bevacizumab maintenance therapy exhibited favorable efficacy and manageable toxicity profiles in patients with EGFR-wild type non-squamous NSCLC (UMIN-CTR number: UMIN000003645).

Clinical analysis of patients treated with afatinib for advanced non-small cell lung cancer: A Nagano Lung Cancer Research Group observational study.

BACKGROUND: Afatinib has been available in Japan for the treatment of epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) since May 2014. We conducted an observational study in patients treated with afatinib in Nagano prefecture, focusing on response and associated toxicities. METHODS: We analyzed the clinical records of NSCLC patients treated with afatinib between May 2014 and February 2015. RESULTS: The records of a total of 73 patients (27 men, 46 women) with a median age of 69 years (range: 42-85 years) were analyzed. Afatinib was administered to 11 patients as a first-line therapy, but it was predominantly administered as a fifth-line or beyond therapy (32 cases, 43.8%). The overall response rates for afatinib as a first-line therapy and beyond second-line therapy were 80% (95% confidence interval [CI]: 55.2-100.0%) and 27.1% (95% CI: 14.5-39.7%), respectively. The main toxicities grade >3 included diarrhea (8.2%), skin rash (6.8%), nausea (6.8%), and appetite loss (6.8%). A low body surface area (BSA) (<1.5m2) was significantly associated with a higher frequency of diarrhea grade >2, compared with a higher BSA (≥ 1.5m2). Forty-eight patients (63.0%) were treated without a dose reduction of afatinib. CONCLUSIONS: Although the survival benefit with afatinib remains unclear, our observational analysis demonstrated the feasibility of using afatinib for EGFR-mutated NSCLC in clinical practice. In particular, a relatively high level of drug delivery is possible. In addition, a lower BSA may be a predictor of diarrhea in patients treated with afatinib.

Phase I/II study of S-1 combined with biweekly irinotecan chemotherapy in previously treated advanced non-small cell lung cancer.

PURPOSE: This phase I/II study was designed to evaluate a combination of irinotecan and S-1 a new regimen for salvage chemotherapy in patients with advanced or metastatic non-small cell lung cancer (NSCLC). METHODS: The study group comprised patients with advanced or metastatic NSCLC who had previously received at least one platinum-containing chemotherapy. Patients received irinotecan on days 1, 15 and oral S-1 (40 mg/m(2) twice daily as a fixed dose) on day 1 to 14 of a 28-day cycle. RESULTS: In the phase I part, irinotecan was given in escalating doses of 70 (Level 1), 80 (Level 2), and 90 mg/m(2) (Level 3). Three of the 5 patients given Level 3 had dose-limiting toxicity, and Level 2 (80 mg/m(2) of irinotecan) was designated as the recommended dose. In phase II, 38 patients received a median of 7.4 cycles of irinotecan at the recommended dose. The overall response rate was 15.8 % (90 % confidence interval (CI): 6.1-25.5 %), and the median progression-free and overall survival times were 4.5 months (95 % CI: 3.5-5.0) and 15.0 months (95 % CI: 9.5-20.6) months, respectively. Toxicity was generally mild. Grade 3 or higher toxicity included neutropenia in 17.9 % of the patients, thrombocytopenia in 5.1 % and nausea in 7.7 %. CONCLUSION: Combination chemotherapy with S-1 and irinotecan was considered an effective salvage regimen in patients with advanced or metastatic NSCLC.

Silica-associated systemic lupus erythematosus in an elderly man.

The predominantly young woman-orientated systemic lupus erythematosus (SLE) is a disease that involves an extremely complicated and multifactorial interaction of various genetic and environmental factors. Crystalline silica (Si) may act as an immunoadjuvant to increase secretions of inflammatory endogenous substances and antibody production. In addition, previous studies have suggested that exposure to Si may induce SLE. Although the biologic mechanism of Si in SLE is unclear, defective apoptosis leading to the prolonged survival of pathogenic lymphocytes was thought to be one of mechanisms of Si-associated SLE (sSLE). In the present study, a rare case of an elderly man suffering from sSLE responded well to glucocorticoid therapy. The present findings were reviewed with reference to previous literature.

Effects of bronchodilators on dynamic hyperinflation following hyperventilation in patients with COPD.

BACKGROUND AND OBJECTIVE: The present study was performed to examine the occurrence of dynamic hyperinflation following hyperventilation in COPD patients and former smokers without COPD, and the efficacy of short-acting anticholinergic agents (SAAC) and beta2-agonists (SABA) for lung hyperinflation following metronome-paced hyperventilation in COPD. METHODS: Fifty-nine patients with COPD, 20 ex-smokers without COPD and 20 healthy subjects who had never smoked were examined for dynamic hyperinflation by metronome-paced hyperventilation with respiratory rate increasing from 20 to 30 and 40 tidal breaths/min. Dynamic hyperinflation was evaluated as the decrease in inspiratory capacity (IC) following hyperventilation, and the effects of SAAC and SABA on dynamic hyperinflation were assessed. RESULTS: COPD patients showed a significant increase in end-expiratory lung volume and a decrease in IC following hyperventilation, and ex-smokers without COPD also showed mild but significant dynamic hyperinflation. Multiple stepwise linear regression analysis revealed that the carbon monoxide transfer coefficient (DLco/VA) and RV/TLC were significant and independent determinants of dynamic hyperinflation in COPD. Treatment with SAAC and SABA significantly increased IC at each respiratory rate, independently of the increases in FEV1. Furthermore, SABA significantly inhibited the decrease in IC due to hyperventilation. CONCLUSIONS: These findings suggest that lung hyperinflation following hyperventilation may be a useful method for detecting dynamic hyperinflation observed not only in patients with COPD but also in ex-smokers without COPD, and both SAAC and SABA are effective in reducing dynamic hyperinflation in COPD.

Reduced lung uptake of iodine-123 metaiodobenzylguanidine in patients with myeloperoxidase antineutrophil cytoplasmic antibodies-positive vasculitis.

BACKGROUND: Iodine-123 metaiodobenzylguanidine ((123)I-MIBG) lung uptake in the early phase has been proposed as a potential marker of endothelial function because MIBG behaves qualitatively similarly to norepinephrine in pulmonary circulation. OBJECTIVES: The purpose of the present study was to examine the lung uptake of (123)I-MIBG in patients diagnosed with myeloperoxidase antineutrophil cytoplasmic antibodies (MPO-ANCA)-associated vasculitis without clinical or radiological abnormalities of the thorax. METHODS: Six patients with MPO-ANCA-associated vasculitis were enrolled. They had severe renal damage (mean creatinine: 5.1 mg/dl, mean blood urea nitrogen: 54.6 mg/dl), but no respiratory symptoms clinically or radiographic findings on chest computed tomography. The total lung to upper mediastinum ratio of (123)I-MIBG uptake (L/M) 15 min after the injection was measured. The result was compared with those for 6 patients with renal damage due to other diseases (mean creatinine: 6.2 mg/dl, blood urea nitrogen: 51.7 mg/dl) and for 8 healthy subjects. RESULTS: The mean value of L/M in patients with MPO-ANCA-positive vasculitis was 1.21 +/- 0.04, which was significantly less than that of other groups (1.41 +/- 0.06 for patients with renal failure and 1.45 +/- 0.03 for normal volunteers). There were no significant differences in MIBG accumulation in the heart among the groups. CONCLUSIONS: The reduction in kinetic behavior of MIBG in the lung reflects the presence of pulmonary endothelial impairment in patients with MPO-ANCA-associated vasculitis, even though there are no clinical manifestations in the lungs.

Phase I trial of bi-weekly paclitaxel and gemcitabine as second-line therapy for patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy.

A phase I study was conducted to evaluate the maximum tolerated dose, feasibility, and efficacy of bi-weekly-administered paclitaxel and gemcitabine in patients with non-small-cell lung cancer (NSCLC) who had previously been treated with platinum-based chemotherapy. In a dose-escalation study, 18 patients, under 75 yr old, with unresectable NSCLC that had relapsed or was resistant after platinum-containing chemotherapy with performance status of 0-2 were enrolled. Patients were treated with paclitaxel and gemcitabine bi-weekly. The dose escalation levels of paclitaxel (mg/m2) at a fixed dose of gemcitabine 1000 mg/m2 were 110 (level 1), 130 (level 2), 150 (level 3), and 170 (level 4), respectively. All patients were eligible for evaluation of toxicities. At level 4, one patient developed an infection with grade 3 neutropenia and two other patients developed severe neurotoxicity (over grade 3). Thus, the recommended dose for phase II was paclitaxel 150 mg/m2 and gemcitabine 1000 mg/m2 due to dose-limiting toxicities including neutropenia and peripheral neurotoxicity. Partial response was seen in 4 cases of the 18 assessable patients, with an overall response of 22%. Bi-weekly paclitaxel and gemcitabine is feasible and appears to be an efficacious combination chemotherapy as second-line chemotherapy in refractory and recurrent patients with NSCLC who had been previously exposed to platinum-containing chemotherapy.

Thymic squamous cell carcinoma producing parathyroid hormone-related protein and CYFRA 21-1.

A 54-year-old man was admitted to our hospital because of dyspnea. Radiographic examination showed an anterior mediastinal mass and pericardial effusion. Serum calcium and parathyroid hormone-related protein (PTHrP) levels were elevated, and serum CYFRA 21-1 level was extremely high. Results of percutaneous needle biopsy under computed tomography guidance led to a diagnosis of moderately differentiated squamous cell carcinoma. Immunohistological staining showed the tumor cells to be positive for PTHrP and cytokeratin monoclonal antibodies. Postmortem findings were considered to indicate thymic carcinoma. Thymic carcinoma is rare, but our case indicates that thymic squamous cell carcinoma can be identified in terms of paraneoplastic hypercalcemia.