Summary
Background
Immune-related hepatotoxicity is often regarded as immune-related hepatitis (irHepatitis) despite including immune-related sclerosing cholangitis (irSC). This study examined the ...clinical differences between irSC and irHepatitis.
Methods
A single-center retrospective study of 530 consecutive patients who received immunotherapy between August 2014 and April 2020 was performed. IrSC and irHepatitis were respectively defined as the radiological presence and absence of bile duct dilation and wall thickness.
Results
Forty-one patients (7.7%) developed immune-related hepatotoxicity. A CT scan was performed on 12 patients, including 11 of 12 with ≥ grade 3 aminotransferase elevations. IrSC and irHepatitis were diagnosed in 4 (0.8%) and 8 (1.5%) patients, respectively. All the irSC patients had been treated with anti-PD-1. IrHepatitis was more common among patients receiving anti-CTLA-4 than among those receiving anti-PD-1/PD-L1 inhibitors (14%, 7/50 vs. 0.2%, 1/480,
P
< 0.001). A ≥ grade 2 alkaline phosphatase (ALP) elevation resulting in a cholestatic pattern was seen in all 4 irSC patients. Among the irSC patients, 3 (3/4, 75%) developed ≥ grade 3 aminotransferases elevation. The median duration from the start of immunotherapy until ≥ grade 2 liver enzymes elevation was 257 and 55.5 days in irSC and irHepatitis patients. The median times for progression from grade 2 to 3 liver enzyme elevation were 17.5 and 0 days, respectively.
Conclusions
IrSC and irHepatitis have different characteristics in the class of immune checkpoint inhibitor and onset pattern. Radiological examination for the diagnosis of irSC should be considered for patients with ≥ grade 2 ALP elevation resulting in a cholestatic pattern. (Registration number J2020-36, Date of registration June 3, 2020)
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CEKLJ, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Circulating tumor cells (CTCs) are a tumor‐derived material utilized for liquid‐based biopsy; however, capturing rare CTCs for further molecular analysis remains technically challenging, especially ...in non‐small‐cell lung cancer. Here, we report the results of a clinical evaluation of On‐chip Sort, a disposable microfluidic chip‐based cell sorter, for capture and molecular analysis of CTCs from patients with lung adenocarcinoma. Peripheral blood was collected from 30 metastatic lung adenocarcinoma patients to enumerate CTCs using both On‐chip Sort and CellSearch in a blind manner. Captured cells by On‐chip Sort were subjected to further molecular analysis. Peripheral blood samples were also used for detection of EGFR mutations in plasma using droplet digital PCR. Significantly more CTCs were detected by On‐chip Sort (22/30; median 5; range, 0–18 cells/5 mL blood) than by CellSearch (9/30; median, 0; range, 0–12 cells/7.5 mL) (P < 0.01). Thirteen of 30 patients who had a negative CTC count by CellSearch had a positive CTC count by On‐chip Sort. EGFR mutations in CTCs captured by On‐chip Sort were observed in 40.0% (8/20) of patients with EGFR‐mutated primary tumor. EGFR mutations were often observed in 53.3% (8/15) of patients detected in plasma DNA. Expressions of EGFR and vimentin protein on CTCs were also successfully assessed using On‐chip Sort. These results suggest that On‐chip Sort is an efficient method to detect and capture rare CTCs from patients with lung adenocarcinoma that are undetectable with CellSearch. Mutation detection using isolated CTCs remains to be further tackled (UMIN000012488).
CTC analysis by a microfluidic chip cell sorter.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Although third‐generation epidermal growth factor receptor‐tyrosine kinase inhibitors (EGFR‐TKI) can overcome T790M‐mediated resistance in non‐small‐cell lung cancer (NSCLC), rebiopsy to confirm ...T790M status is occasionally difficult. We aimed to investigate the current tendency and the limitations of rebiopsy in clinical practice. This study included 139 consecutive NSCLC patients with EGFR mutations, who had experienced progressive disease (PD) after EGFR‐TKI treatment. We retrospectively reviewed patient characteristics, tumor progression sites and rebiopsy procedures. Of 120 patients (out of the original 139) who were eligible for clinical trials, 75 (63%) underwent rebiopsy for 30 pleural effusions, 32 thoracic lesions, four bone, two liver, and seven at other sites. Rebiopsy procedures included 30 thoracocentesis, 24 transbronchial biopsies, 13 computed tomography (CT)‐guided needle biopsies and 8 other procedures. Of the 75 rebiopsied patients, 71 (95%) were pathologically diagnosed with malignancy; and 34 (45%) had available tissue samples for EGFR analyses. Of the 75 biopsied patients, 61 (81%) were analyzed for EGFR mutation, using tissue or cytology samples; T790M mutations were identified in 20 (33%) of the 61 patients. Of the 120 patients, 45 (38%) did not undergo rebiopsy, because of inaccessible tumor sites (n = 19), patient refusal (n = 6) or decision of physician (n = 10). In conclusion, among patients with EGFR mutations who had PD after EGFR‐TKI treatment, 63% underwent rebiopsy. Most rebiopsy samples were diagnosed with malignancy. However, tissue samples were less available and T790M mutations were identified less frequently than in previous studies. Skill and experience with rebiopsy and noninvasive alternative methods will be increasingly important.
Rebiopsy for detecting acquired EGFR T790 M mutations can be challenging for both patients and physicians. We aimed to investigate factors that keep patients from undergoing rebiopsies, and other issues in these procedures and their outcomes.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Summary
Introduction
Durvalumab has been shown to confer a survival benefit after definitive chemoradiotherapy in the patients with locally advanced non-small cell lung cancer, but no studies have ...attempted to identify risk factors for pneumonitis after durvalumab therapy. The purpose of this study was to investigate associations between clinical and radiation dose-volume factors, and the severity of pneumonitis.
Methods
We retrospectively assessed the cases of 30 patients who had been started on durvalumab therapy between July 2018 and February 2019. In this study we evaluated the percentage of lung volume receiving radiation dose in excess of 20 Gy (V20) as radiation dose-volume factor. We compared V20 and some baseline factors between a grade 0 or 1 (Gr 0/1) pneumonitis group and a grade 2 or more (≥Gr 2) pneumonitis group, and we performed a logistic regression analysis to establish the associations between variables and ≥ Gr 2 pneumonitis.
Results
Pneumonitis had developed in 22 patients (73.3%): Gr 1/2/3–5 in 8 (26.7%)/14 (46.7%) /0 (0%), respectively. The difference in V20 between the Gr 0/1 group and Gr 2 group (median: 20.5% vs. 23.5%,
p
= 0.505) was not statistically significant, and thus V20 was not a risk factor for Gr 2 pneumonitis (odds ratio: 1.047,
p
= 0.303). None of the clinical factors, including sex, age, smoking history, presence of baseline pneumonitis, type of radiation therapy, location of lesion and facility, were risk factors.
Conclusions
Our study suggest that the severity of pneumonitis after durvalumab is unrelated to V20 or any of the clinical factors assessed in this study.
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CEKLJ, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Background The ALTA-1L study compared brigatinib with crizotinib in untreated ALK-rearranged non-small cell lung cancer (NSCLC) patients, demonstrating the efficacy of brigatinib. Although the median ...progression-free survival (PFS) of brigatinib group was 24.0 months, the one-year PFS rate was 70%. In the NEJ009 study, patients with EGFR mutations showed improved outcomes with gefitinib plus chemotherapy compared with gefitinib monotherapy. To evaluate the efficacy of the combination of brigatinib with chemotherapy for patients with ALK-rearranged NSCLC, we designed B-DASH study (WJOG 14720L). Methods B-DASH study is a multicenter, two-arm, phase II study. Eligible patients have untreated stage IIIB, stage IIIC, stage IV, or postoperative relapse ALK-rearranged nonsquamous NSCLC. Patients will be randomized in a 1:1 ratio to receive brigatinib (180 mg once daily with a 7-day lead-in period at 90 mg) monotherapy or carboplatin (area under the curve = 5 on day 1) plus pemetrexed (500 mg/m.sup.2 on day 1) and brigatinib in a 3-week cycle for up to four cycles, followed by pemetrexed and brigatinib as maintenance therapy. The target hazard ratio of 0.62 is set based on the NEJ009 study. With one-sided alpha = 0.20 and power = 0.8, the sample size for the B-DASH study was calculated to be 110, considering the possibility of patients dropping out. The primary endpoint is PFS. The key secondary endpoints are the overall response rate and overall survival. We will evaluate tumor-derived DNA from plasma specimens before treatment, 42 days after administering the study drug, and on the day of progressive disease. Recruitment began in November 2021 and is ongoing. Discussion The efficacy of combination therapy with tyrosine kinase inhibitors and cytotoxic chemotherapy was demonstrated in patients with EGFR mutations but remains unclear in patients with ALK-rearranged NSCLC. The B-DASH study is the only trial of brigatinib combined with chemotherapy in patients with untreated ALK-rearranged NSCLC. Trial registration jRCT identifier: jRCTs041210103. Keywords: Non-small cell lung cancer, ALK, Brigatinib, Pemetrexed, Chemotherapy
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Purpose
Programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors plus chemotherapy have become the standard first line of treatment in patients with advanced non-small-cell lung ...cancer (NSCLC). However, few studies have explicitly focused on the impact of weight loss on the efficacy of PD-1/PD-L1 inhibitors plus chemotherapy. Thus, we evaluated the clinical implications of weight loss on the survival outcomes in patients who received this treatment.
Methods
We conducted a retrospective review of medical records of patients with advanced NSCLC who were treated with PD-1/PD-L1 inhibitors plus chemotherapy from December 2018 to December 2020. Significant weight loss was defined as an unintentional weight loss of 5% or more over 6 months. We evaluated the progression-free survival (PFS) and overall survival (OS) of patients with or without weight loss.
Results
Among the 80 included patients, 37 (46%) had weight loss, and were associated with a lower objective response rate (30 vs 51%,
P
< 0.05), poorer PFS (2.3 vs 12.0 months,
P
< 0.05), and poorer OS (10.8 vs 23.9 months,
P
< 0.05) than those without weight loss. The Cox proportional-hazard ratios (95% confidence interval) of weight loss were 1.77 (1.01–3.10) for PFS and 2.90 (1.40–6.00) for OS, with adjustments for Eastern Cooperative Oncology Group performance status, PD-L1 tumour proportion score, histology, and central nervous system metastases.
Conclusion
Pre-treatment weight loss may reduce treatment efficacy and shorten survival time in patients receiving PD-1/PD-L1 inhibitors plus chemotherapy. Early evaluation and intervention for weight loss might improve oncological outcomes in patients with advanced NSCLC.
The efficacy of second-line chemotherapy in patients with pulmonary large cell neuroendocrine carcinoma (LCNEC) is unclear. This study aimed to evaluate the efficacy of second-line chemotherapy in ...patients with pulmonary LCNEC. We retrospectively reviewed patients with pulmonary LCNEC or possible LCNEC (pLCNEC) who received platinum-based chemotherapy as the first-line treatment. Among these patients, we evaluated the efficacy of second-line treatment by comparing patients with small cell lung cancer (SCLC group). Of the 61 patients with LCNEC or pLCNEC (LCNEC group) who received first-line chemotherapy, 39 patients were treated with second-line chemotherapy. Among the 39 patients, 61.5% received amrubicin monotherapy. The median progression-free survival (PFS) and overall survival (OS) in the LCNEC groups were 3.3 and 8.3 months, respectively. No significant differences in the PFS (hazard ratio HR: 0.924, 95% confidence interval CI 0.647-1.320; P = 0.664) and OS (HR: 0.926; 95% CI 0.648-1.321; P = 0.670) were observed between the LCNEC and SCLC groups. In patients treated with amrubicin, the PFS (P = 0.964) and OS (P = 0.544) were not different between both the groups. Second-line chemotherapy, including amrubicin, may be considered as a treatment option for patients with pulmonary LCNEC.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Summary
Osimertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that has exhibited efficacy in patients with EGFR-mutant non-small cell lung cancer ...(NSCLC). Interstitial lung disease (ILD) is a fatal adverse event of osimertinib treatment, and it requires treatment discontinuation. There are few reports regarding the safety and efficacy of osimertinib re-challenge in patients who experienced osimertinib-induced ILD. This retrospective study assessed this treatment option. We retrospectively collected data for patients treated with osimertinib who developed ILD at Shizuoka Cancer Center from April 2016 to March 2020. ILD was diagnosed by two doctors based on imaging tests and blood tests to exclude other causes. Among 215 patients treated with osimertinib, 28 developed ILD. The median age of patients with ILD was 69.5 years (range, 39.0–80.0). In addition, 29% of patients were men, and 46% had a history of smoking. Eleven patients were re-administered EGFR TKIs, including eight patients treated with osimertinib and three patients treated with alternative EGFR TKIs. Among patients re-challenged with osimertinib, none who previously experienced grade 1 ILD exhibited ILD relapse, even with the same osimertinib dose and without the concurrent administration of systemic steroids. Meanwhile, one of the four patients who previously exhibited grade 2 ILD experienced despite a dose reduction for osimertinib and systemic steroid administration. For patients with EGFR-mutant NSCLC who experience grade 1 ILD during osimertinib therapy, osimertinib re-challenge may be suitable when no other treatments are available.
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CEKLJ, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Management of leptomeningeal metastasis-related hydrocephalus (LM-H) is particularly challenging regarding the control of severe headache, nausea, and vomiting due to intracranial hypertension. To ...investigate the improvements of performance status and outcome with cerebrospinal fluid (CSF) shunt surgery for LM-H in patients with lung adenocarcinoma.
Data on patients with leptomeningeal metastasis-related hydrocephalus from lung adenocarcinoma diagnosed by MR imaging and/or cytological examination were retrospectively analyzed. Between August 2008 and July 2017, the authors reviewed 31 patients requiring CSF shunt, who underwent ventriculo-peritoneal or lumbo-peritoneal shunt.
The patients consisted of 11 men and 20 women with a median age of 59 years. Twenty-six patients received EGFR-tyrosine kinase inhibitors (TKIs). CSF shunt surgery yielded rapid improvement in the performance status of 90.3% of patients. Median overall survival from the diagnosis of LM in patients with ECOG performance status less than 2 was 7.7 months, and this was significantly longer than those in patients with PS 3 or 4 (4.4 or 1.5 months; p<0.001). Multivariate analysis by Cox regression revealed survival differences according to PS at diagnosis of LM PS 1-3 vs. PS4, hazard ratio (HR) 0.201, p = 0.034, controlled extracranial disease (HR 0.248, p = 0.005), and post-shunt EGFR-TKI for LM treatment (HR 0.193, p = 0.008). Postoperative symptomatic peritoneal carcinomatosis was observed in one patient (3.2%).
CSF shunting may be a safe and effective strategy in patients with LM-H from lung adenocarcinoma. A prospective study is needed to establish the effectiveness and safety of palliative CSF shunt for LM-H.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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