Long-term experience with tepotinib in Japanese patients with MET exon 14 skipping NSCLC from the Phase II VISION study.

Tepotinib is a highly selective MET tyrosine kinase inhibitor (TKI) that has demonstrated robust and durable clinical activity in patients with MET exon 14 (METex14) skipping non-small-cell lung cancer (NSCLC). In the Phase II VISION study, patients received oral tepotinib 500 mg once daily. The primary endpoint was an objective response by an independent review committee (IRC) according to RECIST v1.1 criteria. The secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Here we report the analysis of the efficacy and safety of tepotinib in all Japanese patients with advanced METex14 skipping NSCLC from VISION (n = 38) with >18 months' follow-up. The median age of the Japanese patients was 73 years (range 63-88), 39.5% of patients were ≥75 years old, 68.4% were male, 55.3% had a history of smoking, 76.3% had adenocarcinoma, and 10.5% of patients had known brain metastases at baseline. Overall, the objective response rate (ORR) was 60.5% (95% confidence interval (CI): 43.4, 76.0) with a median DOR of 18.5 months (95% CI: 8.3, not estimable). ORR in treatment-naïve patients (n = 18) was 77.8% (95% CI: 52.4, 93.6), and in patients aged ≥75 years (n = 15), ORR was 73.3% (95% CI: 44.9, 92.2). The most common treatment-related adverse event (AE) with any grade was blood creatinine increase (65.8%), which resolved following tepotinib discontinuation. Other common treatment-related AEs were peripheral edema (60.5%), hypoalbuminemia (34.2%), diarrhea (28.9%), and nausea (15.8%). In summary, tepotinib demonstrated robust and durable clinical activity irrespective of age or therapy line, with a manageable safety profile in Japanese patients with METex14 skipping NSCLC enrolled in VISION.

EGFR inhibition in EGFR-mutant lung cancer cells perturbs innate immune signaling pathways in the tumor microenvironment.

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) elicit potent cell cycle arrest in EGFR-mutant non-small-cell lung cancer (NSCLC) cells. However, little is known about the mechanisms through which these drugs alter the tumor phenotype that contributes to the immune escape of EGFR-mutant cells. Using EGFR-mutant NSCLC cell lines and tissue samples from patients, we investigated the changes in immune checkpoints expressed in tumor cells following EGFR inhibition. Subsequently, we also analyzed the role of soluble factors from the dying tumor cells in the activation of immune signaling pathways involved in therapy resistance. Upon EGFR-TKI treatment, we found that EGFR-mutant cells upregulated the expression of innate immune checkpoint CD24 in vitro. We then analyzed biopsy samples from six patients who developed resistance to a first-generation EGFR-TKI without the acquired T790M mutation. Immunohistochemistry revealed that levels of tumor CD24 expression were increased upon treatment compared with those from pre-treatment samples. Monocyte-derived macrophages facilitated antibody-dependent cellular phagocytosis when EGFR-TKI-treated EGFR-mutant cells were incubated with anti-CD24 antibodies in vitro, suggesting that CD24 may be a therapeutical target for EGFR-mutant lung cancer. Moreover, EGFR inhibition accelerated the release of cell-free DNA (cfDNA) from dying tumor cells, which activated the type I interferon signaling pathways in human THP-1 monocytes in a stimulator of interferon genes-dependent manner. Our study indicates that EGFR inhibition in EGFR-mutant NSCLC cells fosters a tumor microenvironment associated with immune escape. Thus, CD24 targeted therapy and cfDNA monitoring may contribute to improved treatment outcomes in patients with EGFR-mutant NSCLC.

Notch pathway regulates osimertinib drug-tolerant persistence in EGFR-mutated non-small-cell lung cancer.

Osimertinib is a third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) that has shown marked antitumor activity in patients with EGFR-mutated non-small-cell lung cancer (NSCLC). However, these effects are transient and most patients develop resistance. Reversible drug-tolerant persister (DTP) cells are defined as a small subpopulation of cells with markedly reduced sensitivity and non-genetic acquired resistance to EGFR-TKIs. Notch is a transmembrane receptor that plays an important role in tumorigenesis. We previously reported that there is significant crosstalk between the Notch and EGFR pathways in NSCLC. Moreover, the Notch pathway is associated with resistance to previous-generation EGFR-TKIs. However, the role of Notch in osimertinib resistance is not fully understood. In this study, we evaluated whether Notch is involved in osimertinib resistance. We show that NOTCH1 and Notch target genes are upregulated in osimertinib DTP cells, and that the addition of a γ-secretase inhibitor (GSI), a Notch inhibitor, impairs drug-tolerant persistence in vitro and in vivo. Compared with osimertinib, combined GSI and osimertinib suppress phospho-ERK partly by enhancing DUSP1 expression. Furthermore, Notch1 and HES1 were upregulated after EGFR-TKI treatment in half of human EGFR-mutated NSCLC tumor tissues. These results suggest that the combination of GSI and osimertinib may be a potential therapy for EGFR-mutated NSCLC.

Efficacy of antacids for cisplatin-induced gastrointestinal symptoms in the treatment of lung cancer.

OBJECTIVE: Chemotherapy-induced nausea and vomiting (CINV) and chemotherapy-associated dyspepsia syndrome (CADS) are frequently appearing adverse effects of cisplatin (CDDP)-containing chemotherapy. Antiemetic guidelines suggest that the administration of antacids such as proton pump inhibitors (PPIs) or histamine type-2 receptor antagonists be considered for CADS, although their efficacy for treating these symptoms remains unknown. This study aimed to reveal whether antacids attenuate gastrointestinal symptoms in CDDP-containing chemotherapy. MATERIALS AND METHODS: In total, 138 patients with lung cancer who received ≥ 75 mg/m2 CDDP-containing regimens were enrolled in this retrospective study. Patients were divided into an antacid group including patients administered PPIs or vonoprazan during all chemotherapy periods and controls without antacid administration. The primary endpoint was the comparison of anorexia incidence during the first cycle of chemotherapy. Secondary endpoints were CINV evaluation and risk factor analysis for the incidence of anorexia using logistic regression analysis. RESULTS: The incidence of anorexia during the first cycle was 54.4% in the control group and 60.3% in the antacid group, without significant differences (p = 0.60). The incidence of nausea was also similar between the groups (p = 1.00). Multivariate analysis suggested that antacid administration was not associated with anorexia. CONCLUSION: Baseline antacid administration does not affect gastrointestinal symptoms associated with CDDP-containing treatment in lung cancer.

Effects of obesity on CC16 and their potential role in overweight/obese asthma.

INTRODUCTION: Club cell secretory protein-16 (CC16) is a major anti-inflammatory protein expressed in the airway; however, the potential role of CC16 on overweight/obese asthma has not been assessed. In this study, we examined whether obesity reduces airway/circulatory CC16 levels using experimental and epidemiological studies. Then, we explored the mediatory role of CC16 in the relationship of overweight/obesity with clinical asthma measures. METHODS: Circulating CC16 levels were assessed by ELISA in three independent human populations, including two groups of healthy and general populations and asthma patients. The percentage of cells expressing club markers in obese vs. non-obese mice and human airways was determined by immunohistochemistry. A causal mediation analysis was conducted to determine whether circulatory CC16 acted as a mediator between overweight/obesity and clinical asthma measures. RESULTS: BMI was significantly and monotonously associated with reduced circulating CC16 levels in all populations. The percentage of CC16-expressing cells was reduced in the small airways of both mice and humans with obesity. Finally, mediation analysis revealed significant contributions of circulatory CC16 in the association between BMI and clinical asthma measures; 21.8% of its total effect in BMI's association with airway hyperresponsiveness of healthy subjects (p = 0.09), 26.4% with asthma severity (p = 0.030), and 23% with the required dose of inhaled corticosteroid (p = 0.042). In logistic regression analysis, 1-SD decrease in serum CC16 levels of asthma patients was associated with 87% increased odds for high dose ICS requirement (p < 0.001). CONCLUSIONS: We demonstrate that airway/circulating CC16, which is inversely associated with BMI, may mediate development and severity in overweight/obese asthma.

Evaluation of risk factors associated with carboplatin and nab-paclitaxel treatment suspension in patients with non-small cell lung cancer.

PURPOSE: Carboplatin (CBDCA) + nanoparticle albumin-bound paclitaxel (nab-PTX) is one of the most effective chemotherapeutic regimens for advanced non-small cell lung cancer (NSCLC) treatment. However, neutropenia and neuropathy are well-known dose-limiting toxicities associated with this regimen, frequently resulting in treatment suspension and dose reduction. In the present study, we aimed to identify risk factors associated with CBDCA + nab-PTX treatment suspension. METHODS: Patients with NSCLC who received CBDCA + nab-PTX ± atezolizumab or pembrolizumab regimens were retrospectively evaluated. The risk factor(s) for treatment suspension and primary causes underlying suspension during the first course were assessed; the relative dose intensity (RDI) was compared between patients with and without identified factors. RESULTS: The frequency of treatment suspension was determined as 55%. The causes for suspension were neutropenia (65.2%), infection (24.2%), thrombocytopenia (6.1%), and other conditions. The calculated RDI was 98.5% for CBDCA and 79.3% for nab-PTX. Based on univariate and multivariate analyses, grade 1 or higher liver dysfunction was identified as a risk factor for treatment suspension. We determined primary causes for treatment suspension as neutropenia and/or infection, as they are closely related. Next, we evaluated associated factors and determined age ≥65 years and performance status (PS) 2 as potential factors, in addition to liver dysfunction. CONCLUSION: We observed that liver dysfunction at baseline is a risk factor for treatment suspension. In addition, age ≥65 years and PS 2 can result in treatment suspension owing to neutropenia and/or infection during CBDCA + nab-PTX treatment.

Risk of bleeding associated with transbronchial biopsy using flexible bronchoscopy in patients with echocardiographic or chest CT evidence of pulmonary hypertension.

BACKGROUND: Endobronchial ultrasound (EBUS)-guided transbronchial biopsy (TBB) facilitates the diagnosis of various respiratory diseases. The safety of performing EBUS-guided TBB in patients with a finding of pulmonary hypertension (PH) is controversial. Little is known about the relationship between the risk of bleeding associated with EBUS-guided TBB in the presence of PH suspected on echocardiography or chest CT. METHODS: To assess the risk of bleeding associated with EBUS-guided TBB in patients with presumed PH per echocardiography or chest CT, we retrospectively reviewed the medical records of 314 consecutive patients who underwent EBUS-guided TBB using a guide sheath (GS), as well as echocardiography and chest CT. Bleeding complication was defined as over one minute of suctioning; repeated wedging of the bronchoscope; instillation of cold saline, diluted vasoactive substances, or thrombin due to persistent bleeding. Findings of suspected PH were defined as peak tricuspid regurgitation velocity (TRV) > 2.8 m/s on echocardiography or pulmonary artery to aorta ratio (PA:A ratio) > 0.9 on chest CT. RESULTS: In total, 35 (11.1%) patients developed bleeding, and all cases were managed safely. Furthermore, 17 (5.4%) and 59 (18.8%) patients were suspected to have PH based on echocardiography and chest CT, respectively. Among the patients suspected to have PH on echocardiography, five (5/17 = 29.4%) patients developed bleeding. Among the patients suspected to have PH on chest CT, 11 (11/59 = 18.6%) patients developed bleeding. Univariate analysis revealed that long diameter (≥ 30 mm) of the lesion, lesion location (the biopsy site was inner than the segmental bronchus), bronchoscopic diagnosis of malignancy, and additional biopsy were potential predictive factors for bleeding. The finding of suspected PH on echocardiography correlated significantly with bleeding (p = 0.03). On multivariate analysis, long diameter (≥ 30 mm) of the lesion (p = .021) and findings of suspected PH on echocardiography (p = .049) were significantly associated with bleeding. CONCLUSION: All cases of bleeding in the present study were managed safely. The risk of bleeding is moderately elevated when PH is suspected by echocardiography in patients undergoing EBUS-guided TBB using a GS.

Impact of histamine type-2 receptor antagonists on the anticancer efficacy of gefitinib in patients with non-small cell lung cancer.

PURPOSE: Gefitinib is one of the standard treatments for non-small cell lung cancer (NSCLC) with epidermal growth factor receptor mutations. It has been reported that acid suppressants (AS) decrease the anti-tumor effect of gefitinib by reducing its solubility. AS is sometimes necessary in cancer patients; however, previous reports have not shown the most compatible AS with gefitinib administration in cancer patients. This study was conducted to determine if histamine type 2 receptor antagonists (H2RAs) can affect the anti-tumor efficacy of gefitinib. METHODS: Eighty-seven patients with NSCLC who were administered gefitinib were retrospectively investigated. Patients who were co-administered H2RA were compared with non-AS control patients. H2RA was administered once a day at about 3-5 or 8-12 h after gefitinib intake. The primary endpoint of this study was progression-free survival (PFS), and secondary endpoints were overall survival (OS), overall response rate (ORR), and adverse effects. RESULTS: Median PFS in H2RA group and control group was 8.0 months and 9.0 months, respectively, with no significant difference (p = 0.82). The incidence of liver dysfunction was significantly less in patients administered H2RA, whereas there were no differences between the two groups with regard to skin toxicity and diarrhea. Multivariate analysis suggested that H2RA co-administration is not a risk factor for worse PFS and OS (hazard ratio of 0.95, 0.86; 95% confidence interval of 0.60-1.48, 0.52-1.43; p = 0.82 and 0.60, respectively). CONCLUSION: This study demonstrated that concomitant administration of H2RA with gefitinib does not affect the efficacy of gefitinib.

Tepotinib in patients with NSCLC harbouring MET exon 14 skipping: Japanese subset analysis from the Phase II VISION study.

BACKGROUND: MET exon 14 skipping is an oncogenic driver occurring in 3-4% of non-small cell lung cancer (NSCLC). The MET inhibitor tepotinib has demonstrated clinical efficacy in patients with MET exon 14 skipping NSCLC. Here, we present data from Japanese patients in the Phase II VISION study, evaluating the efficacy and safety of tepotinib. METHODS: In the open-label, single-arm, Phase II VISION study, patients with advanced/metastatic NSCLC with MET exon 14 skipping received oral tepotinib 500 mg once daily. The primary endpoint was objective response by independent review. Subgroup analyses of Japanese patients were preplanned. RESULTS: As of 1 January 2020, 19 Japanese patients received tepotinib and were evaluated for safety, 15 of whom had ≥9 months' follow-up and were also analysed for efficacy. By independent review, objective response rate (ORR) was 60.0% (95% confidence interval [CI]: 32.3, 83.7), median duration of response was not reached (95% CI: 6.9, not estimable [ne]), and progression-free survival was 11.0 months (95% CI: 1.4, ne). ORR in patients with MET exon 14 skipping identified by liquid biopsy (n = 8) was 87.5% (95% CI: 47.3, 99.7), and by tissue biopsy (n = 12) was 50.0% (95% CI: 21.1, 78.9). Patients' quality of life was maintained with tepotinib treatment. Among patients evaluated for safety, the most common treatment-related adverse events (any grade) were blood creatinine increase and peripheral oedema (12 and nine patients, respectively). CONCLUSIONS: Tepotinib demonstrated robust and durable clinical efficacy in Japanese patients with advanced NSCLC harbouring MET exon 14 skipping, identified by either liquid or tissue biopsy. The main adverse events, blood creatinine increase and peripheral oedema, were manageable.

A case of immune checkpoint inhibitor-associated gastroenteritis detected by ultrasonography.

While immune checkpoint inhibitors (ICIs) have antitumor effects, they also have characteristic side effects, including colitis. However, gastritis has rarely been reported. We report a case of a patient with lung adenocarcinoma who presented with epigastric pain and diarrhea following pembrolizumab administration. Sonography of the abdomen demonstrated diffuse, although mild, gastric wall thickening (mainly in the submucosa), as well as a slight decrease in echogenicity throughout the gastric wall. While the mucosal surface was relatively smooth, color Doppler examination showed increased vascularity. Esophagogastroduodenoscopy and pathological examination confirmed the diagnosis of ICI-related gastroenteritis.

Efficacy of additional dexamethasone administration for the attenuation of paclitaxel-associated acute pain syndrome.

PURPOSE: Paclitaxel-associated acute pain syndrome (P-APS) affects 80% of patients undergoing therapy. Although it has been shown that prednisone administration for 5 days relieves P-APS, detailed results have not been reported thus far. Therefore, in this study, we evaluated the preventive effect of dexamethasone (DEX) administration against P-APS. METHODS: A total of 60 patients who received carboplatin (area under the curve; AUC = 5-6) plus paclitaxel (200 mg/m2) (plus bevacizumab 15 mg/kg, if non-squamous carcinoma of lung) were enrolled. Eight milligrams of DEX was orally administered on days 2 and 3 to the DEX group patients, and the frequency, severity, duration of P-APS, and other adverse effects in the first cycle were retrospectively evaluated and compared to those observed in control group patients, who were not administered DEX on days 2 and 3. RESULTS: No difference in terms of patient characteristics, except for type of cancer, was observed between groups. The results showed that the frequency of all grade P-APS was approximately 70% and there was no difference between groups. Frequency of ≥ G2 P-APS was 40% in the control group and 14% in the DEX group, demonstrating a significant reduction. Duration of P-APS was 5.8 days in the control group and 4.3 days in the DEX group, which tended to become shorter following additional DEX administration, although this was not significant. Adverse effects other than P-APS induced by chemotherapy were similar between the two groups. CONCLUSION: Additional DEX administration is safe and useful for the attenuation of the severity of P-APS.

Virtual bronchoscopic navigation without X-ray fluoroscopy to diagnose peripheral pulmonary lesions: a randomized trial.

BACKGROUND: Transbronchial biopsy for peripheral pulmonary lesions is generally performed under X-ray fluoroscopy. Virtual bronchoscopic navigation (VBN) is a method in which virtual images of the bronchial route to the lesion are produced based on CT images obtained before VBN, and the bronchoscope is guided using these virtual images, improving the diagnostic yield of peripheral pulmonary lesions. VBN has the possibility of eliminating the need for X-ray fluoroscopy in the bronchoscopic diagnosis of peripheral lesions. To determine whether VBN can be a substitute for X-ray fluoroscopy, a randomized multicenter trial (non-inferiority trial) was performed in VBN and X-ray fluoroscopy (XRF) -assisted groups. METHODS: The non-inferiority margin in the VBN-assisted group compared with the XRF-assisted group was set at 15%. The subjects consisted of 140 patients with peripheral pulmonary lesions with a mean diameter > 3 cm. In the VBN-assisted group, the bronchoscope was guided to the lesion using a VBN system without X-ray fluoroscopy. In the XRF-assisted group, the same bronchoscope was guided to the lesion under X-ray fluoroscopy. Subsequently, in both groups, the lesion was visualized using endobronchial ultrasonography with a guide sheath (EBUS/GS), and biopsy was performed. In this serial procedure, X-ray fluoroscopy was not used in the VBNA group. RESULTS: The subjects of analysis consisted of 129 patients. The diagnostic yield was 76.9% (50/65) in the VBN-assisted group and 85.9% (55/64) in the XRF-assisted group. The difference in the diagnostic yield between the two groups was -9.0% (95% confidence interval: -22.3% ~ 4.3%). The non-inferiority of the VBN-assisted group could not be confirmed. The rate of visualizing lesions by EBUS was 95.4% (62/65) in the VBN-assisted group and 96.9% (62/64) in the XRF-assisted group, being high in both groups. CONCLUSIONS: On EBUS/GS, a bronchoscope and biopsy instruments may be guided to the lesions using VBN without X-ray fluoroscopy, but X-ray fluoroscopy is necessary to improve the accuracy of sample collection from lesions. During transbronchial biopsy for peripheral pulmonary lesions, VBN cannot be a substitute for X-ray fluoroscopy. TRIAL REGISTRATION: UMIN-CTR (UMIN000001710); registered 16 February 2009.

Endobronchial ultrasonography with a guide sheath for pure or mixed ground-glass opacity lesions.

BACKGROUND: Ground-glass opacity (GGO) lesions are difficult to diagnose by transbronchial biopsy (TBB). OBJECTIVES: We attempted to diagnose solitary peripheral GGO predominant-type lesions by TBB using endobronchial ultrasonography with a guide sheath (EBUS-GS) under X-ray fluoroscopic guidance, and to evaluate several factors associated with diagnostic yield. METHODS: The medical records of 67 patients with GGO predominant-type lesions who underwent TBB using EBUS-GS under X-ray fluoroscopic guidance were retrospectively reviewed. RESULTS: Of the 67 lesions, 38 (57%) were successfully diagnosed by EBUS-GS (5/11 pure GGO lesions and 33/56 mixed GGO lesions). The diagnosable lesions were significantly larger than the nondiagnosable lesions (24 vs. 17 mm, respectively; p < 0.01). Regarding the diagnostic yield by signs on computed tomography, the lesions with a bronchus leading directly to a lesion had a significantly higher diagnostic yield than the others (p < 0.05). When GGO lesions were confirmed under X-ray fluoroscopic guidance, the diagnostic yield was 79% (vs. 40% in lesions not visible on X-ray fluoroscopy; p < 0.05). CONCLUSIONS: EBUS-GS is a useful and valuable diagnostic modality, even for GGO predominant-type lesions located at the lung periphery.

Virtual bronchoscopic navigation combined with ultrathin bronchoscopy. A randomized clinical trial.

RATIONALE: In bronchoscopy, an ultrathin bronchoscope can be advanced to more peripheral bronchi. Because virtual bronchoscopic navigation (VBN) is a method to guide a bronchoscope under direct observation using VB images, VBN may be particularly useful when combined with ultrathin bronchoscopy. OBJECTIVES: This prospective multicenter study evaluated the value of VBN-assisted ultrathin bronchoscopy for diagnosing peripheral pulmonary lesions. METHODS: We randomly assigned 350 patients with peripheral pulmonary lesions (diameter, ≤30 mm) to VBN-assisted or non-VBN-assisted groups. An ultrathin bronchoscope (outer diameter, 2.8 mm) was introduced to the target bronchus using a VBN system in the VBN-assisted group, whereas only computed tomography axial images were referred to in the non-VBN-assisted group. Specimen sampling sites were verified using X-ray fluoroscopy. MEASUREMENTS AND MAIN RESULTS: Subjects for analysis included 334 patients. There was no significant difference in the diagnostic yield between the VBN-assisted group (67.1%) and the non-VBN-assisted group (59.9%; P = 0.173). The subgroup analysis showed that the diagnostic yield was significantly higher in the VBN-assisted group than in the non-VBN-assisted group for right upper lobe lesions (81.3% vs. 53.2%; P = 0.004); lesions invisible on posterior-anterior radiographs (63.2% vs. 40.5%; P = 0.043); and lesions in the peripheral third of the lung field (64.7% vs. 52.1%; P = 0.047). CONCLUSIONS: VBN-assisted ultrathin bronchoscopy does not improve the diagnostic yield for peripheral pulmonary lesions. However, the method improves the diagnostic yield for lesions in the subcategories (right upper lobe, invisible, peripheral third), warranting further study. Clinical trial registered with www.umin.ac.jp/ctr/ (UMIN 000001536).

Association between skin immune-related adverse events (irAEs) and multisystem irAEs during PD-1/PD-L1 inhibitor monotherapy.

PURPOSE: Patients treated with immune checkpoint inhibitors (ICIs) often develop immune-related adverse events (irAEs) in various organs of the body. However, the patient factors associated with the development of multisystem irAEs are not well known. Skin irAEs most frequently occur and appear early after ICI treatment initiation. They may be a predictive marker for the development of multisystem irAEs, and their occurrence should be evaluated. METHODS: Data of patients receiving ICI monotherapy for lung cancer, melanoma, and head and neck cancer treatment were retrospectively evaluated (n = 207); the single irAE development group (n = 69) was compared with the multisystem irAE development group (n = 37). The primary endpoint was the comparison of the incidence of skin irAEs between the two groups. RESULTS: Skin, thyroid, and hepatic irAEs were associated with the development of multisystem irAEs (odds ratio: 3.30, 95% confidence interval: 1.27-8.52, p = 0.01 for skin; 5.07, 2.09-12.3, p = 0.0003 for thyroid; 10.63, 1.19-94.7, p = 0.03 for hepatic). Skin irAEs were the most common type (65.0% of total participants) and appeared earlier than other irAEs, except for gastrointestinal and ocular irAEs (median time to onset of skin irAEs: 7.5 weeks). Skin irAEs occurred more frequently in the multisystem irAE group (81.0%) than in the single irAE group (56.5%, p = 0.02). CONCLUSION: Skin irAEs can be a useful predictive marker for multisystem irAE development due to ICI treatment. Consequently, patients with skin irAEs should be treated and monitored for other types of irAEs.

The peptide nucleic acid-locked nucleic acid polymerase chain reaction clamp-based test for epidermal growth factor receptor mutations in bronchoscopic cytological specimens of non-small cell lung cancer.

OBJECTIVES: Cytological examination of samples obtained by bronchoscopy is a useful method for establishing the diagnosis of non-small cell lung cancer (NSCLC). However, the utility of a highly sensitive method for the detection of epidermal growth factor receptor (EGFR) mutation in the cytological specimens has not been fully evaluated. METHODS: We retrospectively examined the efficacy of the peptide nucleic acid-locked nucleic acid polymerase chain reaction (PNA-LNA PCR) clamp method for detecting EGFR mutations in 122 bronchoscopic cytological specimens from NSCLC patients. RESULTS: Overall, 41 specimens (33.6%) were positive for EGFR mutation. Twenty-nine (39.7%) of 73 specimens obtained by using endobronchial ultrasonography with a guide sheath, 7 (33.3%) of 21 specimens obtained under direct vision by using a conventional bronchoscope, 4 (36.4%) of 11 specimens obtained by using an ultrathin bronchoscope, and 1 (5.9%) of 17 specimens obtained by endobronchial ultrasound-guided transbronchial needle aspiration were positive for EGFR mutation. Furthermore, among 22 resected NSCLC cases, the EGFR mutation status obtained from bronchoscopic materials was consistent with the status obtained from surgical samples, with the exception of 1 case. CONCLUSION: The detection of EGFR mutation by subjecting bronchoscopic cytological specimens to a PNA-LNA PCR clamp assay proves useful.

Diabetes mellitus degenerates cisplatin-induced nephrotoxicity in short hydration method: a propensity score-matching analysis.

Cisplatin (CDDP)-induced nephrotoxicity (CIN) is dose-limiting. We revealed that co-administration of non-steroid anti-inflammatory drugs and baseline comorbidity of diabetes mellitus (DM) are associated with CIN development in the short hydration method; however, the results were accessorily obtained without appropriate power calculation. This study aimed to demonstrate the influence of DM complications on CIN incidence in a real-world setting. Lung cancer patients receiving CDDP (≥ 75 mg/m2)-containing regimens with a short hydration method (n = 227) were retrospectively evaluated. The patients were divided into control and baseline DM complication groups. The primary endpoint was the evaluation of CIN incidence between the groups. Propensity score-matching was performed to confirm the robustness of the primary analysis results. CIN occurred in 6.8% of control and 27.0% of DM patients, respectively, with a significant difference in all-patient populations (P = 0.001). In addition, variation of serum creatinine and creatinine clearance significantly worsened in DM patients. Similar results were obtained in a propensity-matched population. Multivariate logistic regression analysis found that DM complication is a singular risk factor for CIN development (adjusted odds ratio; 4.31, 95% confidence interval; 1.62-11.50, P = 0.003). In conclusion, our study revealed that baseline DM complications significantly worsen CIN.

Suitability of Oral Rehydration Solution (ORS) for Use in the Cisplatin Short Hydration Method.

BACKGROUND/AIM: Short hydration is a method to change partial intravenous hydration to oral to administer cisplatin (CDDP); however, the most suitable form of oral hydration is unknown. This study aimed to determine whether oral rehydration solution (ORS) affects CDDP-induced nephrotoxicity (CIN) and electrolyte imbalance. PATIENTS AND METHODS: Lung cancer patients (n=200) who had received CDDP-including regimens (CDDP dosage ≥75 mg/m2) were retrospectively evaluated. We used logistic analysis to evaluate whether ORS intake could be a preventive factor for CIN (≥grade 2 serum creatinine elevation). Moreover, incidence of CIN and electrolyte imbalance and the variation in serum creatinine and electrolyte levels were compared between ORS and non-ORS (control) patients. RESULTS: CIN occurred in 9.8% of ORS patients, and 7.5% of non-ORS patients (p=0.79). The variation in serum creatinine level was also similar in both groups. Multivariate analysis suggested that ORS intake does not affect CIN, although CIN was associated with the coadministration of non-steroidal anti-inflammatory drugs and the presence of diabetes mellitus. The variations in serum electrolyte levels did not differ, and incidence of hyponatremia, hypokalemia, and hypochloremia was also similar between the groups. Moreover, patients in ORS group experienced significantly more anorexia compared to controls, and approximately 40% of the patients were unable to continue ORS intake. CONCLUSION: ORS intake in CDDP short hydration regimens does not affect CIN and CDDP-induced electrolyte imbalance; however, its intake is associated with the incidence of anorexia suggesting that ORS should not be used for oral hydration.

Randomized, Double-Blind, Phase III Study of Fosnetupitant Versus Fosaprepitant for Prevention of Highly Emetogenic Chemotherapy-Induced Nausea and Vomiting: CONSOLE.

PURPOSE: We evaluated the efficacy and safety of fosnetupitant (FosNTP) versus fosaprepitant (FosAPR) for preventing highly emetogenic chemotherapy-induced nausea and vomiting. This phase III study was the first head-to-head comparison between two different neurokinin-1 receptor antagonists in combination with palonosetron and dexamethasone. PATIENTS AND METHODS: Patients scheduled to receive cisplatin-based chemotherapy were randomly assigned 1:1 to FosNTP 235 mg or FosAPR 150 mg in combination with palonosetron 0.75 mg and dexamethasone. The primary end point was overall (0-120 hours) complete response (CR; no emetic event and no rescue medication) rate, stratified by sex and age category, to show the noninferiority of FosNTP to FosAPR (noninferiority margin, -10% for the difference in the overall CR rate). RESULTS: Overall, 795 patients were randomly assigned, of whom 785 received the study drug (FosNTP [N = 392] v FosAPR [N = 393]) and were evaluated for efficacy and safety. The overall CR rate was 75.2% versus 71.0%, respectively (Mantel-Haenszel common risk difference, 4.1%; 95% CI, -2.1% to 10.3%), demonstrating noninferiority of FosNTP to FosAPR. The CR rates in the acute (0-24 hours), delayed (24-120 hours), and beyond delayed (120-168 hours) phases, and at 0-168 hours were 93.9% versus 92.6%, 76.8% versus 72.8%, 86.5% versus 81.4%, and 73.2% versus 66.9%, respectively. The incidence rates of treatment-related adverse events with FosNTP versus FosAPR were 22.2% versus 25.4%, whereas adverse events or treatment-related adverse events relevant to injection site reactions were 11.0% versus 20.6% (P < .001) and 0.3% versus 3.6% (P < .001), respectively. CONCLUSION: FosNTP demonstrated noninferiority to FosAPR, with a favorable safety profile and lower risk for injection site reactions. Thus, FosNTP is valuable in the prophylaxis of acute, delayed, and beyond delayed chemotherapy-induced nausea and vomiting.

Exploratory Analysis Comparing Fosnetupitant Versus Fosaprepitant for Prevention of Highly Emetogenic Chemotherapy-Induced Nausea and Vomiting (CINV): A Randomized, Double-Blind, Phase 3 Study (CONSOLE).

INTRODUCTION: We describe the results of an exploratory analysis performed on the first head-to-head study (JapicCTI-194611) comparing two different intravenous (IV) neurokinin 1 (NK1) receptor antagonists, fosnetupitant and fosaprepitant, in combination with palonosetron (PALO) and dexamethasone (DEX) for the prevention of highly emetogenic chemotherapy (HEC)-induced nausea and vomiting (CINV). This analysis was performed to validate the findings of the primary analysis (previously published) utilizing a last observation carried forward (LOCF) approach for missing values for the efficacy endpoint of complete response (no emetic event and no rescue medication), while also evaluating the time periods encompassing the 0-168-hour (h) "extended overall phase" interval. METHODS: Patients scheduled to receive cisplatin-based chemotherapy were randomized 1:1 to fosnetupitant 235 mg or fosaprepitant 150 mg in combination with PALO 0.75 mg and DEX. Complete response rates were calculated and compared (stratified by age category and sex with a Mantel-Haenszel test) during the study's primary overall phase (0-120 h) and during additional time intervals of interest [acute (0-24 h), delayed (24-120 h), extended delayed (> 24-168 h), beyond delayed (120-168 h), and extended overall (0-168 h)]. RESULTS: A total of 785 patients were included (fosnetupitant N = 392, fosaprepitant N = 393). Complete response rates were numerically higher for fosnetupitant versus fosaprepitant for all time intervals and statistically significant for the extended overall phase. Complete response rates for fosnetupitant versus fosaprepitant during the overall, acute, delayed, extended delayed, beyond delayed, and extended overall phases were 75.5% vs. 71.0% (p = 0.1530), 93.9% vs. 92.6% (p = 0.4832), 77.0% vs. 72.8% (p = 0.1682), 74.7% vs. 68.4% (p = 0.0506), 86.7% vs. 81.7% (p = 0.0523), and 73.5% vs. 66.9% (p = 0.0450), respectively. CONCLUSION: In this exploratory analysis, fosnetupitant appeared to be more effective than fosaprepitant in preventing CINV associated with cisplatin-based HEC during the extended 7-day period following chemotherapy. INFOGRAPHIC.