Effect of Systemic Corticosteroid Therapy on the Efficacy and Safety of Nivolumab in the Treatment of Non-Small-Cell Lung Cancer.

INTRODUCTION: Corticosteroids are used to treat immune-related adverse events (irAEs) associated with nivolumab. However, patients with non-small-cell lung cancer who are administered corticosteroids before the initiation of nivolumab treatment are commonly excluded from clinical trials. The appropriate timing for corticosteroid administration in relation to nivolumab treatment, effects of corticosteroids on the efficacy of nivolumab, and resulting adverse events are not clearly understood. In this study, the effects of differences in the timing of corticosteroid administration on nivolumab efficacy and the resulting adverse events were examined. METHODS: A retrospective study was conducted with 109 patients who were treated with nivolumab at Sapporo Minami-Sanjo Hospital between December 2015 and March 2018. RESULTS: Of the 109 patients treated with nivolumab, 12 patients were administered corticosteroids before the first cycle of nivolumab (pre-CS), and 33 patients were administered corticosteroids after the first cycle of nivolumab (post-CS). These 2 groups were compared with the control group comprising 64 patients who were not administered corticosteroids (non-CS). The objective response rate in the post-CS group was significantly higher than that in the non-CS group, and the disease control rate in the pre-CS group was significantly lower than that in the non-CS group. The overall survival time and progression-free survival time in the pre-CS group were significantly shorter than those observed in the non-CS group; however, these did not differ from those in the post-CS group. CONCLUSIONS: These results suggest that corticosteroids administered to patients with non-small-cell lung cancer after initiation of nivolumab treatment did not affect the disease prognosis. Thus, corticosteroids can be administered immediately for rapid treatment of irAEs.

An Liquid Chromatography-Tandem Mass Spectrometry Method for the Simultaneous Determination of Afatinib, Alectinib, Ceritinib, Crizotinib, Dacomitinib, Erlotinib, Gefitinib, and Osimertinib in Human Serum.

BACKGROUND: Routine therapeutic drug monitoring is a promising approach for the rational use of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) and anaplastic lymphoma kinase (ALK) inhibitors. The purpose of this study was to develop and validate a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the simultaneous determination of 5 EGFR-TKIs (afatinib, dacomitinib, erlotinib, gefitinib, and osimertinib) and 3 ALK inhibitors (alectinib, ceritinib, and crizotinib). METHODS: A 100-mL aliquot of serum was diluted with 100 µL of 1% aqueous ammonia containing internal standards and then purified using the supported liquid extraction method. LC-MS/MS was conducted in positive ionization mode, and the method was validated according to published guidelines. RESULTS: Calibration curves were linear across concentration ranges examined. The intra- and interassay accuracies were 90.7%-110.7% and 94.7%-107.6%, respectively. All intra- and interassay imprecision values were ≤10.1%. The EGFR-TKIs and ALK inhibitors examined in this study, except osimertinib, which could be stored on ice for at least 5 hours, were stable at room temperature for 3 hours. For the internal standard-normalized matrix factors, the mean recovery and percent coefficient of variation values ranged between 54%-112% and 1.7%-11.7%, respectively. This method successfully determined serum concentrations of afatinib, alectinib, erlotinib, gefitinib, and osimertinib in clinical samples. Serum levels of kinase inhibitors consistently reflected those reported in previous studies. CONCLUSIONS: An LC-MS/MS method suitable for the simultaneous determination of 5 EGFR-TKIs and 3 ALK inhibitors in serum was developed and validated. The newly developed method enabled the determination of 5 of 8 target drugs examined in clinical samples. However, a large number of clinical samples need to be analyzed to verify the usefulness of the method.

[Comparative Study of the Antiemetic Palonosetron for Lung Cancer Patients Treated with a Divided Dose of Cisplatin].

Palonosetron(Palo)is a second-generation 5-hydroxytryptamine 3 receptor antagonist(5-HT3RA)effective in suppressing chemotherapy-induced nausea and vomiting in both acute and delayed phases.Most studies have reported Palo as an effective antiemetic for cisplatin(CDDP)chemotherapy(≥50mg/m2)administered on an intermittent basis.To assess the antiemetic efficacy of Palo, we performed a retrospective study in 16 patients with lung cancer who received Palo with split-dose CDDP, ifosfamide, and irinotecan(CPT-11)triple combination(CIC)therapy at Sapporo Minami-Sanjo Hospital between October 2010 and January 2012.T he CIC regimen consisted of CPT-11(50-60mg/m2)administered on days 1, 8, and 15, in addition to CDDP(15-20mg/m2)and ifosfamide(1,500mg/kg)for 4 consecutive days.On day 1, ramosetron was replaced with Palo in patients who had insufficient antiemetic control in accordance with guidelines on the management of highly emetogenic chemotherapy(HEC).There was a lower incidence of grade 1 or higher nausea(62.5%)in patients in the Palo-combination group than in those in the non-Palo-combination group(87.5%).No incidence of grade 3 or higher nausea was reported in either group.On the fifth day of chemotherapy, the incidence of nausea was significantly lower in the Palo-combination group(43.8%)than in the non-Palo-combination group(81.3%)(p<0.05).In addition, there was a significant decrease in the number of days of incidence and a significant increase in the number of days since the last episode was observed in the Palo-combination group.These results suggest that Palo, in particular, decreases the incidence of nausea and extends the number of days since its occurrence; moreover, it is effective in accelerating recovery.In conclusion, this study suggests that Palo exhibits excellent antiemetic efficacy in patients administered split doses of CDDP.

[Study on the Antiemetic Effects of Aprepitant in Patients with Lung Cancer Receiving Chemotherapy with Carboplatin].

Guidelines for antiemetic therapy, such as the American Society of Clinical Oncology (ASCO) guidelines, recommend that aprepitant, an NK1 receptor antagonist, should be used in addition to conventional antiemetic therapy for acute and delayed nausea/vomiting caused by highly emetogenic chemotherapy. However, only few studies have been conducted to evaluate the efficacy of aprepitant in patients receiving moderately emetogenic chemotherapy. Therefore, we examined the antiemetic effects of additional doses of aprepitant in the next course in patients with lung cancer who were undergoing chemotherapy with carboplatin and who developed chemotherapy-induced nausea and vomiting (CINV) despite the preventive administration of a 5-HT3 receptor antagonist and dexamethasone. Consequently, the incidences of vomiting and nausea significantly decreased from 59% to 0% and from 91% to 64%, respectively, during the entire study period. Furthermore, a significant improvement in dietary intake during the entire study period was confirmed. These results suggest that the additional administration of aprepitant has high antiemetic effects in patients with lung cancer who are undergoing chemotherapy with carbo- platin and who show insufficient control of nausea/vomiting.

Association of Nutritional Indices With Adverse Effects and Time-to-Treatment-Failure in Triple Therapy for Lung Cancer.

BACKGROUND/AIM: Recent lung cancer treatments include an immune checkpoint inhibitor (ICI) pembrolizumab, platinum-based agents, plus an additional cytotoxic anticancer agent. Nutritional indices, such as the geriatric nutritional risk index (GNRI) and the prognostic nutritional index (PNI), are known to correlate with the prognosis of cancer chemotherapy. Several previous studies have investigated the relationship between PNI and treatment response in non-small cell lung cancer patients, reporting significantly increased OS and PFS in the high PNI group before treatment. However, the relationship between the three-drug combination and GNRI/PNI is unclear. The current study aimed to investigate the association of nutritional indices with duration of treatment success and occurrence of side effects in triple therapy. PATIENTS AND METHODS: Seventy-two patients with non-small cell lung cancer, treated with combination of carboplatin, pemetrexed, and pembrolizumab from November 2019 to September 30, 2022, were classified into two groups (High and Low) for GNRI and PNI, and a retrospective study was performed. RESULTS: In terms of time-to-treatment-failure (TTF), univariate and multivariate Cox proportional hazards regression analysis showed the Low-PNI group to have significantly shorter TTF than the High-PNI group (p=0.006); multivariate analysis results also showed PNI as a factor affecting TTF (HR=2.791, 95%CI=1.362-5.721, p=0.005). On the other hand, GNRI was not shown to be a factor affecting TTF. CONCLUSION: PNI at the start of treatment was an independent prognostic factor affecting treatment success time (TTF) in non-small cell lung cancer patients receiving triple therapy. However, PNI was not shown to be a prognostic predictor of irAE development.

Association of Geriatric Nutritional Risk Index With Immune Checkpoint Inhibitor Treatment Duration and Adverse Events in Lung Cancer.

BACKGROUND/AIM: Compared to conventional cytotoxic anticancer agent-based therapy, treatment with immune checkpoint inhibitors (ICI) significantly prolongs overall survival. The Geriatric Nutritional Risk Index (GNRI) has been used as a new prognostic indicator in cancer. As nutritional status is associated with prognosis and indicates treatment response, we investigated the effect of the pretreatment GNRI on the (1) occurrence of ICI-induced immune-related adverse events (ir-AE) and (2) association with time to treatment failure (TTF) in ICI monotherapy for lung cancer. PATIENTS AND METHODS: In this study, 127 patients with lung cancer who were treated with ICI monotherapy were retrospectively enrolled. Based on a cutoff value of 92 for the GNRI, we investigated intergroup differences in the occurrence of adverse events and their association with TTF in the High-GNRI (≥92) and Low-GNRI (<92) groups. For intergroup comparisons, we used the Student's t-test, Welch's t-test, Fisher's direct probability test, and Mann-Whitney's U-test, and factors with p<0.05 in the intergroup comparison were extracted as explanatory variables. RESULTS: Based on the pretreatment GNRI, the median TTF was 5.1 months (95%CI=2.4-7.9 months) in the High-GNRI group and 2.3 months (95%CI=1.6-3.1 months) in the Low-GNRI group, with the High-GNRI group having a significantly longer TTF (p<0.01). The incidence of skin rash (p=0.0129) and pruritus (p<0.01) was significantly higher in the High-GNRI group. CONCLUSION: Pretreatment GNRI influences the continuation of ICI monotherapy. The High-GNRI group demonstrated a significantly higher frequency of skin lesions, which may have influenced the prolongation of TTF.

[Comparative study of an antiemetic NK1 receptor-antagonist in lung cancer patients treated with divided doses for Cisplatin].

Aprepitant is a NK1 receptor-antagonist with a novel mechanism of action for chemotherapy-induced nausea and vomiting (CINV), and is recommended as a prophylactic by many international and domestic guidelines. However, domestic clinical trials of aprepitant have only been conducted using a single dose in patients who were treated with cisplatin(CDDP), and there is no evidence to support administration of aprepitant in divided doses. We administered aprepitant in divided doses to patients who were also being treated with cisplatin, ifosfamide, and irinotecan(CIC), and had CINV due to prophylactic administration of a 5-HT3 receptor antagonist and dexamethasone. This was done in order to evaluate the antiemetic effect of aprepitant. The patients with"No vomiting"increased significantly from 25% to 83%, and the"Days with nausea"in patients also decreased significantly. Consequently, administration of aprepitant in addition to current antiemetic therapy in divided doses, as well as in single doses, exhibited a greater antiemetic effect in CDDP-treated patients.

The Relationship Between Efficacy and Safety of Osimertinib Blood Concentration in Patients With EGFR Mutation-positive Lung Cancer: A Prospective Observational Study.

BACKGROUND/AIM: Osimertinib blood levels and their impact on treatment continuation in patients with EGFR mutation-positive lung cancer is not known. This study investigated the drug blood levels and risk factors affecting treatment continuation. PATIENTS AND METHODS: Fifty-six patients with recurrent and inoperable epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer who received Osimertinib (80 mg once daily, daily dose) between October 1, 2016, and August 31, 2021, were included. Patients were classified into two groups using a cutoff blood level of 155 ng/ml. The primary endpoint was the relationship between Osimertinib exposure and efficacy, and secondary endpoints were the relationship between Osimertinib exposure and side effects, and the effect of covariates on efficacy and blood levels. RESULTS: The median progression-free survival (PFS) for evaluable patients in the steady-state trough concentration (Cmin ss) ≥155 ng/ml and Cmin ss <155 ng/ml groups was 18.7 months and 31.2 months. Serum albumin (Alb) levels were 3.73±0.40 g/dl and 3.93±0.28 g/dl (p=0.030), respectively, and in multivariate analysis, Alb <3.7 g/dl was associated with a hazard ratio of 5.304 (95%CI=1.431-19.66; p=0.013), indicating that Alb <3.7 g/dl significantly shortened PFS. CONCLUSION: Free blood concentration of Osimertinib may have been increased by a combination of factors, including decreased hepatic metabolic function and decreased albumin production caused by systemic inflammation in patients with cancer. However, there was no effect of Osimertinib Cmin ss on PFS.