Pharmacogenomic study of gemcitabine efficacy in patients with metastatic pancreatic cancer: A multicenter, prospective, observational cohort study (GENESECT study).

BACKGROUND: Genetic polymorphisms of molecules are known to cause individual differences in the therapeutic efficacy of anticancer drugs. However, to date, germline mutations (but not somatic mutations) for anticancer drugs have not been adequately studied. The objective of this study was to investigate the association between germline polymorphisms of gemcitabine metabolic and transporter genes with carbohydrate antigen 19-9 (CA 19-9) response (decrease ≥50% from the pretreatment level at 8 weeks) and overall survival (OS) in patients with metastatic pancreatic cancer who receive gemcitabine-based chemotherapy. METHODS: This multicenter, prospective, observational study enrolled patients with metastatic pancreatic cancer patients who were receiving gemcitabine monotherapy or gemcitabine plus nanoparticle albumin-bound paclitaxel combination chemotherapy. Thirteen polymorphisms that may be involved in gemcitabine responsiveness were genotyped, and univariate and multivariate logistic regression analyses were used to determine the association of these genotypes with CA 19-9 response and OS. The significance level was set at 5%. RESULTS: In total, 180 patients from 11 hospitals in Japan were registered, and 159 patients whose CA 19-9 response could be assessed were included in the final analysis. Patients who had a CA 19-9 response had significantly longer OS (372 vs. 241 days; p = .007). RRM1 2464A>G and RRM2 175T>G polymorphisms suggested a weak association with CA 19-9 response and OS, but it was not statistically significant. COX-2 -765G>C polymorphism did not significantly correlate with CA 19-9 response but was significantly associated with OS (hazard ratio, 2.031; p = .019). CONCLUSIONS: Genetic polymorphisms from the pharmacokinetics of gemcitabine did not indicate a significant association with efficacy, but COX-2 polymorphisms involved in tumor cell proliferation might affect OS.

Analysis of Adverse Events Associated with Trastuzumab Deruxtecan in Patients with Gastric and Breast Cancer: A Retrospective Study.

Trastuzumab deruxtecan (T-DXd) has displayed demonstrable efficacy and manageable toxicity in previously treated patients with advanced gastric and breast cancer, and it has been approved in Japan. However, there is a lack of data on the optimal management in clinical practice. Therefore, we assessed the adverse event (AE) profiles of T-DXd in patients with advanced gastric or breast cancer to provide guidance for appropriate management. This retrospective study was conducted at the Cancer Institute Hospital of the Japanese Foundation for Cancer Research. We reviewed the medical records of patients with advanced gastric or breast cancer who received T-DXd between May 2020 and December 2021. AEs occurring within the first three cycles of T-DXd were evaluated according to Common Terminology Criteria for Adverse Events version 5.0. Thirty-six patients were enrolled (gastric: n = 19, breast: n = 17). All 15 males had gastric cancer, whereas 4 and 17 females had gastric and breast cancer, respectively. Interstitial lung disease (ILD) occurred in five patients (14%), but no patients had severe ILD. Gastrointestinal (GI) toxicities, including nausea (61%), vomiting (22%), decreased appetite (33%), and diarrhea (39%), were the most common AEs. The incidence of GI toxicities did not differ by cancer type; however, nausea was significantly more common in females (81 vs. 33%; p < 0.01). T-DXd was safely administered in clinical practice in patients with previously treated advanced gastric or breast cancer. The management of GI toxicities is important in the clinical implementation of T-DXd.

Efficacy and safety of adapalene gel as a reactive treatment for cetuximab-induced skin toxicity in recurrent or metastatic squamous cell carcinoma of the head and neck: A historical cohort comparison study.

INTRODUCTION: Despite the common occurrence of cetuximab (Cmab)-induced skin toxicity, management strategies are not well established. The traditional mainstay method consists of topical steroids, which, if used excessively, may give rise to other concerns. Alternatively, adapalene can activate epidermal growth factor receptor pathways to potentially alleviate these toxicities. METHODS: We prospectively studied 31 patients with recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) who were eligible to use adapalene gel as a reactive treatment for topical steroid-refractory skin toxicity. For comparison, we retrospectively reviewed 99 patients with R/M SCCHN (historical control cohort) whose skin toxicity was mainly treated with topical steroids. We compared the frequency and severity of Cmab-induced skin toxicity, Cmab therapy status (e.g., dose modification), side effects caused by topical steroids and adapalene gel itself, and other medical interventions. RESULTS: Adapalene gel was used by eight patients (25.8%) in the prospective cohort. Patients in the historical control cohort more frequently required escalation of topical steroid potency (34.3% vs. 12.9%, p = 0.022). Although there was no statistically significant difference in the frequency of grade ≥3 facial skin rash and paronychia between the two cohorts, the prospective cohort showed a significantly shorter time to complete recovery from grade 2/3 paronychia (16 vs. 47 days, p = 0.017). Further, while no skin infections were observed in the prospective cohort, 13 patients in the historical control cohort developed skin infections, especially periungual infection (0% vs. 13.1%, p = 0.024). In addition, no patients in the prospective cohort received a dose reduction of Cmab due to skin toxicities, compared to 20 patients in the historical control cohort (0% vs. 20.2%, p = 0.003). No apparent adapalene gel-related side effects were observed. CONCLUSIONS: Adapalene gel may be an effective management option for topical steroid-refractory Cmab-induced skin toxicities and could improve compliance with Cmab therapy.

[Evaluation of the Leftover Capecitabine Tablets in Adjuvant CAPOX Chemotherapy for Gastric Cancer].

Since it is important that patients take their oral anticancer therapy as prescribed, pharmacists need to assess adherence. In addition, oral anticancer drugs are expensive, and reuse of leftover drugs at outpatient pharmacy clinics is useful in reducing drug costs. The present study aimed to clarify when and why patients have leftover capecitabine tablets, and the cost of leftover capecitabine tablets reused at an outpatient pharmacy clinic, focusing on adjuvant capecitabine plus oxaliplatin (CAPOX) chemotherapy for gastric cancer. We retrospectively studied patients who received adjuvant CAPOX chemotherapy for gastric cancer between November 1, 2015, and April 30, 2021, at the Cancer Institute Hospital of the Japanese Foundation for Cancer Research. The cost of leftover capecitabine reused by pharmacists was calculated based on the National Health Insurance drug price standard for the study period. This study included 64 patients who received adjuvant CAPOX chemotherapy. Thirty-seven patients had 152 leftover capecitabine tablets. The most common reasons for leftover capecitabine tablets were nausea and vomiting (21.7%), missed doses (18.4%), and diarrhea (13.2%). The leftover capecitabine tablets for 25 patients were reused at the outpatient pharmacy clinic at a cost of JPY 604142.8 (JPY 24165.7 per patient). The study results suggest that evaluating capecitabine adherence and the reasons for leftover capecitabine tablets at outpatient pharmacy clinics as well as reusing leftover medication can contribute to reducing drug costs.

Factors associated with lenvatinib adherence in thyroid cancer and hepatocellular carcinoma.

BACKGROUND: Lenvatinib is an oral anticancer medication used to treat radioiodine-refractory thyroid cancer and unresectable hepatocellular carcinoma. The purpose of this study is to evaluate lenvatinib adherence by patients and to identify factors associated with decreased lenvatinib adherence. METHODS: Among 153 patients who started treatment with lenvatinib for unresectable thyroid cancer or unresectable hepatocellular carcinoma between May 1, 2015 and August 31 2021 at the Cancer Institute Hospital of the Japanese Foundation for Cancer Research, 102 were eligible for this study (55 thyroid cancer, 47 hepatocellular carcinoma). The lenvatinib adherence rate in a treatment cycle was defined as the number of times a patient took lenvatinib in a 28-day cycle divided by the prescribed 28 doses. The rate was determined by pill counting and self-reporting at the pharmaceutical outpatient clinic. Reasons for non-adherence were established by interview and analyzed. RESULTS: The median adherence rate of lenvatinib in the first cycle was 90.1% (n = 55) in thyroid cancer and 94.9% (n = 47) in hepatocellular carcinoma. In thyroid cancer, there were 255 incidents of lenvatinib non-adherence. Non-adherence was mainly associated with bleeding events (18.6%), followed by hand-foot skin reactions (10.6%). In hepatocellular carcinoma, there were 97 incidents of non-adherence. Hypertension accounted for 20.6%, followed by hoarseness (18.6%) and diarrhea (17.5%). CONCLUSION: The adherence rate for lenvatinib in Japanese patients with thyroid and hepatocellular carcinoma in real-world clinical practice was more than 90% in this study. Hypertension was a major reason for non-adherence, followed by hand-foot skin reactions and diarrhea.

Serum Creatinine Elevation as a Risk Factor for Niraparib-induced Hematologic Toxicity.

BACKGROUND/AIM: Niraparib dosages can be individualized to reduce the starting dose based on body weight and baseline platelet count. However, even with individualized dosing, scattered cases of ≥Grade 3 hematologic toxicity occur. This study explored markers predictive of serious hematologic toxicity in niraparib therapy. PATIENTS AND METHODS: This retrospective observational study investigated patients who started niraparib therapy at the Cancer Institute Hospital of the Japanese Foundation for Cancer Research between December 2020 and March 2022. Associations between hematologic toxicities and serum creatinine ratio (percentage increase in serum creatinine between baseline and after niraparib initiation) were investigated. RESULTS: Out of 50 ovarian cancer patients who initiated niraparib, 45 patients were included in the final analysis. Twenty-three patients (51.1%) developed ≥Grade 3 hematologic toxicity, with neutropenia in 17 (37.8%), anemia in 9 (20.0%), and thrombocytopenia in 4 (8.9%). Patients with Grade 4 hematologic toxicity showed higher serum creatinine ratios than those with ≤Grade 2. Thrombocytopenia ≥Grade 3 occurred only within 2 months of niraparib initiation and was preceded by an increase in serum creatinine in all affected patients. CONCLUSION: Serum creatinine ratio offers a potential marker for predicting severe hematologic toxicity following niraparib therapy.

Influence of menopause on chemotherapy-induced nausea and vomiting in highly emetogenic chemotherapy for breast cancer: A retrospective observational study.

BACKGROUND: Female sex and younger age are reported risk factors for chemotherapy-induced nausea and vomiting (CINV) in highly emetogenic chemotherapy, but the underlying mechanism has not been elucidated. The purpose of this study was to clarify the impact of menopause on CINV. METHODS: This retrospective observational study analyzed data from consecutive patients who received their first cycle of perioperative anthracycline-based chemotherapy for breast cancer between January 2018 and June 2020. The endpoints were association between CINV (vomiting, ≥Grade 2 nausea, complete response [CR] failure) and menopause as well as the association between CINV and follicle-stimulating hormone [FSH]/estradiol [E2]. RESULTS: Data for 639 patients were analyzed. Among these patients, 109 (17.1%) received olanzapine (four antiemetic combinations) and 530 (82.9%) did not (three antiemetic combinations). Premenopausal state (amenorrhea lasting ≥12 months) was significantly associated with ≥Grade 2 nausea and CR failure in univariate analysis but not in multivariate analysis. The premenopausal FSH/E2 group (defined by serum levels; FSH <40 mIU/mL and E2 ≥20 pg/mL) had a significantly higher rate of ≥Grade 2 nausea than the postmenopausal FSH/E2 group (FSH ≥40 mIU/mL and E2 <20 pg/mL) (48.8% vs. 18.8%, p = 0.023). CONCLUSIONS: Our results suggest that changes in FSH and E2 due to menopause may affect the severity of nausea and that FSH and E2 (especially FSH) levels might be useful indicators for CINV risk assessment.

Cancer-Chemotherapy-Related Regimen Checks Performed by Pharmacists of General Hospitals Other than Cancer Treatment Collaborative Base Hospitals: A Multicenter, Prospective Survey.

Although prescription review is an important role for pharmacists in anticancer drug therapy, there are no guidelines in Japan that specify what pharmacists should check for in chemotherapy regimens. This prospective multicenter survey aimed to investigate the implementation of chemotherapy regimen checks by pharmacists in general hospitals by focusing on 19 recommended confirmation items designed to enhance chemotherapy safety. This study involved 14 hospitals within the National Hospital Organization in different regions of Japan. The top five cancers in Japan (gastric, colorectal, lung, breast, and gynecological) were targeted and specific chemotherapy regimens were analyzed. This study assessed the amount of time required for regimen checks, the number of confirmation items completed, the number and the content of inquiries raised regarding prescriptions, and the pharmacists' opinions using a questionnaire that had a maximum score of 10 points. Pharmacists checked 345 and 375 chemotherapies of patients in the control group (CG) and recommended items group (RIG), respectively. The mean time periods required for completing a chemotherapy regimen check were 4 min and 14 s (SD ±1 min and 50 s) and 6 min and 18 s (SD, ±1 min and 7 s) in the CG and RIG, respectively. The mean of the recommended items for the CG = 12.4 and for the RIG = 18.6. The items that the pharmacists did not confirm included urine protein (sixty-nine cases, 18.4%), allergy history (four cases, 1%), previous history (two cases, 0.5%), and a previous history of hepatitis B virus (sixty-nine cases, 18.4%). The number of inquiries for a doctor's prescription order was higher in the RIG than in the CG (41 vs. 27 cases). This multicenter survey demonstrated the potential effectiveness of implementing 19 recommended confirmation items in the regimen checks by pharmacists in general hospitals other than cancer treatment collaborative base hospitals.

[Evaluation of Neutropenia and Usages of Antihypertensive Drugs in Patients Treated with Ramucirumab plus Paclitaxel Therapy].

Hypertension is one of the main side effects of ramucirumab(RAM)plus paclitaxel(PTX)therapy. Although dihydropyridine calcium channel blockers(D-CCBs)are considered to cause drug-drug interactions with PTX based on the inhibition of cytochrome P450, D-CCBs are often administered to patients receiving RAM plus PTX therapy in clinical practice. We retrospectively studied the actual usage of antihypertensive drugs in 133 advanced or recurrent gastric cancer patients who received RAM plus PTX therapy. Antihypertensive drugs were administered to 34(25.6%)patients. Among them, 13 (38.2%)received antihypertensive drugs during the first course, and 19(55.9%)received D-CCBs. We also investigated whether D-CCBs affect the expression of Grade 3 or higher neutropenia caused by PTX. Results of multivariate analysis indicated that D-CCBs did not increase the risk of neutropenia caused by PTX.

Proton pump inhibitors affect capecitabine efficacy in patients with stage II-III colorectal cancer: a multicenter retrospective study.

The association between capecitabine efficacy and proton pump inhibitors (PPIs) is controversial. Here, we determined whether co-administration of PPIs affects the real-world effectiveness of capecitabine. This retrospective observational study included consecutive patients with stage II-III colorectal cancer (CRC) who received adjuvant capecitabine monotherapy or CapeOX (capecitabine and oxaliplatin) between January 2009 and December 2014 at nine participating institutions. The primary endpoint was the difference in relapse-free survival (RFS) between patients who received PPIs and those who did not and was estimated using the Kaplan-Meier method. Overall survival (OS) was the secondary endpoint. Multivariable analysis of RFS and OS was performed using a Cox proportional hazards model, propensity score adjustment, and inverse probability of treatment weighting (IPTW) analyses. Data from 606 patients were evaluated, 54 of whom had received a PPI. PPI-treated patients tended to have poorer RFS and OS than patients treated without PPIs. The hazard ratio for RFS with capecitabine monotherapy was 2.48 (95% confidence interval: 1.22-5.07). These results were consistent with sensitivity analyses performed using propensity score adjustment and IPTW methods. Co-administration of PPIs may reduce the effectiveness of capecitabine and negatively impact patients with stage II-III CRC.

Risk Factors for Hepatic Toxicity of High-dose Methotrexate in Patients With Osteosarcoma.

BACKGROUND/AIM: High-dose methotrexate (HD-MTX) is widely used to treat osteosarcoma. However, some patients develop hepatic toxicity, leading to dose modification and delays in the scheduled chemotherapy. The present study aimed to identify the risk factors of hepatotoxicity in patients with osteosarcoma. PATIENTS AND METHODS: We conducted a retrospective study of patients with osteosarcoma treated with HD-MTX between January 2014 and June 2020 at the National Cancer Center Hospital, Japan. The risk factors for MTX-induced hepatotoxicity (≥grade 3) were identified using multivariate logistic regression analysis. RESULTS: The final analysis included 88 courses of 36 patients. Hepatotoxicity occurred in 51 (58.0%) of the 88 courses. Female sex, MTX dose (>10.2 g/m2), and serum calcium concentration (>9.3 mg/dl) were identified as risk factors for HD-MTX-induced hepatotoxicity. CONCLUSION: Identifying the risk factors of HD-MTX-induced hepatotoxicity may contribute to improvements in the safety and management of HD-MTX therapy.

Investigation of Hypersensitivity Reactions in Carboplatin Desensitization Therapy.

BACKGROUND/AIM: Carboplatin is a key drug in the treatment of ovarian cancer, but hypersensitivity reactions (HSRs) may occur with repeated use. PATIENTS AND METHODS: Thirty-seven ovarian cancer patients treated with carboplatin desensitization therapy were reviewed retrospectively. The treatment completion rate and toxicity were examined. RESULTS: The carboplatin desensitization completion rate was 86.5%. Toxicity was Grade 0, 1, 2, and 3 in 17, 5, 10, and 5 patients, respectively. Erythema was the most frequent toxicity (36.8%), most commonly affecting the arm (23.5%). Furthermore, all HSRs were classified into: skin, respiratory, digestive, circulatory, and neurological. The completion rate of desensitization was significantly lower in patients with two or more target organs affected (p<0.001). CONCLUSION: The main symptoms of HSRs, the most common sites of HSRs, and the criteria for discontinuing desensitization therapy identified in this study are useful information for the safe implementation of carboplatin desensitization therapy.

Evaluation of hepatic CYP3A enzyme activity using endogenous markers in lung cancer patients treated with cisplatin, dexamethasone, and aprepitant.

PURPOSE: Aprepitant is used with dexamethasone and 5-HT3 receptor antagonists as an antiemetic treatment for chemotherapy, including cisplatin. Aprepitant is a substrate of cytochrome P450 (CYP) 3A4 and is known to cause its inhibition and induction. In addition, dexamethasone is a CYP3A4 substrate that induces CYP3A4 and CYP3A5 expression. In this study, we aimed to quantitatively evaluate the profile of CYP3A activity using its endogenous markers in non-small cell lung cancer patients receiving a standard cisplatin regimen with antiemetics, including aprepitant. METHODS: Urinary 11ß-hydroxytestosterone (11ß-OHT)/testosterone concentration ratio and plasma 4ß-hydroxycholesterol (4ß-OHC) concentrations were measured before and after cisplatin treatment (days 1, 4, and 8). CYP3A5 was genotyped, and plasma aprepitant concentrations were measured on day 4 to examine its influence on CYP3A endogenous markers. RESULTS: The urinary 11ß-OHT/testosterone concentration ratio in the 35 patients included in this study increased by 2.65-fold and 1.21-fold on days 4 and 8 compared with day 1, respectively. Their plasma 4ß-OHC concentration increased by 1.46-fold and 1.66-fold, respectively. The mean plasma aprepitant concentration on day 4 was 1,451 ng/mL, which is far lower than its inhibitory constant. The allele frequencies of CYP3A5*1 and CYP3A5*3 were 0.229 and 0.771, respectively. In patients with the CYP3A5*1 allele, the plasma 4ß-OHC concentration was significantly lower at baseline but more potently increased with chemotherapy. CONCLUSION: CYP3A activity was significantly induced from day 4 to day 8 in patients receiving cisplatin and three antiemetic drugs.

Use of Pegfilgrastim in Japanese Pediatric Patients With Solid Tumors: A Retrospective Analysis.

There are no detailed analyses of regarding pegfilgrastim usage in Japanese pediatric solid tumor patients. The approved dose of pegfilgrastim in Japan is 3.6 mg. We retrospectively evaluated the incidence of dose delays and dose reductions due to neutropenia in pediatric patients with solid tumors receiving chemotherapy with pegfilgrastim between 2015 and 2018. The effects of the timing of pegfilgrastim administration were evaluated. In chemotherapies administered every 2 and 3 weeks, prolongation of chemotherapy cycles was analyzed. Fifty-nine patients received chemotherapy with prophylactic pegfilgrastim for a total 247 cycles. No significant incidence of dose delays was observed with pegfilgrastim administration during the first 1 to 3 days after chemotherapy. When 77 cycles in 2-week regimens were compared with 166 cycles in 3-week regimens, mean cycle durations were 15.19±2.06 and 21.97±2.88 days, respectively (P<0.001). A total of 77 chemotherapy cycles administered every 14 days were subdivided. The incidence of dose delays in pediatric patients receiving chemotherapy for 5 consecutive days was similar to that for 1 day and 2 consecutive days. Pegfilgrastim prophylaxis could be of use for Japanese pediatric patients with solid tumors receiving chemotherapy, including administration every 2 weeks. Its use aids in maintaining the chemotherapy schedule.

Prognostic Value of Baseline Medications Plus Neutrophil-to-Lymphocyte Ratio in the Effectiveness of Nivolumab and Pembrolizumab in Patients With Advanced Non-Small-Cell Lung Cancer: A Retrospective Study.

BACKGROUND: Nivolumab and pembrolizumab are the standard treatments for patients with advanced non-small-cell lung cancer (NSCLC). While there are reports on several inflammatory indices and the prognosis of patients with cancer, no study has combined baseline medication with the neutrophil-to-lymphocyte ratio (NLR) to predict clinical outcomes. This study investigated the efficacy of baseline medications plus NLR to predict the effectiveness of nivolumab and pembrolizumab in a real-world clinical setting. METHODS: We conducted a single-center retrospective observational study of consecutive patients with advanced NSCLC who received nivolumab or pembrolizumab as first-line, second-line, or beyond treatment between December 2015 and November 2018 at the National Cancer Center Hospital in Japan. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. The drug-based prognostic score for baseline medications plus NLR was weighed based on the regression ß coefficients. The multivariable Cox proportional hazard model was used to assess the association between the prognostic score-stratified groups and survival outcomes. RESULTS: In total, 259 patients were evaluated in this study. A prognostic score calculated from the baseline medications plus NLR was used to categorize the patients into good (score 0), intermediate (scores 1-2), and poor (scores 3-6) -prognosis groups. The multivariable Cox proportional hazard model revealed a significant association between the poor-prognosis group and reduced OS. The hazard ratio of OS was 1.75 (95% confidence interval: 1.07-2.99; P = 0.031). In contrast, no association between these prognosis groups and PFS was observed. CONCLUSIONS: The findings suggest that the baseline medications with nivolumab or pembrolizumab plus NLR could lead to progressively shorter survival outcomes in patients with advanced NSCLC and could be used as a prognostic index for poor outcomes. However, to ascertain the clinical application of these findings, these concomitant medications need further validation in a large-scale multicenter study.

Risk Factors Associated With Unplanned Acute Care in Outpatient Chemotherapy With Oral Anticancer Drugs as Monotherapy or Combination Therapy With Injectable Anticancer Drugs.

BACKGROUND/AIM: Recently, the number of patients with cancer receiving outpatient chemotherapy using oral anticancer drugs has increased, but the currently available outpatient cancer chemotherapy is not safer than that available before. The present study aimed to identify risk factors associated with unplanned acute care (UAC) requiring outpatient chemotherapy-related consultation and hospitalisation. PATIENTS AND METHODS: We conducted a case- control study among 1,674 patients who received oral anticancer drug treatment either alone or in combination with injectable anticancer drugs at National Cancer Center Hospital East, Japan, between December 1, 2014, and November 30, 2015. RESULTS: Body mass index (BMI) was identified as a risk factor for UAC during chemotherapy. Patients with a BMI of <18.5 kg/m2, classified as underweight according to the World Health Organization classification of nutritional status, had a significantly higher risk of UAC. CONCLUSION: A low BMI immediately before the occurrence of chemotherapy-related UAC is a risk factor for adverse effects; therefore, underweight patients need more careful monitoring and supportive care.

Absolute Lymphocyte Count Predicts Immune-Related Adverse Events in Patients With Non-Small-Cell Lung Cancer Treated With Nivolumab Monotherapy: A Multicenter Retrospective Study.

BACKGROUND: Among patients with advanced non-small-cell lung cancer who were treated with nivolumab monotherapy, the association of peripheral blood count data (at baseline and 2 weeks after treatment initiation) with the early onset of immune-related adverse events (irAEs) and treatment efficacy has not been clearly established. This study aimed to identify peripheral blood count data that may be predictive of the development of nivolumab-induced irAEs in a real-world clinical setting. MATERIALS AND METHODS: This multicenter observational study retrospectively evaluated consecutive patients with advanced non-small-cell lung cancer undergoing nivolumab monotherapy in the second- or later-line setting between December 2015 and November 2018 at the National Cancer Center Hospital and Keio University Hospital in Japan. The primary endpoint was the association between peripheral blood count data and irAEs during the 6-week study period. Receiver operating characteristic curve and multivariable logistic regression analyses were performed. RESULTS: Of the 171 patients evaluated, 73 (42.7%) had ≥1 irAE during the first 6 weeks following treatment initiation. The median time to irAEs from the initiation of nivolumab was 15 (interquartile range: 13-28) days. Receiver operating characteristic curve analyses revealed that the optimal cut-off values of the absolute lymphocyte count, neutrophil-to-lymphocyte ratio, and lymphocyte-to-monocyte ratio 2 weeks after treatment initiation for early irAE onset were 820, 4.3, and 2.2, respectively. In multivariable logistic regression analyses, absolute lymphocyte count >820 at 2 weeks after treatment initiation was significantly associated with an increased risk of early onset of any irAE. In contrast, no significant association was observed for the neutrophil-to-lymphocyte ratio (>4.3) or the lymphocyte-to-monocyte ratio (>2.2) at 2 weeks following treatment initiation. CONCLUSIONS: The absolute lymphocyte count >820 at 2 weeks following nivolumab initiation predicts early onset of irAEs during a 6-week study period. Routinely available absolute lymphocyte count, which is measured after the initiation of nivolumab, may be useful for identifying patients at risk of early onset of irAEs.

Peripheral blood biomarkers predict immune-related adverse events in non-small cell lung cancer patients treated with pembrolizumab: a multicenter retrospective study.

Background: Pembrolizumab is currently the standard treatment for patients with advanced non-small cell lung cancer (NSCLC). However, the association between immune-related adverse events (irAEs) and peripheral blood cell counts remains unclear. We aimed at identifying peripheral blood cell counts that may predict the development of pembrolizumab-induced irAEs. Methods: We retrospectively analyzed data on consecutive patients with advanced NSCLC who received pembrolizumab monotherapy as first-line or later-line therapy at the National Cancer Center Hospital and Keio University Hospital. We used data between December 2015 and November 2018. The primary endpoint was the relationship between peripheral blood cell count data and early-onset irAEs during the 6-weeks study period. Receiver operating characteristic (ROC) curve and multivariable logistic regression analyses were performed. Results: In total, 92 patients were evaluated, of whom 45 (48.9%) had at least one irAE during the first 6-weeks after treatment initiation. The ROC curves revealed that the optimal cutoff of pretreatment absolute lymphocyte count (ALC), neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), and platelet-to-lymphocyte ratio (PLR) for onset of irAEs were 1459, 2.320, 1.538, and 165, respectively. Multivariable logistic regression analyses revealed that pretreatment ALC>1450 and LMR>1.6 were significantly associated with a reduced risk for onset of any irAEs, whereas pretreatment NLR>2.3 and PLR>165 were significantly associated with an increased risk. Conclusions: The findings suggest that considering the routine availability of blood cell count data before the initiation of treatment with pembrolizumab, it may be useful in identifying early-onset irAEs during the 6-weeks study period in clinical practice.

Drug interaction between letermovir and voriconazole after allogeneic hematopoietic cell transplantation.

Letermovir has been approved for the prevention of cytomegalovirus (CMV) infection after allogeneic hematopoietic stem cell transplantation (HCT). Letermovir is a cytochrome P450 (CYP) 2C19 inducer. Voriconazole, which is a broad-spectrum triazole antifungal agent, is mainly metabolized by CYP2C19. Thus, voriconazole trough concentration may decrease due to the drug interaction between voriconazole and letermovir. This study aimed to clarify the effects of letermovir on voriconazole trough concentration in allogeneic HCT recipients. We retrospectively examined voriconazole trough concentration in 24 allogeneic HCT recipients who had letermovir for prevention of CMV infection. The median voriconazole C/D ratios significantly decreased after starting letermovir from 0.25 L/kg to 0.11 L/kg (p < 0.01), and increased after discontinuing letermovir from 0.15 L/kg to 0.24 L/kg (p = 0.02). The median fold change of voriconazole trough concentration during letermovir administration was 0.40. Our results suggest that voriconazole trough concentration decreases when voriconazole is combined with letermovir in allogeneic HCT recipients. Therefore, close therapeutic drug monitoring of voriconazole trough concentration is warranted in allogeneic HCT recipients after starting or discontinuing letermovir.