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.

Background: Potential novel strategies for adverse event (AE) management of osimertinib therapy, including therapeutic drug monitoring and the use of biomarkers, have not yet been fully investigated. This study aimed to evaluate (1) the relationship between exposure to osimertinib, especially its active metabolites (AZ5104 and AZ7550), and AEs, and (2) the relationship between germline polymorphisms and AEs. Methods: We conducted a prospective, longitudinal observational study of 53 patients with advanced non-small cell lung cancer receiving osimertinib therapy from February 2019 to April 2022. A population pharmacokinetic model was developed to estimate the area under the serum concentration–time curve from 0 to 24 h (AUC_0–24) of osimertinib and its metabolites. Germline polymorphisms were analyzed using TaqMan® SNP genotyping and CycleavePCR® assays. Results: There was a significant association between the AUC_0–24 of AZ7550 and grade ≥ 2 paronychia (p = 0.043) or anorexia (p = 0.011) and between that of osimertinib or AZ5104 and grade ≥ 2 diarrhea (p = 0.026 and p = 0.049, respectively). Furthermore, the AUC_0–24 of AZ5104 was significantly associated with any grade ≥ 2 AEs (p = 0.046). EGFR rs2293348 and rs4947492 were associated with severe AEs (p = 0.019 and p = 0.050, respectively), and ABCG2 rs2231137 and ABCB1 rs1128503 were associated with grade ≥ 2 AEs (p = 0.008 and p = 0.038, respectively). Conclusion: Higher exposures to osimertinib, AZ5104, and AZ7550 and polymorphisms in EGFR, ABCG2, and ABCB1 were related to higher severity of AEs; therefore, monitoring these may be beneficial for osimertinib AE management.

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.

The purpose of this study was to assess the impact by switching co-administered triazole antifungal agent from fluconazole (FCZ) to voriconazole (VCZ) on the blood concentration of tacrolimus (FK506) in patients receiving allogeneic hematopoietic stem cell transplantation. We performed a retrospective study presented as case reports. The blood concentration of FK506 was increased after the switch from FCZ to VCZ, resulting in increase of the concentration/dose (C/D) ratio of FK506. Thus, the mean C/D ratios of FK506 with oral administration was surprisingly increased over 4.5-fold after the switch. Therefore, it was necessary to reduce the FK506 dose when co-administered FCZ is switched to VCZ. We should be careful when interpreting the results of these case reports; however, in some patients, it is recommended that the dose of FK506 be reduced to one-fifth after the switch.

Background: Proton pump inhibitors (PPIs) reduce the bioavailability of several anticancer drugs. The impact of PPIs co-administered with cyclin-dependent kinase 4 and 6 inhibitors is controversial. We aimed to clarify whether the concomitant use of PPIs impacts palbociclib and abemaciclib effectiveness in breast cancer treatment. Patients and Methods: This multicenter, retrospective, observational study, conducted across 4 medical institutions in Japan, consecutively included patients with endocrine-resistant metastatic breast cancer, receiving palbociclib or abemaciclib between December 2017 and August 2022. Propensity score-matched analyses were performed. Treatment efficacy and safety with and without PPIs were compared. Progression-free survival and overall survival were estimated using the Kaplan-Meier method and compared using a log-rank test. A Cox proportional hazards model was used to estimate the hazard ratio. Results: The study included 240 patients. After 1:1 matching, 112 patients were treated with and without PPIs. The median progression-free survival period was 1.2 years in the PPI group and 1.3 years in the non-PPI group (hazard ratio, 1.19; 95% CI, 0.70-2.02). The median overall survival period was 3.6 years in the PPI group, whereas it was not reached in the non-PPI group (hazard ratio, 1.23; 95% CI, 0.61-2.47). Consistent results were obtained for subgroups receiving palbociclib (n = 177) and abemaciclib (n = 63) without propensity score matching. Adverse event incidence and severity were similar in both groups. Conclusion: The effectiveness of cyclin-dependent kinase 4/6 inhibitors is unlikely to be affected by concomitant PPI use. Future prospective pharmacokinetic studies are warranted.

This study aimed to compare the antiemetic efficacy and safety of a four-drug combination with those of a standard three-drug combination in Japanese patients with breast cancer treated with anthracycline. We retrospectively analyzed data from Japanese patients with breast cancer, who had received their first cycle of anthracycline and were treated with aprepitant, palonosetron, and dexamethasone with or without olanzapine. This retrospective observational study was performed at Ehime University Hospital using the electronic medical records. Multivariable and propensity score-adjusted analyses were performed to compare the onset of complete response (CR) failure between the groups. One-hundred and thirty patients were included in this study and the four- and three-drug group had 22 and 108 patients, respectively. Similar to multivariable logistic regression analysis, propensity-adjusted logistic regression analysis revealed that the four-drug group was markedly associated with a decreased odds of CR failure in the overall, acute, and delayed phases (odds ratio [OR]: 0.27, 95% confidence interval [CI]: 0.10–0.73; OR: 0.28, 95% CI: 0.10–0.76; and OR: 0.15, 95% CI: 0.04–0.57, respectively). Additionally, treatment-related adverse events were well tolerated in both the groups. These findings suggest that the antiemetic efficacy of the four-drug combination is superior to that of the standard three-drug combination.