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3120 Background: The PD-1 blockers Nivo and Pembro are widely used to treat patients (pts) with various types of cancer, but their PK and immunogenicity have not been adequately characterized in clinical practice. Here we report the first long-term follow-up of PK and anti-drug antibodies (ADAs) of Nivo and Pembro, correlated with efficacy and safety. Methods: We included 147 pts receiving Nivo (n = 98) or Pembro (n = 49) between May 2016 and Jan 2019. Plasma samples were longitudinally collected before each infusion and after discontinuation for as long as samples were obtainable. Drug concentrations were measured by ELISA (LLOQ: 0.0125 µg/mL), and ADAs were evaluated by bridging ELISA. Results: Median (range) follow-up was 6.0 (0.1-38.7) mo, and 1718 samples were analyzed. ADAs were confirmed at baseline or at last sample for both Nivo (2 [2.2%] and 4 [4.5%] pts, respectively) and Pembro (2 [4.2%] and 3 [6.7%] pts). Of the 4 baseline ADA-positive pts, 3 experienced drug-induced fever after initial infusion. Pts developing ADAs at last sample had earlier progression than ADA-negative pts (median PFS: 46 vs. 119 days, log-rank P = 0.0827). Persistent drug exposure until ~1 y beyond discontinuation was observed for both drugs. In 1 Nivo-treated pt with delayed adrenal insufficiency 8.6 mo after discontinuation, Nivo was still detectable (0.2 µg/mL). In 71 and 41 efficacy-evaluable pts receiving Nivo and Pembro, respectively, mean trough levels in the early period (~cycle 6) were significantly higher in pts achieving response than in pts with progressive disease at first assessment (Nivo: 43.5 vs. 31.0 µg/mL, P = 0.0107; Pembro: 30.6 vs. 22.1 µg/mL, P = 0.0174). Conclusions: Our findings provide insight into the etiological mechanism of late-onset adverse events associated with PD-1 blockers. Moreover, ADA may potentially influence clinical outcomes, and it may be possible to optimize dose in certain pts with lower drug exposure for improved efficacy, warranting further investigation. Clinical trial information: UMIN000033036. [Table: see text]

The painful peripheral neuropathy occurring frequently during chemotherapy with paclitaxel or oxaliplatin is one of their dose-limiting factors. We reported previously that substance P is involved in the pathogenesis of pulmonary hypersensitivity reaction to paclitaxel in rats, and an antiallergic agent pemirolast reverses this reaction via the blockade of release of substance P. In the present study, we investigated the involvement of substance P in paclitaxel-induced peripheral neuropathy compared with that by oxaliplatin. In von Frey and acetone tests in rats repeated administration of paclitaxel (6 mg/kg i.p., once a week for 4 weeks) or oxaliplatin (4 mg/kg i.p., twice a week for 4 weeks) induced both mechanical allodynia and cold hyperalgesia. Paclitaxel-induced peripheral neuropathy was reversed primarily by the acute administration of pemirolast (0.1 and 1 mg/kg p.o.). Moreover, coadministration of the receptor antagonists neurokinin 1 [N-acetyl-l-tryptophan 3,5-bis(trifluoromethyl)benzylester (L-732,138), 100 μg/body i.t.] and neurokinin 2 [5-fluoro-3-[2-[4-methoxy-4-[[(R)-phenylsulphinyl]methyl]-1-piperidinyl]ethyl]-1H-indole (GR159897), 100 μg/body i.t.] strongly reversed paclitaxel-induced neuropathy. On the other hand, oxaliplatin-induced peripheral neuropathy was not reversed by pemirolast. In the in vitro study using cultured adult rat dorsal root ganglion neurons paclitaxel (1000 ng/ml) significantly increased the release of substance P, and pemirolast (100 and 1000 nM) significantly inhibited this increase of substance P release. Oxaliplatin, by contrast, did not increase the release of substance P. These results suggest that substance P is involved in paclitaxel-induced neuropathy, and the mechanism of its action is clearly different from that of oxaliplatin.

Acute renal failure is a dose-limiting factor of cisplatin chemotherapy. Here, we show the protective effect of edaravone, a recently developed radical scavenger for clinical use, against cisplatin-induced renal dysfunction in rats. A marked increase in blood urea nitrogen and creatinine in serum, and histological changes including vacuolation, necrosis and protein casts were observed in proximal renal tubules at the fourth day after cisplatin injection (5-10 mg/kg). Repeated injection of edaravone (1-10 mg/kg, i.v. twice a day for 3 days) reversed the cisplatin-induced elevation of blood urea nitrogen and creatinine, and morphological changes in a dose-dependent manner. In particular, the protective effect of edaravone was almost complete at 10 mg/kg. Moreover, the compound was still fully effective, when it was administered only at the second day after cisplatin injection. On the other hand, the glutathione content in renal tissues lowered at the fourth day after cisplatin injection, which was reversed by the late treatment with edaravone. These findings suggest that the clinically available radical scavenger edaravone is potentially useful for the prevention of cisplatin-induced renal toxicity.

The present study was designed to examine the usefulness of 2,3-dimercaptosuccinic acid (DMSA) for the purpose of reducing cis-diamminedichloroplatinum (DDP)-induced nephrotoxicity and effective clinical use of DDP and safe. The effectiveness of DMSA on the DDP-excretion in rat kidney was observed by measuring the platinum concentration using Atomic Absorption Instrument. Co-administration of DMSA (1.0 or 2.0 mmol/kg) 1 hour after DDP injection (20 mumol/kg) showed more decrease in the platinum concentration than that immediately after DDP injection. The alleviating effect of DMSA on DDP toxicity was evaluated by lipid peroxidation, enzymatic antioxidants, and glutathione levels. The administration of DDP alone caused a significant increase in lipid peroxidation and significant decreases in enzymatic antioxidants and glutathione levels in the kidney. Co-administration of DMSA (2.0 mmol/kg) 1 hour after DDP injection showed the most effective reduction of these enzymatic damages caused by DDP. These findings suggested that the co-administration of DMSA (2.0 mmol/kg) 1 hour after DDP injection leads DDP to effective excrete from renal tissue and suppresses the lipid peroxide reaction and results in reduction of nephrotoxicity.

Background: Neutropenia is one of the most frequent and dose-limiting toxicities in amrubicin (AMR) therapy. However, the predictive factors for the development of severe neutropenia in AMR therapy remain unknown. Methods: The subjects were 61 advanced lung cancer patients treated with AMR monotherapy. All data were retrospectively collected from the electronic medical record system. A stepwise logistic regression analysis was performed to identify risk factors for grade 3–4 neutropenia. Results: Of a total 61 patients, 50 were male and 11 were female. The median dose of AMR was 35.0 mg/m2. The incidence of grade 3–4 neutropenia during the first course was 62%. In multivariate analysis, female gender (OR = 6.68; 95% CI 1.01–134.15; p = 0.049), higher AMR doses (40 mg/m2 or more) (OR = 5.98; 95% CI 1.77–23.74; p = 0.003), and lower hematocrit values (OR = 2.04 per 5% decrease; 95% CI 1.04–4.38; p = 0.036) were significantly associated with severe neutropenia induced by AMR. Conclusion: The present results suggest that female gender, higher doses of AMR, and lower baseline hematocrit values are predictive factors associated with severe neutropenia induced by AMR in patients with advanced lung cancer. Patients who have these predictive factors should be monitored carefully and considered for early granulocyte colony-stimulating factor support.