Administration Of Nivolumab Research Articles

Intracerebral administration of CTLA-4 and PD-1 immune checkpoint blocking monoclonal antibodies in patients with recurrent glioblastoma: a phase I clinical trial

BackgroundPatients with recurrent glioblastoma (rGB) have a poor prognosis with a median overall survival (OS) of 30–39 weeks in prospective clinical trials. Intravenous administration of programmed cell death protein 1...

Baseline Neutrophil-to-Lymphocyte Ratio and Glasgow Prognostic Score are Associated with Clinical Outcome in Patients with Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma Treated with Nivolumab.

Recurrent or metastatic head and neck squamous cell carcinoma (R/MHNSCC) has a poor prognosis. Although nivolumab is approved in Japan for treating R/MHNSCC, the response rate is low. Therefore, identifying pretreatment prognostic factors is necessary. This study assessed the utility of the neutrophil-to-lymphocyte ratio (NLR) and Glasgow Prognostic Score (GPS) as biomarkers of response to nivolumab. We retrospectively collected the data of 56 R/MHNSCC patients treated with nivolumab between May 2017 and December 2019. The Kaplan-Meier method and log-rank test were used to estimate overall survival (OS) and progression-free survival (PFS), and multivariate Cox hazard regression analysis was used to identify independent predictors of survival. Patients with a low pretreatment NLR had prolonged OS, and patients with a low pretreatment GPS had increased OS and PFS. A performance score (PS) of 0-1, development of immune-related adverse events, and GPS of 0-1 were significantly associated with OS in multivariate analysis. In summary, baseline pretreatment NLR and GPS are independently associated with OS in R/MHNSCC patients treated with nivolumab. Administration of nivolumab while maintaining the PS reflects a immune status of the host and leads to a good OS.

A case of lichenoid oral mucositis associated with nivolumab therapy

AbstractAn 80‐year‐old man diagnosed with recurrent lung squamous cell carcinoma had complaints of an erosion formation in the lower lip 4 weeks upon nivolumab administration which resulted in the discontinuation of nivolumab. At the first visit, oral candidiasis due to inappropriate handling of the patient's denture was observed. We administered antifungal medicine and treated the patient with a new dental prosthesis. As a result of a biopsy, a pathological diagnosis of oral mucositis similar to lichen planus was obtained. We successfully treated the patient with a beclomethasone spray. The mucosal erosion re‐epithelialized, and pain in the oral cavity completely disappeared.

Pre-treatment status of inflammation-based biomarkers in the patients with advanced gastric cancer who will be treated with nivolumab.

e16107 Background: Nivolumab is currently proved to be one of the most recommended regimens as the third-line chemotherapy for patients with advanced gastric cancer (AGC) in Japan. A variety of scores based on the systemic inflammation-based biomarkers have been reported to reflect survival in cancer patients. Kudou et al. recently reported that newly designed combined score of 5 inflammation-based prognostic scores (IBPSs), composed of neutrophil to lymphocyte ratio, platelet to lymphocyte ratio, Glasgow prognostic scale, prognostic index and prognostic nutritional index, might be predictive for the prognosis of resected gastric cancer (Ann Surg Oncol, 2020). The aim of the study is to investigate the clinical significance of nivolumab monotherapy in patients with AGC, associated with pre-treatment status of IBPSs including Kudou’s combined score (min 0 to max 10). Methods: Thirty-six patients received nivolumab monotherapy in our institute and enrolled to this retrospective study. We conducted a retrospective review of the data of 24 patients with AGC who received ≧ 2 cycles of nivolumab as the 3rd-line chemotherapy. Adverse events, tumor responses, the IBPSs and survival data were analyzed. Results: Three patients quitted the continuation of nivolumab except for the progressive disease, due to non-hematological toxicities higher than grade 3 including myositis, hypothyroidism, dermatitis and liver dysfunction. The rate of hematological toxicities, which showed severe anemia of higher than grade 3 was 20.8%. The ORR and the DCR were 4.2% and 41.7%, respectively. The median PFS and the OS after nivolumab administration were 69 and 274 days, respectively. Pre-chemotherapeutic combined score of IBPSs below 7 was significantly associated with the longer OS (P=0.014) in exposure of nivolumab, compared with the patients group presenting more than 7. Conclusions: Nivolumab monotherapy as the 3rd-line is one of the best regimens for patients with AGC showing better PS or lower combined score of IBPSs.

COMBAT-CRPC: Concurrent administration of bipolar androgen therapy (BAT) and nivolumab in men with metastatic castration-resistant prostate cancer (mCRPC).

5014 Background: During BAT, intramuscular (IM) testosterone (T) is administered, which results in rapid cycling of serum T levels from supraphysiologic to near-castrate in men with metastatic castration resistant prostate cancer (mCRPC). We previously observed anecdotal clinical responses to immune checkpoint blockade (ICB) in mCRPC patients (pts) previously treated with BAT and hypothesized that that a BAT/ICB combination would be synergistic. Here we report a prospective phase 2 study of men with mCRPC treated with BAT in combination with nivolumab. Methods: This was a multi-center, single arm, open label phase 2 trial (NCT03554317) of men with mCRPC who received T cypionate 400mg IM (BAT) every 28 days and nivolumab 480mg IV every 28 days. LHRH agonist treatment was continued. All pts received BAT as single agent therapy for a 12-week lead-in prior to the addition of nivolumab. Eligible pts were those with asymptomatic mCRPC who had soft tissue disease amenable to biopsy and progressed on at least one prior novel AR targeted therapy. Up to one line of chemotherapy was allowed for the treatment of mCRPC disease. The primary endpoint was confirmed PSA50 response rate. Key secondary endpoints included safety, objective response rate (ORR), and radiographic progression-free survival (rPFS). The trial was designed to detect a 20% absolute increase in PSA50 response rate from the null of 25%. Results: 45 pts were enrolled on study and treated. The confirmed PSA50 response rate was 40.0% (N=18/45, 95% CI: 26-56%, P=0.02 against the 25% null hypothesis). For pts with measureable disease, the ORR was 23.8% (N=10/42). Median rPFS on BAT and nivolumab was estimated at 5.7 months (95% CI: 4.9-7.8 months). 11.1% (N=5/45) of pts were free from radiographic progression for 11 or more months. One patient achieved a complete radiographic response, which is ongoing (>13 months). The majority of adverse events (AE) were Grade <2. The most common AEs were edema (20%), nausea (20%), and back pain (13%). Immune related AE (irAE) were generally mild (Grade <2) with N=2 Grade 3 irAE observed (pericarditis, lipase elevation). Serial biopsies were obtained on trial for translational studies. Conclusions: BAT plus nivolumab was well tolerated without concerning safety signals. The combination met the pre-specified primary endpoint of confirmed PSA50 response in a heavily treated population. Durable responses were observed in a subset of pts. Biomarker analysis is ongoing to identify a molecular signature predictive of response. Clinical trial information: NCT03554317. [Table: see text]

Autoimmune hemolytic anemia during long‐term administration of nivolumab for metastatic melanoma

Autoimmune hemolytic anemia during long‐term administration of nivolumab for metastatic melanoma

New-Onset Diabetic Ketoacidosis Secondary to Nivolumab Therapy in a Patient with Primary Central Nervous System Lymphoma

Introduction: Inhibitors of programmed cell death receptor (PD-1) and its ligand (PD-L1), such as nivolumab and pembrolizumab, confer anti-autoimmune activities and are therefore approved for anti-cancer therapy. Their mode of action removes autoimmunity checkpoints, thus increasing the risk of immune-related adverse events.
 Case Presentation: This report describes a clinical case of life-threatening diabetic ketoacidosis (DKA) in a patient after long-term nivolumab administration to treat primary central nervous system lymphoma (PCNSL). The patient presented to the emergency department (ED) with symptoms of fatigue, along with nausea and vomiting for two days; laboratory testing revealed significant hyperglycemia (glucose 673 mg/dL), elevated anion gap (>27), metabolic acidosis, ketonemia, glucosuria and ketonuria, findings of which were consistent with DKA. Given no personal history of diabetes mellitus or other autoimmune conditions and additional tests ruling out alternative causes, the patient was suspected of having newly-onset DKA secondary to nivolumab treatment.
 Management & Outcome: The patient was treated with fluids, electrolytes replenishments and insulin drip, which closed the anion gap and normalized electrolytes. She was transitioned to subcutaneous insulin. The patient recovered well and was discharged on Metformin and longacting insulin, with close follow-up with endocrinology and oncology.
 Discussion: Autoimmune endocrinopathies induced by checkpoint inhibitors for cancer treatment have been reported in the past. Newly-onset hyperglycemia and DKA are common autoimmunemediated side effects of checkpoint inhibitor uses in patients without prior history of diabetes mellitus. Clinicians should be aware to prevent this potentially life-threatening condition.

Pharmacokinetics and clinical outcomes of nivolumab administered every 4 weeks in patients with advanced non-small-cell lung cancer: A four-case pilot study.

This pilot study evaluated the pharmacokinetics and clinical outcome of nivolumab, administered every 4 weeks to patients with advanced non-small-cell lung cancer. The interval of nivolumab administration was changed from 2 to 4 weeks in four patients in whom tumor growth had been controlled for more than 6 months. Pharmacokinetics and clinical outcomes of nivolumab were prospectively investigated. The estimated steady-state nivolumab mean plasma concentration (±standard deviation) of each interval in the four patients was 53.1 (±15.0) at 4 weeks and 105.2 (±29.5) μg/mL at 2 weeks. No disease progression was observed in three patients for at least 1 year after the interval change; however, one patient developed interstitial lung disease within 5.6 months after the change. In conclusion, the pharmacological effects of nivolumab continued with doses administered less frequently than the standard schedule. Nevertheless, further research on nivolumab administration intervals is necessary.

Re-irradiation with concurrent and maintenance nivolumab in locally recurrent and inoperable squamous cell carcinoma of the head and neck: A single-center cohort study

BackgroundThe rate of loco-regional recurrences for locally advanced head and neck squamous cell carcinoma (HNSCC) following standard treatment reaches up to 50%, accompanied by a probability of 20% to develop a second primary tumor in the head and neck region. MethodsTen patients with inoperable, in-field recurrence of HNSCC following previous primary or adjuvant radiotherapy (RT) in combination with concurrent platinum-based chemotherapy were re-irradiated with 60 Gray in 30 fractions between December 2017 and January 2020 with concurrent and maintenance nivolumab administration. Data were retrospectively collected and compared with patients who underwent re-irradiation (ReRT) with concurrent cisplatin following propensity score matching (PSM). Local progression-free survival (LPFS) and overall survival (OS) were visualized using Kaplan-Meier method (log-rank test). ResultsAll patients completed ReRT. Median number of applied courses of nivolumab was 12 (range, 3–38). OS rate was 50% at 12 months and the median OS was 11 (range, 2–23) months. Six and 12 month LPFS rates were 60% and 30%, respectively. Median LPFS was 8 (range, 2–19) months. OS and LPFS rates were not inferior to those of patients treated with concurrent cisplatin. No unexpected radiation-related toxicity occurred. A total of four patients developed any-grade immune-related adverse events of which two presented with grade 3 toxicities. One patient died within 3 weeks after ReRT. Higher blood levels of CRP (p = 0.004), lower levels of hemoglobin (p = 0.029) and higher neutrophil/lymphocyte ratio (p = 0.004) were associated with impaired LPFS. Higher recursive portioning analysis (RPA) class was associated with impaired LPFS (p = 0.022) and OS (p = 0.024). ConclusionThe combination of ReRT and nivolumab for locally recurrent HNSCC was feasible without occurrence of unexpected toxicities. Combined radioimmunotherapy might offer an effective treatment option for carefully selected pre-irradiated patients ineligible for salvage surgery.

A New Method for Optimizing Sepsis Therapy by Nivolumab and Meropenem Combination: Importance of Early Intervention and CTL Reinvigoration Rate as a Response Marker.

Background: Recently, there has been a growing interest in applying immune checkpoint blockers (ICBs), so far used to treat cancer, to patients with bacterial sepsis. We aimed to develop a method for predicting the personal benefit of potential treatments for sepsis, and to apply it to therapy by meropenem, an antibiotic drug, and nivolumab, a programmed cell death-1 (PD-1) pathway inhibitor.Methods: We defined an optimization problem as a concise framework of treatment aims and formulated a fitness function for grading sepsis treatments according to their success in accomplishing the pre-defined aims. We developed a mathematical model for the interactions between the pathogen, the cellular immune system and the drugs, whose simulations under diverse combined meropenem and nivolumab schedules, and calculation of the fitness function for each schedule served to plot the fitness landscapes for each set of treatments and personal patient parameters.Results: Results show that treatment by meropenem and nivolumab has maximum benefit if the interval between the onset of the two drugs does not exceed a dose-dependent threshold, beyond which the benefit drops sharply. However, a second nivolumab application, within 7–10 days after the first, can extinguish a pathogen which the first nivolumab application failed to remove. The utility of increasing nivolumab total dose above 6 mg/kg is contingent on the patient's personal immune attributes, notably, the reinvigoration rate of exhausted CTLs and the overall suppression rates of functional CTLs. A baseline pathogen load, higher than 5,000 CFU/μL, precludes successful nivolumab and meropenem combination therapy, whereas when the initial load is lower than 3,000 CFU/μL, meropenem monotherapy suffices for removing the pathogen.Discussion: Our study shows that early administration of nivolumab, 6 mg/kg, in combination with antibiotics, can alleviate bacterial sepsis in cases where antibiotics alone are insufficient and the initial pathogen load is not too high. The study pinpoints the role of precision medicine in sepsis, suggesting that personalized therapy by ICBs can improve pathogen elimination and dampen immunosuppression. Our results highlight the importance in using reliable markers for classifying patients according to their predicted response and provides a valuable tool in personalizing the drug regimens for patients with sepsis.

Nivolumab for recurrent/metastatic hypopharyngeal squamous cell carcinoma in a liver transplant recipient

Nivolumab administration to patients with organ transplantation history requires careful management. Herein, we report the case of a living-donor liver-transplant recipient, a 52-year-old man, with recurrent and metastatic hypopharyngeal cancer treated with nivolumab. He was diagnosed with T2N2bM0 stage IVA hypopharyngeal squamous cell carcinoma. While using oral immunosuppressants (cyclosporine and mycophenolate mofetil), the patient underwent right neck dissection followed by radiotherapy as an initial treatment. Three months after radiotherapy, positron emission tomography scans revealed multiple bone metastases. We administered two courses of the EXTREME regimen, comprising cisplatin, 5-fluorouracil, and cetuximab, as the first-line treatment for distal metastasis, but the patient presented with progressive disease. The patient was administered nivolumab as the second-line treatment. The programmed death-ligand 1 (PD-L1) expression level in a biopsy specimen of the primary hypopharyngeal tumor and resected specimen of the cervical lymph node metastasis was 40% and 10%, respectively. PD-L1 expression was not detected in hepatocytes of the liver biopsy sample obtained before nivolumab introduction. The patient received four courses of nivolumab 240 mg. Although liver dysfunction was alleviated by adjusting the dose of the hepatoprotective agent and cyclosporine, the progressive disease status persisted after completing nivolumab courses. The patient died of hypopharyngeal cancer progression.

FRONTiER: A feasibility trial of nivolumab with neoadjuvant CF or DCF therapy for locally advanced esophageal carcinoma (JCOG1804E)—The short-term results of cohort A and B.

202 Background: The standard neoadjuvant chemotherapy (NAC) in Japan for locally advanced esophageal squamous cell cancer (ESCC) is CDDP + 5-FU (CF). Immune checkpoint inhibitors (ICI) such as nivolumab provide a survival benefit in ESCC, and have potential as NAC agents in lung, skin, and breast cancers, amongst others. However, whether ICI are efficacious in combination with cytotoxic agents, and whether ICI impact the safety of subsequent surgery after they are used as NAC for ESCC patients (pts) is currently unclear. Methods: FRONTiER is a multi-cohort phase I study designed to evaluate the safety and efficacy of ICI combined with NAC in ESCC. Histologically proven ESCC pts with cT1N1-3M0 or cT2-3N0-3M0 (8th-UICC TNM classification), 20–75 years old, PS ≤ 1, no prior therapies against any cancer were eligible. The primary endpoint was the incidence of dose-limiting toxicities (DLT) from the initial dose to the 30th postoperative day. This study contained 4 experimental cohorts, the NAC regimen of cohort A consisted of 2 courses of CDDP at 80 mg/m2, nivolumab at 360 mg/body on day 1 and 5-FU at 800 mg/m2 on days 1–5, q3wks. The regimen of cohort B consisted of one administration of nivolumab at 240 mg/body 2 weeks before chemotherapy, followed by the same treatments as cohort A. Results: Thirteen pts were enrolled to cohort A (n = 6) and B (n = 7). Characteristics were follows; median age: 62 (range: 34–75), PS 0/1: 9/4 pts, clinical stage I/II/III: 2/1/10 pts. One pt in cohort B was excluded from safety evaluation due to R2 resection, no DLTs were observed in 12 pts. The most frequent adverse events (≥ grade 3) were neutropenia in 6 pts during NAC, lung infection in 1, hyperglycemia in 1, pleural effusion in 1, infection (right neck) in 1, anemia in 1, abdominal pain in 1, and anatomic leakage in 1 during the postoperative period. Within 30 days post-operation, grade 2 adrenal insufficiency was observed in 1 pt of cohort B. No grade 4 adverse events or treatment-related deaths were seen. All pts received two courses of NAC + nivolumab and R0 resection was achieved in 12 pts (92.3%) without interruption of treatment. A pathological complete response was achieved in 2 pts (33.3%) in cohort A. Conclusions: Neoadjuvant CF + nivolumab with/without prior administration of nivolumab followed by surgery for locally advanced ESCC was well tolerated and showed promising efficacy. Clinical trial information: NCT03914443.

Administration of Nivolumab in Metastatic Renal Cell Cancer Following Treatment With mTOR Inhibitors.

Immunotherapy with checkpoint inhibitors is currently considered a cornerstone of metastatic renal clear cell cancer (mRCC) therapy. Despite the general improvement in the survival of patients with mRCC, there are some clinical situations that have not been specifically evaluated in clinical trials, such as the use of everolimus before nivolumab. We performed a retrospective analysis evaluating the efficacy of nivolumab in the real-world setting, including a subset of patients with previous mTOR inhibitor therapy. From a total of 56 patients, 25 were pre-treated with everolimus before receiving nivolumab. The overall progression-free survival (PFS), overall survival (OS), and objective response rate were 10.3, 21.3 months, and 34%, respectively. There were no statistically significant differences in patients who were or were not pre-treated with everolimus. mRCC patients should be treated with checkpoint inhibitors and prior use of mTOR inhibitors should not be a definitive exclusion criterium.

Renal allograft rejection after treatment with nivolumab in patients with metastatic renal cell carcinoma.

In recent years, immune checkpoint inhibitors (ICIs), such as nivolumab, pembrolizumab and ipilimumab, have been introduced into routine clinical practice for treating patients with several types of advanced cancer, including renal cell carcinoma (RCC). However, activation of the immune system against cancer cells by the use of ICIs could result in the induction of allograft rejection in organ transplant patients, and to date, the safety of treatment for organ transplant patients with ICIs has not been well-investigated. Here, we report a case of renal allograft rejection in a kidney transplant recipient with metastatic RCC (mRCC) after the administration of nivolumab. Four weeks after initiating treatment with nivolumab, the renal function, in this case, was markedly impaired, and pathological findings of renal biopsy specimens showed acute rejection characterized by marked infiltration of inflammatory cells. Steroid pulse therapy was performed in this case, and despite the lack of improvement in the renal function, his graft was salvaged. Collectively, these findings suggest that it is necessary to pay special attention to the potential for allograft rejection when introducing ICIs for solid organ transplant recipients.

A Case of Malignant Melanoma with Binocular Ptosis during Nivolumab Administration

A Case of Malignant Melanoma with Binocular Ptosis during Nivolumab Administration

Nivolumab投与2年，完全奏効し投与終了とした再発転移舌癌の1例

Nivolumab投与2年，完全奏効し投与終了とした再発転移舌癌の1例

Acute Demyelinating Polyneuropathy Occurring Four Days After Nivolumab Administration in a Patient with Lung Adenocarcinoma

Acute Demyelinating Polyneuropathy Occurring Four Days After Nivolumab Administration in a Patient with Lung Adenocarcinoma

Use of an alternative signature peptide during development of a LC-MS/MS assay of plasma nivolumab levels applicable for multiple species

Recently, immune checkpoint inhibitors, including anti-programmed cell death protein 1 (PD-1) antibodies, have dramatically changed treatment strategies for several cancers. In pharmacokinetic/pharmacodynamic studies, experiments using a variety of animal species are assumed.We have identified optimal multiple reaction monitoring transitions for signature candidate peptides of nivolumab in human, mouse, and rat plasma and developed a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method to quantify nivolumab (an anti-PD-1 antibody) using trastuzumab as the internal standard.Calibration curves were linear in the range of 1–200 µg/mL. The intra- and inter-day precision and accuracy in human plasma fulfilled Food and Drug Administration guideline criteria for bioanalytical validation. There was no need to change the measurement method in mouse plasma. On the other hand, in rat plasma, an interference peak was observed at a retention time similar to that of the surrogate peptide ASGITFSNSGMHWVR (550.75 > 661.50) employed in human and mouse plasma. Therefore, we confirmed that ASQSVSSYLAWYQQKPGQAPR (785.0 > 940.2) can be used as an alternate nivolumab surrogate peptide in rat plasma at the same concentration range as used in human and mouse plasma. Using our method, the concentration range and a gradual increase in trough value were confirmed in clinical samples from two antibody-treated patients, including one with gastric cancer and one with non-small-cell lung cancer. The time course and blood concentration transition also were evaluated in nivolumab administration experiments in mouse and rat.The present study showed that the selection of the optimal peptide is essential for accurate LC-MS/MS measurement of nivolumab concentration in human, mouse, and rat plasma. The method developed here is expected to be of use in non-clinical and clinical pharmacokinetic studies.

IMMU-09. NIVOLUMAB THERAPY FOR A PEDIATRIC-ONSET PRIMARY INTRACRANIAL MELANOMA

Primary intracranial malignant melanoma (PIMM) is an uncommon cancer in childhood, that accounts for approximately 1% of melanoma, and 0.07% of brain tumors even in all age group. Because extracranial malignant melanoma usually occurs as a cutaneous lesion, affected patients have a chance to receive the early diagnosis and curable resection of the isolated tumor. However, unresectable metastatic cases have a poor prognosis with a median overall survival of 8 months. We report a 12-year-old girl with PIMM who received nivolumab therapy after an administration of dacarbazine. The tumor harbored no BRAF mutation. After the intravenous administration of nivolumab, cerebrospinal fluid 5-S-cysteinyldopa levels declined and circulating CD8+HLA-DR+T cells increased, indicating the initial effect of nivolumab on PIMM. However, multiple lesions progressed for two month-immunotherapy, during which cerebrospinal fluid nivolumab concentrations attained to 1.2% of serum ones. The present case demonstrated the safety and modest effect of nivolumab for CNS melanoma. Nivolumab is a tolerable first-line therapy for diffuse PIMM, but pediatric patients need a more intensified CNS-specific immunotherapy.

65MO A phase I clinical trial on intratumoural (IT) administration of ipilimumab (IPI) plus nivolumab (NIVO) followed by intracavitary (IC) administration of nivolumab in patients with recurrent glioblastoma

65MO A phase I clinical trial on intratumoural (IT) administration of ipilimumab (IPI) plus nivolumab (NIVO) followed by intracavitary (IC) administration of nivolumab in patients with recurrent glioblastoma