PD-1 Inhibitor Nivolumab Research Articles

Efficacy, cellular and molecular determinants of PD-1 checkpoint inhibition in relapsed mesothelioma.

8506 Background: Leveraging adaptive immunity to control mesothelioma is now a standard approach, however the factors that underpin clinical response are poorly understood. Here we report the final analysis of the CONFIRM trial (NCT03063450), a double-blind phase III randomized study of the PD-1 inhibitor nivolumab (N) versus placebo (P) in patients (pts) with unresectable mesothelioma. Genomic, transcriptomic and multiplex spatial phenotypic correlates were explored in mesotheliomas exhibiting either partial response or progressive disease as their best outcome. Methods: Pts with relapsed pleural or peritoneal mesothelioma with ECOG performance status 0–1 were randomized 2:1 to N (3 mg/kg) or P once every 2 weeks until progression, or a maximum of 12 months. Pts were stratified by epithelioid (E) vs non-epithelioid (NE) histology. Co-primary endpoints were progression-free survival (PFS) and overall survival (OS); key secondary endpoints included best overall response, safety and tolerability. PD-L1 tumour proportion score (TPS, Dako22C3) was evaluated. To decipher correlates response to N, blinded multi-omic analysis was conducted in a subset of responders (R, n=16) versus progressors (NR, n=13). Whole exomes (WES) and transcriptomes were sequenced, with immune landscapes profiled by 19x depth 4-panel multiplex immunofluorescence. Acquired resistance was explored by WES in a biopsied responder at the time of progression. Results: Between April 2017-March 2020, 332 pts were randomised to N (n=221) or P (n=111). Median follow up was 37.2m. Baseline characteristics were balanced between arms. Histology: E 88.3%, 3rd line or greater 69.9%. PFS was longer for N vs P (events=324; median, 2.9 vs 1.6 months; HR 0.65; 95% CI, 0.51 – 0.82; P<0.001). Crossover from P was 18.0% (due to widespread availability of N during the covid19 pandemic). OS curves crossed at 32m; 9.5 vs 6.8 months; HR, 0.81; 95% CI, 0.64 – 1.04; P=0.096). Grade 3-4 treatment-related toxicity occurred in 20.4% vs 7.2% of pts; discontinuation occurred in 13.6% (N) versus 9.9%. PD-L1 TPS was not predictive of PFS or OS. The R-subgroup had longer PFS versus NR (319 versus 30 days, Hazard ratio, HR 0.02, p<0.001) and OS (670 vs 122 days HR 0.19, p<0.001). The R-group were enriched for BAP1 inactivation, CD8+ T-cell infiltration, T cell co-stimulation, cytolytic activity and mature tertiary lymphoid structures (TLSs). Conversely, the NR group had significantly more aneuploidy (notably uniparental disomy, UPD), and enrichment of epithelial mesenchymal transition, TGF beta signalling, and E2F transcription. Acquired resistance was associated with increased aneuploidy (UPD) and subclonal evolution including a new DNMT3A c2204A>G mutation. Conclusions: N met its co-primary endpoint of PFS with responding mesotheliomas harbouring a TLS enriched, inflamed tumour microenvironment and stable genome compared to non-responders. Clinical trial information: NCT03063450 .

Efficacy and predictors of response of nivolumab in treatment-refractory MSI solid tumors: Results of a tumor-agnostic DRUP cohort.

2590 Background: Microsatellite unstable (MSI) tumors represent 4% of all cancer diagnoses and are known to be sensitive to immune checkpoint inhibitors (ICI). Despite the progress made, a significant proportion of patients with MSI tumors does not respond, highlighting the urgent need to identify additional predictive biomarkers. In this study, we evaluated the efficacy of the PD-1 inhibitor nivolumab across pre-treated solid MSI tumors and performed extensive biomarker analysis to better characterize ICI-effectiveness in this setting. Methods: Adult patients with MSI tumors who exhausted all standard of care treatment options were eligible for inclusion and were enrolled in the Drug Rediscovery Protocol (DRUP), a clinical trial that treats cancer patients with approved targeted- and immunotherapies outside their registered indication, based on their tumor molecular profile (NCT0295234). Patients were treated with nivolumab (four cycles of 240 mg every 2 weeks, followed by 480 mg every 4 weeks) until disease progression or unmanageable toxicity. Primary endpoint was clinical benefit (CB, objective response (OR) or stable disease ≥ 16 weeks). Whole genome sequencing and RNA sequencing were performed on pre-treatment biopsies to reveal potential predictors of response or resistance to anti-PD1. Results: 130 evaluable patients were enrolled with in total 16 different tumor types. CB was observed in 62% (95% CI 46 – 54) ( N = 80) with an OR in 45% (95% CI 53 – 70) ( N = 58). After a median follow-up of 14.5 months (95% CI 13 – 19), median progression free survival was 18 months (95% CI 9 – not reached) and median overall survival was not reached. HLA class I status and mutational burden were not significantly associated with CB. However, in depth biomarker analyses identified that mutational burden was predictive of CB in HLA-wildtype patients (52%) but not in HLA class I mutants (48%). Strikingly, in contrast to the paradigm that neoantigen-specific adaptive immunity is primarily involved in clearing MSI tumors, transcriptomics indicated that, compared to non-CB, CB was characterized by significantly higher expression of key modulators in innate immunity, including non-classical HLA transcripts (P = 4.2x10-3), NKGD2 ligands MICA/MICB (P = 6.4x10-3), killer immunoglobulin-like receptors ( P = 0.047) and butyrophilins ( P = 0.024). Conclusions: Nivolumab proved highly effective in pre-treated, advanced solid MSI tumors. Genomic analysis revealed that neoantigen burden only determined ICI-effectiveness in patients with wildtype HLA class I. Furthermore, transcriptomics revealed a central role of innate immunity in ICI-effectiveness in MSI tumors, which aligns with the fact that these tumors frequently lose HLA class I antigen presentation. Together, these results inform novel biomarker strategies to further refine precision medicine in this patient population. Clinical trial information: NCT0295234 .

Sequential administration of PD‑1 inhibitor and cetuximab causes pneumonia.

Severe drug-induced lung injury (DLI) has been reported to be associated with sequential administration of osimertinib, a third-generation tyrosine kinase inhibitor, following a programmed cell death ligand 1 (PD-L1) inhibitor. However, the relationship of sequential treatment with an anti-epidermal growth factor receptor (EGFR) antibody and PD-1 inhibitor with the risk of DLI remains to be elucidated. The present study conducted a retrospective review of the medical records of a total of 179 patients with head and neck cancer who had received treatment with cetuximab and/or a PD-1 inhibitor (nivolumab or pembrolizumab) at Chiba University Hospital (Chiba, Japan) between September 2014 and December 2020. The incidence of pneumonia and the clinical background characteristics of the patients were analyzed. The patients were classified into subgroups for analysis of the outcomes in this study: Patients who had received sequential, but not concurrent, cetuximab and PD-1 inhibitor treatment (Group C+P; n=43); patients who had received cetuximab-containing chemotherapy, but not a PD-1 inhibitor (Group C; n=101); and patients who had received PD-1 inhibitor-containing chemotherapy, but not cetuximab (Group P; n=35). The rates of DLI in the three groups were: Group C+P, 18.6%; Group C, 7.9%; and Group P, 11.4%. Prior use of ICI was not associated with any increase in the risk of DLI. DLI is seen frequently in patients receiving sequential PD-1 inhibitor and anti-EGFR antibody therapy.

Cardiovascular Immunotoxicity Associated with Immune Checkpoint Inhibitors in Metastatic Melanoma

Checkpoint inhibitors, such as PD-1 inhibitors (nivolumab, pembrolizumab) and anti-CTLA-4 (CD152) (ipilimumab), are widely used in metastatic melanoma, and most immune-related adverse events are known. Several cardiovascular AEs (CVAEs) associated with immune checkpoint inhibitor exposure have been reported in post-marketing surveillance studies and represent major issues for patients with melanoma during and after cancer treatment. Data on CVAES induced by immune checkpoint inhibitors in melanoma, especially incidence and risk factors, are lacking. A systematic review of the literature up to 31 August 2020 was performed in Medline, the Cochrane Central Register of Controlled Trials (CENTRAL), and the ClinicalTrials.gov register according to prespecified selection criteria from inception to 7 April 2020. Statistics were performed on 3289 patients from five randomized clinical trials on melanoma. Patients with melanoma treated with immune checkpoint inhibitors had a significant risk of presenting dyslipidemia (Peto OR: 4.74, 95% CI: 2.16-10.41, p < 0.01, I2 = 0%, p = 0.94). The Peto OR was numerically significant for pericarditis, myocarditis, heart failure, myocardial infarction, cerebral ischemia, high pulmonary pressure, blood high pressure, arrhythmias, endocarditis, and conduction disturbances, but the confidence interval was not significant. The risk of CVAEs was not statistically different between melanoma treated with immune checkpoint inhibitors and other tumors treated with immune checkpoint inhibitors (range of p-value from 0.13 to 0.95). No interaction between follow-up length and CVAE reporting was found. Our study underlines that checkpoint inhibitors used for melanoma increase CVAEs, especially dyslipidemia, which could pave the way to chronic inflammatory processes, atherosclerosis, and, finally, ischemic cardiopathy. These cardiovascular adverse events could be acute or delayed, justifying the monitoring of lipidic biology and a baseline cardiology consultation.

Abstract 4387: Total toxicity burden of FDA approved immune checkpoint inhibitors in USA

Abstract Immune checkpoint inhibitors (ICIs) have revolutionized the treatment landscape for multiple cancers, demonstrating effective and durable responses and becoming the standard of care for a variety of malignancies. However, ICI-based treatment has resulted in the rise of unique immune-related adverse events (irAEs). To date, very little information is available on the frequency, significance, and management of single-organ or multiorgan irAEs in clinic. In this study, the irAEs associated with the treatment of seven FDA-approved ICIs, including three PD-1 inhibitors (cemiplimab, nivolumab and pembrolizumab), three PD-L1 inhibitors (atezolizumab, avelumab and durvalumab), and one CTLA4 inhibitor (ipilimumab), were analyzed based on the data of 149,303 report cases (January 1, 2015 - June 30, 2022) collected from FDA Adverse Events Reporting System (FAERS) public dashboard. Our data reveal that irAEs associated with the treatment of anti-PD-1 ICIs (e.g., pembrolizumab) require less hospital care resources compared with anti-PD-L1 and anti-CTLA4 ICIs. Tissue and organ toxicity of ICIs are age and gender specific. ‘Cardiac disorders’ is the main disorder caused by these ICIs in cancer patients aged 65-85, while ‘reproductive system and breast disease’ is the main disorder in cancer patients aged 18-64. There are risks of respiratory and urinary system toxicity in male patients and reproductive system toxicity in female patients when they receive the treatment of ICIs. Studies such as this one provide the statistical data for understanding patients at risk of developing irAEs, which will underscore the importance of further exploring research strategies to predict, detect, and mitigate toxicities from ICIs. Citation Format: Fan Yang, Chloe Shay, Zhaohui Qin, Nabil Saba, Yong Teng. Total toxicity burden of FDA approved immune checkpoint inhibitors in USA. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4387.

Evidence-based rationale for low dose nivolumab in critically ill patients with sepsis-induced immunosuppression.

A substantial part of critically ill patients suffer from sepsis-induced immunosuppression. Reversal of immunosuppression through PD-1 checkpoint inhibition has been proposed as a treatment strategy to overcome immunosuppression in these patients. The PD-1 inhibitor nivolumab, currently used in treatment of cancer, has been evaluated in phase I/II studies in patients with sepsis, demonstrating tolerability and signs of clinical efficacy. No proper dose finding was performed in these studies and, after a single high dose of 480 mg or 960 mg nivolumab, PD-1 inhibition persisted beyond 90 days in the majority of cases. As the duration of sepsis is ~7-10 days, prolonged PD-1 inhibition may unnecessarily induce longer-term immune-related side effects. Based on previously published pharmacokinetic and pharmacodynamic data of nivolumab, a thorough in silico dose finding study for nivolumab in critically ill patients was performed. We found that volume of distribution and clearance of nivolumab were not higher in patients with sepsis compared to the cancer population for which nivolumab is currently approved and showed profound variability. We found that with a single dose of 20 mg nivolumab, the PD-1 receptor occupancy is predicted to stay above the 90% threshold for a median of 23 days (90% prediction interval of 7-78 days). We propose to investigate this dose in critically ill patients as a potential safe and cost-effective pharmacotherapeutic intervention to treat sepsis-induced immunosuppression.

Immune-related adverse events induced by programmed death protein-1 inhibitors from the perspective of lymphoma immunotherapy.

Lymphoma, which is highly malignant, stems from lymph nodes and lymphoid tissue. Lymphoma cells express programmed death-ligand 1/2 (PD-L1/PD-L2), which binds with programmed cell death 1 protein (PD-1) to establish inhibitory signaling that impedes the normal function of T cells and allows tumor cells to escape immune system surveillance. Recently, immune checkpoint inhibitor immunotherapies such as PD-1 inhibitors (nivolumab and pembrolizumab) have been introduced into the lymphoma treatment algorithm and have shown remarkable clinical efficacy and greatly improve prognosis in lymphoma patients. Accordingly, the number of lymphoma patients who are seeking treatment with PD-1 inhibitors is growing annually, which results in an increasing number of patients developing immune-related adverse events (irAEs). The occurrence of irAEs inevitably affects the benefits provided by immunotherapy, particularly when PD-1 inhibitors are applied. However, the mechanisms and characteristics of irAEs induced by PD-1 inhibitors in lymphoma need further investigation. This review article summarizes the latest research advances in irAEs during treatment of lymphoma with PD-1 inhibitors. A comprehensive understanding of irAEs incurred in immunotherapy can help to achieve better efficacy with PD-1 inhibitors in lymphoma.

Effect of PD-1 inhibition on macrophage population in human tissue cultures.

463 Background: Moderate response rates of PD-1 inhibition in gastric and esophagogastric junction cancers (GC/EGJC) urge for reliable biomarkers. To further improve treatment outcomes, patients need targeted therapy based on clinically relevant biomarkers and predictive test systems for assessing individual drug susceptibility. We have previously established patient derived tissue cultures (PDTC) as a comprehensive ex-vivo drug testing system for GC/EGJC patients. Methods: The standardized PDTC) model was developed using tissue from surgical resection specimens to investigate response to the PD-1 inhibitor Nivolumab and the macrophage depriving bisphosphonates clodronate and zoledronic acid. Resident macrophage population (CD68, CD163), tumor proliferation (Ki67) and apoptosis (cPARP), as well as bulk gene expression data (nanoString technology) were analysed after 72 hours of PD-1 inhibition. Additionally, supernatants were collected, and cytokine concentrations are measured based on Luminex technology. Results: Macrophage depletion could lead to enhanced anti-tumoral effects in PDTCs after PD-1 inhibition. Gene signatures for Interferon γ-mediated inflammation and myeloid cell activity were identified and found to be relevant indicators for tissue response upon immune checkpoint inhibition. We observed alterations in cytokine and soluble surface marker concentrations, such as IL-8, IL-17A and IL-23 or PD-L2, LAG3 and CTLA4. Conclusions: Yielding an organotypic cell composition, we were able to demonstrate individual response patterns and immunological characteristics to identify responsiveness to PD-1 inhibition in GC and EGJC tissue. PDTCs are potent to define biological marker sets ex vivo and to differentiate and predict clinical patient response as well as their inherent immune cell capacity and plasticity.

Patterns of toxicity burden for FDA-approved immune checkpoint inhibitors in the United States

BackgroundImmune-related adverse events (irAEs) are a common phenomenon in cancer patients treated with immune checkpoint inhibitors (ICIs). Surprisingly, the toxicity burdens of these irAEs have not been illustrated clearly. In this study, we analyzed irAEs for seven FDA-approved ICIs in cancer treatment to show the pattern of toxicity burden among cancer patients.MethodsirAEs associated with seven FDA-approved ICIs, including three PD-1 inhibitors (cemiplimab, nivolumab and pembrolizumab), three PD-L1 inhibitors (atezolizumab, avelumab and durvalumab), and one CTLA-4 inhibitor (ipilimumab), were analyzed based on data from 149,303 reported cases (from January 1, 2015 to June 30, 2022) collected from the FDA Adverse Events Reporting System (FAERS) public dashboard. Proportions of serious irAEs and correlations with tumor type, age and sex were assessed via R package and GraphPad software.ResultsirAEs related to anti-PD-1 ICIs required less hospital care resources compared with anti-PD-L1 and anti-CTLA-4 ICIs. Patients treated with pembrolizumab had relatively fewer serious cases. Treatment with ICIs led to the highest probability of serious irAEs in patients with lung cancer. ‘Respiratory, thoracic and mediastinal disorders’ and ‘gastrointestinal disorders’ were the two most common groups of disorders caused by the seven ICIs studied. ‘Cardiac disorders’ was the main type of disorders caused by these ICIs in cancer patients aged 65–85, while ‘reproductive system and breast disease’ was the main type of disorder in cancer patients aged 18–64. ‘Respiratory, thoracic, mediastinal diseases’ and ‘reproductive system and breast diseases’ were the main types of disorders associated with treatment with these ICIs in male and female patients, respectively.ConclusionTissue and organ toxicities of ICIs are age and sex specific. There are risks of respiratory and urinary system toxicity in male patients and reproductive system toxicity in female patients treated with the ICIs studied. Future studies on the toxicity burden of ICIs should incorporate age and sex differences to better understand the relevance of ICI toxicity burden to human immune function to develop appropriate tumor immune and therapeutic intervention strategies.

Phase Ib open-label, multicenter study of pixatimod, an activator of TLR9, in combination with nivolumab in subjects with microsatellite-stable metastatic colorectal cancer, metastatic pancreatic ductal adenocarcinoma and other solid tumors

BackgroundPixatimod is a unique activator of the Toll-like Receptor 9 pathway. This phase I trial evaluated safety, efficacy and pharmacodynamics of pixatimod and PD-1 inhibitor nivolumab in immunologically cold cancers.Methods3+3...

IMMUNOTHERAPY AS NOVEL TREATMENT OF LUNG CANCER: A SYSTEMATIC REVIEW

Lung cancer is the top cause of cancer-related fatalities in both men and women around the world, and the second most commonly diagnosed cancer in both men and women. For many patients, traditional chemotherapy (CT) fails to give long-term benefit. Moreover, newer medicines targeting activating mutations in EGFR or ALK have shown increased response rates over CT in the minority of patients with these mutations; however, the majority of patients do not have actionable mutations and will not benefit from targeted therapies. In addition, several combinations of chemotherapeutic medicines with the angiogenesis inhibitor bevacizumab have provided only minor additional benefits. However, immunotherapy using checkpoint inhibitors has shown to have a lot of potential in the treatment of advanced non-SCLC (NSCLC) in recent trials. These new medications encourage the host immune system to recognize tumor cells as foreign invaders and halting their growth. They help alleviate immune system suppression, which allows tumor development to be tolerated. In checkpoint immunotherapy, humanized monoclonal antibodies targeting checkpoint signals such as programmed cell death receptor (PD-1) and programmed cell death ligand are employed (PD-L1). The immune system can be triggered to fight the tumor by inhibiting these receptors and signals. Immunotherapy for advanced lung cancer has created a new paradigm of therapeutic options, with increased survival and response rates and a less severe but distinct side profile when compared to CT. The PD-1 inhibitors nivolumab and pembrolizumab, as well as the PD-L1 inhibitor atezolizumab, have been approved by regulatory authorities for the treatment of advanced NSCLC. Hence, the current review article focuses on the role of immunotherapy, newer agents used for checkpoint inhibitors in lung cancer, their epidemiology, risk factors, side-effect profiles, therapeutic indications, and their mechanism of action for the successful treatment of lung cancer.

Risk of Pneumonitis with Immune Checkpoint Inhibitors in Hodgkin's Lymphoma and Other Hematologic Malignancies: A Retrospective Review from Pharmacovigilance

Background: Immune checkpoint inhibitors have revolutionized cancer therapeutics. These drugs block the interaction between PD -1/PDL-1, thus, promoting T-lymphocyte immune destruction of cancer cells. Checkpoint inhibitors are efficacious in cancer treatment and are generally well-tolerated in patients. However, activation of the immune system reacts with both tumor and healthy cells leading to toxicities known as immune-related adverse events(irAEs). Pulmonary irAEs, especially pneumonitis, are rare and difficult to diagnose. Previous studies have shown a 4% (single agent), and 10% (combination studies) risk of developing pneumonitis in solid tumors with exposure to checkpoint inhibitors (Sun et al., 2019, Naidoo et al., 2017). Although rare, pneumonitis has been reported as the most frequent fatal event, accounting for 35% of fatal toxicities from anti-PD-1/PD-L1 (Wang et al., 2018). However, the risk of developing pneumonitis when used for hematologic malignancies is not known especially in classical Hodgkin's Lymphoma (cHL) where it is used both in monotherapy and in combination with chemotherapy in the upfront and relapsed setting, often in patients who subsequently receive radiation and/or autologous stem cell transplant. Objective This study aims to estimate the risk of developing pneumonitis with exposure to immune checkpoint inhibitor (ICI) monotherapies to treat hematologic malignancies: nivolumab and pembrolizumab (anti-PD-1 drugs), durvalumab, and atezolizumab (anti-PD-L1 drugs). Methods We retrospectively reviewed the Food and Drug Administration Adverse Events Reporting System (FAERS), a pharmacovigilance (PV) database from 2012 to 2021. Statistical analysis involved a disproportionality analysis using a reported odds ratio (ROR). We use the ROR to assess the risk of pneumonitis with exposure to the five ICIs. OpenVigil, a software package used to analyze pharmacovigilance data, enabled the calculation of the ROR. The study reports a confidence interval of 95% to evaluate the precision of the ROR; ROR greater than one, p<0.05, and CI not including one indicated a greater odd of developing pneumonitis with an ICI of interest compared with other drugs in the database. Results The total number of events reported in FAERS between 2012 and 2021 was 17,273,403. Of these, 88,099(0.51%) were attributed to the PD-1inhibitors (nivolumab and pembrolizumab) and 21,905(0.13%) to PD-L1 inhibitors of interest. FAERS reported about 187 patients with hematologic malignancies treated with the five ICI monotherapies. Of these, 151(80.75%) patients developed pneumonitis. Ninety percent of the pneumonitis events were due to anti-PD-1drugs; (33(21.85%) with pembrolizumab and 103 (68.21%) with nivolumab). In contrast, 9.27% of the events were from the anti-PD-L1 drugs (7 (4.64%) with both durvalumab and atezolizumab). The combined risk of developing pneumonitis was significant at 1.73[95% CI, 1.48-2.04] p<0.001. About 148(98.01%) of the events were serious (grades > 3), and three (1.99%) were non-serious (grades <2). Healthcare professionals report about 80% of the events in FAERS; this may lead to a biased overreporting of higher-grade adverse events. Forty-six percent of the patients were hospitalized from the pneumonitis event, while 14.56% died from the event. Hodgkin's lymphoma was the most common indication for using the ICIs, 61 (40.40%). The most common regions to report these events were the United States, 110(72.85%), and Japan, 6(3.97%). Conclusion This retrospective study shows a risk of developing pneumonitis with exposure to checkpoint inhibitors. The risk is more significant for PD-1 inhibitors than for PD-L1 inhibitors. Patients with Hodgkin lymphoma are most affected, and while rare, this is a potentially fatal complication of therapy with ICIs. Thus, early detection is essential to initiate management, thus, minimizing patient morbidity and mortality from the event. Given the limitations of the PV database, this data will be compared with actual world data (RWD) at the upcoming meeting in December. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Diabetic ketoacidosis induced by nivolumab in invasive mucinous adenocarcinoma of the lung: a case report and review of the literature

Nivolumab is the first programmed cell death receptor 1 (PD-1) inhibitor approved in China. Compared with chemotherapy, nivolumab has shown advantages of good efficacy and safety in the treatment of a variety of tumors. However, due to its short time of use in China and lack of safety experience, clinical understanding of its adverse reactions has not been sufficiently elucidated. In recent years, cases of diabetic ketoacidosis caused by nivolumab have been reported in the emergency department, which has aroused our concern. Here we present a serious case of diabetic ketoacidosis in a 69-year-old woman with invasive mucinous adenocarcinoma of the lung, which occurred following therapy with the PD-1 inhibitor nivolumab and dendritic cell/cytokine-induced killer cell (DC/CIK) immunotherapy. She presented with diabetic ketoacidosis 5 days after the second cycle of nivolumab administration. The patient presented with dry mouth symptoms, a maximum blood glucose of 511.2 mg/dL, hemoglobin A1c (HbA1c) level of 7.4%, urine ketone body value of 3+, and extracellular fluid residual alkali level of -3.8 mmol/L. Normal saline and insulin was initiated. The patient had no history of obesity or family history of diabetes. She received a single dose of 3.75 mg of dexamethasone treatment during this period of time which resulted in cough improvement, but did not explain the onset of the diabetes. She was treated with insulin, sitagliptin phosphate tablets and acarbose tablets. Diabetic ketoacidosis was considered an immune-related toxicity caused by nivolumab, and consequently, treatment with nivolumab was suspended. Patient was maintained under insulin treatment with a blood glucose levels normalization. The incubation period of nivolumab-induced diabetic ketoacidosis is dispersive and the clinical risk is high. Patients need life-long insulin therapy. Blood glucose and HbA1c should be monitored routinely before and during nivolumab immunotherapy to avoid the occurrence of diabetic ketoacidosis. After the occurrence of diabetic ketoacidosis, insulin should be used to actively control blood glucose and do a good job in medication education to ensure long-term compliance of patients. Nivolumab should only be initiated if the patient has a clinical benefit under stable glucose control.

Hodgkin Lymphoma on Hemodialysis: A Review of Treatment and Recommendations.

Chemotherapy for classic Hodgkin lymphoma (cHL) patients on hemodialysis (HD) is an extremely challenging situation because pharmacokinetic and pharmacodynamic studies of most chemotherapeutics are lacking for the HD patient, and the small amount of evidence available comes mostly from case reports and small case series. In this review, we provide recommendations based on treatment experience of cHL patients on HD in the literature. HD patients undergoing chemotherapy are at risk of overdose and toxicities because many drugs are significantly eliminated by the kidneys, and at the same time, are at risk of undertreatment because many drugs are removed by HD. Therefore, dose modifications and timing of drug administration in relation to HD sessions must be carefully planned according to the distinct traits of each chemotherapeutic. We carried out an exhaustive literature review of reports of actual administrations of chemotherapeutics to cHL on HD, and also extrapolated data from reports of the same chemotherapeutics that were administered to HD patients with malignancies other than cHL. We summarized the information found in the literature, and provide practical and balanced recommendations concerning dose modifications and optimal timing of drug administration in relation to HD sessions for each chemotherapeutic. Chemotherapy regimens and individual chemotherapeutics studied in this review include ABVD (doxorubicin+bleomycin+vinblastine+dacarbazine), BEACOPP (bleomycin+etoposide+doxorubicin+cyclophosphamide+vincristine+procarbazine+prednisolone), MOPP (mechlorethamine+vincristine+procarbazine+prednisolone), gemcitabine, vinorelbine, brentuximab vedotin, and PD-1 inhibitors (nivolumab and pembrolizumab).

PD-1 receptor blocker

PD-1 or the programmed cell death protein 1 plays a major role in eliciting the immune checkpoint response of T cells. They are the inhibitory receptors induced in activated T cells. The application of these receptors earns a great interest to investigate, in-depth, their mechanism of action and therapeutic success. The US FDA has successfully approved three categories of immune checkpoint inhibitors. These are PD-1 inhibitors (Nivolumab, Pembrolizumab, and Cemiplimab), PDL-1 inhibitors (Atezolimumab, Durvalumab and, Avelumab), and CTLA-4 inhibitor (Ipilimumab). But still there lie several limitations in using this mode of treatment. Unlikely, not all patients respond well to these drugs. Apart from these, anti PD-1 monoclonal antibody showed its miraculous activity in treating cancer. It showed a hundred percent cure in patients with colorectal cancer without any kind of major side effects following the treatment procedure. Anti PD-1 monoclonal antibody (Dostarlimab) has shown promising results in endometrial cancer, ovarian cancer, melanoma, head and neck cancer, and breast cancer therapy. The current review focuses on the literature regarding the mechanism of action of immune checkpoint inhibitors, their role in cancer treatment.

Comparison of Second-Line Treatments for Patients with Platinum-Resistant Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: A Systematic Review and Bayesian Network Meta-Analysis.

Simple SummaryWhich second-line treatment is the optimal choice for patients with platinum-resistant recurrent or metastatic head and neck squamous cell carcinoma remains unclear. To inform clinical decisions, we performed a network meta-analysis and systematic review to assess the relative efficacy and safety of second-line treatments for patients with platinum-resistant recurrent or metastatic head and neck squamous cell carcinoma. By synthesizing all available controlled trial evidence, PD-1 inhibitors significantly improved the overall survival, objective response rate, and treatment tolerance compared to the standard of care (docetaxel, methotrexate, or cetuximab). Afatinib presented a better progression-free survival and objective response rate than the standard of care. Compared with afatinib, PD-1 inhibitors had a better overall survival but a worse progress-free survival.Several new drugs and combination strategies can be used to treat patients with recurrent or metastatic head and neck squamous cell carcinoma in the second-line treatment. Questions regarding the relative efficacy and safety of any two of the multiple second-line treatment strategies have emerged. This study aims to compare second-line treatments for patients with platinum-resistant recurrent or metastatic head and neck squamous cell carcinoma. Medline, Embase, and the Cochrane Central Register of Controlled Trials were searched to identify relevant articles. Direct and indirect evidence in terms of the objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and treatment-related adverse events grade ≥ 3 (grade ≥ 3 trAE) were analyzed in this Bayesian network meta-analysis. A total of twenty-three trials involving 5039 patients were included. These studies compared 20 different treatments, including the standard of care (SOC: docetaxel, methotrexate, or cetuximab), PD-1 inhibitors (nivolumab or pembrolizumab), durvalumab, tremelimumab, durvalumab + tremelimumab, palbociclib + SOC, tivantinib + SOC, sorafenib + SOC, EMD1201081 + SOC, vandetanib + SOC, PX-866 + SOC, 5-fluorouracil + SOC, cixutumumab + SOC, gefitinib + SOC, cabazitaxel, nolatrexed, duligotuzumab, zalutumumab, gefitinib, and afatinib. Among the currently available treatment options, compared to the standard of care (SOC: docetaxel, methotrexate, or cetuximab), the PD inhibitor significantly improved OS, ORR, and grade ≥ 3 trAE. Afatinib presented a better PFS and ORR than the SOC. Compared with afatinib, the PD-1 inhibitor had a better OS but a worse PFS. In conclusion, compared to the SOC, the PD-1 inhibitor significantly improved the OS, ORR, and grade ≥ 3 trAE. Afatinib presented a better PFS and ORR than the SOC. Compared with afatinib, the PD-1 inhibitor had a better OS but a worse PFS.

1250P Camrelizumab plus apatinib combined with POF in patients with untreated advanced gastric cancer (UAGC): A single-center, open-label, single-arm, phase II trial (SYLT-017)

Previous reports of POF demonstrated promising efficacy for patients with AGC (ASCO-GI 2019). Apatinib, a small molecule tyrosine kinase inhibitor, can be safely administered up to 850 mg daily combined with POF in AGC (ESMO 2019). The PD-1 inhibitor nivolumab provided superior OS, along with PFS benefit, in combination with chemotherapy in UAGC in the CheckMate-649 study. Camrelizumab, in combination with apatinib, has been demonstrated clinical benefits in multiple advanced solid tumors. On the basis of these results, we conducted this trial to evaluate the safety and efficacy of first-line camrelizumab plus apatinib combined with POF in patients with UAGC.

Cost-effectiveness analysis of tislelizumab, nivolumab and docetaxel as second- and third-line for advanced or metastatic non-small cell lung cancer in China

Objective: Domestic PD-1inhibitor tislelizumab has emerged as a promising treatment for Chinese patients with driver-negative advanced or metastatic non-small cell lung cancer (NSCLC). The purpose of our study to evaluate whether tislelizumab is cost-effective as a second- or third-line treatment for this population compared with docetaxel (conventional chemotherapy) and nivolumab (imported PD-1inhibitor), from the perspective of the Chinese healthcare system. Material and Methods: A Markov model with a 3-week Markov cycle and a 30-year time horizon was built to compare the cost-effectiveness of second- or third-line tislelizumab versus docetaxel and nivolumab. Transition probabilities, including disease progression, survival, and adverse events (AEs)-related treatment discontinuation event, were estimated from the clinical trials. Costs and health utilities were collected from local hospitals, public database and published literature. Results: Compared with docetaxel, tislelizumab provided an additional 0.33 quality-adjusted life-years (QALYs) (1.37 vs. 1.04 QALYs) at an incremental cost of $9,286 ($23,646 vs. $14,360) for Chinese patients with driver-negative advanced or metastatic NSCLC, resulting in an incremental cost-effectiveness ratio (ICER) of $27,959/QALY under the WTP threshold of $35,663/QALY used in the model. Compared with nivolumab, tislelizumab was associated with a lower cost ($23,646 vs. $59,447) and higher QALYs (1.37 vs. 1.20 QALYs), resulting in its dominance of nivolumab. Conclusion: From the perspective of the Chinese healthcare system, domestic PD-1inhibitor tislelizumab immunotherapy represents a cost-effective treatment strategy compared with conventional docetaxel chemotherapy and imported PD-1inhibitor nivolumab immunotherapy in the treatment of driver-negative advanced or metastatic NSCLC beyond the first-line setting. In the era of “Universal Medical Insurance System”, the rational use of domestic anticancer drugs guided by cost-benefit evidence would be an effective means to balance the limited expenditure of medical insurance fund and the growing demand for cancer treatments.

Combined MEK and STAT3 Inhibition Uncovers Stromal Plasticity by Enriching for Cancer-Associated Fibroblasts With Mesenchymal Stem Cell-Like Features to Overcome Immunotherapy Resistance in Pancreatic Cancer

We have shown that reciprocally activated rat sarcoma (RAS)/mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK) and Janus kinase/signal transducer and activator of transcription 3 (STAT3) pathways mediate therapeutic resistance in pancreatic ductal adenocarcinoma (PDAC), while combined MEK and STAT3 inhibition (MEKi+STAT3i) overcomes such resistance and alters stromal architecture. We now determine whether MEKi+STAT3i reprograms the cancer-associated fibroblast (CAF) and immune microenvironment to overcome resistance to immune checkpoint inhibition in PDAC. CAF and immune cell transcriptomes in MEKi (trametinib)+STAT3i (ruxolitinib)-treated vs vehicle-treated Ptf1aCre/+;LSL-KrasG12D/+;Tgfbr2flox/flox (PKT) tumors were examined via single-cell RNA sequencing (scRNAseq). Clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeats associated protein 9 silencing of CAF-restricted Map2k1/Mek1 or Stat3, or both, enabled interrogation of CAF-dependent effects on immunologic remodeling in orthotopic models. Tumor growth, survival, and immune profiling via mass cytometry by time-of-flight were examined in PKT mice treated with vehicle, anti-programmed cell death protein 1 (PD-1) monotherapy, and MEKi+STAT3i combined with anti-PD1. MEKi+STAT3i attenuates Il6/Cxcl1-expressing proinflammatory and Lrrc15-expressing myofibroblastic CAF phenotypes while enriching for Ly6a/Cd34-expressing CAFs exhibiting mesenchymal stem cell-like features via scRNAseq in PKT mice. This CAF plasticity is associated with M2-to-M1 reprogramming of tumor-associated macrophages, and enhanced trafficking of cluster of differentiation 8+ T cells, which exhibit distinct effector transcriptional programs. These MEKi+STAT3i-induced effects appear CAF-dependent, because CAF-restricted Mek1/Stat3 silencing mitigates inflammatory-CAF polarization and myeloid infiltration invivo. Addition of MEKi+STAT3i to PD-1 blockade not only dramatically improves antitumor responses and survival in PKT mice but also augments recruitment of activated/memory T cells while improving their degranulating and cytotoxic capacity compared with anti-PD-1 monotherapy. Importantly, treatment of a patient who has chemotherapy-refractory metastatic PDAC with MEKi (trametinib), STAT3i (ruxolitinib), and PD-1 inhibitor (nivolumab) yielded clinical benefit. Combined MEKi+STAT3i mitigates stromal inflammation and enriches for CAF phenotypes with mesenchymal stem cell-like properties to overcome immunotherapy resistance in PDAC.

Efficacy of nivolumab as second line treatment for recurrent or metastatic head and neck squamous cell carcinoma: a national DAHANCA cohort study

Introduction The aim of this study was to investigate phase IV efficacy, of the PD-1 inhibitor nivolumab among an unselected and unbiased national cohort of recurrent/metastatic Head and Neck Squamous Cell Carcinoma (rmHNSCC) patients. Material and Methods Inclusion criteria included histologically confirmed rmHNSCC and nivolumab as a second-line palliative treatment. Data were collected from patient files at the five Danish head and neck cancer centers and from the DAHANCA database. The iRECIST criteria were used for treatment evaluation. Endpoints were response rate (RR), overall survival (OS), and progression-free survival (PFS), calculated from the start of treatment to the date of event/censoring by the KM-method. Descriptive statistics were used to describe patients and treatment. Analyses were two-sided, with p < .05 considered significant. Results A total of 146 patients were identified in the period 2017–2020. They had a RR of 14%, median OS of 10.2 months [95% CI: 8.2–12.2] and median PFS of 3.1 months [95% CI: 2.3–4.2]. Patient age (≥ 70 years) or comorbidity did not significantly affect outcome. WHO performance status (PS) =1 was associated with an increased risk of death (HR: 2.1 [95% CI: 1.2–4.0], p = .02) and progression (HR: 1.9 [95% CI: 1.2–3.2], p = .01). Concomitant glucocorticoid-treatment during immunotherapy (≥ 50% of treatment time) appeared important for risk of death (HR: 6.4 [95% CI: 2.3–17.8], p < .001) and risk of progression (HR: 4.8 [95% CI: 1.8–12.5], p = .001). PD-L1 expression ≥ 20% was associated with a lowered risk of progression (HR: 0.5 [95% CI: 0.3–0.7], p = .001), but not lowered risk of death. Conclusion In this unselected national cohort, outcome of second-line treatment reflects data from the registration studies. Furthermore, the results suggest that immunotherapy should be used with great care in treatment of rmHNSCC in patients with poor performance.