Real-world evaluation of nivolumab utilization in adjuvant treatment of localized muscle-invasive urothelial carcinoma.

INTRODUCTION: In 2022, nivolumab was granted marketing authorization for adjuvant treatment in patients at high risk of recurrence following surgery for localized invasive muscle urothelial carcinoma, who express PD-L1 on the operative specimen. We aimed to investigate its real-world utilization. MATERIALS AND METHODS: Our bi-centric real-world study, conducted at Foch Hospital and Georges Pompidou European Hospital between July 2022 and January 2024, included patients who underwent surgery for urothelial carcinoma or were referred for adjuvant nivolumab treatment at these centers. RESULTS: A total of 200 patients underwent surgery during the study period, of whom 70 met the high-risk criteria, with 46% of these patients not receiving adjuvant treatment due to ineligibility. Our survival outcomes among patients treated by nivolumab are consistent with the results of the CheckMate 274 study2 (Bajorin DF, N Engl J Med. 2021). Our study population was older and frailer than that of the study cohort, with a mean age of 69 years. Significant PD-L1 expression was observed in 66% of the tested patients. The median disease-free survival was 11.34 months in patients who received neoadjuvant chemotherapy followed by surgery and adjuvant nivolumab. Nivolumab was generally well-tolerated, but 25% of patients discontinued it due to toxicity. Our initial data on treatments for recurrence after adjuvant nivolumab highlighted the effectiveness of conventional chemotherapy (cisplatin or carboplatin combined with gemcitabine) and targeted chemotherapy (enfortumab vedotin). CONCLUSION: Our real-world data align with existing literature regarding adjuvant nivolumab in localized invasive muscle urothelial carcinoma.

A Potential Role for Nivolumab in the Treatment of Fibrous Dysplasia-Related Pain.

Fibrous dysplasia (FD) is a chronic and progressive disorder of bone growth because of decreased osteoblast formation and osteoclast overactivity. Its main symptoms include pain, fracture, and irregular bone growth. Bisphosphonates are the mainstay of therapy for FD with a primary goal of pain relief. A 50-year-old woman presented to ophthalmology in March 2011 with intermittent proptosis, vertical diplopia, and orbital pain. A computed tomography scan of the head revealed a skull base lesion, which was confirmed to be fibrous dysplasia on bone biopsy. Because of significant headache, she was treated with IV pamidronate monthly starting November 2011, which led to pain reduction. Repeated attempts to decrease the frequency of pamidronate were unsuccessful because of breakthrough pain. Oral alendronate and risedronate did not control her symptoms. She remained on risedronate however because of its convenience. In August 2021, she was diagnosed with metastatic melanoma and started nivolumab. Her headache completely resolved for the first time in 10 years. Although nivolumab, a programmed death-1 blocker, has been used in the treatment of bone malignancy, it has not been previously studied in FD. By suppressing RANK ligand-related osteoclastogenesis, nivolumab decreases cancer-associated bone pain. Our case suggests a potential role for nivolumab in treating FD-associated pain.

Association between immune-related adverse events and the prognosis of patients with gastric cancer treated with nivolumab: a meta-analysis.

Background: Nivolumab is an effective treatment option for advanced gastric cancer (GC). This study aimed to conduct a systematic review of existing literature to investigate the relationship between immune-related adverse events (irAEs) and the prognosis of patients with GC treated with nivolumab. Methods: We comprehensively searched four online literature databases: the Cochrane Central Register of Controlled Trials, PubMed, Embase, Web of Science, until 27 March 2024. The outcome measures of interest included: overall survival (OS), progression-free survival (PFS), hazard ratio (HR), median survival ratio (MSR), objective response rate (ORR), and disease control rate (DCR). Results: A total of six studies, including 393 patients, met the eligibility criteria. The OS (pooled hazard ratio [HR] = 0.4, 95% confidence interval [CI]: 0.3-0.6, p < 0.05) and PFS (pooled HR = 0.5, 95% CI: 0.4-0.6, p < 0.05) of patients with irAEs were significantly superior to individuals without irAEs. The MSR for OS and PFS were 2.5 (95% CI: 1.5-4.1, p < 0.05) and 2.8 (95% CI: 1.9-4.1, p < 0.05), respectively. Regarding the ORR and DCR, we found that the development of irAEs was significantly associated with higher rates: patients with irAEs had an ORR of 24.7% compared to 6.4% in those without irAEs (risk ratio [RR] = 2.6, p < 0.05), and a DCR of 86.0% compared to 30.3% in those without irAEs (RR = 3.2, p < 0.05). Conclusion: There appears to be a significant correlation between the development of irAEs and the better survival benefits with nivolumab in patients with GC. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42022341396.

Residue-Specific Epitope Mapping of the PD-1/Nivolumab Interaction Using X-ray Footprinting Mass Spectrometry.

X-ray footprinting coupled with mass spectrometry (XFMS) presents a novel approach in structural biology, offering insights into protein conformation and dynamics in the solution state. The interaction of the cancer-immunotherapy monoclonal antibody nivolumab with its antigen target PD-1 was used to showcase the utility of XFMS against the previously published crystal structure of the complex. Changes in side-chain solvent accessibility, as determined by the oxidative footprint of free PD-1 versus PD-1 bound to nivolumab, agree with the binding interface side-chain interactions reported from the crystal structure of the complex. The N-linked glycosylation sites of PD-1 were confirmed through an LC-MS/MS-based deglycosylation analysis of asparagine deamidation. In addition, subtle changes in side-chain solvent accessibility were observed in the C'D loop region of PD-1 upon complex formation with nivolumab.

Efficacy and safety of different regimens of neoadjuvant therapy in patients with hormone receptor-positive, her2-negative breast cancer: a network meta-analysis.

Introduction: The objective of this systematic review and network meta-analysis (NMA) is to assess the effectiveness and safety of various neoadjuvant treatment protocols in individuals diagnosed with hormone receptor-positive, her2 negative(HR+/HER2-) breast cancer. Materials and methods: A systematic search was conducted in four databases (Medline, Embase, Web of Science, and CENTRAL) from the inception of the databases to January 16, 2024, to identify randomized controlled trials (RCTs) to various neoadjuvant therapy options in patients diagnosed with hormone receptor-positive, HER2-negative breast cancer. A network meta-analysis was conducted to evaluate pathological complete response (pCR). Results: There were 17 randomized controlled trials (RCTs) included in the analysis. These trials examined 16 different treatment regimens and involved a total of 5752 participants. The analysis revealed that the six most effective neoadjuvant treatment regimens for HR+/HER2- breast cancer were: CT(A)+olaparib (82.5%), CT(A)+nivolumab (76.5%), Com (74.9%), CT (72.1%), Mono+eribulin (72.0%), and CT(A)+pembrolizumab (70.4%).Paired meta-analysis for pathological complete response (pCR) found no statistically significant distinction between treatment regimens that included both anthracycline and immunosuppressants and regimens that relied solely on anthracycline chemotherapy(OR:1.14, 95%ci 0.79-1.64, I2 = 71%, P=0.50). Similarly, there was no significant difference between platinum-based chemotherapy and anthracycline-basedchemotherapy(OR:1.37, 95%ci 0.53- 3.56, I2 = 11%, P=0.52). With regards to safety, adverse effects of grade 3-5 were observed, which included haematological toxicity, gastrointestinal reactions, skin and mucous membrane reactions, neuropathy, hepatotoxicity, and cardiac disorders. Conclusions: The CT(A)+Olaparib and CT(A)+nivolumab groups demonstrated superior efficacy in neoadjuvant therapy for HR+/HER2- breast cancer. Furthermore, it is crucial to focus on effectively managing the adverse effects of the treatment plan to enhance patient's ability to tolerate it. Given the constraints of the current research, additional well-executed and suitable RCTs are necessary to validate the findings of this investigation. Although pCR is valuable in assessing the effect of neoadjuvant therapy in some cases, prognostic prediction and efficacy assessment in patients with HR+/HER2- breast cancer should be based on a combination of broader clinical and biological characteristics. Systematic review registration: PROSPERO https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42024534539, CRD42024501740.

Circulating tumor DNA (ctDNA) as a biomarker of response to therapy in advanced Hepatocellular carcinoma treated with Nivolumab.

BACKGROUND: Circulating tumor DNA (ctDNA) is a promising non-invasive marker for detection, diagnosis, treatment selection, and prognosis of hepatocellular carcinoma (HCC). OBJECTIVE: This study aimed to examine the utility of ctDNA as a prognostic and predictive tool in HCC patients treated with nivolumab. METHODS: We analyzed pre-treatment ctDNA from 44 HCC patients using comprehensive genomic testing on a commercially available platform. We utilized log rank test and univariate Cox models to correlate overall survival (OS) and progression-free survival (PFS) with ctDNA expressions. RESULTS: Of 44 patients, 77.3% were men with median age of 67 years. All but 3 patients had at least one alteration identified, and TP53 was the most commonly altered gene (52.3%). Median OS was 17.5 months (95% CI: 12.7, NA). Mutations involving PIK3CA, BRCA1, and CCND1 amplification were associated with shorter OS (P 0.0001, 0.0001 and 0.01, respectively). Median PFS time was 4.01 months (95% CI: 3.06, 9.33). Mutations involving KIT and PIK3CA were associated with shorter PFS (P 0.0001 and 0.0004, respectively), while mutation involving CTNNB1 were associated with longer PFS (p= 0.04). CONCLUSIONS: ctDNA profiling may provide a benefit for prediction of survival and progression of HCC patients treated with nivolumab. Future studies are needed for confirmation.

Stage IV gastric cancer with microsatellite instability-high achieving long-term survival by gastrectomy after nivolumab as third-line therapy: a case report and literature review.

BACKGROUND: The prognosis for stage IV gastric cancer remains poor; however, the advent of immune checkpoint inhibitors (ICIs) such as nivolumab has increased the number of patients with long-term survival. Patients with microsatellite instability (MSI)-high gastric cancer have been recognized as a highly effective population for ICIs. Herein, we report a patient with MSI-high advanced gastric cancer treated with gastrectomy after the administration of nivolumab as third-line therapy. CASE PRESENTATION: A 73-year-old woman presented with a type 3 tumor in the lower part of the gastric body, which was diagnosed as gastric cancer through biopsy. Staging laparoscopy revealed that the tumor had invaded the pancreas and the posterior lobe of the transverse mesocolon, and disseminated nodules were found near the ligament of Treitz. After 4 courses of S-1 plus cisplatin therapy, laparoscopic gastrojejunal bypass was performed because of difficulty in oral intake. She received S-1 plus oxaliplatin therapy after a gastrojejunal bypass; however, her regional lymph nodes were enlarged. After six courses of paclitaxel plus ramucirumab as second-line chemotherapy, computed tomography (CT) showed exacerbation of peritoneal dissemination; thus, nivolumab was selected as the third-line therapy. The tumor was characterized by MSI-high. At 24 courses, CT and gastroscopy revealed a complete clinical response of the tumor; however, re-growth of the primary tumor was observed at 36 courses. The patient underwent distal gastrectomy with D1 + lymph node dissection, and received S-1 monotherapy as adjuvant therapy for 1 year. No recurrence was noted at 39 months after the surgery. CONCLUSIONS: We report a patient with highly advanced gastric cancer with peritoneal dissemination, which worsened during second-line therapy and was successfully treated with gastrectomy after nivolumab administration as a third-line therapy. MSI-high gastric cancer is a target that should be actively considered for the administration of ICIs, such as nivolumab, and multidisciplinary treatment combined with chemotherapy and gastrectomy, including conversion surgery, can lead to patients' long-term survival.

Phase I-IV Drug Trials on Hepatocellular Carcinoma in Asian Populations: A Systematic Review of Ten Years of Studies.

Despite advances in the treatment of hepatocellular carcinoma (HCC) over the last few decades, treatment opportunities for patients with HCC remain limited. HCC is the most common form of liver cancer, accounting for approximately 90% of all cases worldwide. Moreover, apart from the current pharmacological interventions, hepatic resection and liver transplantation are the mainstay curative approaches for patients with HCC. This systematic review included phase I, II, III, and IV clinical trials (CTs) and randomized controlled trials (RCTs) on current treatments for patients with HCC in Asian populations (2013-2023). A total of 427 articles were screened, and 184 non-duplicate publications were identified. After screening the titles and abstracts, 96 publications were excluded, and another 28 were excluded after full-text screening. The remaining 60 eligible RCTs/CTs were finally included. A total of 60 clinical trials fulfilled our inclusion criteria with 36 drugs used as monotherapy or combination therapy for HCC. Most studies used sorafenib alone or in combination with any of the treatment regimens. Lenvatinib or atezolizumab with bevacizumab was used for HCC after initial sorafenib treatment. Eighteen studies compared the efficacy of sorafenib with that of other drugs, including lenvatinib, cabozantinib, tepotinib, tigatuzumab, linifanib, erlotinib, resminostat, brivanib, tislelizumab, selumetinib, and refametinib. This study provides comprehensive insights into effective treatment interventions for HCC in Asian populations. The overall assessment indicates that sorafenib, used alone or in combination with atezolizumab and bevacizumab, has been the first treatment choice in the past decade to achieve better outcomes in patients with HCC in Asian populations.

Efficacy and safety of adjuvant nivolumab after radical surgery for high-risk urothelial carcinoma: a preliminary report of real-world data from a single institution.

BACKGROUND: The phase 3 CheckMate 274 trial demonstrated superiority of adjuvant nivolumab over placebo after radical surgery in patients with high-risk urothelial carcinoma (UC). However, real-world data on the efficacy and safety profile of adjuvant nivolumab in Japan have not been reported. METHODS: This retrospective study enrolled patients with high-risk UC who received adjuvant nivolumab therapy following radical surgery between 2022 and 2024 at our institution. We evaluated immune-related adverse events (irAEs) according to the Common Terminology Criteria for Adverse Events, version 5.0. Kaplan-Meier curves were used to assess disease-free survival (DFS) and overall survival (OS). RESULTS: Thirty-three patients with high-risk UC receiving adjuvant nivolumab therapy following radical surgery were identified, and median follow-up was 11 months. Three patients experienced grade 3 irAEs, and 8 discontinued adjuvant nivolumab therapy due to irAEs. No grade 4 or 5 irAEs were observed. Eight patients have completed 1 year of treatment, and nine are currently on treatment. Nine patients had recurrences and one died of cancer. Of the nine patients with recurrences, six relapsed while on adjuvant nivolumab therapy, two relapsed after completing 1 year of treatment, and one relapsed after discontinuation of irAE. The 1- and 2-year OS rates were 100% and 90%, respectively, and median OS was not reached. The 1- and 2-year DFS rates were 70% and 60%, respectively, and median DFS was 26 months. CONCLUSIONS: Adjuvant nivolumab appears to have some efficacy in Japanese patients. Since this is a postoperative adjuvant therapy, careful patient selection is warranted.

Clinical characteristics, treatment, and outcomes of nivolumab induced immune thrombocytopenia.

Immune thrombocytopenia (ITP) represents an uncommon hematological side effect associated with nivolumab, and its distinct clinical attributes remain poorly defined. This research aimed to explore the clinical manifestations and outcomes of ITP induced by nivolumab. Reports on nivolumab induced ITP up to April 30, 2024, were collected for retrospective analysis. The study involved 34 patients with a median age of 67 years (range 32, 82). The onset of ITP varied from 10 to 100 days post initial dosage, with a median onset at 70 days. The majority of patients exhibited no symptoms, with only 23.5% experiencing clinically significant bleeding and 11.8% facing non-clinically significant bleeding. The median platelet count was 12 × 109/L (range 0, 115), with 67.6% of patients having platelet levels below 25 × 109/L. Bone marrow biopsy revealed mainly elevated megakaryocytes. Platelet-associated IgG levels were elevated with a median of 210 ng/107 cells (range 73, 1130). Subsequent interventions, which included cessation of nivolumab, administration of systemic corticosteroids, intravenous immunoglobulin therapy, a thrombopoietin receptor agonist, platelet transfusion, and rituximab treatment, resulted in 82.4% of subjects achieving normalized platelet counts, whereas 5.9% passed away due to ITP. ITP is a rare life-threatening immune-related adverse event and necessitates close monitoring. Systemic steroids are the primary treatment for ITP, while intravenous immunoglobulin, thrombopoietin receptor agonist and rituximab are other options.

Occult checkpoint inhibitor myocarditis during adjuvant nivolumab plus ipilimumab: a smoldering but severe toxicity.

Checkpoint inhibitor myocarditis is a rare but life-threatening toxicity of immunotherapy, occasionally manifesting as persistent troponin elevation. Dual checkpoint blockade with ipilimumab and nivolumab has been found to induce immune-related myocarditis in patients with metastatic melanoma. We herein report a case of smoldering immune-related myocarditis in a 54-year-old male after a single infusion of nivolumab plus ipilimumab as adjuvant treatment for completely resected stage IV melanoma. High-dose steroid treatment resulted in decrease in the levels of cardiac enzymes, without any major complications.

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Evaluation of emergency department visits and immune-related adverse effects (irAEs) in patients treated with nivolumab.

INTRODUCTION: The development of immune checkpoint inhibitors (ICIs) represents one of the most significant advancements in cancer treatment over the past decade. Nivolumab, a widely used ICI, has been incorporated into the therapeutic regimens for various cancers. As with any drug, this drug also has side effects, including class-specific immune-related adverse effects (irAEs). Although irAEs are not rare, their diagnosis can be challenging. This study examines the emergency department (ED) visits of patients undergoing nivolumab therapy, focusing on diagnostic challenges, evaluating the management, and outcomes of irAEs in the ED setting. MATERIAL AND METHODS: A retrospective cohort study was conducted on adult patients who received nivolumab therapy for any cancer between April 1, 2018, and March 31, 2023, at a large, urban tertiary care center. In this study, we evaluated the ED visits of patients receiving nivolumab. In addition to previous studies, we evaluated irAEs in detail (percentage, recognizability, risk factors, reasons for late recognition, and outcome). Patient data were collected from electronic medical records and patient's medical files. The anamnesis, laboratory, and imaging results, ED management, and consultation notes were examined separately for each ED visit. Logistic regression models were employed to identify significant univariable predictors of ED visits and irAEs. RESULTS: A total of 199 patients were included in the study, all of whom had metastatic cancer. Of these, 154 patients (77.4%) received nivolumab therapy for non-small cell lung cancer. Most patients (71.9%, n = 143) had at least one additional comorbidity. One hundred and eleven patients (55.8%) presented to the ED. Hypertension (OR: 2.425, 95% CI: 1.226-4.795, p = 0.011) and chronic obstructive pulmonary disease (OR: 2.489, 95% CI: 1.133-5.468, p = 0.023) were identified as risk factors for ED visits. A total of 21 irAEs were diagnosed (14 in ED, 6 in the oncology clinic, and 1 in the inpatient ward). Univariate analysis found no significant association between irAE diagnosis and any specific factors. CONCLUSION: A significant proportion of the patients treated with nivolumab for advanced cancer present to ED for ICI-related adverse events, although most cases were not attributable to irAEs. Due to the vague symptomatology of irAEs, their recognition and diagnosis in the ED can be challenging. Close collaboration between ED physicians and oncologists is paramount to the management of patients with cancer in the ED.

Adding-on nivolumab to chemotherapy-stabilized patients is associated with improved survival in advanced pancreatic ductal adenocarcinoma.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are rarely used to treat advanced pancreatic ductal adenocarcinoma (PDAC) due to marginal efficacy. PATIENTS AND METHODS: This study included 92 consecutive patients diagnosed with advanced or recurrent PDAC who received nivolumab-based treatment. Univariate and multivariate analyses were used to identify prognostic factors. A control group of 301 patients with PDAC who achieved disease control with palliative chemotherapy but without ICIs was selected for comparison using propensity score matching (PSM). RESULTS: The median overall survival (OS) since nivolumab treatment was 15.8 (95% confidence interval [CI], 12.5-19.0), 2.4 (95% CI 1.2-3.6), and 1.1 (95% CI 1.0-1.2) months in patients who received add-on nivolumab after achieving disease control with chemotherapy, in those who received concomitant nivolumab and chemotherapy without prerequisite confirmation of disease control, and in those who received nivolumab without concomitant chemotherapy, respectively (P < 0.001). After PSM, the median overall survival (OS) since initiation of the concomitant chemotherapy that achieved disease control was significantly longer (P = 0.026) in patients who received add-on nivolumab (19.8 months; 95% CI 14.5-25.1) than in those who received chemotherapy alone (13.8 months; 95% CI 10.8-16.9). The immune profiling of the tumors in resected patients revealed higher scores of CD8+ T cells to Tregs in patients with add-on nivolumab comparing to those who received chemotherapy alone. CONCLUSION: Adding-on nivolumab was associated with improved OS in patients with advanced PDAC who achieved disease control following chemotherapy.

Measurement of changes in serum-based inflammatory indicators to monitor response to nivolumab monotherapy in advanced gastric cancer: a multicenter retrospective study.

BACKGROUND: Nonresectable gastric cancer develops rapidly; thus, monitoring disease progression especially in patients receiving nivolumab as late-line therapy is important. Biomarkers may facilitate the evaluation of nivolumab treatment response. Herein, we assessed the utility of serum-based inflammatory indicators for evaluating tumor response to nivolumab. METHODS: This multicenter retrospective cohort study included 111 patients treated with nivolumab monotherapy for nonresectable advanced or recurrent gastric cancer from October 2017 to October 2021. We measured changes in the C-reactive protein (CRP)-to-albumin ratio (CAR), platelet-to-lymphocyte ratio (PLR), and neutrophil-to-lymphocyte ratio (NLR) in serum from baseline to after the fourth administration of nivolumab. Furthermore, we calculated the area under the receiver operating characteristic curves (AUC ROCs) for CAR, PLR, and NLR to identify the optimal cutoff values for treatment response. We also investigated the relationship between clinicopathologic factors and disease control (complete response, partial response, and stable disease) using the chi-squared test. RESULTS: The overall response rate (complete and partial response) was 11.7%, and the disease control rate was 44.1%. The median overall survival (OS) was 14.0 (95% CI 10.7‒19.2) months, and the median progression-free survival (PFS) was 4.1 (95% CI 3.0‒5.9) months. The AUC ROCs for CAR, PLR, and NLR before nivolumab monotherapy for patients with progressive disease (PD) were 0.574 (95% CI, 0.461‒0.687), 0.528 (95% CI, 0.418‒0.637), and 0.511 (95% CI, 0.401‒0.620), respectively. The values for changes in CAR, PLR, and NLR were 0.766 (95% CI, 0.666‒0.865), 0.707 (95% CI, 0.607‒0.807), and 0.660 (95% CI 0.556‒0.765), respectively. The cutoff values for the treatment response were 3.0, 1.3, and 1.4 for CAR, PLR, and NLR, respectively. The PFS and OS were significantly longer when the treatment response values for changes in CAR, PLR, and NLR were below these cutoff values (CAR: OS, p < 0.0001 and PFS, p < 0.0001; PLR: OS, p = 0.0289 and PFS, p = 0.0302; and NLR: OS, p = 0.0077 and PFS, p = 0.0044). CONCLUSIONS: Measurement of the changes in CAR, PLR, and NLR could provide a simple, prompt, noninvasive method to evaluate response to nivolumab monotherapy. TRIAL REGISTRATION: This study is registered with number K2023006.

The rapidly changing treatment landscape of first-line advanced urothelial cancer (aUC) or metastatic urothelial cancer (mUC).

The landscape of treatment for first-line therapy in advanced urothelial cancer (aUC) and metastatic urothelial cancer (mUC) has rapidly changed in the last year alone. Maintenance avelumab remains a viable treatment option for many patients across the globe for those who have responded or have achieved stable disease after platinum-based chemotherapy. However, the recent FDA approvals based on EV-302 for enfortumab vedotin (EV) and pembrolizumab, as well as CheckMate-904 with gemcitabine and cisplatin with nivolumab (GC+N) followed by maintenance nivolumab have left clinicians with the complicated decision of determining which regimen is most appropriate for their individual patients with untreated aUC. This commentary highlights the key trials that have set the standard-of-care for front-line aUC treatment and suggestions for choosing different regimens for the appropriate patient.

Development of Subcutaneous Panniculitis-Like T-cell Lymphoma After Immune Checkpoint Inhibitor Treatment.

Program death 1 (PD-1) inhibitors such as nivolumab are immune checkpoint inhibitors that have revolutionized the treatment of metastatic melanoma. Despite its success in treating melanoma, immune activation can lead to immune-related adverse effects, which are experienced by half of melanoma patients treated with PD-1 inhibitors. Despite the common frequency of immune-mediated adverse events, the development of a secondary lymphoma is exceedingly rare. We present the case of a 53-year-old woman diagnosed with stage IV metastatic melanoma, treated with nivolumab, who subsequently developed fatal subcutaneous panniculitis-like T-cell lymphoma (SPTCL).

Downstaging of advanced hepatocellular carcinoma followed by liver transplantation using immune checkpoint inhibitors: Where do we stand?

Liver transplantation (LT) in patients with hepatocellular carcinoma (HCC) and chronic liver disease (CLD) is limited by factors such as tumor size, number, portal venous or hepatic venous invasion and extrahepatic disease. Although previously established criteria, such as Milan or UCSF, have been relaxed globally to accommodate more potential recipients with comparable 5-year outcomes, there is still a subset of the population that has advanced HCC with or without portal vein tumor thrombosis without detectable extrahepatic spread who do not qualify or are unable to be downstaged by conventional methods and do not qualify for liver transplantation. Immune checkpoint inhibitors (ICI) such as atezolizumab, pembrolizumab, or nivolumab have given hope to this group of patients. We completed a comprehensive literature review using PubMed, Google Scholar, reference citation analysis, and CrossRef. The search utilized keywords such as 'liver transplant', 'HCC', 'hepatocellular carcinoma', 'immune checkpoint inhibitors', 'ICI', 'atezolizumab', and 'nivolumab'. Several case reports have documented successful downstaging of HCC using the atezolizumab/bevacizumab combination prior to LT, with acceptable early outcomes comparable to other criteria. Adverse effects of ICI have also been reported during the perioperative period. In such cases, a 1.5-month interval between ICI therapy and LT has been suggested. Overall, the results of downstaging using combination immunotherapy were encouraging and promising. Early reports suggested a potential ray of hope for patients with CLD and advanced HCC, especially those with multifocal HCC or branch portal venous tumor thrombosis. However, prospective studies and further experience will reveal the optimal dosage, duration, and timing prior to LT and evaluate both short- and long-term outcomes in terms of rejection, infection, recurrence rates, and survival.

External validation of hemoglobin and neutrophil levels as predictors of the effectiveness of ipilimumab plus nivolumab for treating renal cell carcinoma.

Introduction: Pretreatment hemoglobin and neutrophil levels were previously reported to be important indicators for predicting the effectiveness of ipilimumab plus nivolumab (IPI + NIVO) therapy for renal cell carcinoma (RCC). Therefore, we aimed to validate this in a large external cohort. Methods: In total, 172 patients with RCC who underwent IPI + NIVO treatment at a multicenter setting were divided into three groups according to their pretreatment hemoglobin and neutrophil levels (group 1: non-anemia; group 2: anemia and low-neutrophil; and group 3: anemia and high-neutrophil). Results: Group 1 showed better survival than groups 2 and 3 (overall survival: 52.3 vs. 21.4 vs. 9.4 months, respectively; progression-free survival: 12.1 vs. 7.0 vs. 3.4 months, respectively). Discussion: In this large cohort, we validated our earlier observation that hemoglobin and neutrophil levels can be reliable predictors of the effectiveness of IPI + NIVO in advanced RCC. Thus, our approach may aid in selecting the optimal first-line therapy for RCC.

Adverse reactions associated with nivolumab and small molecule antiangiogenic drugs: A pharmacovigilance analysis.

AIMS: Immune checkpoint inhibitors, such as nivolumab, combined with small molecule antiangiogenic receptor tyrosine kinase inhibitors (TKIs), present a promising strategy for future immunotherapy. However, combination therapy can lead to specific adverse drug reactions (ADRs) in various clinical settings. Current research on the ADRs associated with combination therapy is limited. Our study aims to assess the safety of combination therapy. METHODS: We extracted ADR reports on combination therapy from the Food and Drug Administration (FDA) Adverse Event Reporting System database, covering the period from the first quarter of 2012 to the third quarter of 2023, and conducted a large-scale retrospective study. We evaluated ADR risk signals using the reporting odds ratio (ROR) and calculated the Ro/e ratio to compare the differences in the risk of fatal ADRs among various tumour types. RESULTS: We comprehensively reported the occurrence of ADRs in pan-cancer patients undergoing combination therapy. The combination therapy significantly increased the risk of sensitive skin (ROR: 231.43, 95% CI: 55.01-973.72, P < .05), metastatic renal cell carcinoma (ROR: 220.71, 95% CI: 28.99-1695.41, P < .05) and renal cell carcinoma (ROR: 188.22, 95% CI: 44.24-800.85, P < .05). We also compared the differences in ADRs resulting from different small molecule drug combinations, as well as the differences in ADRs among patients with different types of tumours under combination therapy. Furthermore, we analysed the characteristics of patients prone to experiencing fatal ADRs. CONCLUSION: These results can help enhance understanding of the ADRs commonly associated with combination therapy and assist oncologists in formulating screening protocols.

Real-world treatment patterns and outcomes of patients with advanced melanoma treated with nivolumab plus relatlimab.

The use of programmed death-1 (PD-1) inhibitors has been a pivotal advancement in treating advanced melanoma, yet their efficacy is limited. The approval of relatlimab (RELA), a lymphocyte activation gene 3 protein (LAG-3) antibody, in combination with nivolumab (NIVO), a PD-1 inhibitor, marked a significant stride toward enhancing treatment efficacy for metastatic and unresectable stage 3 and 4 melanoma. This combination has been shown to synergistically improve antitumor activity and effector T-cell activity in the tumor microenvironment, despite limited data on real-world outcomes. Our retrospective review at a tertiary cancer center of patients with stage 3 and 4 melanoma treated with NIVO-RELA revealed an overall response rate (ORR) of 39%, with notable improvements in median PFS and ORR, especially in first-line treated patients. Our study highlights the superior efficacy of NIVO-RELA over previous reports, demonstrating its significant potential in the treatment landscape of advanced melanoma.