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Aims: Many patients diagnosed with esophageal cancer have dysphagia from their primary tumor and de novo metastatic disease. The purpose of this study was to test the safety and efficacy of nivolumab given concurrently with hypofractionated chemoradiotherapy to patients with oligometastatic and obstructing esophageal tumors. Methods: Patients were enrolled in a planned single‐arm, phase 2 clinical trial. Eligible participants had previously untreated oligometastatic (≤5 metastases on fludeoxyglucose‐18 positron emission tomography scan outside the primary tumor radiotherapy field) esophageal or gastroesophageal carcinoma, dysphagia, and Eastern Cooperative Oncology Group performance status 0–1. Treatment was with 2 weeks of concurrent hypofractionated radiotherapy (30 Gy/10#) to the primary tumor, weekly carboplatin AUC2, weekly paclitaxel 50 mg/m2, and q2weekly nivolumab 240 mg, followed by nivolumab 480 mg continuing q4weekly until disease progression or 24 months total. A single metastasis was treated with stereotactic radiotherapy (SBRT) (24 Gy/3#) in week 7. Results: Five patients were recruited before trial closure to new participants for logistical reasons. Existing participants continued treatment per protocol as a pilot study at one center. All five patients completed chemoradioimmunotherapy and SBRT. All patients derived an improvement in their dysphagia. Two patients completed 24 months of nivolumab without disease progression. Grade 3 adverse events (AEs) occurred in 3 patients, however, there were no grade 4 AEs, AEs due to SBRT, or AEs of special interest as defined by the protocol. Conclusion: Pilot results from five patients at one center found that treatment was well tolerated and effective for dysphagia relief. The efficacy of hypofractionated chemoradiotherapy with concurrent checkpoint inhibition should be tested in a multicentre study. [ABSTRACT FROM AUTHOR]

Background: For advanced non‐small cell lung cancer (NSCLC), combination therapies including a PD‐1 inhibitor plus chemotherapy or a PD‐1 inhibitor, CTLA‐4 inhibitor, and chemotherapy are standard first‐line options. However, data directly comparing these regimens are lacking. This study compared the efficacy of pembrolizumab plus chemotherapy (CP) against nivolumab plus ipilimumab and chemotherapy (CNI) in a real‐world setting. Methods: In this multicenter retrospective study, we compared the efficacy and safety of CP and CNI as first‐line therapies in 182 patients with stage IIIB–IV NSCLC. Primary outcomes were overall survival (OS) and progression‐free survival (PFS), while secondary outcomes included the response rate (RR) and safety profiles. Kaplan–Meier survival curves and Cox proportional hazards models were utilized for data analysis, adjusting for confounding factors such as age, gender, and PD‐L1 expression. Results: In this study, 160 patients received CP, while 22 received CNI. The CP group was associated with significantly better PFS than the CNI group (median 11.7 vs. 6.6 months, HR 0.56, p = 0.03). This PFS advantage persisted after propensity score matching to adjust for imbalances. No significant OS differences were observed. Grade 3–4 adverse events occurred comparably, but immune‐related adverse events were numerically more frequent in the CNI group. Conclusions: In real‐world practice, CP demonstrated superior PFS compared with CNI. These findings can inform treatment selection in advanced NSCLC. [ABSTRACT FROM AUTHOR]

A 76‐year‐old woman with cT1bN2M1b stage IVA spindle cell carcinoma of the right lower lobe of the lung, no driver gene mutation, and programmed death ligand 1 < 1%, was started on ipilimumab+nivolumab+carboplatin+paclitaxel. After two courses, the patient initiated maintenance therapy with ipilimumab+nivolumab. New multiple brain metastases were observed during treatment but resolved with continued treatment. We report a unique case of spindle cell carcinoma treated with ipilimumab+nivolumab+carboplatin+paclitaxel that resulted in long‐term response and resolution of new brain metastasis. [ABSTRACT FROM AUTHOR]

The standard treatment for resectable non‐small cell lung cancer (NSCLC) located in the superior sulcus is neoadjuvant chemoradiotherapy followed by highly invasive resection. Based on the results of the CheckMate 816 trial, which showed a marked improvement in the efficacy of neoadjuvant chemo‐immunotherapy, we report a case of minimally invasive resection after neoadjuvant nivolumab plus chemotherapy for superior sulcus NSCLC, resulting in a pathologic complete response. The patient was a 76‐year‐old man with a 65‐mm right superior sulcus tumour diagnosed as squamous cell carcinoma with 95% PD‐L1. After two courses of neoadjuvant nivolumab plus chemotherapy, the tumour was completely resected through an 11‐cm right lateral thoracotomy with second rib resection and first rib preservation. No residual tumour cells were observed in the specimen, and the patient had a pathologic complete response. This report represents a new treatment option for superior sulcus tumours. [ABSTRACT FROM AUTHOR]

Background: First‐line nivolumab plus chemotherapy and nivolumab plus ipilimumab both demonstrated significant overall survival (OS) benefit versus chemotherapy in previously untreated patients with advanced esophageal squamous cell carcinoma (ESCC) in the CheckMate 648 trial, leading to approvals of both nivolumab‐containing regimens in many countries. We report longer‐term follow‐up data. Methods: This open‐label, phase III trial (NCT03143153) enrolled adults with previously untreated, unresectable, advanced, recurrent, or metastatic ESCC. Patients were randomized 1:1:1 to nivolumab plus chemotherapy, nivolumab plus ipilimumab, or chemotherapy. Primary endpoints were OS and progression‐free survival (PFS) by blinded independent central review. Hierarchical testing was performed first in patients with tumor cell programmed death ligand 1 (PD‐L1) expression of ≥1% and then in the overall population. Results: A total of 970 patients were randomly assigned. After 29 months of minimum follow‐up, nivolumab plus chemotherapy continued to demonstrate improvement in OS versus chemotherapy (hazard ratio [HR] = 0.59 [95% CI: 0.46–0.76]) in patients with tumor cell PD‐L1 expression of ≥1% and in the overall population (HR = 0.78 [95% CI: 0.65–0.93]) and with nivolumab plus ipilimumab versus chemotherapy (HR = 0.62 [95% CI: 0.48–0.80]) in patients with tumor cell PD‐L1 expression of ≥1% and in the overall population (HR = 0.77 [95% CI: 0.65–0.92]). In patients with tumor cell PD‐L1 expression of ≥1%, nivolumab plus chemotherapy demonstrated PFS benefit versus chemotherapy (HR = 0.67 [95% CI: 0.51–0.89]); PFS benefit was not observed with nivolumab plus ipilimumab versus chemotherapy (HR = 1.04 [95% CI: 0.79–1.36]). Among all treated patients (n = 936), Grade 3–4 treatment‐related adverse events were reported in 151 (49%, nivolumab plus chemotherapy), 105 (32%, nivolumab plus ipilimumab), and 110 (36%, chemotherapy) patients. Conclusions: Nivolumab plus chemotherapy and nivolumab plus ipilimumab continued to demonstrate clinically meaningful OS benefit versus chemotherapy with no new safety signals identified with longer follow‐up, further supporting use as first‐line standard treatment options for patients with advanced ESCC. [ABSTRACT FROM AUTHOR]

Aim Methods Results Conclusion A new treatment interval for nivolumab administration at 480 mg every 4 weeks, in addition to 240 mg every 2 weeks, was approved in Japan in 2020. Using model‐based evaluation, it was speculated that the effects or safety of nivolumab do not differ between the two treatment intervals; however, real‐world data on nivolumab efficacy, safety, and economic impact are lacking. Accordingly, we aimed to examine the effects of nivolumab treatment intervals (2 weeks vs. 4 weeks) in terms of efficacy, safety, and economic impact in Japanese patients with cancer.We retrospectively analyzed 126 patients treated with nivolumab. The patients were divided into two groups depending on whether they received nivolumab at 240 mg every 2 weeks (2‐week group) or 480 mg every 4 weeks (4‐week group).Efficacy results found no significant difference between the 4‐ and 2‐week groups considering median overall survival (p = 0.70) and median progression‐free survival (p = 0.57). The incidence of any grade and ≥  grade 3 immune‐related adverse events did not differ between the 4‐week and 2‐week groups (any grade, p = 0.13; ≥  grade 3, p = 0.36). Excluding drug costs, the 4‐week group had significantly lower medical costs than the 2‐week group (2‐week vs. 4‐week: mean, 94,659 JPY [679.0 USD] vs. 58,737 JPY [421.3 USD]; p < 0.05).Collectively, our findings suggest that nivolumab 480 mg every 4 weeks may be more effective than nivolumab 240 mg every 2 weeks in terms of economic impact. [ABSTRACT FROM AUTHOR]

Objective Patients and Methods Results Conclusions To compare the differential efficacy of first‐line immune checkpoint inhibitor (ICI)‐based combined therapies among patients with intermediate‐ and poor‐risk metastatic renal cell carcinoma (mRCC), as recently, the efficacy of triplet therapy comprising nivolumab plus ipilimumab plus cabozantinib has been published.Three databases were searched in December 2022 for randomised controlled trials (RCTs) analysing oncological outcomes in patients with mRCC treated with first‐line ICI‐based combined therapies. We performed network meta‐analysis (NMA) to compare the outcomes, including progression‐free survival (PFS) and objective response rates (ORRs), in patients with intermediate‐ and poor‐risk mRCC; we also assessed treatment‐related adverse events.Overall, seven RCTs were included in the meta‐analyses and NMAs. Treatment ranking analysis revealed that pembrolizumab + lenvatinib (99%) had the highest likelihood of improved PFS, followed by nivolumab + cabozantinib (79%), and nivolumab + ipilimumab + cabozantinib (77%). Notably, compared to nivolumab + cabozantinib, adding ipilimumab to nivolumab + cabozantinib did not improve PFS (hazard ratio 1.02, 95% confidence interval 0.72–1.43). Regarding ORRs, treatment ranking analysis also revealed that pembrolizumab + lenvatinib had the highest likelihood of providing better ORRs (99.7%). The likelihoods of improved PFS and ORRs of pembrolizumab + lenvatinib were true in both International Metastatic RCC Database Consortium (IMDC) risk groups.Our analyses confirmed the robust efficacy of pembrolizumab + lenvatinib as first‐line treatment for patients with intermediate or poor IMDC risk mRCC. Triplet therapy did not result in superior efficacy. Considering both toxicity and the lack of mature overall survival data, triplet therapy should only be considered in selected patients. [ABSTRACT FROM AUTHOR]

Background: Immune checkpoint inhibitors (ICIs) have advanced the therapeutic landscape for malignant melanoma patients. However, they can cause permanent and irreversible dermatologic immune‐related adverse events (irAEs) that may lead to interruption of ICI treatment or become life‐threatening. To assess the risk of severe dermatologic irAEs (grade 3 or higher) among ICIs for advanced melanoma, we conducted a network meta‐analysis (NMA). Methods: Phase II/III randomized controlled clinical trials (RCTs) involving ICIs were retrieved from various databases, including PubMed, Embase, Cochrane Library, and Web of Science. These trials were published from the inception of databases to October 15, 2022. In addition, the risk of severe dermatologic irAEs associated with ICI types and doses was evaluated and compared by NMA. Results: This study included 20 Phase II/III RCTs with a total of 10 575 patients. The results indicated that ICIs carry a higher risk of severe dermatologic irAEs compared to chemotherapy. Additionally, the combinational therapy of Nivolumab + Ipilimumab was associated with a higher risk than ICI monotherapy. Comparatively, the latest treatment option involving dual ICI therapy with Relatlimab + Nivolumab showed a lower toxicity risk, but higher than Ipilimumab alone. Lastly, Nivolumab, at a dose of 3 mg/kg every 2 weeks, was observed as the lowest‐risk dosing regimen for severe dermatologic irAEs in patients with advanced melanoma. Conclusion: The findings suggest that Nivolumab (1 mg/kg) + Ipilimumab (3 mg/kg) administered every 3 weeks should be used cautiously in patients with advanced melanoma at high risk for dermatologic irAEs. While we recommend the preferred regimen of Nivolumab (dose = 3 mg/kg, every 2 weeks). [ABSTRACT FROM AUTHOR]

SMARCA4-deficient undifferentiated thoracic tumors are a rare phenomenon. A 40-year-old male was newly diagnosed with SMARCA4-deficient undifferentiated non-small cell lung cancer. He had a history of heavy smoking and job-related exposure to metal dust and melted nickel. CT imaging showed numerous right-sided pleural masses and soft tissue plaques, but no metastases. CT-guided biopsy of a pleural mass confirmed the diagnosis. He was prescribed six cycles of carboplatin paclitaxel, and follow-up imaging showed largely stable disease. Treatment was changed to nivolumab due to shortness of breath, and he received one cycle of nivolumab without considerable side effects. Unfortunately, during the second cycle of his nivolumab, the patient presented with new weakness. Imaging showed spinal cord metastasis and he underwent a laminectomy; he was subsequently followed up as an outpatient. The objective of this publication was to explore SMARCA4-deficient undifferentiated thoracic tumors, other related SMARCA4-deficient tumors, and their overall pattern of presentation. The genetic aberrations of this case are compared to recent publications that also discuss genetic aberrations commonly occurring with this disease process, with an ultimate goal of hastening detection and adding to the library of treatment results. [ABSTRACT FROM AUTHOR]

Background: Although immunotherapy has emerged as a therapeutic strategy for many cancers, there are limited studies establishing the safety and efficacy in people living with HIV (PLWH) and cancer. Methods: PLWH and solid tumors or Kaposi sarcoma (KS) receiving antiretroviral therapy and a suppressed HIV viral load received nivolumab at 3 mg/kg every 2 weeks, in two dose deescalation cohorts stratified by CD4 count (stratum 1: CD4 count > 200/µL and stratum 2: CD4 count 100–199/µL). An expansion cohort of 24 participants with a CD4 count > 200/µL was then enrolled. Results: A total of 36 PLWH received nivolumab, including 15 with KS and 21 with a variety of other solid tumors. None of the first 12 participants had dose‐limiting toxicity in both CD4 strata, and five patients (14%) overall had grade 3 or higher immune related adverse events. Objective partial response occurred in nine PLWH and cancer (25%), including in six of 15 with KS (40%; 95% CI, 16.3–64.7). The median duration of response was 9.0 months overall and 12.5 months in KS. Responses were observed regardless of PDL1 expression. There were no significant changes in CD4 count or HIV viral load. Conclusions: Nivolumab has a safety profile in PLWH similar to HIV‐negative subjects with cancer, and also efficacy in KS. Plasma HIV remained suppressed and CD4 counts remained stable during treatment and antiretroviral therapy, indicating no adverse impact on immune function. Trial Registration: ClinicalTrials.gov Identifier: NCT02408861. The anti‐PD1 inhibitor nivolumab may be used safely for treatment of cancer, and has activity in Kaposi sarcoma, in people living with HIV receiving antiretroviral therapy, a suppressed HIV viral load, and CD4 lymphocyte count of at least 100/µL. [ABSTRACT FROM AUTHOR]

Pericardial synovial sarcomas (PSS) have a low incidence rate and are highly invasive with a dismal prognosis. Standard treatment includes surgery, radiotherapy and chemotherapy but with limited response. Here, we report the case of a 15‐year‐old nonsmoking youngster diagnosed with PSS who developed disease relapsed from surgery after 1 month. Next‐generation sequencing (NGS) using baseline tissue was performed, and BRCA2 c.968dupT was detected. Then pazopanib (a multitargeted inhibitor) plus nivolumab (an immune checkpoint inhibitor) was administered, with a partial response and progression‐free survival of 14 months. BRCA2 c.968dupT has not previously been reported in PSS and its response to targeted combination immunotherapy are not well characterized. Here, we report the efficacy of pazopanib combined with nivolumab in a PSS patient harboring BRCA2 c.968dupT and also provide the clinical evidence of the utility of NGS in exploring actionable mutations for solid tumor. Combination therapy based on immunotherapy may be a potential treatment choice for PSS harboring BRCA2 mutation. [ABSTRACT FROM AUTHOR]

Body size has historically been considered the primary source of difference in the pharmacokinetics (PKs) of monoclonal antibodies (mAbs) between children aged greater than or equal to 2 years and adults. The contribution of age‐associated differences (e.g., ontogeny) beyond body‐size differences in the pediatric PKs of mAbs has not been comprehensively evaluated. In this study, the population PK of two mAbs (nivolumab and ipilimumab) in pediatric oncology patients were characterized. The effects of age‐related covariates on nivolumab or ipilimumab PKs were assessed using data from 13 and 10 clinical studies, respectively, across multiple tumor types, including melanoma, lymphoma, central nervous system tumors (CNSTs), and other solid tumors. Clearance was lower in pediatric patients (aged 1–17 years) with solid tumors or CNST than in adults after adjusting for other covariates, including the effect of body size. In contrast, clearance was similar in pediatric patients with lymphoma to that in adults with lymphoma. The pediatric effects characterized have increased the accuracy of the predictions of the model, facilitating its use in subsequent exposure comparisons between pediatric and adult patients, as well as for exposure–response analyses to inform pediatric dosing. This study approach may be applicable to the optimization of pediatric dosing of other mAbs and possibly other biologics. [ABSTRACT FROM AUTHOR]

Locally advanced (laBSCs) and metastatic basosquamous carcinomas (mBSCs) represent a therapeutic challenge. By definition, these forms are not amenable to surgery or radiotherapy, but according to literature reports, sonic hedgehog pathway inhibitors (HHIs), anti‐programmed death 1 receptor antibodies (anti‐PD‐1), and other treatment approaches involving chemotherapy, surgery, and radiotherapy have been used. This work features 5 real‐life cases of advanced BSCs, treated at the Dermato‐Oncology Unit of Trieste (Maggiore Hospital, University of Trieste). In addition, a review of the current treatment options reported in the literature for laBSC and mBSC is provided, collecting a total of 17 patients. According to these preliminary data, HHIs such as sonidegib and vismodegib could represent a safe and effective first line of treatment, while the anti‐PD‐1 cemiplimab may be useful as a second‐line option. Chemotherapy and combined approaches involving surgery and radiotherapy have been also reported to be suitable in some patients. [ABSTRACT FROM AUTHOR]

Histiocytic sarcoma is an aggressive haematopoietic malignancy accounting for less than 1% of haematolymphoid neoplasms with a diagnosis based on morphology and immunophenotype of tissue biopsies with a very poor prognosis. Here, we report a 45‐year‐old man who was diagnosed with primary pulmonary histiocytic sarcoma with systemic metastases, with partial remission (PR) treated with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) chemotherapy, but it relapsed soon after therapy above. Tests demonstrated that TMB was 21 Muts/Mb PD‐L1 expression was 90% positive, and the disease has been well‐controlled over 3 years using immune checkpoint inhibitors (nivolumab and pembrolizumab). Bioinformatic pan‐cancer analysis verified that there was the highest genetic alteration frequency of PD‐L1 in which amplification accounted for the majority of sarcoma tumour samples. Following that, we found that the genetic alteration of PD‐L1 was associated with poor prognosis in sarcoma patients in terms of overall survival (OS) (p = 1.51 × 10−4), progress‐free survival (PFS) (p = 4.90 × 10−2) and disease‐specific survival (DSS) (p = 4.90 × 10−2). To our knowledge, this may be the first reported case with high PD‐L1 expression in primary pulmonary histiocytic sarcoma who may benefit from immunotherapy such as nivolumab and pembrolizumab significantly and safely. [ABSTRACT FROM AUTHOR]

Mivavotinib (TAK‐659/CB‐659), a dual SYK/FLT3 inhibitor, reduced immunosuppressive immune cell populations and suppressed tumor growth in combination with anti‐PD‐1 therapy in cancer models. This dose‐escalation/expansion study investigated the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of mivavotinib plus nivolumab in patients with advanced solid tumors. Patients received oral mivavotinib 60–100 mg once‐daily plus intravenous nivolumab 3 mg/kg on days 1 and 15 in 28‐day cycles until disease progression or unacceptable toxicity. The dose‐escalation phase evaluated the recommended phase II dose (RP2D; primary endpoint). The expansion phase evaluated overall response rate (primary end point) at the RP2D in patients with triple‐negative breast cancer (TNBC). During dose‐escalation (n = 24), two dose‐limiting toxicities (grade 4 lipase increased and grade 3 pyrexia) occurred in patients who received mivavotinib 80 mg and 100 mg, respectively. The determined RP2D was once‐daily mivavotinib 80 mg plus nivolumab 3 mg/kg. The expansion phase was terminated at ~50% enrollment (n = 17) after failing to meet an ad hoc efficacy futility threshold. Among all 41 patients, common treatment‐emergent adverse events (TEAEs) included dyspnea (48.8%), aspartate aminotransferase increased, and pyrexia (46.3% each). Common grade ≥3 TEAEs were hypophosphatemia and anemia (26.8% each). Mivavotinib plasma exposure was generally dose‐proportional (60–100 mg). One patient had a partial response. Mivavotinib 80 mg plus nivolumab 3 mg/kg was well tolerated with no new safety signals beyond those of single‐agent mivavotinib or nivolumab. Low response rates highlight the challenges of treating unresponsive tumor types, such as TNBC, with this combination and immunotherapies in general. Trial registration ID: NCT02834247. [ABSTRACT FROM AUTHOR]

Objectives: Immunotherapy with nivolumab for patients with recurrent/metastatic oral squamous cell carcinoma has not been evaluated. Here, we aimed to examine the efficacy, safety, and prognostic factors of nivolumab in these patients. Materials and Methods: This multicenter retrospective observational study involved patients who received nivolumab between April 2017 and June 2019. The patient characteristics were evaluated for association with progression‐free and overall survival. Progression‐free and overall survival rates were calculated; parameters that were significant in the univariate analysis were used as explanatory variables. Independent factors for progression‐free and overall survival were identified using multivariate analysis. Results: Totally, 143 patients were included. The overall response and disease control rates were 27.3% and 46.2%, respectively. The median, 1‐ and 2‐year progression‐free survival rates were 2.7 months, 25.4%, and 19.2%, respectively; those for overall survival were 11.2 months, 47.3%, and 33.6%, respectively. The independent factors affecting progression‐free survival were performance status and immune‐related adverse event occurrence, whereas those affecting overall survival were performance status, target disease, and number of previous lines of systemic cancer therapy. Eight patients reported grade ≥3 immune‐related adverse events. Conclusion: Nivolumab was effective for recurrent/metastatic oral squamous cell carcinoma treatment and was well tolerated by patients. [ABSTRACT FROM AUTHOR]

Key message: Among immune‐related adverse events, pneumonitis is relatively uncommon, and nivolumab‐related pneumonitis may present with a reversed halo sign. [ABSTRACT FROM AUTHOR]

An exposure–response (E–R) safety analysis was conducted across adult and pediatric (<18 years) studies to evaluate the potential impact of higher nivolumab and/or ipilimumab exposures in adolescents (≥12 to <18 years) versus adults with melanoma using the approved adult dosing regimens for nivolumab alone or in combination with ipilimumab. Data from 3507 patients across 15 studies were used to examine the relationship between nivolumab–ipilimumab daily average exposure and time to grade 2+ immune‐mediated adverse events (gr2+ IMAEs). Results from the E–R safety model showed ipilimumab, but not nivolumab, exposure to be a statistically significant predictor of gr2+ IMAEs. Significant covariates included sex (41% higher risk for women than men), line of therapy (19% higher for first‐line than later‐line), and treatment setting (26% lower for adjuvant than advanced melanoma). Younger age and lower body weight (BW) were each associated with a lower risk of gr2+ IMAEs (hazard ratio [HR]: 0.830 for 15‐year‐olds versus 60‐year‐olds and 0.84 for BW 52 kg versus 75 kg). For adolescents with melanoma treated with nivolumab in the advanced or adjuvant settings, these results are supportive of nivolumab flat dosing regimens for adolescents greater than or equal to 40 kg and BW‐based dosing for adolescents less than 40 kg. These results also support adult weight‐based dosing regimens for nivolumab plus ipilimumab in adolescents with advanced melanoma. This analysis suggests that although higher exposures are predicted in adolescents with lower weight compared with adults, there is no predicted immune‐mediated safety risk when treated with the approved adult dosing of nivolumab with/without ipilimumab. [ABSTRACT FROM AUTHOR]

A 75-year-old woman presented at our hospital with bilateral visual impairment. Ophthalmological examination revealed multiple choroidal tumours. Chest computed tomography revealed a tumour shadow in the right lower lobe and multiple lymph node metastases in the mediastinum and pulmonary hilum. Following a detailed examination, the patient was diagnosed with primary lung adenocarcinoma (cT1cN3M1c Stage IVB) with choroid metastases. The tumour proportion score of programmed death ligand 1 (PD-L1) was 1% and EGFR exon 20 insertion mutations were also detected. The patient was administered combination chemotherapy with nivolumab and ipilimumab. Primary lung and metastatic tumours, including the choroid, were reduced, and visual disturbances improved completely. Herein, we describe a rare case in which a combination of chemotherapy with nivolumab and ipilimumab significantly reduced vision loss due to choroidal metastasis. [ABSTRACT FROM AUTHOR]

IgG4‐related diseases are adverse events that occur after receiving treatment with immune checkpoint inhibitors (ICI). This study reports the first case of IgG4‐related retroperitoneal fibrosis after the administration of chemotherapy with nivolumab and ipilimumab (NI therapy). An 80‐year‐old man developed lower abdominal pain eight months after NI therapy was initiated. Although the primary lesion maintained its reduced size on computed tomography, there was an increase in the soft tissue shadows intensity around the abdominal aorta, bladder, and seminal vesicles, suggesting retroperitoneal fibrosis. Blood tests showed elevated IgG4 levels. Computed tomography‐guided biopsy of the retroperitoneum showed B cell‐dominant lymphocyte infiltration consistent with IgG4‐related retroperitoneal fibrosis and characteristic CD8‐positive lymphocyte infiltration, suggestive of the involvement of cytotoxic T cells. Based on the clinical, imaging, and pathological findings, the patient was diagnosed with IgG4‐related retroperitoneal fibrosis due to ICI. Immunotherapy discontinuation alone did not result in improvement; therefore, steroid therapy was initiated. In clinical practice, IgG4‐related retroperitoneal fibrosis can occur as an immune‐related adverse event when administering anti‐PD‐1 and anti‐CTLA‐4 antibodies for cancer immunotherapy. Early steroid therapy could be effective in controlling this immune‐related adverse event. [ABSTRACT FROM AUTHOR]

Background: Second‐line immunotherapy is currently recognized to help only a subset of patients with advanced forms of non‐small cell lung cancer (NSCLC). The current study analyzes the connection between prior treatment host/tumor characteristics and survival in advanced NSCLC patients receiving nivolumab as a second‐line therapy. Methods: A retrospective cohort analysis was carried out on individuals with advanced NSCLC receiving second‐line Nivolumab with palliative intent between February 2016 and May 2019 across three health boards in NHS Greater Glasgow and Clyde, Lanarkshire, Ayrshire, and Arran in Scotland to examine the association between systemic inflammation, body composition, and survival were determined using computed tomography (CT). Results: The current study investigates the connection between prior treatment host/tumor characteristics and survival in advanced NSCLC patients receiving nivolumab as a second‐line therapy. The majority were 65 years of age or older (51%), female (53%), had adenocarcinoma (53%), and had good performance status (ECOG 0/1) (86%). Most patients had high SFI (70%) or VFA (54%). The median overall survival after starting Nivolumab was 15 months. ECOG‐PS and hypoalbuminemia were significant predictors of 12‐month survival in patients with advanced NSCLC following Nivolumab treatment, according to Cox regression (p‐value = 0.047 and 0.014, respectively). Conclusion: In patients with advanced NSCLC receiving Nivolumab as a second‐line therapy, ECOG‐PS and hypoalbuminemia were strongly associated with survival. Systemic inflammation and hypoalbuminemia measurements may enhance the ECOG‐PS stratification of expected outcomes. The relationship between pre‐treatment clinicopathological variables, systemic inflammation, CT‐body composition, and 12 months survival in patients with NSCLC receiving Nivolumab as a second line treatment. [ABSTRACT FROM AUTHOR]

Key clinical message: Nivolumab has been clinically successful in prolonging the overall survival of patients with recurrent and metastatic head and neck cancer, complete remission is rare. Synergistic combinations of immunotherapy and conventional cancer treatments, such as radiotherapy or chemotherapy, are likely to be the most viable strategies for improving patient responses. Immune checkpoint inhibitors have revolutionized recurrent, metastatic oral cancer treatment; however complete remission in advanced stages is unusual. We present a case of complete remission of advanced oral squamous cell carcinoma for >4 years in a 64‐year‐old Japanese woman, that responded poorly to chemoradiotherapy but well to subsequent nivolumab treatment. [ABSTRACT FROM AUTHOR]

Introduction: Immune‐related adverse events (irAEs) are prognostic factors for patients on nivolumab. However, predictors of irAEs have not yet been identified. We aimed to investigate the predictors of irAEs occurrence and nivolumab discontinuation due to irAEs. Methods: Sixty‐two patients with recurrent/metastatic head and neck squamous cell carcinoma received nivolumab therapy between June 2017 and December 2020. Treatment outcome was compared between the groups with or without irAEs. The irAE (+) group was further divided by nivolumab discontinuation. Progression‐free survival (PFS) and overall survival (OS) were compared between the groups. Predictors of irAE occurrence were analyzed. Results: Twenty‐one patients (33.9%) developed irAEs, and six (28.6%) discontinued nivolumab due to severe irAEs. The irAE (+) group had significantly longer PFS and OS than the irAE (−) group (median PFS, 12.7 vs. 1.9 months; median OS, 33.1 vs. 12.8 months). The treatment outcomes in the discontinuation group were comparable to those in the non‐discontinuation group. The maximum absolute eosinophil count (AEC) during nivolumab therapy was significantly higher in the irAE (+) group than in the irAE (−) group (548.8 vs. 182) and higher in the discontinuation group than in the non‐discontinuation group (729.3 vs. 368.6). The receiver operating characteristic curve showed that the maximum AEC had a moderate‐to‐high accuracy for predicting irAE occurrence (area under the curve [AUC], 0.757) and nivolumab discontinuation (AUC, 0.893). Discussion: Monitoring AEC during nivolumab therapy may be useful in predicting irAE occurrence, nivolumab discontinuation, and disease prognosis. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the efficacy of pharmacotherapy for metastatic non‐clear cell renal cell carcinoma (nccRCC) in Japanese population. Methods: In this retrospective analysis, we compared the time to treatment failure (TTF) for molecular‐targeted agents as first‐line therapy, or nivolumab therapy as sequential therapy between ccRCC and nccRCC using the data of Japanese metastatic RCC patients registered in the Michinoku Japan Urological Cancer Study Group database. Results: In total, 511 cases of ccRCC and 77 cases of nccRCC were treated with pharmacotherapy. After excluding the patients who received cytokine therapy, chemotherapy, or others, there were 391 ccRCC patients and 60 nccRCC patients who were treated with tyrosine kinase inhibitors (TKIs), and 7 ccRCC patients and 7 nccRCC patients who were treated with mammalian‐target of rapamycin inhibitors (mTORIs). In addition, 132 ccRCC patients and 16 nccRCC patients received nivolumab. There was no significant difference in IMDC risk classification before first‐line therapy between ccRCC and nccRCC groups, or in each subgroup within the nccRCC group. TTF for TKIs (161 days, 95% CI: 75‐212 days) and mTORIs (21 days, 95% CI: 9‐31 days) didn't differ significantly between nccRCC and ccRCC groups (205 days, 95% CI: 174‐243 days and 33 days, 95% CI: 8‐113 days, respectively). TTF for TKIs was significantly longer than that for mTORIs in nccRCC group (p<0.01). There was no significant difference in TTF between the different TKIs in nccRCC group. In addition, no significant difference in TTF for nivolumab was seen between ccRCC and nccRCC groups. Conclusions: The results showed that the efficacy of molecular‐targeted agents as first‐line therapy was similar oncological outcomes between metastatic nccRCC and ccRCC in Japanese patients. TKIs may be more effective than mTORIs in metastatic nccRCC patients. Nivolumab administration might also be as effective in nccRCC patients as in ccRCC patients in Japanese population. [ABSTRACT FROM AUTHOR]

Background: As the outcome of immunotherapy can be improved when concurrently or sequentially combined with cytotoxic chemotherapy or radiotherapy, we investigated the efficacy of immunotherapy maintenance following platinum‐based chemotherapy in epidermal growth factor receptor (EGFR)‐mutant non‐small cell lung cancer (NSCLC) after EGFR‐tyrosine kinase inhibitor (EGFR‐TKI) failure. Methods: In this prospective, open‐label, single arm phase 2 trial, we enrolled patients aged 18 years or older with EGFR‐mutant NSCLC, which progressed after first‐ or second‐line EGFR‐TKI. Patients received platinum‐based chemotherapy followed by nivolumab maintenance therapy. They were intravenously administered 240 mg of nivolumab every 2 weeks for 3 months followed by 480 mg every 4 weeks until disease progression or unacceptable toxic effects occurred. The primary endpoint was progression‐free survival (PFS). Secondary outcomes were overall survival (OS) and incidence of grade 3–4 treatment‐related adverse events (AEs). Results: We enrolled 26 patients between May 2020 and July 2021. The median PFS was 1.7 months (95% CI: 0.401–2.999 months). The median OS was 21.4 months (95% CI: 18.790–24.010 months) with 6‐ and 12‐month OS rates of 96.2% and 76.9%, respectively. The objective response rate was 7.7% (2/26) and disease control rate, 11.5% (3/26). The tumor mutational burden by next‐generation sequencing in blood was not related to the treatment outcomes. Grade 3–4 treatment‐related AEs occurred in four (15.4%) patients; the most frequent AE was increased alanine aminotransferase (7.7%). Conclusion: Nivolumab maintenance following platinum‐based chemotherapy did not show clinical benefits after EGFR‐TKI failure in patients with EGFR‐mutant NSCLC. [ABSTRACT FROM AUTHOR]

Oncogene-negative, PDL1-negative metastatic non-small cell lung cancer (NSCLC) presents significant treatment challenges due to its complexity and resistance to conventional therapies. The case report presented addresses a 55-year-old male patient with oncogene-negative, PDL1-negative stage IV lung adenocarcinoma, showcasing an exceptional complete metabolic response to a multimodality treatment combining double immune checkpoint inhibition (ICI) and chemotherapy, followed by salvage stereotactic body radiotherapy (SBRT). The patient underwent a treatment regimen incorporating two cycles of carboplatin, pemetrexed, nivolumab, and ipilimumab followed by nivolumab, and ipilimumab maintenance. After a partial response, SBRT was applied to persistent lesions, achieving a complete metabolic response. This case highlights the potential of combining dual ICI with chemotherapy and SBRT in treating oncogene-negative, PDL1-negative NSCLC underscoring the importance of multimodality treatment strategies. [ABSTRACT FROM AUTHOR]

This article discusses a case report of a 75-year-old man with metastatic Merkel cell carcinoma (MCC) that was refractory to anti-PD-1 and anti-PD-L1 monotherapy. The patient showed a durable response to combined immunotherapy with ipilimumab (anti-CTLA-4) plus nivolumab (anti-PD-1). This case is the first to demonstrate a complete response to this combination therapy in a patient who did not respond to PD-L1 and PD-1 monotherapy. The findings suggest that the addition of a CTLA-4 inhibitor may enhance the anti-tumoral immunological response in MCC. [Extracted from the article]

Malignant pleural mesothelioma (MPM) is associated with previous asbestos exposure, while more clinical insights into this disease have come from other case studies. Maximal cytoreduction is critical in disease control and might help to improve the prognosis. Here, a 41‐year‐old female presented with a 6‐month history of a mass detected in the chest wall following resection of a right pleural mesothelioma 2 years previously. A fluorodeoxyglucose positron emission tomography/computed tomography scan showed a right chest wall mass with a blurred boundary 8.9 cm × 3.7 cm in size. The patient had received one cycle of bevacizumab, carboplatin, and pemetrexed, and two cycles of nivolumab, ipilimumab, and gemcitabine 5 months before admission. We subsequently resected the tumor, the involved diaphragm, and the fifth and sixth ribs, and titanium mesh and continuous suture were used to close the thoracic cage. The fixed paraffin‐embedded tissues showed epithelioid pleural mesothelioma. The patient received nivolumab and ipilimumab postoperatively, and no recurrence was detected 16 months after surgery. En bloc resection with reconstructive surgery effectively removed the locally advanced malignancy and restored the biological function of the thorax with a favorable prognosis. Neoadjuvant immunotherapy might therefore be conducive to radical resection and perioperative immunotherapy might improve the prognosis. [ABSTRACT FROM AUTHOR]

Background: Despite improvements in the treatment of primary uveal melanoma (UM), patients with metastatic disease continue to exhibit poor survival. Methods: A retrospective review of metastatic UM patients at Yale (initial cohort) and Memorial Sloan Kettering (validation cohort) was conducted. Cox proportional hazards regression was used to determine baseline factors that are associated with overall survival, including sex, Eastern Cooperative Oncology Group (ECOG) Performance Status Scale, laboratory measurements, metastasis location, and use of anti‐CTLA‐4 and anti‐PD‐1 therapies. Differences in overall survival were analyzed using Kaplan–Meier analysis. Results: A total of 89 patients with metastatic UM were identified; 71 and 18, in the initial and validation cohorts, respectively. In the initial cohort, median follow‐up was 19.8 months (range, 2–127 months) and median overall survival was 21.8 months (95% CI, 16.6–31.3). Female sex, anti–CTLA‐4, and anti–PD‐1 therapy were associated with better survival outcomes with adjusted death hazard ratios (HRs) of 0.40 (95% CI, 0.20–0.78), 0.44 (0.20–0.97), and 0.42 (0.22–0.84), respectively, whereas development of hepatic metastases and ECOG score ≥1 (per 1 U/L) were associated with worse survival outcomes with HRs of 2.86 (1.28–7.13) and 2.84 (1.29–6.09), respectively. In both the initial and validation cohorts, use of immune checkpoint inhibitors was associated with improved overall survival after adjusting for sex and ECOG score, with death HRs of 0.22 (0.08–0.56) and 0.04 (0.002–0.26), respectively. Conclusions: Development of extrahepatic‐only metastases, ECOG of 0, immune checkpoint therapy, and female sex were each associated with more than 2‐fold reductions in risk of death. Plain Language Summary: Metastatic uveal melanoma patients face limited treatment options and poor survival rates. Results from this retrospective analysis indicate that immune checkpoint inhibitors, such as anti–CTLA‐4 and anti–PD‐1 therapies, were associated with improved survival outcomes. Factors such as extrahepatic‐only metastases, better baseline performance status, and female sex contributed to a more than 2‐fold reduction in death risk. These findings highlight the potential of immunotherapy in treating metastatic uveal melanoma. Despite advancements in treatment, metastatic uveal melanoma outcomes remain poor. Female sex, higher baseline performance status, extrahepatic‐only metastases, and immune checkpoint therapy are associated with improved survival. [ABSTRACT FROM AUTHOR]

Summary: Acute myeloid leukaemia (AML) relapse after allogeneic haematopoietic cell transplantation (allo‐HCT) is often driven by immune‐related mechanisms and associated with poor prognosis. Immune checkpoint inhibitors combined with hypomethylating agents (HMA) may restore or enhance the graft‐versus‐leukaemia effect. Still, data about using this combination regimen after allo‐HCT are limited. We conducted a prospective, phase II, open‐label, single‐arm study in which we treated patients with haematological AML relapse after allo‐HCT with HMA plus the anti‐PD‐1 antibody nivolumab. The response was correlated with DNA‐, RNA‐ and protein‐based single‐cell technology assessments to identify biomarkers associated with therapeutic efficacy. Sixteen patients received a median number of 2 (range 1–7) nivolumab applications. The overall response rate (CR/PR) at day 42 was 25%, and another 25% of the patients achieved stable disease. The median overall survival was 15.6 months. High‐parametric cytometry documented a higher frequency of activated (ICOS+, HLA‐DR+), low senescence (KLRG1−, CD57−) CD8+ effector T cells in responders. We confirmed these findings in a preclinical model. Single‐cell transcriptomics revealed a pro‐inflammatory rewiring of the expression profile of T and myeloid cells in responders. In summary, the study indicates that the post‐allo‐HCT HMA/nivolumab combination induces anti‐AML immune responses in selected patients and could be considered as a bridging approach to a second allo‐HCT. Trial‐registration: EudraCT‐No. 2017‐002194‐18. [ABSTRACT FROM AUTHOR]

Background: Nivolumab extends the overall survival (OS) of patients with advanced gastric cancer (AGC). Intramuscular adipose tissue (IMAT) is associated with the prognosis of patients with various cancers. We investigated the effect of IMAT on OS in patients with AGC treated with nivolumab. Methods: We enrolled patients with AGC treated with nivolumab (n = 58, 67 years old, men/women 40/18). The subjects were classified into long‐term or short‐term survival groups according to the median value. The IMAT was evaluated using computed tomography scans at the umbilical level. The decision tree algorithm was employed to reveal the profile associated with prognosis. Results: In decision tree analysis, immune‐related adverse events (irAEs) were the first divergence variable, and prolonged survival was observed in 100% of patients with irAEs (profile 1). However, long survival was observed in 38% of patients with no irAEs. Among these patients, IMAT was identified as the second divergence variable, and long survival was observed in 63% of patients with high IMAT (profile 2). In patients with low IMAT, only 21% showed prolonged survival (profile 3). Median OS was 717 days (95% confidence interval [CI], 223 to not reached) in profile 1, 245 days (95% CI, 126 to 252) in profile 2, and 132 days (95% CI, 69 to 163) in profile 3. Conclusion: Immune‐related adverse events and high IMAT were favorable factors for OS in patients with AGC treated with nivolumab. Thus, along with irAEs, skeletal muscle quality is important in managing patients with AGC treated with nivolumab. [ABSTRACT FROM AUTHOR]

Key clinical message: An 89‐year‐old patient with gallbladder neuroendocrine neoplasms (GB‐NENs) and lung cancer metastasis underwent nivolumab monotherapy, resulting in tumor shrinkage. Surgery and adjuvant nivolumab showed efficiency despite low expression of PD‐L1. [ABSTRACT FROM AUTHOR]

Objectives: Ipilimumab and nivolumab treatment against advanced and metastatic renal cell carcinoma (RCC) causes severe and lethal immune‐related adverse events (irAEs). Predicting irAEs might improve clinical outcomes, however no practical biomarkers exist. This study examined whether eosinophils could be effective biomarkers for ≥grade 2 irAEs in RCC. Methods: We retrospectively analyzed 75 patients with RCC treated with ipilimumab and nivolumab between August 2018 and March 2021 in a multicenter study. Eosinophils were examined before and 2 weeks after treatment, and immediately after irAEs development. The optimal cut‐off value for ≥grade 2 irAEs was determined by a receiver operating characteristic (ROC) curve. Univariate and multivariate analyses were undertaken to identify predictors of ≥grade 2 irAEs. Results: Two weeks after treatment, eosinophils were significantly upregulated in patients who had experienced ≥grade 2 irAEs than in those who had not experienced irAEs (mean, 5.7% vs. 3.2%; p < 0.05). The optimal cut‐off value for eosinophils against ≥grade 2 irAEs was 3.0% (area under the curve = 0.69). In multivariate analyses, an eosinophil level ≥ 3.0% was a risk factor for ≥grade 2 irAEs (odds ratio 4.18, 95% confidence interval 1.16–15.1). The eosinophil level 2 weeks after treatment was upregulated by the onset of any type of irAEs including endocrine, gastrointestinal, pulmonary and skin disorders. Conclusions: An increased eosinophil level 2 weeks after treatment might be an effective biomarker for ≥grade 2 irAEs in patients with RCC treated with ipilimumab and nivolumab. [ABSTRACT FROM AUTHOR]

Background: Monoclonal antibodies, such as cemiplimab and pembrolizumab, against the programmed death receptor (PD)‐1 have become the current standard of care and first‐line treatment of advanced cutaneous squamous cell carcinoma (cSCC), proving remarkable clinical benefit and acceptable safety. Objectives: To assess efficacy and safety of the anti‐PD‐1 antibody nivolumab in patients with locally advanced and metastatic cSCC. Methods: Patients received open‐label nivolumab 240 mg intravenously every 2 weeks for up to 24 months. Patients with concomitant haematological malignancies (CHMs), either non‐progressing or stable under active therapy, were eligible for inclusion. Results: Of 31 patients with a median age of 80 years, 22.6% of patients achieved an investigator assessed complete response, resulting in an objective response rate (ORR) of 61.3% and a disease control rate (DCR) of 64.5%. Progression‐free survival (PFS) was 11.1 months, and the median overall survival (OS) was not reached after 24 weeks of therapy. Median follow‐up was 23.82 months. Subgroup analysis of the CHM cohort (n = 11; 35%) revealed an ORR of 45.5%, a DCR of 54.5%, a median PFS of 10.9 months, and median OS of 20.7 months. Treatment related adverse events were reported in 58.1% of all patients (19.4% grade 3, the remaining grade 1 or 2). PD‐L1 expression and CD‐8+ T‐cell infiltration did not significantly correlate with clinical response, although a trend towards a shorter PFS of 5.6 months was observed with PD‐L1 negativity and low CD8+ intratumoral infiltration. Conclusion: This study demonstrated robust clinical efficacy of nivolumab in patients with locally advanced and metastatic cSCCs and a tolerability comparable to data of other anti‐PD‐1 antibodies. Favourable outcomes were obtained despite involving the oldest hitherto reported study cohort for anti‐PD‐1 antibodies and a significant proportion of CHM patients prone to high risk tumours and an aggressive course otherwise typically excluded from clinical trials. [ABSTRACT FROM AUTHOR]

Objectives: The efficacy of cytoreductive nephrectomy (CN) for metastatic renal cell carcinoma (mRCC) treated with immune checkpoint inhibitors (ICIs) has been suggested in the real‐world setting. We retrospectively examined the efficacy of CN prior to nivolumab plus ipilimumab systemic therapy for synchronous mRCC. Methods: Synchronous mRCC patients who received nivolumab plus ipilimumab at Kobe University Hospital or five affiliated hospitals between October 2018 and December 2021 were included in this study. We compared the outcomes of objective response rate (ORR), progression‐free survival (PFS), overall survival (OS), and adverse events (AEs) between patients with CN prior to systemic therapy and without CN. In addition, patients were 1:1 matched by propensity scores accounting for factors associated with treatment assignment. Results: Twenty‐one patients received CN prior to nivolumab plus ipilimumab (Prior CN) and 33 received nivolumab plus ipilimumab alone (Without CN). PFS of the Prior CN group was 10.8 months (95%CI 5.5–NR) and 3.4 months (95%CI 2.0–5.9) for the Without CN group (p = 0.0158). OS of Prior CN was 38.4 months (95%CI NR–NR) and 12.6 months (95%CI 4.2–30.8) for Without CN (p = 0.0024). Univariate and multivariate analyses identified prior CN as a significant prognostic indicator for PFS and OS. Moreover, propensity score matching analysis showed significant improvements in PFS and OS in Prior CN. Conclusions: Patients who underwent CN prior to nivolumab plus ipilimumab systemic therapy for synchronous mRCC had a better prognosis than patients treated with nivolumab plus ipilimumab alone. These results suggest the efficacy of prior CN for synchronous mRCC with ICI combination therapy. [ABSTRACT FROM AUTHOR]

Objectives: When primary treatment has been inadequate, nivolumab and axitinib are often used as a secondary treatments for patients with metastatic renal cell carcinoma (mRCC). However, there have been few reports comparing the efficacy and safety of these drugs. Methods: We retrospectively investigated 58 patients treated with nivolumab and 57 patients treated with axitinib as secondary treatment between April 2013 and December 2019. We then assessed the clinical efficacy and safety of the treatments in both groups. Results: The most common primary therapy was sunitinib (61.7%). Both nivolumab and axitinib groups showed no significant differences in terms of the objective response rate and disease control rate (p = 0.280 and p = 0.518, respectively). Importantly, progression‐free survival (PFS) and overall survival (OS) seemed to be similar in patients treated with nivolumab and axitinib (p = 0.527 and p = 0.266, respectively), irrespective of the objective response to primary therapy. Furthermore, a Cox proportional hazards model showed that pretreatment Karnofsky Performance Status was significantly associated with PFS and OS. Although the incidence of adverse events was significantly higher in the patients treated with axitinib, there was no significant difference in time to treatment failure between the two groups. Conclusions: Nivolumab and axitinib showed similar clinical benefits as secondary treatment in patients with mRCC; thus, they should be an option in sequential therapy following treatment with tyrosine kinase inhibitors (TKIs). Future studies and feasible therapeutic biomarkers would help predict the clinical response to TKIs or immune checkpoint inhibitors in patients with mRCC. [ABSTRACT FROM AUTHOR]

Background: This study is part of the SNPs in Nivolumab PD‐1 inhibitor for RCC (SNiP‐RCC). Here we aimed to reveal clinical factors for tumor response, progression, and survival in nivolumab for advanced clear cell renal cell carcinoma (RCC) in Japanese patients. Methods: We included patients from 23 institutions in Japan. We evaluated the objective response, radiographic progression‐free survival (PFS), overall survival (OS), and treatment‐related grade ≥ 3 (serious adverse events [SAEs]). Results: We included 222 patients. The median age was 69 years (interquartile range 62–74 years), and 71% of the patients were male. Pancreas metastasis, lung metastases, prior cytokine therapy, and SAEs, were associated with objective response. The median PFS was 18 months. Liver metastases (hazard ratio [HR], 1.61), age ≥ 75 (HR, 0.48), previous resection of primary sites (HR, 0.47), and SAEs (HR, 0.47) were independent prognostic factors for PFS. Karnofsky Performance Status <70 (HR, 2.90), high platelets (HR, 4.48), previous resection of primary sites (HR, 0.23), and pathological grade (HR, 0.19 for grade 2 and HR, 0.12 for grade 3) were independent prognostic factors for OS. SAEs were reported in 45 (20.3%) cases. In the group of patients with prior nephrectomy, SAEs were associated with objective response, PFS, and OS. Conclusion: The SNiP‐RCC study identified clinical parameters correlated with treatment outcomes in Japanese patients with priorly treated advanced clear cell RCC undergoing nivolumab monotherapy. [ABSTRACT FROM AUTHOR]

Objectives: To examine the long‐term effectiveness of nivolumab monotherapy and following subsequent therapies for metastatic renal cell carcinoma (mRCC) in Japanese real‐world settings. Methods: This was a multicenter, retrospective, observational study, with a 36‐month follow‐up, and conducted in Japanese patients with mRCC who initiated nivolumab monotherapy between 1 Feb 2017 and 31 Oct 2017. Endpoints included overall survival (OS), progression‐free survival (PFS), and objective response rate (ORR). Results: Of the 208 patients, 36.5% received nivolumab monotherapy as second‐line, 30.8% as third‐line, and 31.7% as fourth‐ or later‐line therapy. By 36 months, 12.0% of patients continued nivolumab monotherapy; 88.0% discontinued, mainly because of disease progression (66.7%). The median (m) OS was not reached irrespective of treatment line, with a 36‐month OS rate of 54.3% (second‐line, 57.4%; third‐line, 52.6%; fourth‐ or later‐line, 52.9%). The ORR was 24.2% and five patients achieved complete response. The OS from first‐line therapy was 8.9 years. In the 95 patients receiving therapy after nivolumab, 87.4% received vascular endothelial growth factor receptor‐tyrosine kinase inhibitors, with mOS and mPFS of 27.4 and 8.1 months, respectively. Irrespective of treatment line, the mOS was not reached in patients with International Metastatic RCC Database Consortium (IMDC) favorable or intermediate risk at mRCC diagnosis. Conclusions: This 36‐month real‐world follow‐up analysis showed a survival benefit of nivolumab monotherapy for patients with mRCC. The long‐term effectiveness of sequential therapy from first‐line therapy to therapy after nivolumab was also demonstrated. Additionally, nivolumab monotherapy was beneficial for patients with favorable IMDC risk at the time of mRCC diagnosis. [ABSTRACT FROM AUTHOR]

Objective: To identify biomarkers associated with the effectiveness of ipilimumab plus nivolumab against advanced metastatic renal cell carcinoma. Methods: We retrospectively analyzed the data of 75 patients treated with ipilimumab plus nivolumab at seven hospitals between August 2018 and April 2021. Prognostic biomarkers were assessed prior to initiating treatment with ipilimumab plus nivolumab. Median overall survival and progression‐free survival were examined using the Kaplan–Meier method. Univariate and multivariate analyses were performed to identify predictors of disease progression. The International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk factors most important for predicting disease progression were determined using classification and regression tree analysis. Results: Median overall survival and progression‐free survival were longer in the intermediate IMDC risk group than in the poor IMDC risk group (overall: not reached vs. 18.3 months; progression‐free: not reached vs. 13.5 months). The multivariate analysis identified poor IMDC risk as a risk factor for disease progression (hazard ratio 2.61, 95% confidence interval: 1.05–6.51). Based on the results of the classification and regression tree analysis, the cohort was divided into non‐anemia, anemia + neutro‐Low, and anemia + neutro‐High groups. Median overall survival and progression‐free survival were longer in the non‐anemia and anemia + neutro‐Low groups than in the anemia + neutro‐High group (overall: not reached vs. 29.3 months vs. 4.3 months: progression‐free: not reached vs. 29.0 months vs. 3.9 months). Conclusion: Hemoglobin and neutrophil levels may represent crucial biomarkers for predicting the effectiveness of ipilimumab plus nivolumab therapy in patients with renal cell carcinoma. [ABSTRACT FROM AUTHOR]

Objectives: Although nivolumab plus ipilimumab has become a standard treatment regimen for metastatic clear cell renal cell carcinoma (ccRCC), its efficacy in non‐clear cell carcinoma (nccRCC) has not been fully examined. In the current study, we evaluated the clinical outcomes of nivolumab plus ipilimumab in nccRCC compared with ccRCC. Methods: We retrospectively analyzed 22 patients with metastatic and/or locally advanced unresectable nccRCC who received nivolumab plus ipilimumab as a first‐line therapy and compared them with 107 patients with ccRCC. Objective response rate (ORR), progression‐free survival (PFS), overall survival (OS), and toxicity were compared between the nccRCC and ccRCC groups. Results: The histology of nccRCC included eight papillary, six unclassified, three chromophobe, two collecting duct carcinoma, and three other subtypes. Best objective response in nccRCC patients included three complete responses and five partial responses, resulting in an ORR of 36%, while that in ccRCC patients was 50% (p = 0.22). With a median follow‐up of 11.9 months, OS was significantly shorter in patients with nccRCC than in those with ccRCC (median 20.8 months vs. not reached, p = 0.04), while there was no significant difference in PFS (median 6.3 vs. 10.8 months, p = 0.21). Treatment‐related adverse events occurred in 14 (64%) nccRCC patients and 81 (76%) ccRCC patients. Conclusions: Combination treatment with nivolumab and ipilimumab demonstrated modest clinical efficacy in patients with nccRCC compared with patients with ccRCC, suggesting it could be a therapeutic option for metastatic nccRCC patients. [ABSTRACT FROM AUTHOR]

Cytokine release syndrome (CRS) is a severe and life-threatening toxicity typically reported in chimeric antigen receptor T cell therapy and is rarely reported in immune checkpoint inhibitor (ICI) therapy. This study reports the case of a 75-year-old Japanese woman who received nivolumab plus ipilimumab therapy for the postoperative recurrence of non-small cell lung cancer. She was admitted to our hospital with fever, hypotension, hepatic disorder, and thrombocytopenia. We observed slight skin rashes on her neck on admission, which spread rapidly across her body within a few days. We diagnosed CRS complicated by severe rashes. CRS symptoms were resolved with corticosteroid therapy, and did not recur thereafter. CRS is a rare, but important, immune-related adverse event associated with ICI therapy. [ABSTRACT FROM AUTHOR]

Background: ONO‐4538‐52/TASUKI‐52 was performed in Japan, Korea, and Taiwan to determine the oncological effectiveness and safety of combining nivolumab or placebo with bevacizumab plus platinum chemotherapy for the initial (first‐line) treatment of patients with advanced non‐squamous non‐small cell lung cancer (nsNSCLC). At the interim analysis (minimum follow‐up, 7.4 months), the independent radiology review committee‐assessed progression‐free survival was significantly longer in the nivolumab arm, but overall survival (OS) data were immature. Methods: Here, we present the updated OS data. Patients with treatment‐naïve stage IIIB/IV or recurrent nsNSCLC without driver mutations in ALK, EGFR, or ROS1, were randomized 1:1 to receive either nivolumab or placebo. Patients in both arms received paclitaxel, carboplatin, and bevacizumab, administered 3‐weekly for a maximum of 6 cycles. Nivolumab/placebo and bevacizumab were subsequently continued until disease progression or unacceptable toxicity. Results: Overall, 550 patients were randomized. At the time of the analysis (minimum follow‐up: 19.4 months), the median OS was longer in the nivolumab arm than in the placebo arm (30.8 vs. 24.7 months; hazard ratio 0.74, 95% confidence interval 0.58–0.94). The 12‐month OS rates were 81.3% vs. 76.3% in the nivolumab vs. placebo arms, respectively. The respective 18‐month OS rates were 69.0% vs. 61.9%. Conclusion: Nivolumab plus platinum chemotherapy and bevacizumab demonstrated longer OS vs. the placebo combination. We believe this regimen is viable as a standard, first‐line treatment for patients with advanced nsNSCLC without driver mutations in ALK, EGFR, or ROS1. [ABSTRACT FROM AUTHOR]

Background: Previous studies have revealed an association between probiotic use and effectiveness of immune checkpoint inhibitors in renal and lung cancers. However, little is known regarding other cancers, including gastrointestinal cancer. Methods: To address this issue, we conducted a multicenter retrospective cohort study and the duration of nivolumab treatment for various cancers was compared between probiotic users and non‐users. Results and Conclusions: In total, 488 patients who received nivolumab therapy were included. In all cancers, no significant differences in treatment duration of nivolumab were observed between probiotic users and non‐users (median 62.0 vs. 56.0, hazard ratio = 1.02, p = 0.825), whereas probiotic use, compared with non‐use, in patients with gastric cancer was significantly associated with a longer duration of nivolumab treatment (55.0 vs. 31.0 days, hazard ratio = 0.69, p = 0.039). In conclusion, probiotics may improve the response to nivolumab and potentially prolong progression‐free survival in patients with gastric cancer. [ABSTRACT FROM AUTHOR]

Background: Nivolumab plus ipilimumab (NIVO+IPI) is the first‐line treatment for patients with metastatic renal cell carcinoma (mRCC). Approximately 40% of patients achieve a durable response; however, 20% develop primary resistant disease (PRD) to NIVO+IPI, about which little is known in patients with mRCC. Therefore, this investigation aimed to evaluate the clinical implication of PRD in patients with mRCC to select better candidates in whom NIVO+IPI can be initiated as first‐line therapy. Methods: This multi‐institutional retrospective cohort study used data collected between August 2015 and January 2023. In total, 120 patients with mRCC treated with NIVO+IPI were eligible. Associations between immune‐related adverse events and progression‐free survival, overall survival (OS), and objective response rate were analyzed. The relationship between other clinical factors and outcomes was also evaluated. Results: The median observation period was 16 months (interquartile range, 5–27). The median age at NIVO+IPI initiation was 68 years in the male‐dominant population (n = 86, 71.7%), and most patients had clear cell histology (n = 104, 86.7%). PRD was recorded in 26 (23.4%) of 111 investigated patients during NIVO+IPI therapy. Patients who experienced PRD showed worse OS (hazard ratio: 4.525, 95% confidence interval [CI]: 2.315–8.850, p < 0.001). Multivariable analysis showed that lymph node metastasis (LNM) (odds ratio: 4.274, 95% CI: 1.075–16.949, p = 0.039) was an independent risk factor for PRD. Conclusions: PRD was strongly correlated with worse survival rates. LNM was independently associated with PRD in patients with mRCC receiving NIVO+IPI as first‐line therapy and might indicate that a candidate will not benefit from NIVO+IPI. [ABSTRACT FROM AUTHOR]

This analysis was conducted to inform dose selection of a combination of nivolumab plus ipilimumab for the treatment of sorafenib‐experienced patients with hepatocellular carcinoma (HCC). CheckMate 040 is an open‐label, multicohort, phase I/II trial in adults with advanced HCC that evaluated nivolumab monotherapy (0.1–10 mg/kg once every 2 weeks [q2w]) and the following three combinations of nivolumab plus ipilimumab: (1) nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks (q3w) for four doses, followed by nivolumab monotherapy 240 mg q2w (arm A); (2) nivolumab 3 mg/kg plus ipilimumab 1 mg/kg q3w for four doses, followed by nivolumab monotherapy 240 mg q2w (arm B); and (3) nivolumab 3 mg/kg q2w plus ipilimumab 1 mg/kg every 6 weeks continuously (arm C). Exposure‐response relationships (efficacy and safety) were characterized using nivolumab and ipilimumab concentrations after the first dose (Cavg1) as the exposure measure. Objective tumor response (OTR) and overall survival (OS) improvements were associated with increased ipilimumab exposure (OTR: odds ratio 1.45, 95% confidence interval [CI], 1.13–1.86; OS: hazard ratio 0.86, 95% CI 0.75–0.98), but not nivolumab exposure (OTR: odds ratio 0.99, 95% CI 0.97–1.02; OS: hazard ratio 1.08, 95% CI 0.89–1.32). Hepatic treatment‐related and immune‐mediated adverse events were more common in arm A than in arms B or C. Nivolumab 1 mg/kg plus ipilimumab 3 mg/kg q3w for four doses, followed by nivolumab monotherapy 240 mg q2w had the most favorable benefit:risk profile in patients with advanced HCC. [ABSTRACT FROM AUTHOR]

Background: The efficacy of immune checkpoint inhibitors (ICIs) in pleural mesothelioma has recently been established. The response to ICIs can be predicted by quantitative analysis of cells and their spatial distribution in the tumor microenvironment (TME). However, the detailed composition of the TME in pleural mesothelioma has not been reported. We evaluated the association between the TME and response to ICIs in this cancer. Methods: A retrospective analysis of 22 pleural mesothelioma patients treated with nivolumab in different centers was performed using surgical specimens. Four patients had a partial response to nivolumab (response group) and 18 patients had stable or progressive disease (nonresponse group). The number of CD4, CD8, FoxP3, CK, and PD‐L1 positive cells, cell density, and cell‐to‐cell distance were analyzed by multiplex immunofluorescence. Results: PD‐L1 expression did not differ significantly between the response and nonresponse groups. The density of total T cells and of CD8+ T cells was significantly higher in the response than in the nonresponse group. CD8+ T cells were more clustered and located closer to tumor cells, whereas regulatory T cells were located further from tumor cells in the response than in the nonresponse group. Conclusions: High density and spatial proximity of CD8+ T cells to tumor cells were associated with better response to nivolumab, whereas the proximity of regulatory T cells to tumor cells was associated with worse response, suggesting that the distinct landscape of the TME could be a potential predictor of ICI efficacy in pleural mesothelioma. [ABSTRACT FROM AUTHOR]

Background: Immune‐related adverse events (irAEs) associated with immune checkpoint inhibitors (ICIs) are often managed via immunosuppressive agents (ISAs); however, their impact on ICI efficacy is not well studied. The impact of the use of ISAs on ICI efficacy in patients with advanced melanoma was therefore investigated. Methods: This is a real‐world, multicenter, retrospective cohort study of patients with advanced melanoma who received ICIs (n = 370). Overall survival (OS) and time to treatment failure (TTF) from the time of ICI initiation were compared among patients in subgroups of interest by unadjusted and 12‐week landmark sensitivity‐adjusted analyses. The association of irAEs and their management with OS and TTF were evaluated using univariate and multivariable Cox proportional hazards regression models. Results: Overall, irAEs of any grade and of grade ≥3 occurred in 57% and 23% of patients, respectively. Thirty‐seven percent of patients received steroids, and 3% received other ISAs. Median OS was longest among patients receiving both (not reached [NR]), shorter among those receiving only systemic steroids (SSs) (84.2 months; 95% CI, 40.2 months to NR), and shortest among those who did not experience irAEs (10.3 months; 95% CI, 6–20.1 months) (p <.001). Longer OS was significantly associated with the occurrence of irAEs and the use of SSs with or without ISAs upon multivariable‐adjusted analysis (p <.001). Similar results were noted with anti–programmed death 1 (PD‐1) monotherapy and combination anti–PD‐1 plus anti–cytotoxic T‐lymphocyte antigen 4 (CTLA‐4) therapy, and with 12‐week landmark sensitivity analysis (p =.01). Conclusions: These findings in patients with melanoma who were treated with ICIs suggest that the use of SSs or ISAs for the management of irAEs is not associated with inferior disease outcomes, which supports the use of these agents when necessary. This real‐world, multicenter, retrospective study of patients with advanced melanoma who received immune checkpoint inhibitors (ICIs) suggests that the use of systemic steroids (SSs) or immunosuppressive agents (ISAs) for the management of immune‐related adverse events (irAEs) is not associated with inferior ICI efficacy, which supports their use when necessary. These data further suggest that irAEs and their management with SSs or other ISAs are predictive biomarkers of ICI efficacy. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Key Clinical Message: Baseline assessment and interval monitoring with a careful history, clinical examination, laboratory work‐up, and noninvasive imaging modalities may be beneficial for early detection of immune checkpoint inhibitor‐associated side effects. Previous reports of immune checkpoint inhibitors' cardiotoxic effects include pericarditis, myocarditis, myocardial infarction, ventricular dysfunction, vasculitis, and electrical abnormalities. The authors report a case of acute heart failure caused by nivolumab‐induced cardiotoxicity in a middle‐aged man with advanced esophageal carcinoma with no previous cardiac history or significant cardiovascular risk factors. [ABSTRACT FROM AUTHOR]

An 82‐year‐old man was treated with ipilimumab and nivolumab for malignant pleural mesothelioma. Although he was previously treated with prednisolone (1 mg/kg/day) for immune‐related adverse event (irAE) hepatitis by a previous doctor, he still had worsening liver function and was transferred to our hospital. Blood tests and imaging findings were negative for autoimmune and infectious hepatitis, and liver biopsy results were consistent with irAE hepatitis. Steroid pulse therapy improved liver function, but tapering to prednisolone (1 mg/kg/day) again worsened his liver function. Concomitant use of mycophenolate mofetil was initiated, but no improvement in liver function was observed, therefore azathioprine, a thiopurine immunosuppressant, was administered in combination with steroids. During the course of treatment, hepatic dysfunction due to azathioprine was suspected, and the concomitant use of mercaptopurine and prednisolone was started. Afterward, the liver function improved, and the prednisolone dose was gradually reduced to 10 mg/day. This is a rare case in which a thiopurine‐based immunosuppressant was effective against irAE hepatitis, therefore thiopurine‐based immunosuppressants may be effective against steroid‐refractory hepatitis. [ABSTRACT FROM AUTHOR]