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PurposeMethodsResultsConclusionTo report a case of Cogan-Like Syndrome following treatment with nivolumab for metastatic cutaneous melanoma.A case report.A 54-year-old female sought a second opinion from us regarding the recently diagnosed uveitis in both eyes. She had a diagnosis of metastatic cutaneous melanoma in the right arm and was undergoing treatment with nivolumab. Four weeks following the initiation of nivolumab therapy, she experienced tinnitus and bilateral sensorineural hearing loss, which was treated with oral and intratympanic steroids. While tapering the oral steroids, she developed iridocyclitis with papillitis in both eyes. This combination of vestibuloauditory symptoms and ocular inflammation was strikingly reminiscent of Cogan’s syndrome. Because of the timing in relation to the nivolumab therapy and the steroid responsiveness of her presentation, this was speculated to be due to immune overactivation from the nivolumab. Given her complex condition, which involved toxicity and multiple metastases, the patient was advised to consider either topical and/or local corticosteroids or intravenous immunoglobulin. The patient chose to persist with corticosteroid therapy.Nivolumab could potentially be linked to an immune-related condition resembling Cogan syndrome. In cases involving patients with a complex condition necessitating nivolumab treatment, the use of topical and/or local corticosteroids or intravenous immunoglobulin, might constitute the sole viable treatment options. [ABSTRACT FROM AUTHOR]

Background: Resistance to immune checkpoint inhibitors (ICIs) represents a major unmet medical need in non-small cell lung cancer (NSCLC) patients. Vascular endothelial growth factor (VEGF) inhibition may reverse a suppressive microenvironment and recover sensitivity to subsequent ICIs. Methods: This phase Ib/IIa, single-arm study, comprised dose-finding (Part A) and expansion (Part B) cohorts. Patients with ICIs-refractory NSCLC were enrolled to receive anlotinib (a multi-target tyrosine kinase inhibitor) orally (from days 1 to 14 in a 21-day cycle) and nivolumab (360 mg every 3 weeks, intravenously) on a 21-day treatment cycle. The first 21-day treatment cycle was a safety observation period (phase Ib) followed by a phase II expansion cohort. The primary objectives were recommended phase 2 dose (RP2D, part A), safety (part B), and objective response rate (ORR, part B), respectively. Results: Between November 2020 and March 2022, 34 patients were screened, and 21 eligible patients were enrolled (6 patients in Part A). The RP2D of anlotinib is 12 mg/day orally (14 days on and 7 days off) and nivolumab (360 mg every 3 weeks). Adverse events (AEs) of any cause and treatment-related AEs (TRAEs) were reported in all treated patients. Two patients (9.5%) experienced grade 3 TRAE. No grade 4 or higher AEs were observed. Serious AEs were reported in 4 patients. Six patients experienced anlotinib interruption and 4 patients experienced nivolumab interruption due to TRAEs. ORR and disease control rate (DCR) was 19.0% and 76.2%, respectively. Median PFS and OS were 7.4 months (95% CI, 4.3-NE) and 15.2 months (95% CI, 12.1-NE), respectively. Conclusion: Our study suggests that anlotinib combined with nivolumab shows manageable safety and promising efficacy signals. Further studies are warranted. Trial registration: NCT04507906 August 11, 2020. [ABSTRACT FROM AUTHOR]

Background: Guidelines such as the National Comprehensive Cancer Network recommend mycophenolate mofetil (MMF) for the treatment of severe steroid-refractory immune-related hepatotoxicity. Mycophenolic acid (MPA) is an active form of MMF that suppresses T- and B-lymphocyte proliferation and immune-related adverse events caused by immune checkpoint inhibitors. MPA has a narrow therapeutic range (37–70 µg·h/mL) and overexposure increases the risk of leukopenia in transplantation. However, the optimal use of MMF in oncology has not yet been established; thus, monitoring plasma MPA concentrations is necessary to avoid excessive immunosuppression in oncology practice. Case presentation: We evaluated plasma MPA concentration in a 75-year-old man with immune-related hepatotoxicity following nivolumab and ipilimumab combination therapy for malignant melanoma. The patient developed severe hepatotoxicity after immunotherapy, and immunosuppressant therapy with corticosteroids was initiated. The patient then developed steroid-refractory immune-related hepatotoxicity; therefore, MMF (1,000 mg twice daily) was co-administered. Seven days after the administration of MMF, the plasma MPA concentration was measured using an enzyme multiplied immunoassay technique. The area under the plasma concentration–time curve for MPA from 0 to 12 h was 41.0 µg·h/mL, and the same dose of MMF was continued. Grade 2 lymphocytopenia, which could be attributed to MMF, was observed during the administration period. Unfortunately, the patient was infected with SARS-CoV-2 and died from respiratory failure. Conclusion: Our patient did not exceed the upper limit of MPA levels as an index of the onset of side effects of kidney transplantation and achieved rapid improvement in liver function. Prompt initiation of MMF after assessment of the steroid effect leads to adequate MPA exposure. Therapeutic drug monitoring should be considered when MMF is administered, to avoid overexposure. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors help treat malignant melanoma, but show limited use in treating malignant vaginal melanoma, an aggressive, rare gynecological malignancy. We identified two patients treated with ipilimumab and nivolumab for vaginal melanoma; both were immunonegative for programmed cell death-ligand 1 and wild-type BRAF. Case 1, a 56-year-old female who underwent radical surgery for stage 1 malignant vaginal melanoma, experienced recurrence 15 months postoperatively. She briefly responded to ipilimumab and nivolumab combination therapy before showing disease progression. Tumor shrinkage occurred with nivolumab and local radiotherapy and, 45 months postoperatively, she survives with the melanoma. Case 2, a 50-year-old female, presented with a 4-cm blackish polypoid vaginal tumor with metastatic pelvic lymph nodes. She received ipilimumab and nivolumab combination therapy for stage III unresectable malignant vaginal melanoma. The vaginal tumor shrank after the third course of treatment, and the lymphadenopathy disappeared. The patient underwent radical surgery and is currently disease-free, using nivolumab for maintenance therapy. Both patients had immune-related adverse events coinciding with periods of high therapeutic efficacy of immune checkpoint inhibitors. Neoadjuvant therapy with immune checkpoint inhibitors and radiotherapy for immune checkpoint inhibitor resensitization may effectively treat advanced or recurrent vaginal melanoma. [ABSTRACT FROM AUTHOR]

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]

Nivolumab plus ipilimumab demonstrated promising clinical activity and durable responses in sorafenib-treated patients with advanced hepatocellular carcinoma (HCC) in the CheckMate 040 study at 30.7-month median follow-up. Here, we present 5-year results from this cohort. Patients were randomized 1 : 1 : 1 to arm A [nivolumab 1 mg/kg plus ipilimumab 3 mg/kg Q3W (four doses)] or arm B [nivolumab 3 mg/kg plus ipilimumab 1 mg/kg Q3W (four doses)], each followed by nivolumab 240 mg Q2W, or arm C (nivolumab 3 mg/kg Q2W plus ipilimumab 1 mg/kg Q6W). The primary objectives were safety, tolerability, investigator-assessed objective response rate (ORR), and duration of response (DOR) per RECIST version 1.1. A total of 148 patients were randomized across treatment arms. At 60-month minimum follow-up (62.6-month median follow-up), the ORR was 34% (n = 17), 27% (n = 13), and 29% (n = 14) in arms A, B, and C, respectively. The median DOR was 51.2 months [95% confidence interval (CI) 12.6 months-not estimable (NE)], 15.2 months (95% CI 7.1 months-NE), and 21.7 months (95% CI 4.2 months-NE), respectively. The median overall survival (OS) was 22.2 months (34/50; 95% CI 9.4-54.8 months) in arm A, 12.5 months (38/49; 95% CI 7.6-16.4 months) in arm B, and 12.7 months (40/49; 95% CI 7.4-30.5 months) in arm C; 60-month OS rates were 29%, 19%, and 21%, respectively. In an exploratory analysis of OS by response (6-month landmark), the median OS was meaningfully longer for responders versus nonresponders for all arms. No new safety signals were identified with longer follow-up. There were no new discontinuations due to immune-mediated adverse events since the primary analysis. Consistent with the primary analysis, the arm A regimen of nivolumab plus ipilimumab continued to demonstrate clinically meaningful responses and long-term survival benefit, with no new safety signals in patients with advanced HCC following sorafenib treatment, further supporting its use as a second-line treatment in these patients. • After 5 years, nivolumab plus ipilimumab continued to show clinically meaningful benefit in sorafenib-treated advanced HCC. • The ORR in arm A [nivolumab 1 mg/kg + ipilimumab 3 mg/kg Q3W (four doses), then nivolumab 240 mg Q2W] was 34%. • Responses were durable (median DOR 51.2 months) and long-term survival benefit was achieved (5-year OS rate 29%) in arm A. • No new safety signals were identified, and there were no additional discontinuations due to immune-mediated adverse events since primary analysis. • These results further support the use of the arm A regimen of nivolumab plus ipilimumab for sorafenib-treated advanced HCC. [ABSTRACT FROM AUTHOR]

• This ESMO Clinical Practice Guideline eUpdate addresses developments in first-line therapy in advanced urothelial carcinoma. • Enfortumab vedotin–pembrolizumab (EV–P) is the new standard of care in first-line advanced urothelial carcinoma. • Nivolumab–cisplatin–gemcitabine or platinum-based ChT and maintenance avelumab are alternatives if EV–P is not possible. [ABSTRACT FROM AUTHOR]

Simple Summary: Different immunotherapy combinations improved prognosis for advanced non-oncogene driven NSCLC, but they were not directly compared. The aim of our study is to present the real-world data for 122 patients treated at the Institute of Oncology in Cluj-Napoca with three different consecutive immunotherapy combinations (dual immunotherapy—18 patients, dual immunotherapy plus short course chemotherapy—33 patients, mono-immunotherapy plus full course chemotherapy—71 patients). Efficacy results using different immunotherapy combination strategies were in line with those from the registration trials, with 22.2 months median overall survival and 49% actuarial 2-year survival. Results were not significantly different between the three protocols. Older age, impaired performance status, corticotherapy in the first month of immunotherapy, and >3.81 neutrophils to lymphocytes ratio were independent unfavorable prognostic factors in the multivariate survival analysis. Long-term data are available for the dual immunotherapy cohorts, with 30.5% and 18.8% of patients alive at 5 years. Purpose. Different combination modalities between an anti-PD-1/PD-L1 agent and a platinum-based chemotherapy or another checkpoint inhibitor (with or without a short course or full course of a platinum doublet) proved superior to chemotherapy alone in multiple clinical trials, but these strategies were not directly compared. The aim of this study is to report the real-world data results with different immunotherapy combinations in a series of patients treated in consecutive cohorts at the Ion Chiricuță Oncology Institute. Methods. A total of 122 patients were successively enrolled in three cohorts: (1A) nivolumab + ipilimumab (18 patients), (1B) nivolumab + ipilimumab + short-course chemotherapy (33 patients), and (2) pembrolizumab plus full-course chemotherapy (71 patients). Endpoints included overall survival (OS), progression-free survival (PFS), objective response (ORR), and univariate and multivariate exploratory analysis of prognostic factors. RESULTS. Median follow-up in the consecutive cohorts 1A, 1B, and 2 was 83 versus 59 versus 14.2 months. Median OS and PFS for all patients were 22.2 and 11.5 months, respectively, and 2-year actuarial OS and PFS were 49% and 35%, respectively. For the nivolumab + ipilimumab (cohorts 1A and 1B) versus pembrolizumab combinations (cohort 2), median OS was 14 vs. 24.8 months (p = 0.18) and 2-year actuarial survival 42% vs. 53%; median PFS was 8.6 vs. 12.7 months (p = 0.41) and 2-year actuarial PFS 34% vs. 35%; response rates were 33.3% vs. 47.9% (p = 0.22). Older age, impaired PS (2 versus 0–1), corticotherapy in the first month of immunotherapy, and >3.81 neutrophils to lymphocytes ratio were independent unfavorable prognostic factors in the multivariate analysis of survival (limited to 2 years follow-up). The 5-year long-term survival was 30.5% and 18.8% for cohorts 1A and 1B, respectively (not enough follow-up for cohort 2). Conclusions. Efficacy results using different immunotherapy combination strategies were promising and not significantly different between protocols at 2 years. Real-world efficacy and long-term results in our series were in line with those reported in the corresponding registration trials. [ABSTRACT FROM AUTHOR]

AbstractBackgroundObjectiveMethodsResultsConclusionsImmune Checkpoint Inhibitors (ICI) have been widely used in treating different types of cancer. They increase survival in many oncologic patients and enable cancer-specific therapy. Acute Kidney Injury (AKI) is one of the adverse effects associated with using ICI, where knowledge of the prevalence and renal histological findings are still reasons for discussion.Therefore, this meta-analysis evaluates the association between ICI use and AKI.The search was performed in PubMed, Lilacs, and Cochrane platforms. Studies published up to December 1, 2022, were included.A total of 16 studies met the established PICOT criteria and were included in this review. Comparing the ICI plus chemotherapy against chemotherapy alone, the relative risk (RR) for AKI’s development with ICI use was 2.89 (95%CI 1.37–6.10). In the analyses by class and drug type, programmed cell death 1 monoclonal antibody (anti-PD-1) showed an increased risk of 2.11 (95%CI 1.26–3.52), and pembrolizumab demonstrated a risk of AKI (RR= 2.77, 95%CI 1.46–5.26). Likewise, regarding the severity of AKI, AKI grade 3 or higher was more common in the ICI plus chemotherapy compared to the chemotherapy group: 3.66 (95%CI 1.19–11.30), while the subgroup analyses pooled studies comparing ICI alone versus chemotherapy alone in the control group did not demonstrate an association with AKI.These findings suggest that ICI use is associated with an increased risk of AKI and that anti-PD-1 use is associated with a higher incidence of renal adverse events than programmed cell death ligand 1 monoclonal antibody (anti-PD-L1). Studies with adequate power and well-defined criteria for acute interstitial nephritis, nowadays taken as a synonym for AKI related to ICI, are necessary. [ABSTRACT FROM AUTHOR]

Recent progress in adjuvant immunotherapy offers hope for improving disease-free survival in high-risk bladder cancer (BC) and renal cell carcinoma (RCC). This review focuses on key trials such as CheckMate 274 and KEYNOTE-564, which show promising results with nivolumab in BC and pembrolizumab in RCC, including a 30% reduction in progression risk. Pembrolizumab also demonstrated overall survival (OS) benefit in RCC. The review also explores the potential of circulating tumor DNA (ctDNA) as a biomarker for better therapy selection and patient stratification. It emphasizes the need for ongoing research to establish survival benefits and suggests integrating biomarkers and risk stratification to optimize adjuvant immunotherapy in BC and RCC. [ABSTRACT FROM AUTHOR]

In the past decade, immune checkpoint inhibitors (ICI) have been approved for treatment of genitourinary malignancies and have revolutionized the treatment landscape of these tumors. However, despite the remarkable success of these therapies in some GU malignancies, many patients' tumors do not respond to these therapies, and others may experience significant side effects, such as immune-related adverse events (iRAEs). Accordingly, biomarkers and improved prognostic tools are critically needed to help predict which patients will respond to ICI, predict and mitigate risk of developing immune-related adverse events, and inform personalized choice of therapy for each patient. Ongoing clinical and preclinical studies continue to provide an increasingly robust understanding of the mechanisms of the response to immunotherapy, which continue to inform biomarker development and validation. Herein, we provide a comprehensive review of biomarkers of the response to immunotherapy in GU tumors and their role in selection of therapy and disease monitoring. [ABSTRACT FROM AUTHOR]

FAN score is reportedly associated with prognostic outcomes in patients with urothelial carcinoma being treated with immune check point inhibitors. However, the prognostic impact of pre-treatment FAN score in patients with metastatic renal cell carcinoma (RCC) treated with nivolumab plus ipilimumab remains unclear. We retrospectively evaluated the association between pre-treatment FAN score and prognostic outcomes in 154 patients with metastatic RCC treated with nivolumab plus ipilimumab. The pre-treatment FAN score was '0' in 56 patients (36%), '1' in 60 patients (40%), '2' in 37 patients (24%) and '3' in one patient (1%). Progression-free survival was not significantly different between patients with different FAN scores, but second progression-free survival (PFS2), cancer-specific survival (CSS) and overall survival (OS) were significantly different. In multivariable Cox proportional hazard analyses, FAN score ≥ 2 was a significant predictor of poor PFS2 (vs. FAN score 0, HR: 2.43, 95% CI 1.21–4.87, P = 0.01), poor CSS (vs. FAN score 0, HR: 2.71, 95% CI 1.13–6.47, P = 0.02) and poor OS (vs. FAN score 0, HR: 2.42, 95% CI 1.11–5.25, P = 0.02). High pre-treatment FAN score could be a significant independent predictor of poor prognosis in patients receiving nivolumab plus ipilimumab for metastatic RCC. [ABSTRACT FROM AUTHOR]

Background: Immune checkpoint inhibitors (ICIs) have demonstrated superior clinical efficacy in prolonging overall survival (OS) as the second-line treatment for advanced or metastatic esophageal squamous cell carcinoma (ESCC), and were recommended by the guidelines. However, it remains uncertain which ICI is the most cost-effective. This study assessed the cost-effectiveness of ICIs as the second-line treatment for ESCC based on the perspective of the Chinese healthcare system. Methods: A network meta-analysis (NMA) was performed to obtain the Hazard ratios (HRs) for indirect comparisons. A three-state Markov model with a 10-year time horizon was conducted to assess the cost-effectiveness. The state transition probabilities were calculated with Kaplan-Meier (KM) curves data from clinical trial and HRs from the NMA. Utilities and costs were derived from local charges or previously published studies. Univariate and probabilistic sensitivity analyses (PSA) were performed to examine model robustness. The results were assessed based on the total costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs). Results: Five clinical trials (ATTRACTION-3, ESCORT, KEYNOTE-181, ORIENT-2, RATIONALE-302) with a total of 1797 patients were included in the NMA. The NMA showed that both camrelizumab and tislelizumab received relatively high rankings for progression-free survival (PFS) and OS. Compared with sintilimab, treatment with tislelizumab and camrelizumab gained 0.018 and 0.034 additional QALYs, resulting in incremental ICERs of $75,472.65/QALY and $175,681.9/QALY, respectively. Nivolumab and pembrolizumab produced lower QALYs and greater costs, suggesting that both were dominated in comparison to sintilimab. HRs and health state utilities were the most influential parameters in most univariate sensitivity analyses of paired comparisons. PSA results suggested that sintilimab had an 84.4% chance of being the most cost-effective treatment regimen at the WTP threshold of $38,223.34/QALY. In the scenario analysis, sintilimab would no longer be cost-effective, if the price of camrelizumab was assumed to decrease by 64.6% or the price of tislelizumab was assumed to decrease by 16.9%. Conclusions and relevance: Among the five potential competing ICIs, sintilimab was likely to be the most cost-effective regimen as the second-line treatment for locally advanced or metastatic ESCC in China. Key points: Question: Which immune checkpoint inhibitor (ICI) is the most cost-effective for the second-line treatment of the patients with metastatic esophageal squamous cell carcinoma (ESCC)? Findings: At a willingness-to-pay threshold of $38,223.34/QALY, sintilimab was cost-effective in 84.4% of the simulations, the highest of the ICIs. Meaning: Sintilimab was the most cost-effective option compared to other ICIs as the second-line therapy for ESCC in China. [ABSTRACT FROM AUTHOR]

AbstractObjectiveMethodsResultsConclusion\nPLAIN LANGUAGE SUMMARYTo evaluate the efficacy and safety of nivolumab in the second-line (2L) or later-line (LL) treatment of patients with locally advanced/metastatic non-small cell lung cancer (NSCLC) in real-life setting in Türkiye.This study was designed as a national, multi-center, retrospective study. The study population was evaluated in two groups for the line of nivolumab therapy: those receiving nivolumab in the 2L (Group 2L) and third-line (3L) or LL (Group 3L/LL). Efficacy was evaluated based on one-year overall survival (OS) and progression-free survival (PFS). Safety was evaluated based on treatment-related adverse events (AEs) and nivolumab discontinuation rate.Of 244 patients, 52.9% were in Group 2L and 47.1% were in Group 3L/LL. Demographic and clinical characteristics did not differ between the groups. In Group 2L and Group 3L/LL, one-year OS and PFS rates were 60.8% and 61.4% (p = 0.592) and 31.2% and 21.3% (p = 0.078), respectively. The objective response rate (ORR) was 34.7% in Group 2L and 27.3% in Group 3L/LL (p = 0.262). The percentage of patients reporting at least one AE in Groups 2L and 3L/LL was 34.9% and 43.5%, respectively (p = 0.169). Fatigue was the most common (16.4%) treatment-related AE in each group. The groups were comparable regarding the AE frequency. Nivolumab was discontinued in 61 patients in Group 2L and 53 patients in Group 3L/LL, with the most common reason being disease progression (57.4% and 66.0%, respectively).Nivolumab is safe and effective in the 2L or 3L/LL treatment of locally advanced/metastatic NSCLC and associated with acceptable AEs in real-life setting.Non-small cell lung cancer (NSCLC) is the most common type of lung cancer (around 85% of all lung cancers). Patients with NSCLC are usually diagnosed at advanced or metastatic stages. When cancer cells spread to other areas from where they first formed, it is called metastatic cancer. Surgery may not be a treatment option for such patients. Currently, immunotherapeutic agents are used in the treatment of NSCLC. Nivolumab is one of the approved immunotherapeutic agents in the treatment of patients with metastatic NSCLC, who have failed after receiving chemotherapy. Our study explored the efficacy and safety of nivolumab in real-life setting in Türkiye. Nivolumab effectiveness was evaluated by overall survival (OS) and progression-free survival (PFS) rates. OS indicates the proportion of patients who are still alive at a given time after diagnosis or treatment initiation. PFS refers to “the length of time during and after cancer treatment that a person lives with the disease but does not get worse.” In the present study, one-year OS for 244 patients who received nivolumab was 61.1% and one-year PFS was 26.4%. Nivolumab safety was evaluated based on the frequency of adverse events observed during nivolumab therapy. Of the patients 38.9% had at least one side effect, with fatigue being the most common (16.4%). Our results support the earlier studies and showed that nivolumab was a safe and effective agent and is associated with acceptable side effects. [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]

Although immune checkpoint inhibitors (ICIs) have gained approval for metastatic renal cell carcinoma (mRCC), the response rate is still limited. Therefore, it is urgent to explore novel markers of responses to ICIs that can help assess clinical benefits. Recently, it has been noted that peripheral blood eosinophil counts are an independent factor correlated with clinical outcome of ICIs in some types of cancer. We investigated peripheral blood absolute eosinophil counts (AECs) at baseline and 4 weeks after the initiation of nivolumab for mRCC patients between February 2016 and May 2022. In addition, we examined clinicopathological features including irAEs and analyzed the correlation between AECs and clinical efficacy of nivolumab. The median progression-free survival (PFS) and overall survival (OS) for all patients were 5.7 and 25.5 months, respectively. The median AECs in patients with irAEs were significantly higher at baseline and 4 weeks after the treatment compared to those without irAEs (p < 0.001 and p = 0.001). With the cutoff value of AECs of 329 cells/µL at 4 weeks after the treatment for prediction of irAEs, high-AECs groups had significantly higher number of responders compared with that in low-AECs group (p < 0.001). Accordingly, the PFS and OS were significantly better in patients with high-AECs group than those in low-AECs group (p = 0.03 and p = 0.009). High-AECs at 4 weeks after the treatment serve as the prominent surrogate marker associated with the incidence of irAEs and better clinical outcome in mRCC patients receiving nivolumab. [ABSTRACT FROM AUTHOR]

Background: Patients with irresectable stage III or metastatic melanoma presenting with poor prognostic factors are usually treated with a combination of immune checkpoint inhibitors (ICIs), consisting of ipilimumab and nivolumab. This combination therapy is associated with severe immune related adverse events (irAEs) in about 60% of patients. In current clinical practice, patients are usually treated with ICIs for up to two years or until disease progression or the occurrence of unacceptable AEs. The incidence of irAEs gradually increases with duration of treatment. While durable tumour responses have been observed after early discontinuation of treatment, no consensus has been reached on optimal treatment duration. The objective of the Safe Stop IPI-NIVO trial is to evaluate whether early discontinuation of ICIs is safe in patients with irresectable stage III or metastatic melanoma who are treated with combination therapy. Methods: The Safe Stop IPI-NIVO trial is a nationwide, multicentre, prospective, single-arm, interventional study in the Netherlands. A total of 80 patients with irresectable stage III or metastatic melanoma who are treated with combination therapy of ipilimumab-nivolumab and have a complete or partial response (CR/PR) according to RECIST v1.1 will be included to early discontinue maintenance therapy with anti-PD-1. The primary endpoint is the rate of ongoing response at 12 months after start of ICI. Secondary endpoints include ongoing response at 24 months, disease control at different time points, melanoma specific and overall survival, the incidence of irAEs and health-related quality of life. Discussion: From a medical, healthcare and economic perspective, overtreatment should be prevented and shorter treatment duration of ICIs is preferred. If early discontinuation of ICIs is safe for patients who are treated with the combination of ipilimumab-nivolumab, the treatment duration of nivolumab could be shortened in patients with a favourable tumour response. Trial registration: ClinicalTrials.gov ID NCT05652673, registration date: 08–12-2022. [ABSTRACT FROM AUTHOR]

Background: Programmed cell death-1 (PD-1) and PD ligand-1 (PD-L1) expression predict the biological behaviour, aggressiveness, and response to immune checkpoint inhibitors in different cancers. We reviewed the published data on PD-L1 expression in pituitary tumours from the perspective of its biological role and prognostic usefulness. Summary: A literature review focused on PD-L1 expression in pituitary tumours was performed. Six immunohistochemistry-based studies which assessed PD-L1 positivity in pituitary tumours were included, encompassing 704 patients. The cohort consisted of 384 (54.5%) nonfunctioning tumours and 320 (43.5%) functioning pituitary tumours. PD-L1 expression was positive in 248 cases (35.2%). PD-L1 positivity rate was higher in functioning than in nonfunctioning tumours (46.3% vs. 26.0%; p < 0.001) but also higher in growth hormone-secreting tumours (56.7%) and prolactinomas (53.6%) than in thyrotroph (33.3%) or corticotroph tumours (20.6%). While proliferative pituitary tumours showed higher rate of PD-L1 positivity than non-proliferative tumours (p < 0.001), no association with invasion or recurrence was found. Key Messages: PD-L1 is expressed in a substantial number of pituitary tumours, predominantly in the functioning ones. PD-L1 positivity rates were significantly higher in proliferative pituitary tumours in comparison to non-proliferative tumours, but no differences were found concerning invasive or recurrent pituitary tumours. More studies following homogeneous and standardised methodologies are needed to fully elucidate the role and usefulness of PD-L1 expression in pituitary tumours. [ABSTRACT FROM AUTHOR]

BACKGROUND Standard treatment with neoadjuvant nivolumab plus chemotherapy significantly improves outcomes in patients with resectable non-small-cell lung cancer (NSCLC). Perioperative treatment (i.e., neoadjuvant therapy followed by surgery and adjuvant therapy) with nivolumab may further improve clinical outcomes. METHODS In this phase 3, randomized, double-blind trial, we assigned adults with resectable stage IIA to HIB NSCLC to receive neoadjuvant nivolumab plus chemotherapy or neoadjuvant chemotherapy plus placebo every 3 weeks for 4 cycles, followed by surgery and adjuvant nivolumab or placebo every 4 weeks for 1 year. The primary outcome was event-free survival according to blinded independent review. Secondary outcomes were pathological complete response and major pathological response ac-cording to blinded independent review, overall survival, and safety. RESULTS At this prespecified interim analysis (median follow-up, 25.4 months), the percentage of patients with 18-month event-free survival was 70.2% in the nivolumab group and 50.0% in the chemotherapy group (hazard ratio for disease progression or recurrence, abandoned surgery, or death, 0.58; 97.36% confidence interval [CI], 0.42 to 0.81; PcO.OOl). A pathological complete response occurred in 25.3% of the patients in the nivolumab group and in 4.7% of those in the chemotherapy group (odds ratio, 6.64; 95% CI, 3.40 to 12.97); a major pathological response occurred in 35.4% and 12.1%, respectively (odds ratio, 4.01; 95% CI, 2.48 to 6.49). Grade 3 or 4 treatment-related adverse events occurred in 32.5% of the patients in the nivolumab group and in 25.2% of those in the chemotherapy group. CONCLUSIONS Perioperative treatment with nivolumab resulted in significantly longer event-free survival than chemotherapy in patients with resectable NSCLC. No new safety signals were observed. (Funded by Bristol Myers Squibb; CheckMate 77T ClinicalTrials.gov number, NCT04025879.) [ABSTRACT FROM AUTHOR]

Simple Summary: This study focused on immune checkpoint inhibitor therapy effectiveness in patients with non-small cell lung cancer (NSCLC), particularly concerning programmed death ligand 1 (PD-L1) status and tumor mutational burden (TMB). The study utilized an Israeli multi-center registry spanning from January 2018 to December 2022, compiling detailed clinicopathological and molecular epidemiological data alongside treatment modalities. Clinical endpoints were assessed through Kaplan–Meier curves and Cox-regression models based on treatment assignment. While evidence on PD-L1 status and immune checkpoint inhibitors is established, data on TMB efficacy in both clinical trials and real-world settings are lacking. This study presents the largest academic real-world dataset on PD-L1 and TMB status in advanced NSCLC patients, suggesting comparable survival benefits despite limited direct comparisons. The efficacy of immune checkpoint inhibitor (ICI) therapy concerning programmed death ligand 1 (PD-L1) status is well established in patients diagnosed with non-small cell lung cancer (NSCLC). However, there remains a paucity of evidence regarding the efficacy concerning tumor mutational burden (TMB) in both clinical trials and real-world data (RWD). In the current article, clinicopathological and molecular epidemiological data were meticulously collected, and treatment modalities were meticulously recorded. The final analysis included a study population of 194 patients. Median age was 67 years (range 37–86), with the majority being male (71.13%), and 85.71% of patients were either current or former smokers at diagnosis. Adenocarcinoma accounted for most diagnoses (71.65%), followed by squamous cell carcinoma (24.23%). In terms of PD-L1 status, 42.78% had an expression level below 1%, 28.35% had an expression between 1–49%, and 28.87% had an expression above 50%. The TMB ranged from 0 to 75, with a median of 10.31 (range 0–75) for PD-L1 expression below 1%, with a median of 9.73 (range 0.95–39.63) for PD-L1 expression between 1–49%, and a median of 9.72 (range 0.95–48) for PD-L1 expression above 50%. Corresponding to patients with low PDL-1 less than 1% and low TMB (0–5), the median overall survival (mOS) was 16 (p = 0.18), and 15 months (p = 0.22), patients with medium PDL-1 (1–49%) and medium TMB (5–10), the mOS was 15 (p = 0.18) and 16 months (p = 0.22), patients with high PDL-1 (>50) and high TMB (>10), the mOS was 24 (p = 0.18) and 21 (p = 0.22) months. This study represents the largest academic RWD dataset concerning PD-L1 and TMB status in patients with locally advanced and metastatic NSCLC. [ABSTRACT FROM AUTHOR]

Background: Nivolumab has been shown to improve the overall survival (OS) of patients with recurrent and metastatic head and neck squamous cell carcinoma (R/M HNSCC). However, there is a need to identify factors associated with long-term survival (beyond 2 years) in these patients. This study investigated the relationship between pretreatment factors and long-term survival in patients with R/M HNSCC treated with nivolumab. Methods: Forty-nine patients with R/M HNSCC who were treated with nivolumab were retrospectively reviewed. Baseline characteristics, clinical data, and survival outcomes were evaluated. Univariate and multivariate analyses were performed to identify factors associated with long-term survival (OS ≥ 2 years). Results: The median OS in the overall cohort was 11.0 months, and the 2-year survival rate was 34.7%. Long-term survivors (OS ≥ 2 years) had significantly higher proportions of patients with Eastern Cooperative Oncology Group (ECOG) performance status (PS) scores of 0 or 1, serum albumin levels ≥ 3.5 g/dL, and neutrophil-to-eosinophil ratio (NER) < 32.0 compared to non-long-term survivors. On multivariate analysis, serum albumin levels ≥ 3.5 g/dL, in addition to ECOG-PS score of 0 or 1, were independent predictors of long-term survival. Conclusions: Pretreatment serum albumin levels may be useful for predicting long-term survival in R/M HNSCC patients treated with nivolumab. [ABSTRACT FROM AUTHOR]

Background RECIST criteria for progressive disease, partial response, and complete response, reflecting +20%, −30%, and −100% tumor size changes, respectively, are critical outcome variables in oncology clinical trials. Herein, we evaluated post-immunotherapy tumor size change correlation with outcomes. Methods We used a unique clinical trial data resource, a multicenter basket trial in patients with rare solid tumors treated with nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4) between 2017 and 2023 (National Cancer Institute/Southwest Oncology Group-sponsored DART trial [NCT02834013]) (open at 1083 sites at its peak). Outcome associations were evaluated by survival analysis techniques including Martingale residuals. Results In 638 evaluable patients, we found strong linear relationships between percent change in tumor measurement up to a 40%-50% increase and progression-free (PFS) and overall survival (OS) (both Cox regression P  < .001; landmark analyses based on day 65). Pearson R correlation between survival estimates and tumor change category were −0.94, −0.89, and −0.89 (PFS) and −0.84, −0.90, and −0.90 (OS) for median, 6-month (PFS), and 1-year (OS) and for 1-year (PFS) and 2-year (OS) estimates. Conclusions Percent change in tumor measurement per RECISTv1.1 (the sum of longest dimensions of target lesions) has a linear association with PFS and OS up to a 40% to 50% increase in tumor measurement in this cohort of patients with rare cancers who received combination immune checkpoint blockade. Quantitative first scan tumor measurement changes include important information to evaluate the potential efficacy of a therapy beyond the proportion of patients who achieve an objective response. [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]

In preliminary findings from the recurrent or metastatic cervical cancer cohort of CheckMate 358, nivolumab showed durable anti-tumour responses, and the combination of nivolumab plus ipilimumab showed promising clinical activity. Here, we report long-term outcomes from this cohort. CheckMate 358 was a phase 1–2, open-label, multicohort trial. The metastatic cervical cancer cohort enrolled patients from 30 hospitals and cancer centres across ten countries. Female patients aged 18 years or older with a histologically confirmed diagnosis of squamous cell carcinoma of the cervix with recurrent or metastatic disease, an Eastern Cooperative Oncology Group performance status of 0 or 1, and up to two previous systemic therapies were enrolled into the nivolumab 240 mg every 2 weeks group, the randomised groups (nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks [NIVO3 plus IPI1] or nivolumab 1 mg/kg every 3 weeks plus ipilimumab 3 mg/kg every 3 weeks for four cycles then nivolumab 240 mg every 2 weeks [NIVO1 plus IPI3]), or the NIVO1 plus IPI3 expansion group. All doses were given intravenously. Patients were randomly assigned (1:1) to NIVO3 plus IPI1 or NIVO1 plus IPI3 via an interactive voice response system. Treatment continued until disease progression, unacceptable toxicity, or consent withdrawal, or for up to 24 months. The primary endpoint was investigator-assessed objective response rate. Anti-tumour activity and safety were analysed in all treated patients. This study is registered with ClinicalTrials.gov (NCT02488759) and is now completed. Between October, 2015, and March, 2020, 193 patients were recruited in the recurrent or metastatic cervical cancer cohort of CheckMate 358, of whom 176 were treated. 19 patients received nivolumab monotherapy, 45 received NIVO3 plus IPI1, and 112 received NIVO1 plus IPI3 (45 in the randomised group and 67 in the expansion group). Median follow-up times were 19·9 months (IQR 8·2–44·8) with nivolumab, 12·6 months (7·8–37·1) with NIVO3 plus IPI1, and 16·7 months (7·2–27·5) with pooled NIVO1 plus IPI3. Objective response rates were 26% (95% CI 9–51; five of 19 patients) with nivolumab, 31% (18–47; 14 of 45 patients) with NIVO3 plus IPI1, 40% (26–56; 18 of 45 patients) with randomised NIVO1 plus IPI3, and 38% (29–48; 43 of 112 patients) with pooled NIVO1 plus IPI3. The most common grade 3–4 treatment-related adverse events were diarrhoea, hepatic cytolysis, hyponatraemia, pneumonitis, and syncope (one [5%] patient each; nivolumab group), diarrhoea, increased gamma-glutamyl transferase, increased lipase, and vomiting (two [4%] patients each; NIVO3 plus IPI1 group), and increased lipase (nine [8%] patients) and anaemia (seven [6%] patients; pooled NIVO1 plus IPI3 group). Serious treatment-related adverse events were reported in three (16%) patients in the nivolumab group, 12 (27%) patients in the NIVO3 plus IPI1 group, and 47 (42%) patients in the pooled NIVO1 plus IPI3 group. There was one treatment-related death due to immune-mediated colitis in the NIVO1 plus IPI3 group. Nivolumab monotherapy and nivolumab plus ipilimumab combination therapy showed promise in the CheckMate 358 study as potential treatment options for recurrent or metastatic cervical cancer. Future randomised controlled trials of nivolumab plus ipilimumab or other dual immunotherapy regimens are warranted to confirm treatment benefit in this patient population. Bristol Myers Squibb and Ono Pharmaceutical. [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]

Simple Summary: In this prospective cohort study of metastatic melanoma patients receiving immune checkpoint inhibitors, we identified a serum chemokine CCL20 increase at baseline with a significantly impaired progression-free and overall survival and as an independent negative prognostic factor for PFS and OS in univariate as well as in multivariate analysis. CCL20 may represent a novel blood biomarker for the prediction of prognosis in advanced melanoma under immunotherapy with a special emphasis on progression. Background: Immune checkpoint inhibition has revolutionized melanoma therapy, but many patients show primary or secondary resistance. Biomarkers are, therefore, urgently required to predict response prior to the initiation of therapy and to monitor disease progression. Methods: In this prospective study, we analyzed the serum C-C motif chemokine ligand 20 (CCL20) concentration using an enzyme-linked immunosorbent assay. Blood was obtained at baseline before the initiation of immunotherapy with anti-PD-1 monotherapy or Nivolumab and Ipilimumab in advanced melanoma patients (stages III and IV) enrolled at the University Medical Center Hamburg-Eppendorf. The CCL20 levels were correlated with clinico-pathological parameters and disease-related outcomes. Results: An increased C-C motif chemokine ligand 20 (CCL20) concentration (≥0.34 pg/mL) at baseline was associated with a significantly impaired progression-free survival (PFS) in the high-CCL20 group (3 months (95% CI: 2–6 months) vs. 11 months (95% CI: 6–26 months)) (p = 0.0033) and could be identified as an independent negative prognostic factor for PFS in univariate (Hazard Ratio (HR): 1.98, 95% CI 1.25–3.12, p = 0.004) and multivariate (HR: 1.99, 95% CI 1.21–3.29, p = 0.007) Cox regression analysis, which was associated with a higher risk than S100 (HR: 1.74). Moreover, high CCL20 levels were associated with impaired overall survival (median OS not reached for low-CCL20 group, p = 0.042) with an HR of 1.85 (95% CI 1.02–3.37, p = 0.043) in univariate analysis similar to the established prognostic marker S100 (HR: 1.99, 95% CI: 1.02–3.88, p = 0.043). Conclusions: CCL20 may represent a novel blood-based biomarker for the prediction of resistance to immunotherapy that can be used in combination with established strong clinical predictors (e.g., ECOG performance score) and laboratory markers (e.g., S100) in advanced melanoma patients. Future prospective randomized trials are needed to establish CCL20 as a liquid biopsy-based biomarker in advanced melanoma. [ABSTRACT FROM AUTHOR]

AbstractMelanoma is the most common skin cancer in children. While the current literature establishes treatment protocols for adult-type melanoma, very few pediatric-specific studies exist, and children are often excluded from melanoma clinical trials2. We report a case series of 23 pediatric patients aged 2–20 years old diagnosed with melanoma at the University of Rochester Medical Center between 1/1/2011 and 1/1/2022. 9/23 patients were Stage III; all patients underwent wide local excision and 9 received adjuvant therapies. 2/23 (8.7%) patients had recurrence of their malignancy after therapy while 21/23 (91.3%) remained without disease progression; 1 patient died from unknown cause, but the rest are alive and currently without disease. All patients whose initial therapy included nivolumab in addition to wide local excision did not have recurrence or progression of their disease. This case series highlights trends in the presentation, treatment, and outcomes of pediatric melanoma; however, additional multi-center studies are needed to establish the clinical utility of such features in pediatric melanoma. [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]

Background: Immune checkpoint inhibitors (ICIs) have expanded the arsenal of cancer therapeutics over the last decade but are associated with a spectrum of immune-related adverse events (irAEs), including inflammatory arthritis. While these complications are increasingly recognized in the adult population, no cases of inflammatory arthritis irAEs have been reported in the pediatric literature. Case Presentation: A 14-year-old female with metastatic epithelioid mesothelioma was referred to the pediatric rheumatology clinic after developing progressive inflammatory joint pain in her bilateral shoulders, hips, and small joints of hands following the second cycle of Nivolumab and Ipilimumab. Initial examinations showed bilateral shoulder joint line tenderness, positive FABERs test bilaterally, tenderness over bilateral greater trochanters, and bilateral second PIP effusions. Her serological profile was notable for positive HLA-B27, positive anti-CCP, negative Rheumatoid Factor, and negative ANA. PET-CT scan performed for disease response following immunotherapy showed symmetric increased metabolic activity primarily involving the supraspinatus, gluteus medius and minimus, and semimembranosus tendon insertions. Her presentation was consistent with a grade 1 irAE that worsened to a grade 2 irAE despite NSAID therapy, prompting a short course of oral prednisolone. She achieved clinical remission of her mesothelioma following six cycles of Nivolumab and Ipilimumab and her inflammatory arthritis was controlled on Celebrex monotherapy. Conclusions: To our knowledge, this is the first pediatric case of ICI-induced inflammatory arthritis and enthesitis. This case highlights the importance of increasing awareness of diagnosis and management of irAEs in children. [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: In Japan, preoperative adjuvant chemotherapy followed by surgical resection is the standard treatment for patients with locally advanced esophageal squamous cell carcinoma. However, the risk of recurrence after surgical resection remains high. Although a randomized controlled trial evaluating the efficacy of nivolumab, a fully human monoclonal anti-programmed death 1 antibody, as postoperative adjuvant therapy after neoadjuvant chemoradiotherapy and surgery established its superior efficacy as adjuvant therapy, the efficacy for patients who received preoperative adjuvant chemotherapy has not been demonstrated. This study aims to elucidate the efficacy and safety of nivolumab as postoperative adjuvant therapy for patients with esophageal squamous cell carcinoma after preoperative adjuvant chemotherapy with docetaxel and cisplatin plus 5-fluorouracil followed by surgical resection. Methods: This study is a multi-institutional, single-arm, Phase II trial. We plan to recruit 130 esophageal squamous cell carcinoma patients, who have undergone preoperative adjuvant chemotherapy with docetaxel and cisplatin plus 5-fluorouracil followed by surgical resection. If the patient did not have a pathological complete response, nivolumab is started as a postoperative adjuvant therapy within 4–16 weeks after surgery. The nivolumab dose is 480 mg/day every four weeks. Nivolumab is administered for up to 12 months. The primary endpoint is disease-free survival; the secondary endpoints are overall survival, distant metastasis-free survival, and incidence of adverse events. Discussion: To our knowledge this study is the first trial establishing the efficacy of nivolumab as postoperative adjuvant therapy for patients with esophageal squamous cell carcinoma after preoperative adjuvant chemotherapy with docetaxel and cisplatin plus 5-fluorouracil followed by surgical resection. In Japan, preoperative adjuvant chemotherapy followed by surgery is a well-established standard treatment for resectable, locally advanced esophageal squamous cell carcinoma. Therefore, developing an effective postoperative adjuvant therapy has been essential for improving oncological outcomes. [ABSTRACT FROM AUTHOR]

Objective: Unusual clinical course Background: CRS (cytokine release syndrome) is a massive activation of the inflammatory system characterized by a supra- physiological rate of inflammatory cytokines. The interleukin 6 cytokine plays a central role in CRS. The main clinical sign of CRS is fever, but CRS can lead to multiple organ failure in severe cases. CRS is usually described in sepsis, more recently in SARS COV-2 infection, and in chimeric antigen receptor T-cell therapy. However, it can also be associated with immune checkpoint inhibitors (ICIs), which is infrequently described. ICI have growing indications and can lead to CRS by causing an uncontrolled activation of the immune system. There are currently no treatment guidelines for ICI-induced CRS. Case Report: We report a rare case of grade 3 CRS induced by nivolumab associated with 5-fluorouracil and oxaliplatin for gastric cancer. The patient was 65-year-old man with an adenocarcinoma of the cardia. CRS developed during the tenth course of treatment and was characterized by fever, hypotension requiring vasopressors, hypoxemia, acute kidney injury, and thrombopenia. The patient was transferred quickly to the Intensive Care Unit. He was treated for suspected sepsis, but it was ruled out after multiple laboratory examinations. There was rapid resolution after infusion of hydrocortisone. Conclusions: The use of ICIs is expanding. Nivolumab-induced CRS is rarely described but can be severe and lead to multiple organ dysfunction; therefore, intensive care practitioners should be informed about this adverse effect. More studies are needed to better understand this condition and establish treatment guidelines. [ABSTRACT FROM AUTHOR]

Background: In patients with previously treated RAS-mutated microsatellite-stable (MSS) metastatic colorectal cancer (mCRC), a multicenter open-label phase 1b/2 trial was conducted to define the safety and efficacy of the MEK1/MEK2 inhibitor binimetinib in combination with the immune checkpoint inhibitor (ICI) nivolumab (anti–PD-1) or nivolumab and another ICI, ipilimumab (anti-CTLA4). Methods: In phase 1b, participants were randomly assigned to Arm 1A (binimetinib 45 mg twice daily [BID] plus nivolumab 480 mg once every 4 weeks [Q4W]) or Arm 1B (binimetinib 45 mg BID plus nivolumab 480 mg Q4W and ipilimumab 1 mg/kg once every 8 weeks [Q8W]) to determine the maximum tolerable dose (MTD) and recommended phase 2 dose (RP2D) of binimetinib. The MTD/RP2D was defined as the highest dosage combination that did not cause medically unacceptable dose-limiting toxicities in more than 35% of treated participants in Cycle 1. During phase 2, participants were randomly assigned to Arm 2A (binimetinib MTD/RP2D plus nivolumab) or Arm 2B (binimetinib MTD/RP2D plus nivolumab and ipilimumab) to assess the safety and clinical activity of these combinations. Results: In phase 1b, 21 participants were randomized to Arm 1A or Arm 1B; during phase 2, 54 participants were randomized to Arm 2A or Arm 2B. The binimetinib MTD/RP2D was determined to be 45 mg BID. In phase 2, no participants receiving binimetinib plus nivolumab achieved a response. Of the 27 participants receiving binimetinib, nivolumab, and ipilimumab, the overall response rate was 7.4% (90% CI: 1.3, 21.5). Out of 75 participants overall, 74 (98.7%) reported treatment-related adverse events (AEs), of whom 17 (22.7%) reported treatment-related serious AEs. Conclusions: The RP2D binimetinib regimen had a safety profile similar to previous binimetinib studies or nivolumab and ipilimumab combination studies. There was a lack of clinical benefit with either drug combination. Therefore, these data do not support further development of binimetinib in combination with nivolumab or nivolumab and ipilimumab in RAS-mutated MSS mCRC. Trial registration: NCT03271047 (09/01/2017). [ABSTRACT FROM AUTHOR]

Bladder cancer is predominantly a disease of older individuals. Concurrent chemotherapy and radiation is a bladder-sparing strategy for management of muscle-invasive bladder cancer; however, many patients are not candidates for chemotherapy due to comorbidities or impaired performance status. We conducted a study in a chemotherapy-ineligible patient population with the objectives of evaluating the safety, efficacy, and quality-of-life effect of the combination of nivolumab and radiation therapy in patients with localized/locally advanced urothelial cancer. Eligible patients had muscle-invasive bladder cancer and were not candidates for standard chemoradiation strategy due to at least one of the following: performance status of 2, creatinine clearance ≤60 mL/min, cardiac disease, neuropathy, and intolerance to previous treatment. Creatinine clearance ≥40 mL/min, normal marrow, and liver function were required. The primary endpoint was progression-free survival at 12 months. Nivolumab was started within 3 days of radiation therapy and administered at a dose of 240 mg intravenously every 2 weeks for a maximum of 6 months. Radiation therapy was per standard of care for bladder cancer. Imaging and cystoscopy and biopsy evaluation were required at months 3, 6, and 12 and then annually until progression. Twenty patients were enrolled, with a median age of 78.5 years (range, 58-95 years); 80% of patients were >70 years of age, and 8 (40%) were >80 years of age. Median creatinine clearance was 52 mL/min. Nine patients (48%) were progression free at 12 months. Median progression-free survival was 11.4 months (90% CI, 7.5-23.7 months), and median overall survival was 15.6 months (90% CI, 9.1-26.1 months). Concurrent nivolumab and radiation therapy is tolerable but demonstrated limited efficacy in an older population with multiple comorbidities. Immune correlates demonstrated that patients with baseline programmed cell death ligand 1 combined prognostic score ≥5% had numerically longer progression-free survival. [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]

Purpose Programmed death-1/programmed death-ligand 1 (PD-L1) inhibitors have shown efficacy in metastatic esophageal squamous cell carcinoma (ESCC) therapy. However, data is still limited regarding neoadjuvant immunotherapy for operable ESCC. Materials and Methods Patients with clinical stage T2 or T3 and N0 ESCC received three cycles of nivolumab therapy every two weeks before surgical resection. The primary endpoint is major pathologic responses (MPR) rate (= 10% of residual viable tumor [RVT]). Results Total 20 patients completed the planned nivolumab therapy. Among them, 17 patients underwent surgery as protocol, showing MPR in two patients (MPR rate, 11.8%), including one pathologic complete response, on conventional pathologic response evaluation. Pathologic response was re-evaluated using the immune-related pathologic response criteria based on immune-related RVT (irRVT). Three patients were classified as immunologic major pathologic response (iMPR; = 10% irRVT, iMPR rate: 17.6%), five as pathologic partial response (> 10% and < 90% irRVT), and nine as pathologic nonresponse (= 90% irRVT). The combined positive score (CPS) for PD-L1 in the baseline samples was predictable for iMPR, with the probability as 37.5% in CPS = 10 (3/8) and 0% in CPS < 10 (0/9). Conclusion Although the efficacy of neoadjuvant nivolumab therapy was modest in unselected ESCC patients, further researches on neoadjuvant immunotherapy are necessary in patients with PD-L1 expressed ESCC. [ABSTRACT FROM AUTHOR]

The use of conventional chemotherapy in conjunction with targeted and immunotherapy drugs has emerged as an option to limit the severity of side effects in patients diagnosed with head and neck cancer (HNC), particularly oropharyngeal cancer (OPC). OPC prevalence has increased exponentially in the past 30 years due to the prevalence of human papillomavirus (HPV) infection. This study reports a comprehensive review of clinical trials registered in public databases and reported in the literature (PubMed/Medline, Scopus, and ISI web of science databases). Of the 55 clinical trials identified, the majority (83.3%) were conducted after 2015, of which 77.7% were performed in the United States alone. Eight drugs have been approved by the FDA for HNC, including both generic and commercial forms: bleomycin sulfate, cetuximab (Erbitux), docetaxel (Taxotere), hydroxyurea (Hydrea), pembrolizumab (Keytruda), loqtorzi (Toripalimab-tpzi), methotrexate sodium (Trexall), and nivolumab (Opdivo). The most common drugs to treat HPV-associated OPC under these clinical trials and implemented as well for HPV-negative HNC include cisplatin, nivolumab, cetuximab, paclitaxel, pembrolizumab, 5-fluorouracil, and docetaxel. Few studies have highlighted the necessity for new drugs specifically tailored to patients with HPV-associated OPC, where molecular mechanisms and clinical prognosis are distinct from HPV-negative tumors. In this context, we identified most mutated genes found in HPV-associated OPC that can represent potential targets for drug development. These include TP53, PIK3CA, PTEN, NOTCH1, RB1, FAT1, FBXW7, HRAS, KRAS, and CDKN2A. [ABSTRACT FROM AUTHOR]

Background: Lung cancer is one of the major causes of cancer related death worldwide, while non-small cell lung cancer (NSCLC) consists of 85% of all lung cancer cases. Despite adequate treatment, most of the NSCLC patients progress to advance stages. Single or doublet-chemotherapy are considered as standard care for advance NSCLC patients. Gefitinib is considered as standard therapy for epidermal growth factor receptor (EGFR) mutant advanced NSCLC. Recently, a human monoclonal antibody called Nivolumab has shown encouraging efficacy for advanced NSCLC patients. The aim of this systematic review is to show the efficacy of nivolumab in comparison to single or doublet chemotherapy and gefitinib. Method: A systematic search was performed in PubMed, Google Scholar and Cochrane Library to identify primary research, published in English language between 2000 and 2018, involving Nivolumab, chemotherapy and gefitinib for advanced NSCLC patients. The primary outcome of interest was median overall survival (mOS). The secondary outcome of interest were progression free survival, objective response rate and grade-3 and treatment related adverse effects. Results: After screening 600 full-text articles, 17 clinical studies involving 9284 patients of advanced NSCLC were included. All treatment regimen seemed to be feasible. The mOS for nivolumab was ranging between 9.2 months and 16.2 months; for chemotherapy between 6 months and 18.8 months; and for gefitinib between 7.6 months and 30.5 months. Conclusion: Nivolumab is more effective and safe for EGFR non-mutant advanced NSCLC patients than either chemotherapy or gefitinib. However, gefitinib is more effective than nivolumab for EGFR-mutant NSCLC patients. [ABSTRACT FROM AUTHOR]

Background: There are few comparative studies on dual immune checkpoint inhibitors (ICIs) (i.e., IO-IO) and combination therapies comprising ICIs plus tyrosine kinase inhibitors (TKIs) (i.e., IO-TKI) for advanced renal cell carcinoma (RCC), especially in real-world settings. Methods: We retrospectively evaluated data of 175 patients with IMDC intermediate-risk or poor-risk RCC; as first-line therapy, 103 received IO-IO, and 72 received IO-TKI. An inverse probability of treatment weighting (IPTW) analysis was conducted to balance patients' backgrounds in the IO-IO and IO-TKI groups. Results: Based on the IPTW analysis, progression-free survival (PFS) was longer in the IO-TKI group than in the IO-IO group (median: 15.6 vs. 8.3 months; p = 0.0386). In contrast, overall survival was not different between groups (median: 46.7 vs. 49.0 months; p = 0.465). Although the IPTW-adjusted objective response rate was not significantly different (51.2% vs. 43.9%; p = 0.359), the progressive disease rate as the best overall response was lower in the IO-TKI group than in the IO-IO group (3.3% vs. 27.4%; p < 0.0001). Regarding the safety profile, the treatment interruption rate was higher in the IO-TKI group than in the IO-IO group (70.3% vs. 49.2%; p = 0.005). In contrast, the IO-IO group had a higher corticosteroid administration rate (43.3% vs. 20.3%; p = 0.001). Conclusion: IO-TKI therapy exhibited superior effectiveness over IO-IO therapy in terms of PFS improvement and immediate disease progression prevention and was associated with a higher risk of treatment interruption and a lower risk of needing corticosteroids. [ABSTRACT FROM AUTHOR]

BACKGROUND: Pembrolizumab and nivolumab are PD-1–blocking antibodies that are FDAapproved for a variety of malignancies. Previously, only 1 fixed dosing schedule was approved for these agents, with nivolumab dosed at 240 mg intravenously (IV) every 2 weeks and pembrolizumab dosed at 200 mg IV every 3 weeks. Recently, the FDA approved an alternate dosing schedule for nivolumab dosed at 480 mg IV every 4 weeks and pembrolizumab dosed at 400 mg IV every 6 weeks following the results of pharmacokinetic simulation models that showed a similar risk-benefit profile based on a relatively small sample size. OBJECTIVE: To compare the incidence of immune-related adverse events (irAEs) and infusion reactions of different FDA-approved dosing regimens for nivolumab and pembrolizumab. METHODS: This single-center, retrospective chart review included 171 adults with cancer who received at least 2 doses of nivolumab or pembrolizumab at either dosing schedule for any diagnosis of cancer at Duke University Health System between January 1, 2018, and June 30, 2021. The primary end point was the incidence of any-grade irAEs occurring in each of the 4 study groups (nivolumab 240 mg IV every 2 weeks, nivolumab 480 mg IV every 4 weeks, pembrolizumab 200 mg IV every 3 weeks, and pembrolizumab 400 mg IV every 6 weeks) within 6 months of treatment initiation. RESULTS: The incidence rates of any-grade irAEs were 40% for the patients who received nivolumab 240 mg IV every 2 weeks and 46% for the patients who received nivolumab 480 mg IV every 4 weeks. The rates of any-grade irAEs were 34% in the patients who received pembrolizumab 200 mg IV every 3 weeks and 47.6% in those who received pembrolizumab 400 mg IV every 6 weeks. Although the number of patients with irAEs was higher in the groups that received nivolumab 480 mg IV every 4 weeks or pembrolizumab 400 mg IV every 6 weeks, the incidence of irAEs was not significantly different between the group that received nivolumab 240 mg IV every 2 weeks versus nivolumab 480 mg IV every 4 weeks (P=.54, chi-square) and the group that received pembrolizumab 200 mg IV every 3 weeks versus pembrolizumab 400 mg IV every 6 weeks (P=.28, chi-square). The patients who received nivolumab 480 mg IV every 4 weeks had a higher incidence of infusion reactions than those who received nivolumab 240 mg IV every 2 weeks (10% vs 4%, respectively). Patients who received pembrolizumab 200 mg IV every 3 weeks had a higher incidence of infusion reactions than those who received pembrolizumab 400 mg IV every 6 weeks (6% vs 0%, respectively). CONCLUSION: The incidence of irAEs was not significantly different among patients receiving nivolumab or pembrolizumab at either dosing schedules. The incidence of infusion reactions was higher in the groups that received nivolumab 480 mg IV every 4 weeks or pembrolizumab 200 mg IV every 3 weeks than in the groups that received nivolumab 240 mg IV every 2 weeks or pembrolizumab 400 mg IV every 6 weeks. Further studies are warranted to validate these results. [ABSTRACT FROM AUTHOR]

We aimed to clarify whether clinical outcomes following immune checkpoint inhibitor-based combination therapy differed according to the baseline kidney function of patients with advanced renal cell carcinoma. CKD did not affect the efficacy of IO-IO and IO-TKI regiments. In contrast, the risks of adverse events might be increased depending on the CKD severity, especially among those receiving IO-TKI regimens. Background: It remains unclear whether kidney function affects outcomes following immune checkpoint inhibitor (ICI)- based combination therapy for advanced renal cell carcinoma (RCC). Methods: We retrospectively evaluated data of 167 patients with advanced RCC, including 98 who received ICI dual combination therapy (ie, immunotherapy [IO]-IO) and 69 who received ICI combined with tyrosine kinase inhibitor (TKI) (ie, IO-TKI). In each regimen, treatment profiles were assessed according to the grade of chronic kidney disease (CKD) as defined by the KDIGO 2012 cr iter ia. Results: Of the 98 patients who received IO-IO, 31 (32%), 30 (31%), 15 (15%), and 22 (22%) had CKD G1/2, G3a, G3b, and G4/5, respectively. Of the 69 patients who received IO-TKI, 18 (26%), 25 (36%), and 26 (38%) had G1/2, G3a, and G3b/4/5, respectively. Regarding efficacy, progression-free survival, overall survival, or objective response rate was not different according to the CKD grade in both treatment groups (P > .05). Regarding safety, the rate of adverse events, treatment interruption, or corticosteroid administration was not different according to the CKD grade in the IO-IO group (P > .05), whereas in the IO-TKI group, the incidence of grade = 3 adverse events were significantly higher (P = .0292), and the rates of ICI interruption (P = .0353) and corticosteroid administration (P = .0685) increased, according to the CKD grade. Conclusion: There is a differential safety but comparable efficacy profile between the IO-IO and IO-TKI regimens in patients with CKD. Further prospective studies are required to confirm these findings. [ABSTRACT FROM AUTHOR]

Given the treatment landscape evolution for aRCC, real-world data are needed. All French patients newly treated for aRCC initiated in 2016 were included. In first-line, patients were mainly treated with sunitinib, and in secondline half were treated with nivolumab. The highest OS was observed for patients treated with sunitinib in firstline and for patients treated with nivolumab in second-line. Background: Treatment landscape for advanced renal cell carcinoma (aRCC) has evolved quickly and few data about the real-world treatment patterns are available. This study aimed at describing the real-world treatment patterns and effectiveness of all systemic treatments available for aRCC in first and second-line treatment. Materials and Methods: A cohort of patients initiating a first-line systemic treatment for aRCC in 2016 was extracted from the French nationwide healthcare insurance system database (SNDS). The first-line treatment initiation date constituted the index date and patients were followed until death, loss to follow-up, or December 31, 2019, whichever occurred first. aRCC was identified using hospital diagnosis, long-term disease, or renal biopsy before index date. All analyses were performed for first and second-line treatment. Overall survival (OS) and time-to-next treatment or death (TNT-D) were estimated using Kaplan-Meier approach. Results: In 2016, 1629 patients initiated a first-line treatment for aRCC. Most of them were male (75.9%) and the median age was 67 years. Most of patients (91.7%) had received a tyrosine kinase inhibitor as first-line treatment, mainly sunitinib (64.4%), and 53.5% received a second-line, among which 43.7% nivolumab. Median OS (95% confidence interval [CI]) was 20.7 (95% CI:18.2-22.4) months from first-line treatment initiation and 15.4 (13.9-17.5) months from second-line treatment initiation. Median TNT-D were respectively 9.3 (9.7-12.1) months and 6.9 (5.9-7.7) months. Conclusion: This study highlights the limited survival of aRCC patients These results provide a valuable baseline and highlight the need for innovation, such as immune checkpoint inhibitor-based combinations that have recently became first-line standard of care. [ABSTRACT FROM AUTHOR]

Introduction: Immune-related adverse events (irAEs) due to immune checkpoint inhibitors may lead to discontinuation and treatment-related death. Acute aortitis is a rare but severe irAE. Case presentation: A 67-year-old man with recurrent lower gingival carcinoma received nivolumab therapy. Twenty-three months later, he experienced chest compression, which resulted in syncope. Following a whole-body computed tomography (CT) scanning, which revealed diffuse thickening of the aorta, and systemic assessments of the causes of aortitis, he was diagnosed with acute aortitis due to irAE. Nivolumab discontinuation and oral steroids improved CT findings. However, 11 months after nivolumab discontinuation, he developed an aortic aneurysmal rupture. Endovascular aortic repair rescued him. A durable anti-cancer response was still observed 4 months after the aortic rupture. Conclusion: Although severe irAE, such as acute aortitis, occurred, the patient may still achieve a durable response. A broad examination and prompt treatment of irAE can help improve the patient's survival. [ABSTRACT FROM AUTHOR]

Background: We report the case of a patient with melanoma and liver failure with encephalopathy, successfully treated with nivolumab without major side effects and encouraging prolonged disease control. Case presentation: In June 2022, metastatic lesions appeared in the liver associated with melanoma progression under treatment. Liver biopsy was non-diagnostic. The patient developed fever, abdominal distension, and jaundice. Liver function tests (LFTs) began to deteriorate. Hepatic encephalopathy developed in accordance with the worsening liver functions in the patient. Upper abdominal MRI with primovist showed multiple, progressive, metastatic lesions in the liver and mild to moderate dilatation of the intrahepatic biliary tract. Patient was evaluated as acute cholangitis associated with the compression of the biliary tract by progressive liver metastases. In December 2022, the patient was started antibiotherapy for cholangitis and Nivolumab (240 mg flat dose, every 2 weeks) therapy. After the first dose, both LFT and constitutional symptoms began to improve. Subsequently, LFTs almost completely returned to normal, clinical response was achieved. Multiple metastatic lesions in the liver regressed in the radiological evaluation performed at the third month of nivolumab treatment. With partial response, nivolumab treatment is continued. Conclusion: In this case is reported patient with hepatic encephalopathy due to an advanced refractory melanome successfully, and safely, treated with programed cell death-1 (PD-1) inhibitors. Clinical trials to explore the benefits of these immunotherapies in the hepatic failure population with advanced solid tumors should be supported. [ABSTRACT FROM AUTHOR]

Background: Anti-programmed cell death (PD)-1 and anti-PD-L1 medications inhibit the PD-1 and PD-L1 interaction and have been shown to be effective in treating several forms of advanced cancers. Since the approval of these agents, standard dosing protocols have been utilized. However, a small population of patients in the community setting has received dose-modified PD-1 and PD-L1 inhibitors secondary to a lack of tolerability. Data from this study suggests possible benefit with different dosing strategies. Objectives: The purpose of this retrospective study is to assess the efficacy and tolerability in terms of time to progression and adverse effects in patients receiving dose-modified PD-1 and PD-L1 inhibitors in Food and Drug Administration (FDA)-labeled indications. Methods: This single-institution retrospective chart review was conducted in an outpatient community setting on patients with cancer that received nivolumab, pembrolizumab, durvalumab, or atezolizumab for an FDA indication at one of the Houston Methodist Hospital infusion clinic site between September 1, 2017 and September 30, 2019. Data collection included demographics, adverse effects, dosing, treatment delay, and number of immunotherapy cycles administered per patient. Results: This study included 221 patients, who received either nivolumab (n = 81), pembrolizumab (n = 93), atezolizumab (n = 21), or durvalumab (n = 26). There were 11 patients who experienced a dose reduction and 103 patients who experienced a treatment delay. Of the patients with a treatment delay, the median time to progression was 197 days, and for patients with a dose reduction, the median time to progression was 299 days. Conclusion: The results of this study found that the immunotherapy associated adverse effects led to dosing and frequency changes for tolerance with continued therapy. Our data suggests that there could be potential benefits of dose modifications to immunotherapy treatment, but further large studies are needed to assess the efficacy of specific immunotherapy dose modifications on both outcomes and adverse effects. [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]

Patients with advanced hepatocellular carcinoma (aHCC) have a poor prognosis and high mortality. Nivolumab monotherapy demonstrated clinical benefit with an acceptable safety profile in patients with aHCC in the CheckMate 040 study. Five-year follow-up of the sorafenib-naive and sorafenib-experienced groups of CheckMate 040 is presented here. Patients received nivolumab monotherapy at dose levels of 0.1-10.0 mg/kg (dose-escalation phase) or 3 mg/kg (dose-expansion phase) every 2 weeks until disease progression or unacceptable toxicity. Primary endpoints were safety and tolerability (dose escalation), and objective response rate (ORR) by blinded independent central review (BICR) and by investigator as per RECIST version 1.1 (dose expansion). Eighty sorafenib-naive and 154 sorafenib-experienced patients were treated. Minimum follow-up in both groups was 60 months. ORR as per BICR was 20% [95% confidence interval (CI) 12% to 30%] and 14% (95% CI 9% to 21%) in the sorafenib-naive and sorafenib-experienced groups, respectively. Responses occurred regardless of HCC etiology or baseline tumor cell programmed death-ligand 1 (PD-L1) expression levels. Median overall survival (OS) was 26.6 months (95% CI 16.6-30.6 months) and 15.1 months (95% CI 13.0-18.2 months) in sorafenib-naive and sorafenib-experienced patients, respectively. The 3-year OS rates were 28% in the sorafenib-naive and 20% in the sorafenib-experienced groups; 5-year OS rates were 14% and 12%, respectively. No new safety signals were identified; grade 3/4 treatment-related adverse events were observed in 33% and 21% of patients in the sorafenib-naive and sorafenib-experienced groups, respectively. Biomarker analyses showed that baseline PD-L1 expression ≥1% was associated with higher ORR and longer OS compared with PD-L1 <1%. In the sorafenib-naive group, patients with OS ≥3 years exhibited higher baseline CD8 T-cell density compared with those with OS <1 year. With 5 years of follow-up, nivolumab monotherapy continued to provide durable clinical benefit with manageable safety in sorafenib-naive and sorafenib-experienced patients with aHCC. • At 5 years of follow-up, nivolumab monotherapy continued to provide durable clinical benefit in patients with aHCC. • ORR was 20% in the sorafenib (SOR)-naive group and 14% in the SOR-experienced group. • 3-year OS rates were 28% in the SOR-naive and 20% in the SOR-experienced groups; 5-year rates were 14% and 12%, respectively. • The safety profile of nivolumab monotherapy was manageable and no new safety signals were identified. • Higher ORR and longer OS were noted with baseline PD-L1 ≥1% versus <1% and were more prominent in the SOR-experienced group. [ABSTRACT FROM AUTHOR]

Simple Summary: The clinical significance of nivolumab plus ipilimumab in patients with recurrence after chemoradiotherapy followed by durvalumab remains unclear. We investigated the efficacy and safety of nivolumab plus ipilimumab in patients who relapsed after chemoradiotherapy followed by durvalumab. The 6- and 12-month PFS rates for nivolumab plus ipilimumab for relapse after durvalumab were 46.7% and 36.4%, indicating a long-tail plateau. Nivolumab plus ipilimumab was particularly effective in patients treated with durvalumab for 6 months or more. Therefore, nivolumab plus ipilimumab is a promising treatment option for patients who have relapsed after CCRT–durvalumab, with good tolerability. Nivolumab plus ipilimumab showed promising efficacy in patients with metastatic non-small-cell lung cancer (NSCLC). The efficacy of the nivolumab plus ipilimumab combination regimen in NSCLC patients who relapse after durvalumab consolidation following concurrent chemoradiotherapy (CCRT) has not been determined. Between January 2021 and June 2022, clinical data were retrospectively extracted from the medical records of patients with NSCLC who received nivolumab plus ipilimumab after CCRT and durvalumab consolidation. A total of 30 patients were included in this analysis. The median number of durvalumab treatment cycles was 11. Median PFS and OS with nivolumab plus ipilimumab were 4.2 months (95% confidence interval [CI]: 0.7–7.7) and 18.5 months (95% CI: 3.5–33.5), respectively. The 6-month and 12-month PFS rates were 46.7% (95% CI: 28.8–64.5) and 36.4% (95% CI: 19.0–53.7). In multivariate analysis, a significant correlation was observed between a durvalumab treatment duration of 6 months or more and PFS (p = 0.04) as well as OS (p = 0.001). Grade 3 adverse events, including pneumonitis, dermatitis, and colitis, occurred in 10% of the patients. This study suggests that nivolumab plus ipilimumab is effective, especially in patients who have received durvalumab for 6 months or more, and tolerable for patients who relapsed after durvalumab following CCRT. [ABSTRACT FROM AUTHOR]

Simple Summary: Two Israeli studies about medical marijuana potentially interfering with immunotherapies like nivolumab for cancer treatment have received substantial attention. However, there have been anonymous but detailed concerns about these reports on PubPeer. This team attempted to verify the data analysis and statistics of these two reports and the published correction. Many findings, including some that could impact the statistical conclusions, could not be verified. Of 22 statistical in the prospective report, 4 could not be repeated using the same statistics or with the provided N. The p-value on 17 corresponded with that of a different statistical test than was listed in the methods. Re-analysis also identified some previously unreported significant differences (e.g., age) between cannabis users and non-users at baseline. Further study of the safety of immunotherapy and cannabis combination may be warranted using patient groups that have been matched on key demographic and medical variables. A retrospective (N = 140) and a prospective (N = 102) observational Israeli study by Bar-Sela and colleagues about cannabis potentially adversely impacting the response to immunotherapy have together been cited 202 times, including by clinical practice guidelines. There have also been concerns on PubPeer outlining irregularities and unverifiable information in their statistics and numerous errors in calculating percentages. This reanalysis attempted to verify the data analysis while including non-parametric statistics. The corrected prospective report contained 22 p-values, but only one (4.5%) could be verified despite the authors being transparent about the N and statistics employed. Cannabis users were significantly (p < 0.0025) younger than non-users, but this was not reported in the retrospective report. There were also errors in percentage calculations (e.g., 13/34 reported as 22.0% instead of 38.2%). Overall, these observational investigations, and especially the prospective, appear to contain gross inaccuracies which could impact the statistical decisions (i.e., significant findings reported as non-significant or vice-versa). Although it is mechanistically plausible that cannabis could have immunosuppressive effects which inhibit the response to immunotherapy, these two reports should be viewed cautiously. Larger prospective studies of this purported drug interaction that account for potential confounds (e.g., greater nicotine smoking among cannabis users) may be warranted. [ABSTRACT FROM AUTHOR]