Early change of plasma Epstein-Barr virus DNA load and the viral lytic genome level could positively predict clinical outcome in recurrent or metastatic nasopharyngeal carcinoma receiving anti-programmed cell death 1 monotherapy.

PURPOSE: Patients with recurrent or metastatic nasopharyngeal carcinoma (RM-NPC) have proven benefit from anti-programmed cell death 1 (anti-PD-1) monotherapy. Here, we retrospectively analyze the association of plasma Epstein-Barr virus (EBV) DNA load and tumor viral lytic genome with clinical outcome from 2 registered phase I trials. METHODS: Patients with RM-NPC from Checkmate 077 (nivolumab phase I trial in China) and Camrelizumab phase I trial between March 2016 and January 2018 were enrolled. Baseline EBV DNA titers were tested in 68 patients and EBV assessment was performed in 60 patients who had at least 3 post-baseline timepoints of EBV data and at least 1 post-baseline timepoint of radiographic assessment. We defined "EBV response" as 3 consecutive timepoints of load below 50% of baseline, and "EBV progression" as 3 consecutive timepoints of load above 150% of baseline. Whole-exome sequencing was performed in 60 patients with available tumor samples. RESULTS: We found that the baseline EBV DNA load was positively correlated with tumor size (spearman p < 0.001). Both partial response (PR) and stable disease (SD) patients had significantly lower EBV load than progression disease (PD) patients. EBV assessment was highly consistent with radiographic evaluation. Patients with EBV response had significantly improved overall survival (OS) than patients with EBV progression (log-rank p = 0.004, HR = 0.351 [95% CI: 0.171-0.720], median 22.5 vs. 11.9 months). The median time to initial EBV response and progression were 25 and 36 days prior to initial radiographic response and progression, respectively. Patients with high levels of EBV lytic genomes at baseline, including BKRF2, BKRF3 and BKRF4, had better progression-free survival (PFS) and OS. CONCLUSION: In summary, early clearance of plasma EBV DNA load and high levels of lytic EBV genes were associated with better clinical outcome in patients with RM-NPC receiving anti-PD-1 monotherapy.

The role of cytoreductive nephrectomy in metastatic renal cell carcinoma in immune-oncology era (SEVURO-CN): study protocol for a multi-center, prospective, randomized trial.

BACKGROUND: The role of cytoreductive nephrectomy (CN) in the treatment of metastatic renal cell carcinoma (mRCC) remains unclear in the immuno-oncology (IO) era. The results of two randomized trials, CARMENA and SURTIME, questioned the role and timing of CN. However, despite the latest advances in the systemic treatment of mRCC, previous trials have only used targeted therapy, and no studies have fully investigated the role of CN in immune checkpoint inhibitor (CPI) settings, and there is an urgent need for future studies to better define the role and timing of CN. METHODS: This study is an open-label, multi-center, parallel, prospective, randomized, interventional clinical study to evaluate the efficacy of CN in combination with CPIs in mRCC patients with International mRCC Database Consortium (IMDC) intermediate- and poor-risk. Synchronous mRCC patients with ≤ 3 IMDC risk features will be randomly allocated to three groups (1, upfront CN; 2, deferred CN; and 3, systemic therapy [ST] only). For ST, the nivolumab plus ipilimumab combination regimen, one of the standard regimens for intermediate- and poor-risk mRCC, is chosen. The primary endpoint is overall survival. The secondary endpoints are progression-free survival, objective response rate, number of participants with treatment-related adverse events, and number of participants with surgical morbidity. We will analyze the genetic mutation profiles of the tumor tissue, circulating tumor DNA, urine tumor DNA, and tumor-infiltrating lymphocytes. The gut and urine microbial communities will be analyzed. The study will begin in 2022 and will enroll 55 patients. DISCUSSION: This study is one of the few prospective randomized trials to evaluate the benefit of CN in the treatment of synchronous mRCC in the IO era. The SEVURO-CN trial will help identify the role and timing of CN, thereby rediscovering the value of CN. TRIAL REGISTRATION: ClinicalTrials.gov, NCT05753839. Registered on 3 March 2023.

A combination of 5-azacytidine and nivolumab is a potentially effective rescue therapy in relapsed/refractory AITL.

Introduction: Angioimmunoblastic T-cell lymphoma (AITL) is a peripheral T-cell lymphoma characterized by a T follicular helper cell phenotype expressing PD-1 (programmed cell death-1). AITL exhibits a poor response to conventional chemotherapy, with a median 5-year overall survival of 44% and a progression-free survival of 32%. Relapse is common, resulting in a median overall survival of 6 months. Recurrent mutations are detected in genes regulating DNA methylation, including TET2, DNMT3A, and IDH2 variants, along with the prevalent RHOA G17V mutation. In this context, patients treated with the hypomethylating agent 5-azacytidine achieved overall response and complete response rates of 75% and 41%, respectively. We hypothesized that targeted therapies combining anti-PD-1 checkpoint blockers with hypomethylating agents could be efficient in AITL patients and less toxic than standard chemotherapy. Methods: Here, we report the efficacy of a regimen combining 5-azacytidine and nivolumab in nine relapsed or refractory AITL patients. Results: This regimen was well-tolerated, especially in elderly patients. The overall response rate was 78%, including four partial responses (44%) and three complete responses (33%). Allogeneic hematopoietic stem cell transplantation was performed in two patients who reached complete response. Discussion: These preliminary favorable results may serve as a basis for further investigation in prospective studies.

Quality of life and patient-reported toxicities in patients with advanced Merkel cell carcinoma treated with combined nivolumab and ipilimumab with or without stereotactic body radiation therapy.

BACKGROUND: Merkel cell carcinoma is a rare skin cancer associated with poor survival. Based on a previous Phase II trial of adults with advanced Merkel cell carcinoma by Kim and colleagues (2022), there is now a strong rationale for combination therapy (i.e., nivolumab and ipilimumab) to become a treatment option for patients with advanced Merkel cell carcinoma. The goal of this paper was to report on the secondary outcome of quality of life (QOL) among patients on this trial. METHODS: Patients receiving combined nivolumab and ipilimumab, with or without stereotactic body radiation therapy (SBRT), completed the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 prior to starting treatment and every 2 weeks thereafter. Changes in QOL during treatment and post-treatment were evaluated using piecewise random-effects mixed models. Exploratory analyses compared changes in QOL between study arms. The original trial was registered with ClinicalTrials.gov (NCT03071406). RESULTS: Study participants (n = 50) reported no changes in overall QOL (ps > 0.05), but emotional functioning improved during treatment (p = 0.01). Cognitive and social functioning worsened post-treatment (ps < 0.01). In general, patients treated with combination therapy only (n = 25) reported no change in QOL over time, whereas patients also treated with SBRT (n = 25) consistently demonstrated worsening QOL post-treatment. CONCLUSION: QOL is generally preserved in patients treated with combination therapy, but the addition of SBRT may worsen QOL. Combined with clinical efficacy data published previously, results support the use of combination therapy with nivolumab and ipilimumab as a treatment option for patients with advanced Merkel cell carcinoma.

Intrapleural nivolumab in cancer patients with pleural effusion.

ABSTRACT: We assessed the preliminary efficacy and toxicity of intrapleural instillation of nivolumab in patients with large pleural effusion. Patients with metastatic cancers who have a large volume of pleural effusion and required evacuation were eligible. Thoracentesis followed by nivolumab (40 mg, single intrapleural instillation) was performed. The primary endpoint was 3-month recurrence-free survival. A total of 13 patients were enrolled. The study was terminated after stage 1 as no efficacy was observed; 7 patients (54%) had a recurrence of pleural effusion at 3 months. Thirteen (100%) patients had no recurrence, dyspnea, or cough within 1 month, and the median time to recurrence was 1.9 months (95% confidence interval [CI], 1.35-2.5). No adverse events were identified. We concluded that a single intrapleural instillation of the nivolumab at 40 mg was ineffective and well-tolerated in cancer patients with pleural effusion.

Dual immunotherapy alternating with anti-PD-1 antibody plus liposomal doxorubicin show good efficacy in prostate epithelioid hemangioendothelioma: a case report.

Epithelioid hemangioendothelioma is a rare vascular malignancy, and currently, there is no standard treatment regimen for this disease and existing treatment options have limited efficacy. In this case report, we present a patient with lung and lymph node metastases from prostate epithelioid hemangioendothelioma who achieved a significant partial response. This was accomplished through alternating nivolumab therapy with ipilimumab and liposomal doxorubicin, resulting in a progression-free-survival more than 6 months to date. The treatment was well-tolerated throughout. Our report suggests that dual immunotherapy alternating with anti-PD-1antibody plus doxorubicin may be a potential treatment modality for epithelioid hemangioendothelioma. However, larger sample studies are necessary to ascertain the effectiveness of this treatment strategy and it is essential to continue monitoring this patient to sustain progression-free survival and overall survival.

Long-term responders to nivolumab in previously treated advanced renal cell carcinoma: a sub-analysis of meet-URO15 study.

BACKGROUND: Although nivolumab prolongs overall survival (OS) in pretreated patients with metastatic renal cell carcinoma (mRCC), underlining clinical and biological features of long-term responses are still to be determined. This study aims to investigate clinical and pathological characteristics of mRCC patients who achieved long-term responses during nivolumab treatment. MATERIALS AND METHODS: A retrospective analysis was performed on mRCC patients receiving nivolumab as second or further therapy line between May 2016 and January 2019 in 34 Italian Oncology Centres. Outcome assessments and logistic regression were performed to evaluate factors influencing long-term responses. RESULTS: A total of 571 patients with a median age of 61 years (range 17-85) were included in the analysis. With a median follow-up of 22.1 (1.0-89.0) months, 23.1% of patients were 2-year progression-free on treatment with nivolumab, hence they were categorized as long-term responders. Baseline characteristics, including age, gender, and histology, were similar between long- and short-term responders. Karnofsky Performance Status ≥ 80% was significantly associated with long-term response (p = 0.02), while bone metastases (p = 0.03), International mRCC Database Consortium intermediate-poor risk (p < 0.01) and Neutrophil-to-Lymphocyte Ratio ≥ 3.2 (p = 0.02) were associate with short-term responses. Long-term responders exhibited a median progression-free survival of 55.0 months versus 4.0 months of the short-term responders. The median OS was not reached in long-term responders while it was 17.0 months for short*term responders. CONCLUSION: This retrospective analysis sheds light on factors associated with long-term response to nivolumab in mRCC. Understanding these clinical features will be essential for selecting patients who may mostly benefit from immunotherapy.

Comparison of the Efficacy and Safety of Nivolumab Plus Cabozantinib versus Sunitinib in the Treatment of Elderly Patients with Advanced Clear Cell Renal Cell Carcinoma.

OBJECTIVE: Advanced clear cell renal cell carcinoma (ccRCC) seriously affects the life and health of patients, but effective treatment for this disease is still lacking in clinic. This study investigated the efficacy of nivolumab plus cabozantinib versus sunitinib in the treatment of elderly patients with advanced ccRCC. METHODS: The clinical data of 216 elderly patients with advanced ccRCC in our hospital from January 2020 to January 2022 were retrospectively analysed. On the basis of different treatment regimens, patients were divided into the cabozantinib group (n = 111, receiving nivolumab and cabozantinib) and the sunitinib group (n = 105, receiving nivolumab and sunitinib). The overall survival time, disease control rates, health status, incidence of adverse events and identification of prognostic risk were compared between the two groups. RESULTS: The cabozantinib group had higher overall survival time, disease control rate and scores in the Functional Assessment of Cancer Therapy-Kidney Symptom Index and EuroQol-Five Dimensions-Three Levels Questionnaire than the sunitinib group. The incidence of adverse events in the cabozantinib group was lower than that in the sunitinib group (p < 0.001). However, no difference existed in the identification of prognostic risk between the two groups (p > 0.05). CONCLUSIONS: The effect of nivolumab plus cabozantinib on the treatment of elderly patients with advanced ccRCC is better than that of nivolumab plus sunitinib, with fewer adverse reactions and higher safety. However, the research results require further clinical studies to confirm and promote.

In vitro T cell responses to PD-1 blockade are reduced by IFN-α but do not predict therapy response in melanoma patients.

PD-1 blockade therapy has revolutionized melanoma treatment, but still not all patients benefit and pre-treatment identification of those patients is difficult. Increased expression of inflammatory markers such as interleukin (IL)-6 in blood of patients correlates with poor treatment response. We set out to study the effect of inflammatory cytokines on PD-1 blockade in vitro. For this, we studied the effect of IL-6 and type I interferon (IFN) in vitro on human T cells in a mixed leukocyte reaction (MLR) in the absence or presence of PD-1 blockade. While IL-6 reduced IFN-γ secretion by T cells in both the presence and absence of PD-1 blockade, IFN-α specifically reduced the IFN-γ secretion only in the presence of PD-1 blockade. IFN-α reduced T cell proliferation independent of PD-1 blockade and reduced the percentage of cells producing IFN-γ only in the presence of PD-1 blockade. Next we determined the type I IFN score in a cohort of 22 melanoma patients treated with nivolumab. In this cohort, we did not find a correlation between clinical response and type I IFN score, nor between clinical response and IFN-γ secretion in vitro in a MLR in the presence of PD-1 blockade. We conclude that IFN-α reduces the effectiveness of PD-1 blockade in vitro, but that in this cohort, type I IFN score in vivo, nor IFN-γ secretion in vitro in a MLR in the presence of PD-1 blockade correlated to decreased therapy responses in patients.

Efficacy of adjuvant immune checkpoint inhibitors pembrolizumab or nivolumab in melanoma patients ≥ 75 years: results of a real-world cohort including 456 patients.

BACKGROUND: Immune checkpoint inhibitors (ICI) applied in patients with melanoma in an adjuvant setting have proven safety and efficacy in several studies, but data on elderly patients aged 75 years or more is scarce. Aim of this study was to investigate efficacy and safety of adjuvant ICI in patients aged ≥ 75 years compared to patients < 75 years in a real-world setting. METHODS: We retrospectively analyzed clinical data, including occurrence of immune-related adverse events (irAE) and outcome of 456 patients that had been treated with adjuvant ICI between January 1st, 2018 and December 20th, 2022. We then compared patients aged ≥ 75 years (n = 117) to patients < 75 years (n = 339) in terms of safety and disease-free survival (DFS). RESULTS AND CONCLUSION: ICI were well tolerated in both groups, with no significant difference observed in the overall occurrence of irAE. However, within the elderly subgroup, there was a significantly higher proportion of skin or nephrological toxicity and colitis/diarrhea compared to the other group. In terms of efficacy, a significantly shorter DFS in patients aged ≥ 75 years was observed. Adjuvant ICI in patients ≥ 75 years was less effective and furthermore associated with an increased risk for skin, renal or bowel toxicity. Therefore, in elderly patients, adjuvant ICI should be used with precaution.

Systemic capillary leak syndrome in a patient treated with nivolumab/ipilimumab immunotherapy for metastatic melanoma with concurrent COVID-19 vaccination.

Systemic capillary leak syndrome (SCLS) is a rare and life-threatening disorder characterised by leaking of intravascular fluid to extravascular tissues. An association with immunotherapy and COVID-19 vaccination has been reported as potential triggers. A case of a patient in her 70s developing SCLS after the BNT162b2 (Pfizer-BioNTech) COVID-19 vaccination with a history of metastatic melanoma treated with nivolumab (PD-1 monoclonal antibody) and ipilimumab (anti-CTLA4 monoclonal antibody) is reported. The aetiology and management of SCLS are also reviewed in this case context.

An Efficacy and Safety Comparison of Regorafenib and Nivolumab in Unresectable Hepatocellular Cancer Patients: A Systematic Review.

OBJECTIVE: This systematic review aimed to compare the efficacy and safety of regorafenib and nivolumab, two FDA-approved second-line treatments for unresectable Hepatocellular Carcinoma (HCC). METHODS: Literature comparing the efficacy and safety of regorafenib and nivolumab in unresectable HCC patients was systematically searched across seven databases, including: PubMed, SCOPUS, Cochrane Database of Systematic Reviews, ScienceDirect, EBSCOhost, EMBASE, and ProQuest, using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. The search was done on April 2nd, 2023. Study quality and risk of bias were assessed using the Agency for Healthcare Research and Quality (AHRQ) and ROBINS-1 tools. The selected studies were included in the qualitative data synthesis. RESULTS: Three trials found that HCC patients taking nivolumab had statistically insignificantly longer OS, TTP, and progression-free survival than those on regorafenib. Nivolumab increased ORR, with largely partial responses, and mixed DCR, with little statistical significance. All three studies showed that nivolumab had fewer side effects and improved tolerance. DISCUSSION: Three retrospective cohort studies with a total of 383 regorafenib-receiving cohorts and 230 nivolumab-receiving cohorts were included in the qualitative analysis. Nivolumab was found to be superior in regards of longer overall survival, longer time to progression, higher objective response rate, and lower adverse event occurrence. However, statistical significance was not achieved in most of the parameters. CONCLUSIONS: The use of nivolumab is preferable as the second-line systemic therapy for unresectable HCC. More high-quality studies are urgently needed to generate quantitative analysis, and to encourage the formation of guidelines for second-line systemic therapy.

TNFSF9 Is Associated with Favorable Tumor Immune Microenvironment in Patients with Renal Cell Carcinoma Who Are Treated with the Combination Therapy of Nivolumab and Ipilimumab.

Combination therapy of nivolumab and ipilimumab (NIVO + IPI) for metastatic renal cell carcinoma (mRCC) has shown efficacy, but approximately 20% of patients experience disease progression in the early stages of treatment. No useful biomarkers have been reported to date. Therefore, it is desirable to identify biomarkers to predict treatment responses in advance. We examined the tumor microenvironment (TME)-related gene expression in mRCC patients treated with NIVO + IPI, between the response and non-response groups, using tumor tissues, before administering NIVO + IPI. In TME-related genes, TNFSF9 expression was identified as a candidate for the predictive biomarker. Its expression discriminated between the response and non-response groups with 88.89% sensitivity and 87.50% specificity (AUC = 0.9444). We further analyzed the roles of TNFSF9 in TME using bioinformatics from The Cancer Genome Atlas (TCGA) cohort. An adaptive immune response was activated in the TNFSF9-high-expression tumors. Indeed, T follicular helper cells, plasma B cells, and tumor-infiltrating CD8+ T cells were increased in the tumors, which indicates the promotion of humoral immunity due to enhanced T-B interactions. However, as the number of regulatory T cells (Treg) increased in the tumors, the percentage of dysfunctional T cells also increased. This suggests that not only PD-1 but also CTLA-4 inhibition may have suppressed Treg activation and improved the therapeutic effect in the TNFSF9 high-expression tumors. Therefore, TNFSF9 may predict the therapeutic efficacy of NIVO + IPI for mRCC and allow more appropriate patient selection.

Impact of immune checkpoint inhibitors on survival outcomes in advanced gastric cancer in Japan: A real-world analysis.

BACKGROUND: Nivolumab was approved for the treatment of advanced gastric cancer in 2017 in Japan. The aim of this study was to assess the impact of nivolumab in a real-world clinical setting. METHODS: This single-institutional retrospective study included patients with advanced gastric or esophagogastric junction adenocarcinoma and a history of first-line chemotherapy with platinum-based doublet or triplet regimens between 2010 and 2020. To assess the impact of nivolumab on survival, the patients were divided based on the year of nivolumab approval into a pre-2017 (2010-2016) group and a post-2017 (2017-2020) group. RESULTS: From a total of 1918 patients, 1093 were excluded. There were 533 patients in the pre-2017 group and 292 in the post-2017 group. Immune checkpoint inhibitors were used significantly more often in the post-2017 group than in the pre-2017 group (8.6% vs. 47.9%). Median overall survival was significantly longer in the post-2017 group (16.9 vs. 13.9 months; hazard ratio [HR] 0.75, 95% confidence interval [CI] 0.63-0.90; p < 0.01). The proportion of patients transitioning to third-line treatment was higher in the post-2017 group than in the pre-2017 group (56.3% vs. 43.8%, p < 0.01). Median survival outcomes following progression on second-line treatment were significantly longer in the post-2017 group (4.3 vs. 3.2 months; HR 0.70, 95% CI 0.57-0.86; p < 0.01). CONCLUSION: The proportion of patients transitioning to third-line treatment and survival outcomes following progression on second-line treatment have improved since the approval of nivolumab. This drug might help to prolong overall survival in real-world practice.

A case of pulmonary tuberculosis that developed during nivolumab and ipilimumab treatment for pulmonary adenocarcinoma that recurred two months after completion of anti-tuberculous treatment.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have become key agents in the treatment of non-small cell lung cancer worldwide. However, immune-related adverse events (irAEs) must be addressed to maximize the efficacy of ICIs. Mycobacterium tuberculosis (Mtb) infection is considered as a type of irAE associated with ICIs, but the underlying mechanism is not completely understood. Here, we present a case of pulmonary tuberculosis (TB) that developed during administration of nivolumab and ipilimumab for pulmonary adenocarcinoma that recurred just 2 months after completion of anti-TB treatment. CASE DESCRIPTION: A 67-year-old man with lung adenocarcinoma was referred to our hospital for chemotherapy. He was a former smoker and had been diagnosed with stage IVA (cT4N1M1a) lung adenocarcinoma. Interferon-gamma release assay (IGRA) yielded positive results at the start of treatment. One month after initiating treatment with nivolumab and ipilimumab, he presented with productive cough and Mtb complex was cultured from sputum samples. Two months after completing anti-TB treatment, recurrence of TB was observed. The series of strains were found to be identical. CONCLUSIONS: This represents the first report of pulmonary TB that developed during nivolumab and ipilimumab treatment, and recurred 2 months after completing anti-TB treatment. Physicians should be mindful of the potential for TB recurrence following the use of ICIs, particularly in patients showing positive results from IGRA.

Projecting long-term clinical outcomes with larotrectinib compared with immune checkpoint inhibitors in metastatic nonsmall cell lung cancer and differentiated thyroid cancer.

BACKGROUND: Larotrectinib is approved for patients with advanced NTRK gene fusion-positive solid tumors. Prior studies demonstrated promising results with larotrectinib compared with other systemic therapy. However, comparisons to checkpoint inhibitors, such as nivolumab or pembrolizumab, have not been done. OBJECTIVE: To estimate and compare expected life-years (LYs) and quality-adjusted LYs (QALYs) for patients with nonsmall cell lung cancer (NSCLC) eligible for larotrectinib vs patients with unknown NTRK gene fusion status on nivolumab or pembrolizumab. We also assessed patients with metastatic differentiated thyroid cancer (DTC), as pembrolizumab may be considered in certain circumstances. METHODS: We developed partitioned survival models to project long-term comparative effectiveness of larotrectinib vs nivolumab or pembrolizumab. Larotrectinib survival data were derived from an updated July 2021 analysis of 21 adult patients (≥18 years of age) with metastatic NTRK gene fusion-positive NSCLC and 21 with DTC. Survival inputs for nivolumab and pembrolizumab were obtained from published articles. Progression-free and overall survival were estimated using survival distributions (Exponential, Weibull, Log-logistic, and Log-normal). Exponential fits were chosen based on goodness-of-fit and clinical plausibility. RESULTS: In NSCLC, larotrectinib resulted in gains of 5.87 and 5.91 LYs compared to nivolumab and pembrolizumab, respectively, which translated to gains of 3.53 and 3.56 QALYs. In DTC, larotrectinib resulted in a gain of 5.23 LYs and 4.24 QALYs compared to pembrolizumab. CONCLUSIONS: In metastatic NSCLC and DTC, larotrectinib may produce substantial life expectancy and QALY gains compared to immune checkpoint inhibitors. Additional data with longer follow-up will further inform this comparison.

Time-dependent efficacy analysis of first-line immunotherapies for advanced non-small cell lung cancer.

BACKGROUND: Many randomized controlled trials (RCTs) and network meta-analyses have demonstrated that the progression-free survival (PFS) and overall survival (OS) of advanced non-small cell lung cancer (NSCLC) patients can be improved through combination immunotherapy or monotherapies. However, time-dependent analysis of the treatment effect is currently lacking. Thus, we aimed to evaluate the efficacy of first-line immunotherapy, and establish a hazard ratio function to reflect the time-varying progression or mortality risk of patients with NSCLC. METHODS: Seventeen clinical trials were selected based on search strategy. Baseline characteristics, including the age, sex, smoking status, geographical region, and Eastern Cooperative Oncology Group (ECOG) performance status of patients, were balanced, resulting in ten immunotherapies from nine appropriate clinical trials to conduct treatment effect comparison. RESULTS: We found that nivolumab plus ipilimumab (nivo + ipi) improved the PFS and OS over time. The hazard ratio of nivo + ipi, relative to that of pembrolizumab, decreased from 1.11 to 0.36 for PFS, and from 0.93 to 0.49 for OS over a 10-year period. In terms of the response to immunotherapy in patients with different PD-L1 expression levels, patients with PD-L1 > = 50% experienced lower rates of progression and a reduced mortality risk over time. The hazard ratio of patients with PD-L1 > = 50% relative to all of the patients decreased from 0.73 to 0.69 for PFS, and from 0.78 to 0.67 for OS. CONCLUSIONS: Based on the fact that time-dependent progression and mortality risk existed during the treatment duration, physicians should select a suitable treatment regimen for patients based on the hazard ratio.

JAK inhibition enhances checkpoint blockade immunotherapy in patients with Hodgkin lymphoma.

Unleashing antitumor T cell activity by checkpoint inhibitor immunotherapy is effective in cancer patients, but clinical responses are limited. Cytokine signaling through the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway correlates with checkpoint immunotherapy resistance. We report a phase I clinical trial of the JAK inhibitor ruxolitinib with anti-PD-1 antibody nivolumab in Hodgkin lymphoma patients relapsed or refractory following checkpoint inhibitor immunotherapy. The combination yielded a best overall response rate of 53% (10/19). Ruxolitinib significantly reduced neutrophil-to-lymphocyte ratios and percentages of myeloid suppressor cells but increased numbers of cytokine-producing T cells. Ruxolitinib rescued the function of exhausted T cells and enhanced the efficacy of immune checkpoint blockade in preclinical solid tumor and lymphoma models. This synergy was characterized by a switch from suppressive to immunostimulatory myeloid cells, which enhanced T cell division.

A Case of Gallbladder Metastasis of Malignant Melanoma.

In the clinical course of malignant melanoma, which can metastasize to multiple organs, gallbladder metastases are rarely detected. A 69-year-old man who underwent resection of a primary malignant melanoma was subsequently treated with nivolumab for lung metastases and achieved complete response. Seven years after surgery, multiple nodules were found in the gallbladder, and he underwent laparoscopic cholecystectomy. The postoperative diagnosis was metastases of malignant melanoma. He has been recurrence-free 8 months after surgery. If radical resection is possible, such surgery should be performed for gallbladder metastases found in patients with other controlled lesions of malignant melanoma.

Checkpoint Inhibitor Induced Acute Liver Failure.

Immune checkpoint inhibitors have become essential antineoplastic agents in medical oncology over the past decade. However, they are associated with potentially fatal multisystem abnormalities, with increasing concern in gastrointestinal tract and its associated organs. We present a patient with advanced renal cell carcinoma, who presented with acute liver failure after the first dose of combined immunotherapy with nivolumab and ipilimumab. A thorough evaluation for viral, metabolic, and autoimmune causes was unremarkable. He was managed with steroids and made significant improvement. To our knowledge, this is the first documented case of acute liver failure following ipilimumab and nivolumab.