Nivolumab Monotherapy and Nivolumab Plus Ipilimumab in Recurrent Small Cell Lung Cancer: Results From the CheckMate 032 Randomized Cohort

IntroductionNivolumab monotherapy is approved in the United States for third-line or later metastatic small cell lung cancer based on pooled data from nonrandomized and randomized cohorts of the multicenter, open-label, phase 1/2 trial of nivolumab ± ipilimumab (CheckMate 032; NCT01928394). We report updated results, including long-term overall survival (OS), from the randomized cohort.MethodsPatients with small cell lung cancer and disease progression after one to two prior chemotherapy regimens were randomized 3:2 to nivolumab 3 mg/kg every 2 weeks or nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four cycles followed by nivolumab 3 mg/kg every 2 weeks. Patients were stratified by number of prior chemotherapy regimens and treated until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) by blinded independent central review.ResultsOverall, 147 patients received nivolumab and 96 nivolumab plus ipilimumab. Minimum follow-up for ORR/progression-free survival/safety was 11.9 months (nivolumab) and 11.2 months (nivolumab plus ipilimumab). ORR increased with nivolumab plus ipilimumab (21.9% versus 11.6% with nivolumab; odds ratio: 2.12; 95% confidence interval: 1.06–4.26; p = 0.03). For long-term OS, minimum follow-up was 29.0 months (nivolumab) versus 28.4 months (nivolumab plus ipilimumab); median (95% confidence interval) OS was 5.7 (3.8–7.6) versus 4.7 months (3.1–8.3). Twenty-four–month OS rates were 17.9% (nivolumab) and 16.9% (nivolumab plus ipilimumab). Grade 3 to 4 treatment-related adverse event rates were 12.9% (nivolumab) versus 37.5% (nivolumab plus ipilimumab), and treatment-related deaths were n =1 versus n = 3, respectively.ConclusionsWhereas ORR (primary endpoint) was higher with nivolumab plus ipilimumab versus nivolumab, OS was similar between groups. In each group, OS remained encouraging with long-term follow-up. Toxicities were more common with combination therapy versus nivolumab monotherapy.     

Association Between Early Immune-related Adverse Events and Clinical Outcomes in Patients With Non–Small Cell Lung Cancer Treated With Immune Checkpoint Inhibitors

IntroductionPrevious studies have described an association between immune-related adverse events (irAEs) and better outcomes in patients administered nivolumab for advanced non–small-cell lung cancer. However, the patients in previous studies were not stratified by potential predictive factors, such as programmed cell death ligand 1 status and treatment lines. Additionally, little is known of whether the timing and type of irAEs can inform the prediction of outcomes.Patients and MethodsWe prospectively investigated the association between irAEs and outcomes in the single-center cohort that included patients administered nivolumab in the second or later line of therapy. Subsequently, we confirmed these findings in a retrospective multicenter cohort that included patients with programmed cell death ligand 1 tumor proportion score of ≥ 50% who had received first-line pembrolizumab. The primary outcome was progression-free survival (PFS).ResultsIn the prospective cohort (n = 76), the median PFS was significantly longer for the patients experiencing irAEs within 2 weeks of beginning nivolumab compared with the PFS for those who did not (median, 5.0 months [95% confidence interval (CI), 2.1-8.6 months] vs. median, 2.0 months [95% CI, 1.9-2.5 months]; P = .046). The association was stronger with earlier (within 2 weeks) than with later (within 6 weeks) irAEs. In the retrospective cohort (n = 148), the median PFS was significantly longer for the patients with early irAEs (within 3 weeks) than for those without (median, not reached [95% CI, 5.9 months to not reached] vs. median, 6.9 months [95% CI, 4.2-9.7 months]; P = .04). Rash was common and a better predictor of outcomes in both cohorts.ConclusionOur results have provided firmer evidence of the association between the occurrence of irAEs and outcomes and suggest that early irAEs (especially rash) might better predict outcomes.     

Central diabetes insipidus related to anti-programmed cell-death 1 protein active immunotherapy

Cancer immunotherapy is a breakthrough strategy entwined with toxicity. Immune-related hypophysitis is conventionally considered distinctive of cytotoxic T-lymphocyte antigen 4 (CTLA-4) inhibitors. Immune-related central diabetes insipidus (CDI) is exceptional. CDI rarely manifests as hypernatremia, which is almost always euvolemic. We report a 71-years-old male patient with advanced lung cancer who experienced severe chronic hypernatremia presented as alterations in mental status five months after initiation of treatment with the anti-PD-1 checkpoint inhibitor nivolumab. Combination of persistent hypernatremia, polyuria, high plasma osmolality and hyposthenuria raised suspicion of diabetes insipidus, prompting measurement of serum concentration of arginine vasopressin (AVP). The inappropriately undetectable serum levels of AVP confirmed central diabetes insipidus (CDI). Nivolumab-related hypophysitis was recognized as possible cause of CDI. Further hormonal assessment excluded any endocrinopathy indicating disorder of posterior pituitary. Pituitary MRI was normal with persistence of hyperintensity of posterior pituitary on T1-weighted images (bright spot). The patient was scheduled to receive 1-deamino-8-D-arginine vasopressin (DDAVP), but he died suddenly due to cardiac arrest before initiation of treatment. Our report describes the first case of nivolumab related CDI, building on existing literature through: (I) underscoring hypovolemic hypernatremia as CDI manifestation; (ii) bringing into spotlight the rare anti-PD-1 treatment related hypophysitis; (iii) enriching the limited evidence on immune-related CDI. Increased awareness of nivolumab related CDI will enable prompt recognition and therapeutic intervention.     

Artificial Neural Networks as a Way to Predict Future Kidney Cancer Incidence in the United States

IntroductionThe incidence of kidney cancer is increasing; it could be counteracted with new ways to predict and detect it. We aimed to implement an artificial neural network in order to predict new cases of renal-cell carcinoma (RCC) in the population using population rate, obesity, smoking incidence, uncontrolled hypertension, and life expectancy data in the United States.Patients and MethodsStatistics were collected on US population numbers, life expectancy, obesity, smoking, and hypertension. We used MATLAB R2018 (MathWorks) software to implement an artificial neural network. Data were repeatedly and randomly divided into training (70%) and validation (30%) subsets.ResultsThe number of new RCC cases will grow from 44,400 (2020) to 55,400 (2050), an increase of +24.7%. Our data show that preventing hypertension would have the greatest impact on reduction of the incidence, estimated at ?775 and ?575 cases per year in 2020 and in 2030, respectively. The prevention of obesity and smoking would have a more limited impact, estimated at ?64 and ?180 cases per year in 2020 and in 2030, respectively, for obesity, and ?173 and ?21 cases per year in 2020 and in 2030, respectively, for smoking.ConclusionsOur predictions underline the need for accurate studies on RCC-related risk factors to reduce the incidence.     

纳武利尤单抗联合DP方案超选择性支气管动脉栓塞灌注治疗晚期非小细胞肺癌的临床研究

目的 探讨纳武利尤单抗联合DP方案超选择性支气管动脉栓塞灌注治疗晚期非小细胞肺癌（NSCLC）患者的临床疗效。方法 选取2018年12月—2020年12月在成都医学院第一附属医院呼吸与危重症医学科收治的晚期NSCLC患者187例,将患者按照治疗方法分为对照组（92例）和观察组（95例）。对照组使用超选择支气管动脉栓塞灌注化疗治疗,输注2 000 mL 0.9%氯化钠溶液或糖盐水水化,0.9%氯化钠溶液100 mL分别稀释多西他赛注射液及顺铂注射液,37.5 mg/m²,先缓慢注入稀释后多西他赛,间隔30 min再注入稀释后顺铂。灌注化疗间隔3周,共4个疗程。观察组患者在对照组的基础上静脉输注纳武利尤单抗注射液,3 mg/kg,每2周用药1次,直至患者不耐受或病情进展。观察两组患者临床疗效,比较治疗前后Karnofsky功能状态评分（KPS）、肿瘤标志物和T淋巴细胞亚群变化以及化疗期间不良反应情况。结果 治疗后,观察组的总有效率为65.26%,显著高于对照组的40.22%,两组比较差异具有统计学意义（P<0.05）。治疗后,两组患者KPS评分较化疗前均增加（P<0.05）,且观察组KPS评分增加程度明显较对照组大（P<0.05）。治疗后,两组患者血清癌抗原125（CA125）、癌胚抗原（CEA）、CYFRA21-1水平较化疗前降低（P<0.05）;且观察组肿瘤标志物水平显著低于对照组（P<0.05）。治疗后,对照组患者CD3⁺、CD4⁺和CD4⁺/CD8⁺均显著降低（P<0.05）,而观察组患者显著升高（P<0.05）;观察组免疫功能指标显著优于对照组（P<0.05）。两组患者化疗期间不良反应发生率比较差异无统计学意义。结论 纳武利尤单抗联合DP方案超选择性支气管动脉栓塞灌注治疗对晚期NSCLC患者近期疗效良好,且可以改善患者生存资料和免疫功能,降低肿瘤标志物水平,不良反应轻,患者耐受性较好。     

Peripheral Blood Biomarkers Associated with Clinical Outcome in Non–Small Cell Lung Cancer Patients Treated with Nivolumab

Objective

The aim of this study was to identify baseline peripheral blood biomarkers associated with clinical outcome in patients with NSCLC treated with nivolumab.