Nivolumab-Induced Alopecia Areata: A Case Report and Literature Review

Nivolumab (anti-PD-1) currently used in many cancers. With the usage of nivolumab increased, many cutaneous side effects were reported including maculopapular rash, lichenoid reactions, vitiligo, bullous disorders, psoriasis exacerbation, and alopecia areata (AA). Here, we report AA after nivolumab for treatment of hepatocellular carcinomas (HCC). A 55-year-old male presented with multiple hairless patch from 1 month ago. He suffered HCC and treated with nivolumab for 6 months after hepatectomy. He treated for hair loss with triamcinolone intra-lesional injection without improvement. We performed skin biopsy on the scalp. Histopathologic findings revealed decreased of hair follicles on the horizontal section with lymphocyte infiltration on the perifollicular area on the vertical section. Clinicopathologic findings were agreed with AA. Considering lack of previous history of AA and hairless patches with 6 months after nivolumab injection, we diagnosed him as nivolumab induced AA. Treatment included topical steroid, and minoxidil. No regrowth of hair was noted after 4 months of follow-up. Nivolimumab induced AA is rare side effect. Pathogenesis of nivolumab induced AA remain unclear. But our case is likely related to nivolumab, known to induce immune related adverse events, and given in the delay of a few months between introduction and the occurrence of the hair loss. Here, we reports nivolmumab induced AA; rare side effect.     

纳武利尤单抗联合安罗替尼治疗晚期非小细胞肺癌的临床研究

目的 探究纳武利尤单抗注射液联合盐酸安罗替尼胶囊治疗晚期非小细胞肺癌的临床疗效。方法 选取2019年1月—2020年1月临汾市中心医院收治的60例晚期非小细胞肺癌患者为研究对象,根据患者治疗方法不同分为对照组（29例）和治疗组（31例）。对照组患者早餐前口服盐酸安罗替尼胶囊,12 mg/次,1次/d,连续服药2周,停药1周。治疗组患者在对照组治疗的基础上静脉输注纳武利尤单抗注射液,3 mg/kg,1次/2周,评估患者耐受性和疗效。两组患者均持续治疗9周。观察两组近期临床疗效,比较治疗前后两组生活质量、T淋巴细胞亚群、血管内皮细胞生长因子（VEGF）水平变化和生存情况。结果 治疗后,治疗组客观缓解率（ORR）、疾病控制率（DCR）均较高于对照组,组间比较差异具有显著差异（P<0.05）。治疗后,两组患者CD3⁺、CD4⁺、CD4⁺/CD8⁺均明显升高,CD8⁺、VEGF均明显降低（P<0.05）;治疗组CD3⁺、CD4⁺、CD4⁺/CD8⁺均明显高于对照组,CD8⁺、VEGF均明显低于对照组（P<0.05）。治疗后2、4、6个月,两组EORTC QLQ-C30总评分均明显降低（P<0.05）,且治疗组EORTC QLQ-C30总评分明显低于同期对照组（P<0.05）。治疗后,治疗组中位无进展生存期（PFS）、总生存期（OS）较对照组明显增长（P<0.05）。结论 纳武利尤单抗注射液联合盐酸安罗替尼胶囊治疗晚期非小细胞肺癌具有较好的临床疗效,可改善患者的生活质量,调节患者免疫功能,降低VEGF水平,且不增加不良反应。     

Progression-Free and Overall Survival for Concurrent Nivolumab With Standard Concurrent Chemoradiotherapy in Locally Advanced Stage IIIA-B NSCLC: Results From the European Thoracic Oncology Platform NICOLAS Phase II Trial (European Thoracic Oncology Platform 6-14)

IntroductionThe NICOLAS study is the first completed single-arm phase II trial in stage III NSCLC evaluating hierarchically first the safety and then the efficacy of adding nivolumab concurrently to standard definitive concurrent chemoradiotherapy. The safety end point was reported earlier; here, we present the efficacy results.MethodsStage IIIA-B unresectable treatment-naive patients with NSCLC received three cycles of platinum-based chemotherapy and concurrent radiotherapy (66 Gy, 33 fractions), along with nivolumab (360 mg, 3-weekly). Nivolumab was continued as monotherapy consolidation for a maximum of 1 year (480 mg, 4-weekly). The primary end point was 1-year progression-free survival (PFS), with a target improvement compared with historical data of at least 15%, from 45% to 60%. To test this efficacy hypothesis, a sample size of 74 assessable patients provided a power of 83% with a one-sided alpha of 5%.ResultsA total of 79 patients were enrolled with a median follow-up of 21.0 months (interquartile range: 15.8–25.8 mo) for the primary PFS analysis. A total of 35.4% of the patients had stage IIIA, and 63.3% had stage IIIB disease. The 1-year PFS was 53.7% (95% confidence interval [CI]: 42.0%–64.0%) and the median PFS was 12.7 months (95% CI: 10.1–22.8 mo). Because 37 PFS events occurred in the first year posttreatment among the first 74 assessable patients, a 1-year PFS rate of at least 45% could not be rejected (p = 0.23). At an extended follow-up (median 32.6 mo), 37 deaths have been recorded, with a median overall survival (OS) of 38.8 months (95% CI: 26.8 mo–not estimable) and a 2-year OS rate of 63.7% (95% CI: 51.9%–73.4%). The OS of patients with stage IIIA disease was found to be significantly higher than patients with stage IIIB disease, with a 2-year OS of 81% and 56%, respectively (p = 0.037).ConclusionsPFS and OS are arithmetically higher in studies involving the same population. However, on the basis of the formal hierarchical efficacy analysis, we could not reject that the 1-year PFS rate is at least 45%.     

An update on the safety of nivolumab for the treatment of advanced melanoma

ABSTRACT

Introduction: Due to its unique mechanism of action as an immune checkpoint inhibitor, nivolumab has high antitumor activity, but at the same time this mechanism is responsible for immune-related adverse events that may limit patients’ safety and therapy continuation.

Areas covered: Long-term safety of nivolumab including 5-year follow-up, safety of nivolumab treatment after ipilimumab therapy, safety of nivolumab in challenging subgroups (elderly, patients with brain metastases, patients with autoimmune disorders), safety of nivolumab in with rare melanoma subtypes (including mucosal melanoma), as well as specificity of AEs reported for nivolumab treatment in melanoma patients in comparison to other cancer types and other immunotherapy molecules, and impact of AEs on response rates and PFS on nivolumab treatment are discussed.

Expert opinion: Search for biomarkers that would help us to identify patient populations that may suffer from severe nivolumab toxicity could help in selecting patients that should not be treated with this type of therapy. Novel combinations and immunotherapy drugs including use of NKTR-214 (IL-2 pathway), lymphocyte-activation gene 3 (LAG-3), local injections of talimogene laherparepvec (T-VEC), or systemic use of T-cell receptors agonists such as OX40, CD137, ICOS-1, could provide regimens with limited toxicity and higher activity.     

Ceritinib plus Nivolumab in Patients with Advanced ALK-Rearranged Non–Small Cell Lung Cancer: Results of an Open-Label,Multicenter, Phase 1B Study

IntroductionInduction of programmed death ligand 1 (PD-L1) expression due to constitutive oncogenic signaling has been reported in NSCLC models harboring echinoderm microtubule associated protein like 4 gene (EML4)–ALK receptor tyrosine kinase gene (ALK) rearrangements. We assessed the safety and activity of ceritinib plus nivolumab in these patients.MethodsIn this open-label, phase 1B, multicenter, dose escalation and expansion study, previously treated (with ALK receptor tyrosine kinase [ALK] inhibitor [ALKI]/chemotherapy) or treatment-naive patients with stage IIIB or IV ALK-rearranged NSCLC received nivolumab, 3 mg/kg intravenously every 2 weeks, plus ceritinib, 450 mg/300 mg daily, with a low-fat meal.ResultsIn total, 36 patients were treated (a 450-mg cohort [n=14] and a 300-mg cohort [n=22]). In the 450-mg cohort, four patients experienced dose-limiting toxicities. In the 300-mg cohort, two patients experienced dose-limiting toxicities. Among ALKI-naive patients, the overall response rate (ORR) was 83% (95% confidence interval [CI]: 35.9–99.6) in the 450-mg cohort and 60% (95% CI: 26.2–87.8) in the 300-mg cohort. Among ALKI-pretreated patients, the ORR was 50% (95% CI: 15.7–84.3) in the 450-mg cohort and 25% (95% CI: 5.5–57.2) in the 300-mg cohort. The ORR point estimate was observed to be greater in patients who were positive for PD-L1 than in those who were negative for PD-L1, with overlapping CIs (e.g., at a cutoff ≥1% PD-L1, 64% of patients [95% CI: 35.1–87.2] had confirmed responses as compared with those with negative PD-L1 staining (31% [95% CI: 11.0–58.7]). The most frequently reported grade 3 or 4 adverse events were increased alanine aminotransferase level (25%), increased gamma-glutamyl transferase level (22%), increased amylase level (14%), increased lipase level (11%), and maculopapular rash (11%). The incidence of all-grade rash (grouped term) was 64% in both cohorts; grade 3 rash was reported in 29% and 14% of patients in the 450-mg and 300-mg cohorts, respectively; no grade 4 rash was reported.ConclusionCeritinib plus nivolumab has activity; ORR appears to correlate with PD-L1 at baseline. Toxicity, especially rash, is more common than with either single agent.     

Pseudoprogression in Previously Treated Patients with Non–Small Cell Lung Cancer Who Received Nivolumab Monotherapy

Introduction

Nivolumab is effective in the treatment of previously treated patients with advanced NSCLC. However, its radiological evaluation is challenging because of atypical patterns of response such as pseudoprogression. We examined the characteristics and outcomes of previously treated patients with NSCLC who were treated with nivolumab and experienced development of pseudoprogression.