抗PD-1单抗联合化疗及抗血管生成药物治疗晚期黑色素瘤的疗效和安全性

目的： 探讨抗PD-1单抗联合化疗及抗血管生成药物治疗晚期黑色素瘤的疗效和安全性。 方法： 收集2020年4月至2021年6月在北京大学肿瘤医院接受抗PD-1单抗联合化疗药物替莫唑胺±顺铂、白蛋白结合型紫杉醇及抗血管生成药物贝伐珠单抗治疗的14例（男6、女8例）不可切除的晚期黑色素瘤患者的临床资料。主要研究终点为无进展生存期（PFS）,次要终点为客观有效率（ORR）、疾病控制率（DCR）、总生存期（OS）及安全性数据（CTCAE 5.0标准）。 结果： 14例晚期黑色素瘤患者均纳入生存分析,中位随访时间为5.50个月（95% CI: 0~13.12个月）,中位PFS为7.43个月（95% CI: 3.07~11.79个月）,中位OS为13.50个月（95% CI: 5.19~21.81个月）,中位起效时间为1.5个月;ORR为28.6%（4例均为部分缓解）,DCR为85.7%;不良反应多为1~2级。结论： 抗PD-1单抗联合化疗及抗血管生成药物治疗在晚期黑色素患者中显示出初步的有效性及良好的安全性,此可能为晚期黑色素瘤的联合治疗策略提供了新思路。     

Nivolumab and pembrolizumab as immune-modulating monoclonal antibodies targeting the PD-1 receptor to treat melanoma

Malignant melanoma is an important issue in oncology due to its high incidence, high mortality, and resistance to systemic therapy; however, targeted immunotherapy has noticeably improved the survival rates of melanoma patients. Promising targeted immunotherapies for malignant melanoma include the blockade of immune checkpoints with antibodies targeting cytotoxic T lymphocyte-associated antigen 4 and the programmed cell death protein 1 pathway. The US FDA-approved antibody ipilimumab targets cytotoxic T lymphocyte-associated antigen 4; however, it was limited by toxicity and a low response. Nivolumab and pembrolizumab (formerly lambrolizumab), the two FDA-approved anti-programmed death-1 monoclonal antibodies, show highly durable response rates and long-term safety, validating the importance of the programmed cell death protein 1 pathway blockade for treatment of malignant melanoma.     

Serum lactate dehydrogenase as an early marker for outcome in patients treated with anti-PD-1 therapy in metastatic melanoma

Background:

Treatment with programmed death receptor-1 (PD-1) antibodies is associated with high response rates in patients with advanced melanoma. Reliable markers for early response and outcome are still sparse.

Methods:

We evaluated 66 consecutive patients with advanced/metastatic melanoma treated with nivolumab or pembrolizumab between 2013 and 2014. The main objectives of this study were to investigate whether, first, serum lactate dehydrogenase (LDH) at baseline (normal vs above the upper limit of normal) correlates with overall survival (OS), and, second, whether the change of LDH during treatment predicts response before the first scan and OS in patients with an elevated baseline LDH.

Results:

After a median follow-up of 9 months, patients with an elevated baseline LDH (N=34) had a significantly shorter OS compared with patients with normal LDH (N=32; 6-month OS: 60.8% vs 81.6% and 12-month OS: 44.2% vs 71.5% (log-rank P=0.0292). In those 34 patients with elevated baseline LDH, the relative change during treatment was significantly associated with an objective response on the first scan: the 11 (32%) patients with partial remission had a mean reduction of −27.3% from elevated baseline LDH. In contrast, patients with progressive disease (N=15) had a mean increase of +39%. Patients with a relative increase over 10% from elevated baseline LDH had a significantly shorter OS compared with patients with ⩽10% change (4.3 vs 15.7 months, log-rank P<0.00623).

Conclusions:

LDH could be a useful marker at baseline and during treatment to predict early response or progression in patients with advanced melanoma who receive anti-PD-1 therapy.     

Improved survival and complete response rates in patients with advanced melanoma treated with concurrent ipilimumab and radiotherapy versus ipilimumab alone

There is a growing body of evidence supporting the synergistic roles of radiotherapy and immunotherapy in the treatment of malignancy. Published case studies of the abscopal effect have been reported with the use of ipilimumab and radiotherapy in metastatic melanoma, but evidence supporting the routine use of this combination of therapy is limited. We conducted a retrospective analysis to evaluate patients treated with ipilimumab for advanced melanoma at a single institution from May 2011 to June 2015. Patients were grouped into those who had received concurrent radiotherapy while on ipilimumab (Ipi-RT), and those who did not. We then evaluated the treatment response following completion of ipilimumab. A total of 101 patients received ipilimumab in the prespecified time frame. 70 received Ipi-RT and 31 received ipilimumab without concurrent radiotherapy. Median overall survival (OS) was significantly increased in the concurrent Ipi-RT arm at 19 months vs. 10 months for ipilimumab alone (p = 0.01). Median progression free survival (PFS) was marginally increased in the Ipi-RT group compare with the ipilimumab alone group (5 months vs. 3 months, p = 0.20). Rates of complete response (CR) were significantly increased in the Ipi-RT group vs. ipilimumab alone (25.7% vs. 6.5%; p = 0.04), and rates of overall response (OR) in the groups were 37.1% vs. 19.4% (p = 0.11). No increase in toxicities was observed in the Ipi-RT group compare with ipilimumab alone. Prospective trials are needed to further clarify the role of radiotherapy with ipilimumab, but these encouraging preliminary observations suggest that this combination can induce more durable responses to immunotherapy.     

Efficacy of hypofractionated radiotherapy in patients with non‐melanoma skin cancer: Results of a systematic review

Radiation oncologists are increasingly tasked with the management of elderly patients with non‐melanoma skin cancer, unsuitable for surgical intervention due to inoperable lesions and/or poor performance status. In this cohort, hypofractionated radiotherapy, delivered either daily, alternative daily or once weekly is highly effective. A systematic literature search was conducted of PUBMED, MEDLINE and EMBASE databases using the algorithm (‘radiotherapy’ OR ‘radiation therapy’ OR ‘brachytherapy’) AND (‘hypofraction’ OR ‘hypofractionated’ OR ‘hypofractionation’) AND (‘skin neoplasms’ OR ‘carcinoma’ OR ‘malignancy’) AND (‘skin’ OR ‘epidermis’ OR ‘epidermal’ OR ‘cutaneous’). Forty relevant publications (1983–2017) encompassing 12,337 irradiated lesions were retrieved. Studies documented a mean age of 71.73 years and male predilection (54.5%). Both external beam radiotherapy and brachytherapy were utilized. Tumour subtype was squamous cell carcinoma (23.5%), basal cell carcinoma (75.2%) or others (1.3%). Irradiated lesions were primary (or denovo) (92.6%), located on the head and neck (95.7%) and received definitive therapy (96.5%). Analysis demonstrated a mean weighted total radiotherapy dose (38.15 Gy), dose per fraction (7.95 Gy) and treatments per week (2.98). Despite significant heterogeneity in the study population, the radiotherapy delivered and follow‐up, local recurrence rate (crude or Kaplan–Meier analysis) did not exceed 7.9% in all but three of the 36 publications providing these data. Twenty‐nine publications documented local control exceeding 90%. There is a body of evidence documenting the efficacy of hypofractionated radiotherapy as an option that confers no obvious disadvantage in local control when compared to traditional more protracted radiotherapy schedules.     

Radiosurgery/stereotactic radiotherapy in combination with immunotherapy and targeted agents for melanoma brain metastases

Introduction: The clinical landscape of advanced melanoma drastically changed after the introduction of both targeted therapies and immunotherapy. This rapid development in systemic therapies led to a change in the management of patients with brain metastases, with the subsequent need to re-assess the role of local therapies, in particular stereotactic radiosurgery (SRS).

Areas covered: In this non-systematic review, we report on the current knowledge on the use of SRS in combination with immunotherapy and BRAF/MEK inhibitors for patients with melanoma brain metastases, as well as ongoing trials in this field.

Expert commentary: It is now more common to observe patients with melanoma brain metastases with better performance status and prolonged life expectancy. A combination of targeted therapy and immunotherapy, in different sequences, has been shown to be feasible and well tolerable, on the basis of retrospective reports. Additional data from ongoing prospective trials are however needed to confirm or not these findings and better explore the efficacy of the combination.     

Efficacy and safety of nivolumab in Japanese patients with previously untreated advanced melanoma: A phase II study

Treating advanced or recurrent melanoma remains a challenge. Cancer cells can evade the immune system by blocking T‐cell activation through overexpression of the inhibitory receptor programmed death 1 (PD‐1) ligands. The PD‐1 inhibitor nivolumab blocks the inhibitory signal in T cells, thus overcoming the immune resistance of cancer cells. Nivolumab has shown promising anticancer activity in various cancers. We carried out a single‐arm, open‐label, multicenter, phase II study to investigate the efficacy and safety of nivolumab in previously untreated Japanese patients with advanced melanoma. Twenty‐four patients with stage III/IV or recurrent melanoma were enrolled and received i.v. nivolumab 3 mg/kg every 2 weeks until disease progression or unacceptable toxicity. The primary endpoint was overall response rate evaluated by an independent radiology review committee. The independent radiology review committee‐assessed overall response rate was 34.8% (90% confidence interval, 20.8–51.9), and the overall survival rate at 18 months was 56.5% (90% confidence interval, 38.0–71.4). Treatment‐related adverse events (AEs) of grade 3 or 4 only occurred in three patients (12.5%). Two patients discontinued nivolumab because of AEs, but all AEs were considered manageable by early diagnosis and appropriate treatment. Subgroup analyses showed that nivolumab was clinically beneficial and tolerable regardless of BRAF genotype, and that patients with treatment‐related select AEs and with vitiligo showed tendency for better survival. In conclusion, nivolumab showed favorable efficacy and safety profiles in Japanese patients with advanced or recurrent melanoma, with or without BRAF mutations. (Trial registration no. JapicCTI‐142533.)     

奥沙利铂联合替吉奥同步三维适形放疗治疗中晚期贲门癌的疗效观察

目的:探讨奥沙利铂联合替吉奥同步三维适形放疗治疗中晚期贲门癌的临床疗效及不良反应。方法:将我科收治的102例中晚期贲门癌患者,随机分为2组,同步放化疗组50例,单纯放疗组52例。单纯放疗组放疗采用（1.8-2.0）Gy/次,共（57.6-62.0）Gy/（5.8-7.0）周;同步放化疗组放疗同单纯放疗组,同时以奥沙利铂100mg/m2,静滴,第1天,替吉奥胶囊80mg/(d·m2),分2次餐后口服,第1-14天,每28天一个周期,连续化疗3个周期。结果:同步放化疗组与单纯放疗组比较:CR分别为36.0%、11.5%,PR分别为54.0%、53.8%,SD分别为6.0%、17.3%,PD分别为4.0%、17.3%,RR分别为90.0%、65.4%,有显著性差异（χ2=8.884,P=0.003 ）。同步放化疗组与单纯放疗组1年生存率分别为58.0%、36.5%,2年生存率分别为36.0%、13.5%,3年生存率分别为22.0%、0,有显著性差异(χ2=10.131,P=0.001)。两组不良反应比较:同步放化疗组与单纯放疗组Ⅱ-Ⅳ度白细胞计数下降发生率分别为52.0%、46.2%,恶心、呕吐发生率分别为18.0%、9.6%,两者无显著性差异（P均＞0.05）。结论:奥沙利铂联合替吉奥同步三维适形放疗治疗中晚期贲门癌较单纯放疗疗效好,不良反应能耐受。     

Ipilimumab alone or in combination with nivolumab after progression on anti-PD-1 therapy in advanced melanoma

BackgroundThe anti-programmed cell death-1 (PD-1) inhibitors pembrolizumab and nivolumab alone or in combination with ipilimumab have shown improved objective response rates and progression-free survival compared to ipilimumab only in advanced melanoma patients. Anti-PD-1 therapy demonstrated nearly equal clinical efficacy in patients who had progressed after ipilimumab or were treatment-naïve. However, only limited evidence exists regarding the efficacy of ipilimumab alone or in combination with nivolumab after treatment failure to anti-PD-therapy.Patients and methodsA multicenter retrospective study in advanced melanoma patients who were treated with nivolumab (1 or 3 mg/kg) and ipilimumab (1 mg or 3 mg/kg) or ipilimumab (3 mg/kg) alone after treatment failure to anti-PD-1 therapy was performed. Patient, tumour, pre- and post-treatment characteristics were analysed.ResultsIn total, 47 patients were treated with ipilimumab (ipi-group) and 37 patients with ipilimumab and nivolumab (combination-group) after treatment failure to anti-PD-1 therapy. Overall response rates for the ipi- and the combination-group were 16% and 21%, respectively. Disease control rate was 42% for the ipi-group and 33% for the combination-group. One-year overall survival rates for the ipi- and the combination-group were 54% and 55%, respectively.ConclusionsIpilimumab should be considered as a viable treatment option for patients with failure to prior anti-PD-1 therapy, including those with progressive disease as best response to prior anti-PD-1. In contrast, the combination of ipilimumab and nivolumab appears significantly less effective in this setting compared to treatment-naïve patients.     

治疗后嗜酸性粒细胞水平评价预测PD-1单抗治疗胰腺癌患者疗效和预后的价值（附2例）

目的:观察PD-1单抗治疗后长期持续获益的晚期胰腺癌患者外周血嗜酸性粒细胞水平的变化。方法:分析我院2例应用PD-1单抗治疗后长期持续获益的晚期胰腺癌患者的临床资料,探究在治疗过程中嗜酸性粒细胞水平的变化与疗效之间的关系。结果:2例晚期胰腺癌患者采用PD-1单抗治疗后肿瘤病灶均显著缩小,无进展生存期均明显延长,疗效持续时间已分别大于25个月和15个月,治疗期间定期复查发现外周血嗜酸性粒细胞计数及比率较基线均有明显升高,尤其是治疗半年后增高特别显著,且均未出现免疫相关不良反应。结论:嗜酸性粒细胞水平可能是PD-1单抗治疗胰腺癌长期获益的潜在评价指标,治疗过程中嗜酸性粒细胞显著增多提示免疫获益时间长,对于临床疗效评价和预后判断具有一定的预测价值。