Pembrolizumab for primary malignant melanoma of the central nervous system

Journal of Neuro-Oncology -     

Pembrolizumab for the treatment of bladder cancer

Introduction: Until recently, patients with locally advanced or metastatic urothelial carcinoma after progression on cisplatin-containing chemotherapy had limited systemic treatment options with no significant survival benefit and poor tolerability. Advances in the field of immunotherapy with the introduction of checkpoint inhibitors have led to paradigm shifts in the treatment of various malignancies.

Areas covered: The current review will summarize the clinical evidence of checkpoint inhibitors in bladder cancer, with a focus on pembrolizumab.

Expert commentary: Category 1 evidence indicates that the checkpoint inhibitor pembrolizumab improves overall survival in patients with locally advanced or metastatic urothelial carcinoma who progressed after or during cisplatin-containing therapy as compared to current standard of care chemotherapy. Phase 1 and 2 evidence also indicates that checkpoint inhibitors are active in first line in patients who are ineligible for cisplatin-containing chemotherapy.     

Pembrolizumab for the treatment of gastric cancer

Introduction: Gastric cancer is one of a few gastrointestinal malignancies in which immunotherapy has shown meaningful activity. Pembrolizumab is the first and only immune checkpoint inhibitor to be FDA-approved in gastric cancer.

Areas Covered: This review summarizes the current and emerging clinical evidence for immune checkpoint inhibitors in advanced and metastatic gastric cancer, with a focus on pembrolizumab.

Expert Commentary: Pembrolizumab has shown impressive activity in the third-line treatment of locally advanced and metastatic gastric cancer. It is currently being studied as upfront therapy in combination with chemotherapy. The emerging understanding of the molecular alterations and tumor immune microenvironment as predictors of immunotherapy response in gastric cancer are discussed. The impact of gastric mucosal dysbiosis on gastric carcinogenesis and the modulation of immunotherapy response by the gut microbiome are also reviewed.     

Pembrolizumab for advanced melanoma: experience from the Spanish Expanded Access Program

Background

The programmed death (PD-1) inhibitor pembrolizumab has been recently approved for the treatment of advanced melanoma. We evaluated the clinical activity of pembrolizumab in melanoma patients treated under the Spanish Expanded Access Program.

Methods

Advanced melanoma patients who failed to previous treatment lines were treated with pembrolizumab 2 mg/kg every three weeks. Patients with brain metastases were not excluded if they were asymptomatic. Data were retrospectively collected from 21 centers in the Spanish Melanoma Group.

Results

Sixty-seven advanced melanoma patients were analyzed. Most patients were stage M1c (73.1%), had high LDH levels (55.2%) and had ECOG PS 1 or higher (59.7%). For cutaneous melanoma patients, median overall survival was 14.0 months; the 18-month overall survival rate was 47.1%. Overall response rate was 27%, including three patients with complete responses (6.5%). Median response duration was not reached, with 83.3% of responses ongoing (3.5 m+ to 20.4 m+). From ten patients included with brain metastases, four (40%) had an objective response, two (20%) of them achieved a complete response. Significant prognostic factors for overall survival were LDH level, ECOG PS and objective response. There were no serious adverse events.

Conclusion

Although this was a heavily pretreated cohort, pembrolizumab activity at the approved dose and schedule was confirmed in the clinical setting with long-term responders, also including patients with brain metastases.

     

Pembrolizumab for the treatment of non-small cell lung cancer

Introduction: In the last years, a spectacular development of immunotherapeutic agents aimed at the PD-1/PD-L1 axis has taken place. This development of these checkpoint inhibitors has greatly influenced our approach to the treatment of lung cancer in first and second line. The limited toxicity profile and the ability to treat for prolonged periods, even in smokers, is a welcome expansion of the therapeutic arsenal of the oncologist.

Areas covered: This review highlights the results of recent clinical trials on pembrolizumab for the treatment of non-small cell lung cancer. The authors discuss both first and second line treatment with pembrolizumab as monotherapy and in combination therapies. Additionally, implications of the PD-L1 immunohistochemistry assay with the 22C3 antibody and its use in clinical practice and trials is discussed.

Expert commentary: A higher overall response, overall survival and a moderate toxicity profile is observed with the use of pembrolizumab, compared to chemotherapy, in both first and second line. These promising results have already translated into the registration of pembrolizumab in first and second line in patients with a high expression of PD-L1. However, as PD-L1 staining does not sufficiently discriminate responders from non-responders for all checkpoint inhibitors, there still is a need for a better predictive biomarker.     

Individual treatment for malignant melanoma

Much has been learned in the recent decade about the predictable biologic behavior of cutaneous malignant melanoma. Indeed, such knowledge permits highly individualized treatment based on simple demographic data on the patient, location of the lesion, and its thickness according to the Breslow scale. The thoughtful surgeon may individualize his treatment according to the likely biologic behavior of the tumor, minimizing treatment morbidity while maintaining optimum results from primary and secondary surgical treatment.     

Adoptive cell transfer therapy following non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with refractory metastatic melanoma.

PURPOSE: We investigated the combination of lymphodepleting chemotherapy followed by the adoptive transfer of autologous tumor reactive lymphocytes for the treatment of patients with refractory metastatic melanoma. PATIENTS AND METHODS: Thirty-five patients with metastatic melanoma, all but one with disease refractory to treatment with high-dose interleukin (IL) -2 and many with progressive disease after chemotherapy, underwent lymphodepleting conditioning with two days of cyclophosphamide (60 mg/kg) followed by five days of fludarabine (25 mg/m(2)). On the day following the final dose of fludarabine, all patients received cell infusion with autologous tumor-reactive, rapidly expanded tumor infiltrating lymphocyte cultures and high-dose IL-2 therapy. RESULTS: Eighteen (51%) of 35 treated patients experienced objective clinical responses including three ongoing complete responses and 15 partial responses with a mean duration of 11.5 +/- 2.2 months. Sites of regression included metastases to lung, liver, lymph nodes, brain, and cutaneous and subcutaneous tissues. Toxicities of treatment included the expected hematologic toxicities of chemotherapy including neutropenia, thrombocytopenia, and lymphopenia, the transient toxicities of high-dose IL-2 therapy, two patients who developed Pneumocystis pneumonia and one patient who developed an Epstein-Barr virus-related lymphoproliferation. CONCLUSION: Lymphodepleting chemotherapy followed by the transfer of highly avid antitumor lymphocytes can mediate significant tumor regression in heavily pretreated patients with IL-2 refractory metastatic melanoma.     

Actinomycin-D, levamisole chemoimmunotherapy of refractory malignant melanoma.

Sixty adult patients with disseminated melanoma refractory to DTIC or Dacarbazine were given chemoimmunotherapy with intermittent high single dose Actinomycin-D and Levamisole. Actinomycin-D was given at a dose of 1.5-2.0 mg/m2 intravenously every 3 to 4 weeks. Levamisole was given in a dose of 150 mg/day for two consecutive days each week (50 patients) and in a dose of 200 mg every other day (10 patients). Antitumor responses consisted of 2% complete remissions (CR), 2% partial remissions (PR), and 33% disease improvement less than PR or stabilization (S). Comparison of these patients who received Actinomycin-D + Levamisole with those on an immediately preceding study in a similar population where Actinomycin-D was given as a single agent revealed no difference in response rates. Patients who responded to Actinomycin-D + Levamisole (CR + PR + S) survived significantly longer (35 weeks) than nonresponders (12 weeks, p less than 0.01). Survival was not longer (p less than .05) in responding patients (CR + PR + S) receiving Actinomycin-D + Levamisole (35 weeks) compared to those responding to Actinomycin-D alone (18 weeks, p = 0.09). Hematologic toxicity was tolerable with median lowest granulocyte counts of 1.6 x 10(3)/microliter and platelet counts of 134,000/microliter. Other toxic effects were predominantly nausea, vomiting, and mucositis. In those patients who received alternate day Levamisole there was greater gastrointestinal upset as well as fever, rash and central nervous system toxicity which was unacceptable.     

皮肤恶性黑素瘤的外科治疗

目的:探讨皮肤恶性黑素瘤的外科治疗方式.方法:回顾性分析2007年10月—2011年12月共93例皮肤恶性黑素瘤患者的临床资料、外科手术方式和预后.按照美国癌症联合委员会(American Joint Committee on Cancer,AJCC)外科分期标准: ⅠA期1例, Ⅰ B期2例,Ⅱ A期8例,Ⅱ B期9例,Ⅱ C期20例,Ⅲ A期18例,Ⅲ B期17例,Ⅲ C期16例,Ⅳ期2例;外科手术方式:广泛切除术26例,广泛切除术十游离植皮或转移皮瓣重建术7例,截指(趾)8例,髂腹股沟淋巴结清扫术32例,腋窝淋巴结清扫术3例,广泛切除术十一期髂腹股沟淋巴结清扫术15例,广泛切除术十一期腋窝淋巴结清扫术2例;术后辅助化疗53例,干扰素或白细胞介素治疗78例.对77例患者进行了随访,平均随访时间为20 (2～50)个月.结果:Ⅰ期3例患者均存活;Ⅱ期获随访的28例患者中,8例于术后12个月时出现腹股沟淋巴结转移,2例于术后18个月时出现骨转移,6例于术后36个月时出现皮内转移;Ⅲ期获随访的44例患者中,11例于随访期间死于肺转移,5例死于肝转移;Ⅳ期2例患者中,1例于术后12个月时因肺转移而死亡,1例于术后11个月时因肝转移而死亡.随访期间,77例患者中的43例患者为无进展生存.结论:早期发现以及早期手术治疗皮肤恶性黑素瘤可以获得较好的疾病控制率,规范化的区域淋巴结清扫术是控制疾病进展的重要手段,术后辅助治疗可使生存获益.     

Antibody-based vaccines for the treatment of melanoma

Malignant melanoma remains a difficult clinical problem. Chemotherapy is not effective and immunotherapy has long been contemplated as the preferred approach to this disease. Extensive passive and active immunotherapy trials have been conducted. Active vaccination with whole cells or defined antigens, administered with a panoply of techniques to increase immunogenicity, has yielded inconsistent results. The development of antibody-based vaccines has allowed vaccination without the need for tumor tissue material or purified antigens. The idiotype network theory originally proposed by Lindemann and by Jerne provided the basis for the development of anti-idiotype (anti-Id) antibody vaccines, which mimic the internal image of the epitope targeted for immunization. Preclinical and phase I clinical data are available for various malignancies. In melanoma, some of the anti-Id vaccines have targeted gangliosides. One of these vaccines, TriGem, has been successful in generating a robust and specific humoral immunity in melanoma patients. Phase II data suggest this anti-Id vaccine has clinical activity.     

肢体恶性黑色素瘤的外科治疗

目的 探讨外科治疗在肢体恶性黑色素瘤中的临床作用.方法 回顾性分析1993年8月-2007年12月就诊于我院骨肿瘤科22例肢体恶性黑色素瘤病例.男性12例,女性10例;年龄20～73岁,平均50.1岁;发病部位足底14例,足背1例,第二足趾1例,拇指甲下2例,腹股沟、大腿、膝部软组织各1例,胫骨1例.按照AJCC外科分期,Ⅱ期8例,Ⅲ期12例,Ⅳ期2例.保肢14例,截肢（趾）8例;保肢病例中局部切除后采用游离植皮或转移皮瓣重建10例,胫骨病变1例采用瘤段截除、人工关节置换术.外科边界：边缘切除4例,广泛切除14例,根治性切除4例.二期行区域淋巴结清扫14例.术后辅助达卡巴嗪化疗6例（同时加用放疗1例）,干扰素和白介素生物治疗13例,中医药辅助治疗3例.有完整随访资料的17例,随访时间3-96个月,平均随访时间34.2个月.结果 Ⅱ期患者8例中1例术后91个月局部复发,1例随访19个月后出现骨转移,1例术后12个月腹股沟淋巴结转移,均再次行手术治疗;余5例随访未发现局部复发及远隔转移.Ⅲ期患者12例均行淋巴结清扫术,2例随访肺转移死亡,4例失访,余6例随访无局部复发及远隔转移.Ⅳ期患者2例,1例术后3个月因肺转移死亡.最终完整随访资料的17例患者中13例随诊无进展生存,原病灶局部无复发,植皮或转移皮瓣均成活或经过二期处理后愈合良好.结论 肢体黑色素瘤手术治疗后局部肿瘤可得到良好控制,并为肿瘤的综合治疗奠定基础.     

Binimetinib for the treatment of NRAS-mutant melanoma

Introduction: Activating NRAS mutations occur in approximately 15–20% of melanomas and are the second most common oncogenic driver mutation in this disease, after BRAF mutations. There is an unmet medical need for new targeted therapy opportunities in metastatic patients whose tumors harbor an NRAS mutation. Binimetinib, a mitogen-activated protein kinase kinase (MEK) inhibitor, has shown clinical activity in this group of patients.

Areas covered: The purpose of this paper was to review the safety, activity and efficacy of the MEK inhibitor binimetinib for the treatment of NRAS-mutant melanoma, as well as to discuss future therapeutic perspectives such as multiple pathways, targeted therapy, and combinations with immunotherapy.

Expert commentary: Only a modest progression-free survival (PFS) benefit was observed in NRAS-mutated patients who received binimetinib compared with dacarbazine in a randomized phase 3 clinical trial, with no improvement in overall survival. Nevertheless, binimetinib represents another promising treatment option for advanced melanoma and the first molecularly targeted therapy for the NRAS-mutant population. Binimetinib may also have a role in treating NRAS-mutated melanoma patients after failure of immunotherapy.