Phase II trial of fotemustine in patients with metastatic malignant melanoma

Summary Fotemustine is a novel chloroethylnitrosourea, that readily penetrates the blood brain barrier. Preliminary French studies reported encouraging results with fotemustine in patients with cerebral metastases of malignant melanoma. Thirty-one patients with histologically confirmed metastatic malignant melanoma were entered on a phase II trial. The treatment regimen consisted of fotemustine, administered intravenously as a rapid infusion, at a dose of 100 mg/m² on day 1, 8 and 15 every 4 to 5 weeks. Objective response (CR+PR) was documented in 3 patients. Median time to treatment failure (TTF) was 44 days and median survival was 164 days. Life threatening toxicity did not occur; hematological toxicity and nausea and vomiting were the most common toxicities. Despite a somewhat disappointing response rate, objective responses were documented in patients with cerebral metastases. Since no other chemotherapeutic agent has shown therapeutic efficacy in cerebral metastases from malignant melanoma fotemustine therefore warrants further study.     

Comparison of treatment patterns,resource utilization,and cost of care in patients with metastatic pancreatic cancer treated with first-line nab-paclitaxel plus gemcitabine or FOLFIRINOX

Background: We compared real-world treatment patterns, resource utilization, and cost of care for patients with metastatic pancreatic cancer treated with first-line nab-paclitaxel + gemcitabine or FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, oxaliplatin).

Methods: This was a retrospective study of inpatient and hospital-based outpatient data in the United States. Primary endpoints included median time to treatment discontinuation (TTD) and total cost of care per patient per month. Secondary endpoints included supportive care costs and hospitalization rate and length.

Results: Overall, 345 patients were included (nab-paclitaxel + gemcitabine, n = 182; FOLFIRINOX, n = 163). Median TTD was significantly longer with nab-paclitaxel + gemcitabine vs FOLFIRINOX (4.3 vs 2.8 months; P = .0009). Mean acquisition cost was higher with nab-paclitaxel + gemcitabine ($10,643 vs $6549; P = .0043), but mean total cost of care was lower ($16,628 vs $19,936; P = .1740). Supportive care cost was significantly lower with nab-paclitaxel + gemcitabine ($1995 vs $6456; P < .0001). Hospitalization rate and length were both significantly lower with nab-paclitaxel + gemcitabine.

Conclusions: Despite higher acquisition costs with nab-paclitaxel + gemcitabine, FOLFIRINOX-treated patients had higher total costs driven by supportive care. Toxicity-related costs and drug acquisition costs should be considered when evaluating total cost of care.     

Nab-paclitaxel in the treatment of metastatic breast cancer: a comprehensive review

The novel paclitaxel formulation (nanoparticle albumin-bound [nab] paclitaxel (Abraxane^®) has recently been approved by the US FDA for treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months after adjuvant chemotherapy. Apart from its superior efficacy, as demonstrated in the pivotal Phase III study, less toxicity compared with the traditional solvent-containing paclitaxel (Taxol^®) seems to contribute to its favorable therapeutic index. While approved as a single agent, nab-paclitaxel may prove more effective in combination with either biologic agents and/or other cytotoxic chemotherapeutic agents, as summarized in this article.     

Dolastatin-10 in metastatic melanoma: a phase II and pharmokinetic trial of the California Cancer Consortium

Dolastatin-10 is a novel pentapeptide agentoriginally isolated from the marine molluskDolabella auricularia with amechanism of antitumor activity thatinvolves the inhibition of microtubuleassembly. We performed a Phase II trial ofDolastatin-10, 400 g/m², inpatients with advanced melanoma who hadreceived no prior chemotherapy. Dolastatin-10 pharmokinetics wereevaluated in a subset of patients followingcourses 1 and 2. Twelve patients weretreated with a median of 2 cycles ofDolastatin-10, and no patient experiencedan objective response. The only grade >2toxicities were grade 3 neutropeniauncomplicated by infection, occurring in 4patients following the first treatmentcycle. The total systemic clearance andvolume of distribution at steady-state were2.61 ± 1.9 L/h/m² and 28.4 ± 13 L/m²,respectively. Due toprolonged terminal elimination,Dolastatin-10 plasma concentrations ofgreater than 1 nM were sustained for 24h in all patients studied. Dolastatin-10 is unlikely to havesubstantial activity in the treatment ofmelanoma.     

Phase II study of AMSA alone and in combination with DTIC in patients with metastatic melanoma

Summary A randomized phase II study of AMSA (amsacrine) alone and AMSA combined with DTIC (dacarbazine) was carried out in 31 and 39 patients with metastatic melanoma respectively. AMSA was used at a starting dose of 40 mg/m²/day × 3 days with escalation to 50–60 mg/m²/day × 3 days in 8 pts. For AMSA + DTIC the starting dose was: AMSA 30 mg/m²/day × 3 days; DTIC, 800 mg/m² × 1 day. Additionally, seven pts received AMSA in a similar dose schedule but DTIC was used in a 5-day schedule of 250 mg/m²/day. Twentyfive patients were evaluable for response in the AMSA group and 36 in the AMSA + DTIC group. The objective response to AMSA included 1(4%) partial response compared with 11 complete or partial responses (30%) with AMSA + DTIC therapy. The median lowest absolute granulocyte count was 1100/l in AMSA group compared with 1000/l in the AMSA + DTIC group. Severe neutropenia of < 500 granulocytes/l was observed in 5 pts in the AMSA group compared with 13 pts in the AMSA + DTIC group. We concluded that AMSA has no significant activity against melanoma, although the combination of AMSA + DTIC seemed to be more active than DTIC alone.     

肺转移性恶性黑色素瘤误诊为透明细胞瘤的分析

目的探讨肺转移性恶性黑色素瘤误诊的原因。方法对1例肺转移性恶性黑色素瘤误诊为肺透明细胞瘤作回顾性分析。结果肿瘤细胞呈巢状分布,胞浆透明或粉染,间质有薄壁的窦状血管,免疫组化染色结果显示：瘤细胞S-100、HMB45、Melan-A均阳性,与肺透明细胞瘤的组织学改变及免疫组化表型极为相似。由于患者曾有皮肤背部色素痣的切除史,且现发现原皮肤活检处存在肿瘤原发灶,应诊断为肺转移性恶性黑色素瘤。结论恶性黑色素瘤的临床特点多样,组织学形态复杂,诊断时应仔细观察病理切片,同时详细了解临床病史,并结合临床相关辅助检查,以减少误诊。     

Systemic chemotherapy in the treatment of malignant melanoma

Different postsurgical therapies are used for the treatment of metastatic melanoma. This article reviewes the use of chemotherapeutic agents in the treatment of patients with metastatic malignant melanoma. A variety of single chemotherapy agents have been evaluated, although the most widely used chemotherapeutic in the treatment of metastatic melanoma is dacarbazine. In order to improve the rate and duration of responses, combination chemotherapy was developed. The most common combined chemotherapy regimens used as standard for the treatment of metastatic melanoma are Dartmouth regimen, CVD (cisplatin + vinblastine + dacarbazine) and BOLD (bleomycin + vincristine + lomustine + dacarbazine). However, Phase III trials have failed to demonstrate a significant benefit in survival in patients treated with polychemotherapy compared to those treated with dacarbazine alone. The use of classical systemic chemotherapy still has a role in the treatment of patients with metastatic melanoma. Immunotherapy and biochemotherapy have no additional advantage over chemotherapy.     

MicroRNA expression in BRAF-mutated and wild-type metastatic melanoma and its correlation with response duration to BRAF inhibitors

Objective: Currently, the treatment of BRAF V600-mutated metastatic melanoma with BRAF inhibitors gives a response rate of ～ 50% with a progression-free survival of ～ 6 – 7 months. In order to identify predictive biomarkers capable of stratifying BRAF-mutated patients at high risk of shorter response duration to anti-BRAF therapy, the authors analyzed the expression of 15 microRNAs (miRNAs) targeting crucial genes involved in melanoma biology and drug response.

Research design and methods: A total of 15 miRNAs and target gene expression were investigated in 43 patients (30 BRAF-mutated, and 13 BRAF wild-type). Moreover, 20 BRAF-mutated patients treated with vemurafenib were analyzed for miRNA expression in respect to time-to-progression.

Results: All miRNAs except miR-192 showed low expression in BRAF-mutated as compared with BRAF wild-type patients. In particular, miR-101, miR-221, miR-21, miR-338-3p and miR-191 resulted in significant downregulation in BRAF-mutated patients. Moreover, high expression of miR-192 and miR-193b* and low expression of miR-132 resulted in significant association with shorter progression.

Conclusion: Three miRNAs were significantly associated with clinical outcome in metastatic melanoma patients. An increased understanding of the molecular assessment of BRAF-mutated melanomas could allow development of specific molecular tests able to predict response duration.     

Intralesional therapy for metastatic melanoma

Introduction: Intralesional therapy for metastatic melanoma has some advantages over systemic therapy. Local drug administration allows for delivery of an increased concentration of the agent and reduced systemic exposure, thereby increasing local efficacy and limiting toxicity. Moreover, since in vivo tumor nodules contain the tumor antigens, this tumor tissue may serve as an autologous vaccine to induce systemic immunity. This so-called ‘bystander effect’, where uninjected distant lesions exhibit a response, has been reported in select intralesional therapy trials.

Areas covered: This review will give an overview of the working mechanisms, clinical evidence and side effects for available intralesional and topical therapies and summarize the most recent developments in this field.

Expert opinion: The ideal treatment approach for locoregionally advanced melanoma should be multidisciplinary and tailored to the patient, taking into consideration patient-related, tumor-related factors (such as location, tumor burden, mutation status) and previous treatments received. It will likely not be a single therapy, but rather a combination of injectable treatments, regional perfusions and systemic therapies.     

The discovery of vemurafenib for the treatment of BRAF-mutated metastatic melanoma

ABSTRACT

Introduction: In the era of precision medicine and sophisticated modern genetics, the discovery of the BRAF^V600 inhibitor, vemurafenib, quickly became the model for targeted therapy in melanomas. As early as 2002, the majority of metastatic melanomas were described to harbor the BRAF^V600 mutation, setting the stage for an explosion of interest for targeting this protein as a novel therapeutic strategy. The highly selective BRAF^V600 inhibitor, vemurafenib, was identified initially through a large-scale drug screen.

Areas covered: Here we examine vemurafenib’s journey from discovery to clinical use in metastatic melanoma. Topics covered include preclinical data, single agent Phase 1,2 and 3 clinical trials, resistance issues and mechanisms, adverse effects including the development of squamous cell cancers, and combination trials.

Expert opinion: Due to its tolerance, low toxicity profile, rapid tumor response, and improved outcomes in melanoma patients with BRAF^V600 mutations, vemurafenib was advanced rapidly through clinical trials to receive FDA approval in 2011. While its efficacy is well documented, durability has become an issue for most patients who experience therapeutic resistance in approximately 6–8 months. In addition, a concerning toxicity observed in patients taking the drug include development of localized cutaneous squamous cell carcinomas (SCCs). It is hypothesized that drug resistance and SCC development result from a similar paradoxical activation of protein signaling pathways, specifically MAPK. Identification of these mechanisms has led to additional treatment strategies involving new combination therapies.     

ER stress‐induced autophagy in melanoma

The activation of RAF‐MEK–extracellular signal‐regulated kinase (ERK) mitogen‐activated protein kinase cascade by v‐raf murine sarcoma viral oncogene homolog B1 (BRAF)^V600E mutation is a key alteration in melanoma. Although BRAF inhibitor (BRAFi) has achieved remarkable clinical success, the positive response to BRAFi is not sustainable, and the initial clinical benefit is eventually barred by the development of resistance to BRAFi. There is growing evidence to suggest that endoplasmic reticulum (ER) stress‐induced autophagy could be a potential pro‐survival mechanism that contributes to genesis of melanoma and to the resistance to BRAFi. ER stress‐induced autophagy is an evolutionarily conserved membrane process. By degrading and recycling proteins and organelles via the formation of autophagous vesicles and their fusion with lysosomes, the autophagy plays a key role in homeostasis as well as pathological processes. In this review, we examine the autophagy phenomenon in melanocytic nevus, primary and metastatic melanoma, and its significance in BRAFi‐resistant melanoma.     

Protein kinase inhibitors in melanoma

Introduction: The most commonly mutated oncogene identified to date in melanoma is BRAF (～ 50%), an upstream mediator of the mitogen-activated protein kinase (MAPK) pathway. Recently, BRAF-kinase inhibitors as well as MEK-kinase inhibitors were introduced into the clinics.

Areas covered: Substantial Phase II and III clinical trials were searched in patients with advanced melanoma treated with BRAF-kinase inhibitors, MEK-kinase inhibitors and cKIT inhibitors.

Expert opinion: For patients with a BRAF, NRAS or cKIT mutation the treatment with selective, targeted drugs is considered as feasible and results in a high rate of confirmed tumor responses. In patients with BRAF mutation the progression free survival and overall survival is prolonged in patients who were treated with BRAF kinase inhibitors or MEK kinase inhibitors compared to patients receiving chemotherapy with dacarbazine. A major problem is the development of resistance to the inhibitors through multiple different mechanisms. One approach to overcome resistance is to combine BRAF and MEK inhibitors. Treatments with kinase inhibitors are more efficacious than chemotherapies, however, they compete with the newly developed immune checkpoint blockers, and may in future be preferentially applied in second- or x-line.     

Systemic effects of angiogenesis inhibition alter pharmacokinetics and intratumoral delivery of nab-paclitaxel

Angiogenesis is critical to the growth of tumors. Vascularization-targeting agents, with or without cytotoxic drugs, are widely used for the treatment of several solid tumors including esophagogastric adenocarcinoma. However, little is known about the systemic effects of anti-angiogenic therapies and how this affects the pharmacokinetics and intratumoral delivery of cytotoxic agents. In this study, patient-derived xenograft mouse models of esophageal adenocarcinoma were used to identify the effects of DC101, a murine vascular endothelial growth factor receptor 2 (VEGFR2) inhibitor, on the pharmacokinetics and the intratumoral uptake of nab-paclitaxel (NPTX). We showed that DC101 had large systemic effects resulting in decreased vasculature of intraperitoneally located organs. As a consequence, after intraperitoneal administration of NPTX, plasma uptake (5.029?±?4.35 vs. 25.85?±?2.27?µM) and intratumoral delivery (5.48?±?5.32 vs. 38.49?±?2.805?pmol/mg) of NPTX were greatly impaired in DC101-treated animals compared to control animals. Additionally, routes of NPTX elimination were altered upon angiogenesis inhibition; unchanged renal clearance and intraperitoneal accumulation of NPTX were observed, but NPTX levels were significantly lower in the liver. Histological examination of the intestine revealed a reduced thickness of the intestinal wall following DC101 therapy and suggested seepage of intraperitoneally injected NTPX through the intestinal wall to explain its reduced uptake in liver, plasma, and tumor tissue. These data explain several adverse effects observed in the clinic when using anti-angiogenic therapies and also imply that the combined use of anti-angiogenesis and cytotoxic agents in both preclinical and clinical setting is still suboptimal.     

Phase II trial of carbetimer in metastatic melanoma

A phase II study of the synthetic polyelectrolyte Carbetimer 6500 mg/m² IV daily for five days every 21-day cycle was conducted in patients with metastatic melanoma. No responses were seen in 18 evaluable patients. Two patients had stable disease for five months. Toxicity was generally manageable and included mild hyperphosphatemia, mild proteinuria, fatigue, pain at the injection site, and nausea. Carbetimer is inactive in metastatic melanoma at this dose and schedule.     

Phase II trial of N-methylformamide in patients with metastatic melanoma

Summary Sixteen patients with metastatic melanoma were treated with N-methylformamide (NMF), a polar-planar compound with in vitro cytotoxic and differentiating properties. Sixteen patients were evaluable for toxicity and 14 for response. The initial four patients received an intravenous bolus of NMF 800 mg/m² daily for 5 consecutive days every 28 days. Because of excessive gastrointestinal toxicity, the dose was reduced to 700 mg/m²/day for the subsequent 12 patients. Two patients had immediate adverse effects from NMF; one had a grand mal seizure and the other developed severe abdominal pain. Nausea, vomiting and abdominal pain were dose-limiting. Transient elevation of liver function tests occurred in all patients. Myelosuppression was not observed. There were no objective responses among 14 evaluable patients (95% confidence limits 0–20%). One patient with pulmonary metastases had a minor response lasting 13 months. Median time to progression of disease was one month. NMF in these doses and schedule lacks clinical efficacy in the treatment of metastatic melanoma.     

An overview of binimetinib for the treatment of melanoma

ABSTRACT

Introduction

Approximately 50% of patients with metastatic melanoma have mutations in BRAF. Based on the results of prior phase III trials, the combination of a BRAF inhibitor (BRAFi) and a MEK inhibitor (MEKi) is the standard of care in patients with BRAF-mutant metastatic melanoma.     

西妥昔单抗联合化疗治疗转移性结直肠癌的观察

目的 观察西妥昔单抗联合化疗方案治疗转移性结直肠癌的近期疗效及不良反应.方法 11例经病理组织学确诊的转移性结直肠癌患者,给予西妥昔单抗联合FOLFOX方案治疗,西妥昔单抗首次给予负荷剂量400 mg/m2,每周给予维持剂量为250 mg/m2.结果 全组11例患者中,完全缓解1例,部分缓解5例,稳定2例,进展3例,有效率54.5％ (6/11),疾病控制率为72.7％ (8/11),中位肿瘤进展时间为8.4个月.主要不良反应为痤疮样皮疹(9例)和腹泻(6例).5例合并肝转移患者中经治疗后1例转化为可切除病灶.患者耐受良好,无治疗相关死亡.结论 西妥昔单抗联合FOLFOX方案治疗转移性结直肠癌疗效较好,不良反应多可耐受.