Importance of the timing of combined electrochemotherapy and immunotherapy in the treatment of advanced melanoma.

The use of interleukin-2 (IL-2) and interferon-alpha (IFNalpha) in combination with chemotherapy for the treatment of advanced malignant melanoma has generated considerable interest. In particular, the relatively high number of durable complete responses has suggested this may be a significant advance in the treatment of malignant melanoma. We report our experience at the University of Colorado in 43 patients, including many with poor prognostic factors. Patients received cisplatin 20 mg/m2 on days 1-4, vinblastine 1.6 mg/m2 on days 1-4, dacarbazine 800 mg/m2 on day 1, IL-2 9 x 10(6) IU/m2 per day intravenously over 24h on days 1-4 and IFNalpha 5 x 10(6) IU/m2 per day subcutaneously on days 1-5 every 3 weeks. The median follow-up for all patients was 34 months. Responses were seen in 20 patients (47%, 95% confidence interval 31-62%) and comprised five complete responses (CRs) (12%) and 15 partial responses (PRs) (35%). Two patients achieving a CR remain disease free at 45 and 47 months follow-up. In addition three patients who obtained a surgical CR and another with only minor residual changes on computed tomography scan have not progressed at 27, 30, 40 and 27 months, respectively. Toxicity was manageable, but all patients had at least one grade 3 or 4 toxicity, predominantly hypotension and neutropenia. There were no treatment-related deaths. In conclusion, the response rate and duration is within the range previously reported for biochemotherapy. The results of ongoing randomized studies are awaited to better define the value of biochemotherapy in the treatment of advanced melanoma.

Immunotherapy with immune checkpoint inhibitors is the standard of care in the treatment of advanced melanoma. Treatment outcome of these agents is less defined for the rare subtype of mucosal melanoma. In this single-institutional case series, the objective response rate was low at 11.8%, but durable response was seen, including a complete response to first-line ipilimumab and to second-line pembrolizumab. Survival remained poor; at the median follow-up of 10.1months, the median progression-free survival and overall survival were 3.1 and 8.8months respectively. Nevertheless, among the few responders, survival of up to 56+ months was observed. Other treatment strategies need to be explored to improve treatment outcome for this rare subtype.

ABSTRACTImmune checkpoint inhibitors have revolutionized treatment of advanced cutaneous melanoma. This group of novel therapeutic agents differs from other systemic treatments and has necessitated a new approach for several fundamental aspects of clinical practice in oncology. Marked differences in outcomes associated with immune checkpoint inhibitors compared with other systemic therapies has required a new paradigm for prognostication in the setting of advanced melanoma. Distinct patterns of tumor response have required new norms for disease monitoring. A unique spectrum of toxicity is associated with use of immune checkpoint inhibitors which can be severe and refractory. Patients and clinicians must be informed regarding immune-related adverse events, yet in the published literature, there is substantial variability in reporting. As immune checkpoint inhibitors gain a prominent role in cancer treatment, standardization of adverse event reporting will be vital to ensure validity of evidence and to promote safe clinical practice.

9045 Background: Melanoma is a rare but serious subtype of skin cancer that can infiltrate deep skin layers and commonly metastasizes. Although it makes up only a small proportion (<5%) of all skin cancer cases, it causes 75% of deaths from skin cancer. Melanoma affects all ages with 38% of patients less than 55 years old causing significant work productivity and life impact. Median survival of patients with advanced (unresectable or metastatic) melanoma is less than a year. Conventional chemotherapy provides no overall survival benefit. Within the last 2 years, the EMA approved two new drugs for advanced melanoma: ipilimumab for second-line and vemurafenib for patients with BRAF mutation-positive tumors; both drugs provide survival benefits. The objective of this study was to investigate physicians' perceptions of the unmet need in the treatment of advanced melanoma in the new treatment landscape. Methods: 150 oncologists and dermatologists from France, Germany, Italy, Spain, and the UK who had treated at least 12 patients with advanced melanoma in the last 12 months prior to September 2012 were asked by a web-based survey to describe their treatment of advanced melanoma and the current issues in treatment. Results: Overall, 76% of respondents had used ipilimumab and 79% had used vemurafenib in the 12 months prior to September 2012. Toxicity and tolerability of treatment was the most commonly mentioned issue (cited by 43% of respondents). Limited treatment effectiveness (29% respondents) was also highlighted by respondents in all countries. Limited treatment options were identified as a key issue by 30% of respondents in Germany, France, and the UK. Other commonly mentioned issues were low response rates and poor survival. Conclusions: The majority of physicians surveyed had experience using vemurafenib and ipilimumab. However, a number of issues remain in the treatment of advanced melanoma, suggesting that unmet need remains high.

Talimogene laherparepvec (TVEC) is a genetically modified oncolytic herpes simplex virus (HSV-1) that is used for the intralesional treatment of advanced or metastatic melanoma. Given that TVEC produces the granulocyte-macrophage colony-stimulating factor (GM-CSF), recent reports have suggested that radiation treatment (RT) given in conjunction with TVEC may provide synergistic immune activation at the site, and possibly systemically. However, studies on combining RT with TVEC remain limited. We conducted a retrospective review of melanoma patients from a single cancer center who received TVEC and RT in the same region of the body and compared them to patients who received TVEC with RT at another site (other than the site of TVEC injection). Between January 2015 and September 2022, we identified twenty patients who were treated with TVEC and RT; fourteen patients received TVEC and RT in the same region, and six had treatments in separate regions. Regions were determined at the time of analysis and were based on anatomic sites (such as arm, leg, torso, etc.). Kaplan-Meier analysis of progression-free survival (PFS), analyses of time to distant metastasis (DM), overall survival (OS), and locoregional control (LRC), and the corresponding log-rank test were performed. With a median follow-up of 10.5 months [mos] (range 1.0-58.7 mos), we found an improvement in PFS with TVEC and RT in the same region compared to different regions, which were 6.4 mos (95% CI, 2.4-NR mos) and 2.8 mos (95% CI, 0.7-4.4 mos), respectively; p = 0.005. There was also a significant improvement in DM when TVEC and RT were used in the same region compared to different regions: 13.8 mos (95% CI, 4.6-NR mos) and 2.8 mos (95% CI, 0.7-4.4 mos), respectively (p = 0.001). However, we found no difference in overall survival (OS) between patients who had TVEC and RT in the same region (19.0 mos, 95% confidence interval [CI], 4.1-not reached [NR] mos) and those who received treatments in different regions (18.5 mos, 95% CI, 1.0-NR mos); p = 0.366. There was no statistically significant improvement in locoregional control (LRC) in patients who had TVEC and RT in the same region was 26.0 mos (95% CI, 6.4-26.0 mos) compared to patients who received TVEC and RT in different regions (4.4 mos) (95% CI, 0.7-NR mos) (p = 0.115). No grade 3 or higher toxicities were documented in either group. Overall, there were improvements in PFS and DM when TVEC and RT were delivered to the same region of the body compared to when they were used in different regions. However, we did not find a significant difference in locoregional recurrence or OS. Future studies are needed to assess the sequence and timing of combining RT and TVEC to potentially enhance the immune response both locally and distantly.

We report a new immunological treatment for advanced cutaneous melanoma which combines laser stimulation with topical application of a toll-like receptor agonist. This treatment, in situ photoimmunotherapy (ISPI), provides an alternative to traditional therapies for melanoma patients with cutaneous metastases. A 6-week cycle of ISPI is carried out on cutaneous metastases located in a designated 20 x 20 cm treatment area: 2 weeks of pretreatment with twice-daily topical applications of imiquimod (5% cream under plastic occlusion), with a laser treatment session at week 2 and again at week 4. Topical imiquimod is continued for the entire 6-week cycle. Two patients with late-stage melanoma were treated with ISPI. Patient 1 had the primary tumour and local metastases on the left arm, as well as metastatic tumours in the lungs [American Joint Committee on Cancer (AJCC) stage IV]. Patient 2 had a head and neck melanoma with multiple local metastases (AJCC stage IIIC), which had failed repeated attempts at surgical resection and high-dose radiation therapy. Patient 1 is now free of all clinically detectable tumours (including the lung metastases) >20 months after the first treatment cycle. Patient 2 has been free of any clinical evidence of the tumour for over 6 months. These two cases demonstrate that ISPI can clear local tumour and trigger beneficial systemic responses, with a side-effect profile that compares favourably with other treatments for advanced melanoma.

Introduction: Melanoma is the most aggressive of the cutaneous malignancies and caused over 35,000 deaths worldwide in 2013. Treatment options have been greatly expanded by the development of effective small-molecule inhibitors which target recurrent somatic mutations in melanoma (e.g., in BRAF and NRAS). Trametinib (GSK1120212) is an inhibitor of MEK1/2 which has received regulatory approval for the treatment of advanced BRAFV600-mutant melanoma. Trametinib has also demonstrated preclinical and early clinical activities as a single agent and in combination with other targeted therapies for melanoma with NRAS mutations in BRAF/NRAS wild-type melanoma.Areas covered: This article reviews melanoma genetics with a focus on MAPK signaling, and the preclinical and clinical evidence for treatment of melanoma with trametinib. The focus will be on a Phase III study of trametinib in BRAFV600-mutant melanoma, a Phase I/II study combining this agent with dabrafenib (a BRAF inhibitor) and most recently on a Phase III placebo-controlled trial assessing this combination. Finally, we will explore the role of trametinib in other, non-BRAF mutant subsets of this disease (e.g., NRAS mutations and atypical BRAF alterations) and in other malignancies.Expert opinion: Trametinib is a promising therapy which is playing a major role in combination with a BRAF inhibitor for the treatment of advanced BRAF-mutant melanoma. Increasing evidence suggests that trametinib will also play an expanding role in other genetically defined cohorts of this disease.

Following decades of relative ostracism, advances in the treatment of melanoma have brought a new reality for patients, physicians and researchers. While antibodies targeting molecules involved in the modulation of the interaction between melanoma and immune cells changed the meaning of the term "cancer immunotherapy," a better characterization of the molecular aberrations involved in melanoma carcinogenesis prompted the development of inhibitors of the mitogen-activated protein kinase pathway (MAPK) that also led to significant improvements both in response rates and survival. As a result, new drugs have been approved for clinical use in the United States and Europe, including the immune-checkpoint blockers ipilmumab, pembrolizumab and nivolumab, the oncolytic herpesvirus talimogene laherparepvec, and the targeted-agents vemurafenib, dabrafenib, cobimetinib and trametinib. In this article, we review the results of studies that brought new approaches to the bedside and discuss how these developments are being incorporated into the care of patients in Brazil.

Introduction: Ipilimumab has become an important treatment option for patients with advanced melanoma; however, active research perseveres to resolve many clinical practice issues and to further improve the therapeutic index of this agent.Areas covered: This article aims to provide an update on long-term data, current challenge and recent progress relating to the clinical application of ipilimumab in the treatment of advanced melanoma. A literature search using PubMed database was conducted using search words ipilimumab, melanoma, treatment sequencing, adjuvant therapy, combination therapy, and biomarkers. Data were also obtained from meeting abstracts and clinical trial registries.Expert opinion: Signal of clinical activity as adjuvant therapy in patients with resected high-risk melanoma begins to emerge, but longer follow-up is required for confirmation. Many issues, such as optimal dosing schedules and therapeutic sequences, remain unraveled. At present, treatment should be individualized based on patient- and disease-specific factors. Immunotherapy like ipilimumab still represents the best treatment option for durable remission; however, targeted therapies are more appropriate for patients with BRAF V600-mutated tumor who are symptomatic or have rapidly growing disease. With novel therapeutic options in the pipeline, the role of ipilimumab continues to evolve in the rapidly changing treatment landscape of advanced melanoma. Most likely, this agent will be utilized in combinatorial or sequential approach.

Twenty-eight patients with advanced malignant melanoma were treated with high dose methotrexate (HDMTX) and folinic acid (FA) rescue. Nineteen patients were treated with 6-hour infusions and 10 patients with 24-hour infusions. One patient in the 6-hour infusion group showed a partial response. In the 24-hour infusion group there were no responses but there was a significant increase in renal toxicity. It is concluded that HDMTX and FA rescue are not useful agents in the treatment of advanced malignant melanoma.

The incidence of melanoma is increasing steadily both in Poland and worldwide. Until 2010 three drugs were approved for the treatment of metastatic melanoma – dacarbazine (DTIC) in Europe and USA, fotemustine in Europe and interleukin-2 (IL-2) in USA. Approval of ipilimumab and vemurafenib in Europe and USA has changed the standard of care, while the next candidates such as dabrafenib and trametinib have improved survival in phase III studies in metastatic melanoma patients. An encouraging treatment strategy is the combination of dabrafenib and trametinib, evaluated in a phase I/II study with an ongoing phase III trial. Another promising new immune modulating monoclonal antibody (mAb) is anti-PD1 (BMS-936558), tested in an early phase trial in monotherapy or in combination with a multipeptide vaccine in metastatic melanoma patients. Ipilimumab or BRAF inhibitors (vemurafenib, dabrafenib) seem to be active in patients with brain metastases. Intensive research of melanoma vaccines is currently being carried out in a number of countries worldwide. However, no vaccine in the treatment of melanoma has been approved by regulatory authorities so far. Lack of effective therapy in patients with high-risk resected melanoma led to a number of clinical studies of adjuvant treatment. Interferon-α (INF-α) therapy in this setting is still controversial. A dendritic cell-based vaccine in a randomized phase II trial showed a survival benefit over the control group in patients with high-risk resected melanoma. Promising results of long-term survival of advanced resected melanoma patients in a phase II study evaluating the genetically modified tumour vaccine (GMTV) AGI-101 were reported.This review provides an update on clinical strategies used or tested in patients with metastatic melanoma.

BackgroundObserving and studying clinical efficacy and safety of apatinib mesylate tablet in the treatment of advanced malignant melanoma (MM).MethodsRetrospectively analyzing the clinical data of 22 patients with metastatic MM who had failed conventional chemotherapy from June 2016 to January 2018. All patients took 500 mg of apatinib mesylate tablets per day. The efficacy should be evaluated according to RECIST 1.1 criteria. Adverse events (AEs) should be graded according to NCI-CTCAE 4.0.ResultsThere were two cases of partial remission (PR), 11 of stable disease (SD) and nine of progressive disease (PD) in the 22 patients with advanced MM, where the objective remission rate (ORR) was 9.1% and the disease control rate (DCR) was 59.1%. The median progression-free survival (PFS) was 7.5 months, and the 6-month progression-free survival rate (PFR) was 54.7%. Six patients died and the overall survival (OS) was not reached. AEs were controllable and all were in Grade 1–3.ConclusionApatinib mesylate tablets have a certain curative effect on patients with malignant melanomas of Stage IV who failed conventional chemotherapy. Apatinib mesylate tablets at a daily dose of 500 mg are well tolerated by most patients.

To investigate efficacy of masitinib mesylate for the treatment of advanced malignant melanoma in dogs. Prospective clinical trial on 17 dogs with stage III and IV malignant melanoma (two digital, one anal and 14 oral mucosal). Only dogs with advanced gross disease for which the owner declined conventional treatment or dogs with progressive tumour despite conventional treatment were included. There was a partial response in two dogs, stable disease in seven and tumour progression in eight dogs. Median survival time for all 17 dogs was 119 days (range 21-255). Masitinib was generally well-tolerated but grade 2 anaemia, grade 1 neutropenia, grade 1 diarrhoea and grade 2 anorexia were observed in one dog each. There was only mild effectiveness in end-stage disease, indicating that masitinib mesylate is not an appropriate sole-agent option for treatment of advanced malignant melanoma in dogs.

Malignant melanoma is the most severe form of skin cancers in humans. Incidence of this malignancy is still increasing worldwide. The highest incidence is mentioned in Australia (50–60/100,000 of cases). Success of malignant melanoma therapy depends on the stage of disease revelation. Localized cutaneous melanoma is generally well curable. The main problem is the treatment of advanced malignant melanoma with distant metastases. Therapy of this malignancy is based on surgical resection of lesion, chemotherapy, immunotherapy, biochemotherapy, and so on. The current results of malignant melanoma treatment are unfortunately often unsatisfactory. Improvement and enhancement of efficacy of contemporary immunotherapeutic methods should be in the forefront of interest. Renaissance of the old concepts of immunotherapy (Coley's toxin and Bacillus Calmette-Guérin vaccine administration) could be one way to reduce possible adverse effect of standard methods of malignant melanoma treatment.

7573 Background: Temozolomide and thalidomide (TT) are active agents in the treatment of melanoma. The optimal dose and schedule have not been defined. Methods: Temozolomide was administered at 75 mg/m2/day for 6 out of 8-weeks cycle. Thalidomide was given at 200 mg daily for the first two weeks and increased by 100 mg/day weekly up to a maximum of 400 mg/day without interruption. Responses were assessed every 2 cycles by using the RECIST guidelines. Results: From May 2002 through December 2004, 30 patients with advanced and symptomatic melanoma were enrolled. 17 subjects are evaluable for toxicity and 9 for response. Median age 59.3 years (39–79), PS 1 (0–2). Sites of metastasis: 3 skin, 8 lymph nodes, 4 brain, 3 liver, 2 bones, 3 adrenals, 15 lungs, 1 kidney, 2 spleen, 1 heart 2 mesenteric and 1 tongue. Prior therapies: 5 surgeries (3 local, 2 brain), 2 brain radiotherapy, 3 adjuvant interferon, 7 biochemotherapy, 2 vaccine. 47 cycles of TT have been administered (range 1–8 cycles). 70% of the patients received the maximum thalidomide dose whereas 17% had dose reduction due to fatigue and neuropathy, the rest could not be escalated. Out of 9 patients, 1 had a complete response after 2 cycles, 1 partial response, 1 stable disease after 2 cycles and 6 patients progressed after 1 cycle of TT. Toxicity grade 3: anemia 5%, thrombocytopenia 17%, thromboembolic disease 5% and shingles 5%; grade 2: constipation 17%, fatigue 17%. 1 patient with brain metastasis developed seizures attributed to a low level of antiepileptic and 1 had gastrointestinal bleed due to gastric melanoma. No other hematologic or non-hematologic toxicities were observed. Results will be updated for the meeting. Conclusions: TT is an active and well tolerated treatment for patients with advanced melanoma. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Schering