Rechallenge with checkpoint inhibitors in metastatic melanoma

To date, there have been only few studies investigating rechallenge with checkpoint inhibitors in melanoma patients. Herein, we present the first review of all internationally published, English‐language articles. A total of 570 patients were included in our analysis, divided into four groups: 1) rechallenge with anti‐PD1 following disease progression on anti‐PD1 therapy; 2) rechallenge with anti‐PD1 and anti‐CTLA4 following disease progression on anti‐PD1 therapy; 3) rechallenge with anti‐CLTA‐4 following disease progression on anti‐CTLA‐4 therapy; and 4) rechallenge following toxicity‐related treatment discontinuation. In the first group (85 patients), the mean disease control rate (DCR) was 45.8 %, with a mean overall response rate (ORR) of 15.5 %. The second group (114 patients) showed a mean DCR of 40.6 % and an ORR of 20 %. In the third group (182 patients), the mean DCR was 50.9 %, with an ORR of 20.4 %. Thus, even patients with a history of disease progression on initial checkpoint inhibitor therapy may benefit from rechallenge. Patients in the fourth group (189 patients) showed a mean DCR of 89.5 % and an ORR of 70.2 %. Of these individuals, 18 % saw recurrence of the same toxicity; 23 % were affected by adverse events different from the ones previously experienced.     

Update on the clinical use of kinase inhibitors in melanoma

The identification of targetable molecules in cellular signaling pathways represents a milestone in the treatment of melanoma. Selective inhibitors of these molecules, known as phosphokinases, allow for individual signaling pathways to be “switched off”. This is of particular importance for tumors in which these pathways are constitutively activated by mutations in genes encoding said molecules. Especially patients with BRAF‐mutated melanomas significantly benefit from kinase inhibitor therapies, with the current standard of combined BRAF and MEK inhibition providing very good long‐term disease control. Such regimens have been shown to achieve a progression‐free survival of more than ten months and an overall survival of more than two years, along with good quality of life. Given that the majority of patients develop secondary resistance during long‐term kinase inhibitor therapy, current clinical trials are geared towards finding suitable drug combinations including inhibitors of other signaling pathways as well as immune checkpoint inhibitors. The present review highlights targeted therapies for melanoma currently available as well as potential future options presently under clinical investigation.     

Aktuelle Fortschritte und Ausblicke in der Therapie des metastasierten Melanoms

Melanoma has long been considered as an extremely therapy‐resistant tumour. Recent developments in the area of immunotherapy as well as targeted therapy showed rapid development and excellent results. The anti‐CTLA‐4 antibody ipilimumab, which was approved in the USA and Europe in 2011, was the first substance in melanoma therapy to demonstrate an overall survival benefit. Another approval is expected in Europe for the specific BRAF‐inhibitor vemurafenib, which has shown a significant impact on progression‐free survival and overall survival in patients with the BRAF^V600E mutation. In this review the relevant agents in the substance classes of immunomodulatory drugs and small molecules are presented and discussed, and future prospects for combination therapies and developments in melanoma treatment are outlined.     

Pazopanib does not bring remarkable improvement in patients with angiosarcoma

Pazopanib is a potent and selective multi‐targeted tyrosine kinase inhibitor that has been reported to extend progression‐free survival in cases of metastatic soft‐tissue sarcoma. However, the efficacy of pazopanib for cutaneous angiosarcoma has not been confirmed. We report eight cases of angiosarcoma treated with pazopanib, and review the efficacy and safety of pazopanib therapy. We retrospectively investigated the clinical information, including age, sex, body surface area, location, performance status, lung or pleural metastasis, preceding treatment, oral dose of pazopanib, response rate, progression‐free survival and adverse effects. Five of the eight patients needed to stop the pazopanib treatment due to severe adverse effects, including thrombocytopenia, anemia, drug‐associated pancreatitis, acute fulminant hepatitis and general fatigue. Progression‐free survival ranged 0.5–3.5 months (mean ± standard deviation, 1.81 ± 1.03). Overall survival ranged 3–26 months (14.13 ± 9.47). Six of the eight cases showed progressive disease, and two of the eight cases showed stable disease. To assess overall survival in angiosarcoma treated with pazopanib, we compared the pazopanib‐treated group (n = 8) with the non‐pazopanib‐treated control group (n = 10). There was no significant difference between two groups (P = 0.19, log–rank test). In conclusion, our case series suggests that pazopanib does not bring remarkable improvement in patients with angiosarcoma.     

Combined total skin radiotherapy and immune checkpoint inhibitors: A promising potential treatment for mycosis fungoides and Sezary syndrome

Radiotherapy, particularly total skin electron beam therapy (TSEB), is one of the main pillars in the strategy for treatment of cutaneous T‐cell lymphoma (CTCL). Low‐dose TSEB has gained considerable attention since it has a minimal toxicity profile. Low‐dose TSEB has been shown to yield an overall response rate up to 95 %, although the response duration is usually short. Few studies have been published on treatment outcomes after combined treatment of CTCL with TSEB and systemic therapy. Remission rates of patients who received immune checkpoint inhibitors alone ranged from 15–38 % with a two‐year progression‐free survival of 69 %. Given that TSEB results in rapid reduction of the disease burden in almost all patients, we hypothesized that TSEB followed by immune checkpoint inhibitors might be a reasonable treatment with a sustained effect for treatment‐experienced patients with mycosis fungoides and Sezary syndrome.     

Pretherapeutic laboratory findings,extent of metastasis and choice of treatment as prognostic markers in ocular melanoma– a single centre experience

Background Uveal melanoma is the most common intraocular neoplasm with a high tendency to metastasize predominantly to the liver. Prognostic parameters for progression and overall survival are not well defined. The aim of this study was to assess the value of pretherapeutic serum levels of C‐reactive protein (CRP), lactate dehydrogenase, albumin and fibrinogen in patients with uveal melanoma and to evaluate their significance as prognostic parameters for survival. Methods Forty‐nine patients with metastatic uveal melanoma treated between 2000 and 2010 were retrospectively analysed. The potential influence of levels of CRP, lactate dehydrogenase, fibrinogen and albumin as well as other commonly known prognostic variables on progression‐free and overall survival were investigated. Results Patients’ age and treatment with systemic chemotherapy were the only variables to show significant influences on progression‐free and overall survival in a univariate analysis. Multivariate analysis confirmed the influence of these variables on progression‐free survival, presence of metastasis, pretherapeutic CRP levels and treatment with systemic chemotherapy were associated with overall survival. Conclusion In this patient cohort elevated pretherapeutic CRP and extent of metastasis are independent prognostic factors for decreased overall survival, whereas treatment with systemic chemotherapy showed a significant association with improved overall survival.     

Trends in the prognosis of metastatic melanoma in the era of targeted therapy and immunotherapy: A single‐institution survey in Japan

Advances in anticancer therapy, including the development of targeted therapy and immunotherapy, have drastically changed treatment options for metastatic melanoma. However, to date, only a few studies have been published that directly compare overall survival (OS) before and after introduction of these new therapeutic options in Japan. We retrospectively surveyed patients with metastatic melanoma treated in our hospital between 1989 and 2019 to investigate the OS benefit of the new therapies. A total of 115 patients with metastatic melanoma (cutaneous origin, 92; mucosal, 14; uveal, two) were included in the study. Kaplan–Meier analysis showed that the patient group receiving targeted therapy/immunotherapy (TT/IT) (n = 47) had a median OS of 19.0 months, which was longer than that in patients receiving conventional chemotherapy (n = 42, 8.0 months) or no treatment (n = 26, 6.0 months) (P < 0.001). In the subgroup analysis performed for the TT/IT group, patients of younger age and with the BRAF mutation had significantly improved OS. As the number of treatment lines increased, the median OS tended to become longer. Our real‐world data confirmed an improvement of median OS upon the introduction of the new therapies for metastatic melanoma. However, the long‐term OS benefit was limited, possibly because of racial differences in some of the clinical characteristics. To improve the overall melanoma prognosis, the entire treatment strategy, including perioperative therapy needs strengthening.     

Systemic therapy of metastatic melanoma

For patients with metastatic melanoma, there are currently several effective therapeutic options. The BRAF inhibitors vemurafenib and dabrafenib are characterized by rapid tumor control and high response rates. In combination with one of the two MEK inhibitors trametinib and cobimetinib, they achieve response rates (CR + PR, complete plus partial remissions) of 70 %, while delaying the development of treatment resistance, as well as a median overall survival of > 2 years with tolerable side effects. Showing long‐term survival rates of approximately 20 %, the anti‐CTLA‐4 antibody ipilimumab is the first substance that has led to a significant prolongation of overall survival in patients with metastatic melanoma. However, delayed treatment response and severe immune‐mediated side effects may pose limitations to its therapeutic benefit. Usually well tolerated, anti‐PD‐1 antibody monotherapy using nivolumab and pembrolizumab has yielded response rates (CR + PR) of up to 45 % and one‐year survival rates of > 70 %. The combination of ipilimumab and nivolumab has shown response rates of up to 58 % and a median progression‐free survival of > 11 months. While this combination is expected to result in a rapid and long‐lasting response, this potential benefit comes at the expense of a high level of toxicity. Strategies for treatment sequencing and treatment combinations are currently being investigated in clinical studies. Overall, the prognosis for patients with metastatic melanoma has significantly improved. With long‐term survival a possibility, not only acute but also long‐term therapeutic side effects must be taken into account.     

Japanese real‐world study of sequential nivolumab and ipilimumab treament in melanoma

To describe the treatment patterns of nivolumab and ipilimumab in Japan, a retrospective observational study was conducted in melanoma patients who received nivolumab and ipilimumab sequentially. Patients who received nivolumab and ipilimumab in combination were excluded from this study. Efficacy was evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST) in terms of the overall response rate (ORR), progression‐free survival (PFS), and disease control rate (DCR). Overall survival (OS) was also evaluated. Safety was assessed by the Common Terminology Criteria for Adverse Events (CTCAE). The treatment for all 68 patients enrolled involved switching from nivolumab to ipilimumab in 61 patients and switching from ipilimumab to nivolumab in seven patients. Switching occurred because of progressive disease in 55 patients and adverse events in eight patients. The median number of ipilimumab doses was three. Ipilimumab treatment achieved an ORR and DCR of 4.9% and 21.3%, respectively, and the median OS from start of ipilimumab was 7.0 months. During the study period, no new safety signals were noted. Independent factors which were indicative of poor prognosis for PFS were high neutrophil‐to‐lymphocyte ratio (NLR) and high C‐reactive protein (CRP) levels before ipilimumab treatment. An evaluation over a washout period indicated that no significant relationship existed with efficacy or safety. For the sequential administration of nivolumab and ipilimumab in Japanese melanoma patients, switch from nivolumab to ipilimumab was common, and the major reason for switching was progressive disease. The major prognostic factors for ipilimumab PFS after nivolumab were NLR and CRP before ipilimumab treatment.     

Correlation between vitiligo occurrence and clinical benefit in advanced melanoma patients treated with nivolumab: A multi‐institutional retrospective study

Vitiligo is occasionally seen in melanoma patients. Although several studies indicate a correlation between vitiligo occurrence and clinical response in melanoma patients receiving immunotherapy, most studies have included heterogeneous patient and treatment settings. The aim of this study is to investigate the correlation between the occurrence of vitiligo and clinical benefit of nivolumab treatment in advanced melanoma patients. We retrospectively reviewed unresectable stage III or IV melanoma patients treated with nivolumab. Of 35 melanoma patients treated with nivolumab, 25.7% (9/35) developed vitiligo during treatment. The time from the start of nivolumab treatment to occurrence of vitiligo ranged 2–9 months (mean, 5.2). Of nine patients who developed vitiligo, two (22.2%) had a complete response to nivolumab and two (22.2%) had a partial response. The objective response rate was significantly higher in patients with vitiligo than in patients without vitiligo (4/9 [44.4%] vs 2/26 [7.7%]; P = 0.027). The mean time to vitiligo occurrence in patients achieving an objective response was significantly less than that in patients who showed no response (3.1 vs 6.8 months, P = 0.004). Vitiligo occurrence was significantly associated with prolonged progression‐free and overall survival (hazard ratio, 0.24 and 0.16; 95% confidence interval, 0.11–0.55 and 0.03–0.79; P = 0.005, and 0.047, respectively). At the 20‐week landmark analysis, however, vitiligo was not associated with a statistically significant overall survival benefit (P = 0.28). The occurrence of vitiligo during nivolumab treatment may be correlated with favorable clinical outcome.     

Real-world efficacy and safety data of nivolumab and ipilimumab combination therapy in Japanese patients with advanced melanoma

The efficacy and safety of nivolumab + ipilimumab combination therapy were retrospectively examined in Japanese patients with unresectable advanced melanoma in clinical practice. Fifty-seven patients with advanced melanoma received the nivolumab + ipilimumab combination therapy. The primary site was cutaneous, mucosal, uveal and unknown in 35, 16, two and four patients, respectively. The overall response rate was 26.3%, with complete response observed in two (3.5%) patients, partial response in 13 (22.8%), stable disease in 12 (21.1%) and progressive disease in 30 (52.6%). The response rate in the treatment-naive and prior systemic therapy group was 40.7% and 13.3%, respectively. For those treated with a single immune checkpoint inhibitor followed by the nivolumab + ipilimumab combination therapy as second-line therapy after disease progression, the response rate was 18.8%. Median progression-free survival (PFS) and overall survival (OS) in all patients was 3.3 and 14 months, respectively. Median PFS in the treatment-naive and prior systemic therapy groups was 13 and 2 months, respectively. Median OS was unreached in the treatment-naive group and was 6.3 months in prior systemic therapy groups. There was no significant difference in PFS and OS for non-acral, acral and mucosal melanoma. Adverse events occurred in 86% of patients; 56.1% were grade 3 or worse. The response rate in an actual clinical setting, including the prior systemic therapy group, was lower than that in the global study and the Japanese phase II study. However, in the treatment-naive group, the rate was equivalent to that in the Japanese phase II study. PFS and OS in the treatment-naive group were comparable with those in the global study and Japanese phase II study, suggesting that the treatment was effective. The proportion of grade 3 and 4 immune-related adverse events was as high as that in the global study and Japanese phase II study.     

Treatment of High Risk Resected Melanoma in Australia: Current Landscape and Practises

Stage III melanoma involves regional lymph nodes and/or in-transit or satellite disease, without spread to distant metastatic sites. Stage IIIA melanoma includes a T1a-T2a primary lesion with N1a or N2a nodal involvement, whilst stage IIID melanoma includes a T4b primary lesion with N3a-N3c nodal involvement. With surgery alone, patients with stage IIIA melanoma have 10-year survival rates of ~88%; however, patients with stage IIID melanoma have 10-year survival rates of only ~24%. Targeted therapy and immunotherapy are being explored in stage III disease as adjuvant therapy after surgical resection, to eliminate micro-metastatic disease and thereby prevent relapse of melanoma and increase patient survival. A number of pivotal trials published in the last two years have shown improved relapse-free survival (RFS) and overall survival in patients with stage III melanoma treated with adjuvant therapy. COMBI-AD showed adjuvant dabrafenib and trametinib improving RFS compared with placebo (HR 0.49; 95% CI 0.40–0.59). Checkmate-238 demonstrated an improvement in RFS of adjuvant nivolumab over ipilimumab (HR 0.68, P < 0.001) whilst Keynote-054 demonstrated an improvement in RFS with adjuvant pembrolizumab over placebo (HR 0.57, P < 0.001). Many nuances need to be considered when interpreting this data, including implications of an updated staging system, which patients are suitable for adjuvant therapy and the choice between adjuvant targeted therapy and immunotherapy in BRAF mutant patients. This review article summaries the currently available literature on adjuvant targeted therapy and provides a guide on applying this data in everyday practise.     

Phase I/II study of vemurafenib in patients with unresectable or recurrent melanoma with BRAFV600 mutations

We investigated the efficacy and safety of vemurafenib in Japanese patients with unresectable or recurrent melanoma with BRAF^V600 mutations. This was a two‐step open‐label multicenter phase I/II study. Step 1 evaluated the initial safety of vemurafenib 960 mg administrated p.o. twice daily in three patients. In step 2, eight patients received vemurafenib 960 mg administrated p.o. twice daily for 28‐day treatment cycles; the primary outcome measure was response rate, as determined by independent review committee using Response Evaluation Criteria in Solid Tumors version 1.1. Adverse events (AE) experienced by five or more patients were arthralgia (n = 10), myalgia (n = 8), alopecia (n = 7), and rash, maculopapular rash and decreased appetite (n = 5 each). Three patients had grade 3 AE. One serious AE occurred in one patient (abnormal hepatic function). Six patients required dose reduction because of AE. One patient died within 28 days after the last dose, but death was caused by disease progression and not associated with the study drug. In the eight patients in step 2, overall response rate was 75.0%, none had a complete response and six had a partial response (75.0%). Median response duration was 240.0 days, disease control rate 87.5%, median progression‐free survival 416.0 days and median overall survival 443.0 days. In conclusion, vemurafenib treatment resulted in an overall response rate of 75% in Japanese patients with metastatic melanoma with BRAF^V600 mutations. All toxicities were manageable.     

Low-dose total skin electron beam therapy as a debulking agent for cutaneous T-cell lymphoma: an open-label prospective phase II study

Background Total skin electron beam therapy (TSEBT) is a powerful treatment for cutaneous T‐cell lymphoma (CTCL). Based on the occurrence of relapses with low radiation doses, doses of 30–36 Gy are commonly used but most patients still eventually relapse and repeat treatment courses are limited due to the cumulative toxicity. Complete response (CR) rates are about 60–90% for T2–4 stages with a 5‐year relapse‐free survival of 10–25% for stages IB–III. Objectives To evaluate prospectively the efficacy of low‐dose TSEBT (10 Gy) in terms of complete cutaneous response rate, overall response rate and response duration in CTCL. Methods Ten patients with stage IB–IV mycosis fungoides (MF) were treated in an open‐label manner with four fractions of TSEBT 1 Gy weekly to a total skin dose of 10 Gy. Treatment responses were assessed at 1 and 3 months after treatment and subsequently at least every 6 months for a total period of 2 years or to disease relapse or progression. Results Patients achieved an overall response rate of 90%. The rate of CR or very good partial response (VGPR; < 1% skin affected with patches/plaques) was 70%. The median response duration was 5·2 months (range 83–469 days) for CR and VGPR. Adverse effects were generally mild to moderate in severity. Conclusions Low‐dose TSEBT (10 Gy) gave a satisfactory response rate and was well tolerated in patients with MF stage IB–IV. Future studies should determine if the combination of low‐dose TSEBT with other agents could increase the rate of CR and response duration.     

Usefulness of docetaxel as first‐line chemotherapy for metastatic extramammary Paget's disease

In invasive extramammary Paget's disease (EMPD), distant metastases may develop and the condition may become fatal; however, no standardized treatment has been established. Although based on only a few cases, several chemotherapy regimens were reported to be promising. We conducted a multicenter, retrospective study to evaluate the efficacy of docetaxel for metastatic EMPD. We retrospectively collected data on 18 metastatic EMPD patients treated using docetaxel from 1998 to 2012 in 12 institutes in Japan. The following clinical data were collected: tumor response, time to progression, overall survival and adverse effects. Of those, three patients treated combined with S‐1, one patient treated with weekly schedule and one patient treated combined with radiotherapy were excluded from the further analysis. All 13 patients received monthly docetaxel as the first‐line treatment. The average number of treatment cycles was 9.1. Among the 12 patients with a confirmed response, seven (58%) showed a partial response, three (25%) stable disease and two (17%) progressive disease. The disease control rate (partial response + stable disease) was as high as 83%. The time to progression and median overall survival were 7.1 and 16.6 months, respectively. The 1‐year overall survival rate determined by the Kaplan–Meier method was 75.0%. All adverse effects were manageable and no treatment‐related deaths were observed. The high disease control rate and overall survival shown by this study suggest that first‐line use of docetaxel may be a promising treatment for metastatic EMPD. A prospective clinical trial is required to confirm our results.     

Temozolomid als Therapieoption bei Patienten mit fernmetastasiertem Melanom und ungünstiger Prognose

Background and objective. Stage IV melanoma patients with a very advanced disease are usually excluded from clinical trials. We treated 25 stage IV patients with temozolomide – a cytostatic drug with 100% oral bioavailability and considerable penetration of CNS tissue. Patients/Methods. 25 patients (17 female, 8 male) between 24 and 82 years (mean: 55.5 years) were included in this retrospective study. 19 patients had received at least one and up to four previous chemotherapy regimens during the course of stage IV disease. 11 (44%) patients showed cerebral metastases prior to therapy with temozolomide. 200 mg/m2 temozolomide were given orally at home on day 1 to 5 in week 1 and in week 5, respectively. Results. Out of 23 evaluable patients 2 (8.7%) showed a partial remission, 2 (8,7%) a minor response, 6 (26.1%) had stable disease, 1 (4,3%) a mixed response, and 12 (52.1%) patients experienced disease progression. Sites of remission included brain, lung, liver, lymph nodes and muscle. Two patients interrupted therapy due to severe leuko- and thrombocytopenia (WHO grade 3 and 4). All other patients tolerated treatment with temozolomide well and no dose reduction was necessary. The median overall survival was 7 months (2–28+ months) since beginning of therapy and 15 months (4–63+ months) since onset of stage IV disease. Conclusion. Temozolomide represents a safe treatment option in patients with metastatic melanoma and poor prognosis.     

Interferon-alpha therapy for melanoma

Although surgery may be curative in early malignant melanoma, its effect on survival lessens with each succeeding stage of the disease. A wide variety of immunological strategies have therefore been used to improve the prognosis of patients with malignant melanoma, but adjuvant therapy with interferon (IFN)-alpha is the only treatment to show a therapeutic benefit in randomized controlled studies. The current data indicates that where IFN-alpha is used at low dose, its main effect is on disease-free survival, whereas high-dose regimens may improve overall survival as well. This paper will review the published data on IFN-alpha therapy in patients with intermediate and high-risk melanoma and explore future avenues for managing patients with this difficult disease.     

Cutaneous melanoma: interferon alpha adjuvant therapy for patients at high risk for recurrent disease

Systemic adjuvant therapy in melanoma patients is the systemic treatment that is administered with the goal of eradicating micrometastatic deposits in patients who are clinically free of disease after surgical removal of the primary melanoma, but with a high risk of systemic recurrence. Interferon-alpha (IFN-alpha) is one of the most frequently used adjuvant therapies. Several randomized trials evaluated the efficacy of IFN-alpha in melanoma patients. However, results from conducted trials are controversial. Twelve randomized IFN-alpha trials are discussed in detail. All trials, including meta-analysis, failed to demonstrate a clear impact of IFN-alpha therapy on overall survival in melanoma patients. Based on currently available evidence, IFN-alpha therapy in the adjuvant setting should not be considered standard of care for patients who have melanoma. Results from ongoing studies are awaited. Further research for this therapy is required.     

Current advances and perspectives in the treatment of advanced melanoma

Melanoma has long been considered as an extremely therapy-resistant tumour. Recent developments in the area of immunotherapy as well as targeted therapy showed rapid development and excellent results. The anti-CTLA-4 antibody ipilimumab, which was approved in the USA and Europe in 2011, was the first substance in melanoma therapy to demonstrate an overall survival benefit. Another approval is expected in Europe for the specific BRAF-inhibitor vemurafenib, which has shown a significant impact on progression-free survival and overall survival in patients with the BRAF(V600E) mutation. In this review the relevant agents in the substance classes of immunomodulatory drugs and small molecules are presented and discussed, and future prospects for combination therapies and developments in melanoma treatment are outlined.     

Intradermal injection of Newcastle disease virus‐modified autologous melanoma cell lysate and interleukin‐2 for adjuvant treatment of melanoma patients with resectable stage III disease

Background: The value of active specific immunotherapy (ASI) for the treatment of solid tumours still has to be assessed. The objective was to test an autologous tumour cell vaccine for adjuvant treatment of stage III melanoma patients. Patients and Methods: After open vaccination of 12 patients, another 17 patients were recruited for a randomized double‐blind trial comparing treatment with the vaccine (n = 9) and with a placebo (n = 8). Intracutaneous vaccinations were given postoperatively in weeks 2, 4, 6, 12, 24 and thereafter every 6 months if sufficient vaccine material was available. Patients were followed for 60 – 84 months. Results: Median disease‐free survival time was 5 months for open‐treated, 4 months for verum‐treated and 6 months for placebo‐treated patients. Corresponding median overall survival times were 30.5, 18 and 18.5 months, respectively. There were no remarkable differences between the verum and the placebo group. Conclusions: Adjuvant treatment of melanoma patients with an autologous ASI vaccine did not show clinical efficacy in this cohort of melanoma patients.