The incidence of melanoma is increasing worldwide, and the prognosis for patients with high‐risk or advanced metastatic melanoma remains poor despite advances in the field. Standard treatment for ...patients with thick (≥2.0 mm) primary melanoma with or without regional metastases to lymph nodes is surgery followed by adjuvant therapy or clinical trial enrollment. Adjuvant therapy with interferon‐α and cancer vaccines is discussed in detail. Patients who progress to stage IV metastatic melanoma have a median survival of ≤1 year. Standard treatment with chemotherapy yields low response rates, of which few are durable. Cytokine therapy with IL‐2 achieves durable benefits in a greater fraction, but it is accompanied by severe toxicities that require the patient to be hospitalized for support during treatment. A systematic literature review of treatments for advanced, metastatic disease was conducted to present the success of current treatments and the promise of those still in clinical development that may yield incremental improvements in the treatment of advanced, metastatic melanoma.
The incidence of melanoma is increasing worldwide, and the prognosis for patients with high‐risk or advanced metastatic melanoma remains poor despite advances in the field. A systematic literature review of treatments for advanced, metastatic disease was conducted to present the success of current treatments and the promise of those still in clinical development that may yield incremental improvements in the treatment of advanced, metastatic melanoma. Advances in the understanding of the mechanism of chemotherapy resistance offer the hope for improved results with chemotherapy, and the triumvirate of more effective chemotherapy, immunotherapy, and targeted therapy are likely to be combined with one another for significant advances in melanoma over the coming few years.
The inhibition of the mitogen-activated protein kinases signalling pathway through combined use of BRAF and MEK inhibitors (BRAFi+MEKi) represents an established therapeutic option in patients with ...BRAF-mutated, advanced melanoma. These efficient therapies are well tolerated with mostly moderate and reversible side effects and a discontinuation rate due to adverse events of 11.5%–15.7%. Median duration of therapy ranges between 8.8 and 11.7 months. Based on data from confirmatory trials, safety profiles of three BRAFi+MEKi combinations were reviewed, that is, dabrafenib plus trametinib, vemurafenib plus cobimetinib and encorafenib plus binimetinib. Many adverse events are class effects, such as cutaneous, gastrointestinal, ocular, cardiac and musculoskeletal events; some adverse events are substance associated. Fever (dabrafenib) and photosensitivity (vemurafenib) are the most common and clinically prominent examples. Other adverse events are less frequent and the association to one substance is less strong such as anaemia, facial paresis (encorafenib), neutropenia (dabrafenib), skin rash, QTc prolongation and increased liver function tests (vemurafenib). This narrative review provides recommendations for monitoring, adverse event evaluation and management focusing on the clinically relevant side effects of the three regimens.
Immunotherapy with PD-1 antibodies has greatly increased prognosis of patients with advanced melanoma. Identifying biomarkers that predict overall survival (OS) and response to immunotherapy is ...important.
OS and best overall response according to RECIST version 1.1 were analysed, and S100B and lactate dehydrogenase (LDH) serum levels were assessed retrospectively in 152 patients treated with anti-PD-1, and in 86 patients treated with anti-PD-1 plus anti-CTLA-4 antibodies at University Hospital Tuebingen, Germany.
In the pembrolizumab group, patients with elevated baseline S100B or LDH exhibited significantly impaired OS compared with patients with normal S100B (1-year OS: 51.1% vs 83.1%, log-rank P < .0001) and normal LDH (1-year OS: 44.4% vs 80.8%, P = .00022), respectively. LDH increases of >25% and S100B increases of >145% compared to baseline were significantly associated with impaired OS (both P < .0001). In patients treated with ipilimumab and nivolumab, baseline S100B and increasing S100B levels of >145% as well as baseline LDH were associated with impaired OS (P < .0001, P = .00060, and P = .0050, respectively), whereas increasing LDH of >25% was not (P = .64).
S100B could serve as a strong baseline marker for OS in melanoma patients receiving anti-PD-1 therapy. Rising S100B levels during the first weeks of therapy could help guide treatment decisions.
Cutaneous squamous cell carcinoma (cSCC) is an increasing health burden in white populations. We prospectively assessed risk factors for tumor-specific and overall survival in 1,434 patients who ...underwent surgery for cSCC between January 24, 2005, and May 29, 2015. A total of 2,149 invasive cSCCs were analyzed. Univariate and multivariate survival analyses included tumor thickness, horizontal size, body site, histological differentiation, desmoplastic growth, history of multiple cSCCs, and immunosuppression. The primary endpoint was time to tumor-specific death. During a median follow-up period of 36.5 months (range = 0–137 months), 515 patients died; 40 because of cSCC (2.8%). Of those, 12 died because of visceral metastases and 28 because of tumor growth by local infiltration. On multivariate analyses, prognostic factors for tumor-specific survival were increased vertical tumor thickness (hazard ratio = 6.73; 95% confidence interval = 3.47–13.08; P < 0.0001), desmoplastic growth (hazard ratio = 4.14; 95% confidence interval = 2.68–9.83; P < 0.0001), and immunosuppression (hazard ratio = 2.07; 95% confidence interval = 1.04–4.12; P = 0.039). Defining a point list out of those factors and grouping them into four cohorts resulted in comprehensively separating survival curves (P < 0.001). Using a cut-off for tumor thickness of 6 mm or greater, the presence of desmoplastic growth and immunosuppression identifies patients at high risk for tumor-specific death.
Summary Background The IMMUNED trial previously showed significant improvements in recurrence-free survival for adjuvant nivolumab plus ipilimumab as well as for adjuvant nivolumab alone in patients ...with stage IV melanoma with no evidence of disease after resection or radiotherapy. Here, we report the final analysis, including overall survival data. Methods IMMUNED was an investigator-sponsored, double-blind, placebo-controlled, three-arm, phase 2 trial conducted in 20 academic medical centres in Germany. Eligible patients were aged 18–80 years with stage IV melanoma with no evidence of disease after surgery or radiotherapy. Patients were randomly assigned (1:1:1) to either nivolumab plus ipilimumab (nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four doses followed by nivolumab 3 mg/kg every 2 weeks), nivolumab monotherapy (nivolumab 3 mg/kg every 2 weeks), or matching placebo, for up to 1 year. The primary endpoint was recurrence-free survival in the intention-to-treat population. Secondary endpoints were time-to-recurrence, overall survival, progression-free survival or recurrence-free survival 2 (in patients in the placebo group who crossed over to nivolumab monotherapy after experiencing disease recurrence), and safety endpoints. This trial is registered on ClinicalTrials.gov (NCT02523313), and is complete. Findings Between Sept 2, 2015, and Nov 20, 2018, 175 patients were enrolled in the study, and 167 were randomly assigned to receive either nivolumab plus ipilimumab (n=56), nivolumab plus ipilimumab-matching placebo (n=59), or double placebo control (n=52). At a median follow-up of 49·2 months (IQR 34·9–58·1), 4-year recurrence-free survival was 64·2% (95% CI 49·2–75·9) in the nivolumab plus ipilimumab group, 31·4% (19·7–43·8) in the nivolumab alone group, and 15·0% (6·7–26·6) in the placebo group. The hazard ratio (HR) for recurrence for the nivolumab plus ipilimumab group versus placebo was 0·25 (97·5% CI 0·13–0·48; p<0·0001), and for the nivolumab group versus placebo was 0·60 (0·36–1·00; p=0·024). Median overall survival was not reached in any treatment group. The HR for overall survival was significantly in favour of the nivolumab plus ipilimumab group versus placebo (HR 0·41; 95% CI 0·17–0·99; p=0·040), but not for the nivolumab group versus placebo (HR 0·75; 0·36–1·56; p=0·44). 4-year overall survival was 83·8% (95% CI 68·8–91·9) in the nivolumab plus ipilimumab group, 72·6% (57·4–83·2) in the nivolumab alone group, and 63·1% (46·9–75·6) in the placebo group. The median progression-free survival or recurrence-free survival 2 of patients in the placebo group who crossed over to nivolumab monotherapy after experiencing disease recurrence was not reached (95% CI 21·2 months to not reached). Rates of grade 3–4 treatment-related adverse events remained largely unchanged compared with our previous report, occurring in 71% (95% CI 57–82) of the nivolumab plus ipilimumab group, and 29% (95% CI 17–42) of patients receiving nivolumab alone. There were no treatment-related deaths. Interpretation Both active regimens continued to show significantly improved recurrence-free survival compared with placebo in patients with stage IV melanoma with no evidence of disease who were at high risk of recurrence. Overall survival was significantly improved for patients receiving nivolumab plus ipilimumab compared with placebo. Use of subsequent anti-PD-1-based therapy was high in patients in the placebo group after recurrence and most likely impacted the overall survival comparison of nivolumab alone versus placebo. The recurrence-free and overall survival benefit of nivolumab plus ipilimumab over placebo reinforces the change of practice already initiated for the treatment of patients with stage IV melanoma with no evidence of disease. Funding Bristol-Myers Squibb.
In mice, injection of messenger RNA (mRNA) coding for tumor-associated antigens can induce antitumor immune responses and therefore offers a broadly applicable immunotherapy approach. We injected ...intradermally protamine-stabilized mRNAs coding for Melan-A, Tyrosinase, gp100, Mage-A1, Mage-A3, and Survivin in 21 metastatic melanoma patients. In 10 patients keyhole limpet hemocyanin (KLH) was added to the vaccine. Granulocyte macrophage colony-stimulating factor was applied as an adjuvant. Endpoints were toxicity and immune responses. No adverse events more than grade II have been observed. During treatment the frequency of Foxp3+/CD4+ regulatory T cells was significantly decreased upon mRNA vaccination in peripheral blood of the patients in the KLH arm, whereas myeloid suppressor cells (CD11b+HLA-DR lo monocytes) were reduced in the patients not receiving KLH. A reproducible increase of vaccine-directed T cells was observed in 2 of 4 immunologically evaluable patients. One of 7 patients with measurable disease showed a complete response. In conclusion, we show here that direct injection of protamine-protected mRNA is feasible and safe. The significant influence of the treatment on the frequency of immunosuppressive cells, the increase of vaccine-directed T cells upon treatment in a subset of patients together with the demonstration of a complete clinical response encourage further clinical investigation of the protamine-mRNA vaccine.
Cutaneous squamous cell carcinoma (cSCC) is a common tumor of elderly Caucasian patients.
Competing multivariable risk models to analyze different types of cSCC associated death (local infiltration ...LI, locoregional LR, and distant metastases DM) in terms of prognostic factors.
1400 patients were analyzed. In the adjusted multivariable subdistribution hazard approach for tumor volume, the best model for death of cSCC overall revealed the presence of desmoplasia (HR 4.52; p < 0.001), bone invasion (HR 10.06; p < 0.01), and immunosuppression (HR 3.19; p = 0.003) as significant factors. Death due to LI indicated desmoplasia (HR 15.39; p < 0.01) and bone invasion (HR 16.9; p < 0.001) as significant factors. For death by LM, immunosuppression with a HR of 3.27; p = 0.004 was the only significant prognostic factors as well as in death by DM with a HR of 4.54; p = 0.02.
The three types of death caused by cSCC can be distinguished based on risk factors with different weights. Patients with these factors should be monitored closely.
•Cutaneous squamous cell carcinoma causes few deaths.•We identify risk factors for different death caused by cSCC in competing risk models.•Immunosuppression, desmoplasia, and bone invasion were the leading risk factors.•Patients with such risk features should be closely followed-up.
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