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In advanced cutaneous squamous cell carcinoma (cSCC), efficient medical treatment options are limited in case surgery and radiotherapy failed, particularly since most patients are of higher age and suffer from comorbidities. In many tumor entities, the epidermal growth factor receptor (EGFR) has been established as an important therapeutic target, and blockade of EGFR signaling by monoclonal antibodies or small molecules achieves a therapeutic benefit. EGFR expression is also often dysregulated in cSCC. We report here two patients with advanced cSCC treated with the EGFR inhibitor cetuximab and summarize the current published experience with the use of EGFR inhibitors in cSCC. © 2013 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: The combination of BRAF and MEK inhibitors has become standard of care in the treatment of metastatic BRAF V600-mutated melanoma. Clinical factors for an early prediction of tumor response are rare. The present study investigated the association between the development of an early exanthema induced by vemurafenib or vemurafenib plus cobimetinib and therapy outcome., Methods: This multicenter retrospective study included patients with BRAF V600-mutated irresectable AJCC-v8 stage IIIC/D to IV metastatic melanoma who received treatment with vemurafenib (VEM) or vemurafenib plus cobimetinib (COBIVEM). The development of an early exanthema within six weeks after therapy start and its grading according to CTCAEv4.0 criteria was correlated to therapy outcome in terms of best overall response, progression-free (PFS), and overall survival (OS)., Results: A total of 422 patients from 16 centers were included (VEM, n=299; COBIVEM, n=123). 20.4% of VEM and 43.1% of COBIVEM patients developed an early exanthema. In the VEM cohort, objective responders (CR/PR) more frequently presented with an early exanthema than non-responders (SD/PD); 59.0% versus 38.7%; p=0.0027. However, median PFS and OS did not differ between VEM patients with or without an early exanthema (PFS, 6.9 versus 6.0 months, p=0.65; OS, 11.0 versus 12.4 months, p=0.69). In the COBIVEM cohort, 66.0% of objective responders had an early exanthema compared to 54.3% of non-responders (p=0.031). Median survival times were significantly longer for patients who developed an early exanthema compared to patients who did not (PFS, 9.7 versus 5.6 months, p=0.013; OS, not reached versus 11.6 months, p=0.0061). COBIVEM patients with a mild early exanthema (CTCAEv4.0 grade 1-2) had a superior survival outcome as compared to COBIVEM patients with a severe (CTCAEv4.0 grade 3-4) or non early exanthema, respectively (p=0.047). This might be caused by the fact that 23.6% of patients with severe exanthema underwent a dose reduction or discontinuation of COBIVEM compared to only 8.9% of patients with mild exanthema., Conclusions: The development of an early exanthema within 6 weeks after treatment start indicates a favorable therapy outcome upon vemurafenib plus cobimetinib. Patients presenting with an early exanthema should therefore be treated with adequate supportive measures to provide that patients can stay on treatment., Competing Interests: KK has served as consultant or/and has received honoraria from Amgen, Roche, Bristol Myers Squibb, Merck Sharp and Dohme, Pierre Fabre, and Novartis, and received travel support from Amgen, Merck Sharp and Dohme, Bristol Myers Squibb, Amgen, Pierre Fabre, Medac, and Novartis. RG received honoraria for lectures and advisory boards, research support and meeting support from Almirall Hermal, Amgen, Astra Zeneca, Bristol Myers Squibb, Leo, Merck Serono, Merck Sharp and Dohme, Pierre Fabre, Roche, Sanofi Genzyme, Regeneron, Sun Pharma, Takeda, Pfizer, Novartis, Johnson&Johnson, 4SC, and Incyte. FM has received travel support or/and speaker’s fees or/and advisor’s honoraria by Novartis, Roche, BMS, MSD and Pierre Fabre, and research funding from Novartis and Roche. LZ has served as consultant and/or has received honoraria from Roche, Bristol Myers Squibb, Merck Sharp and Dohme, Novartis, Pierre Fabre, and Sanofi, and received travel support from Bristol Myers Squibb, Merck Sharp and Dohme, Amgen, Pierre Fabre, and Novartis. MH has received consultant and/or speaker honoraria form Bristol Myers Squibb, Novartis, Merck Sharp and Dohme, Sanofi, Roche and travel support from Novartis, and Bristol Myers Squibb. AG reports speakers honoraria from Bristol Myers Squibb, Merck Sharp and Dohme, and Roche, advisory board honoraria from Bristol Myers Squibb, Novartis, Merck Sharp and Dohme, Pierre Fabre, Pfizer, Roche and Sanofi Genzyme, and travel support from Bristol Myers Squibb, Merck Sharp and Dohme, Novartis, and Roche. K-MT received honoraria for lectures and advisory boards from Bristol-Myers Squibb, Roche, Novartis, Merck Sharp and Dohme, Pierre Fabre, LEO, Galderma, AbbVie, La Roche-Posay and Candela, and travel support from Bristol-Myers Squibb, Roche, Novartis, Merck Sharp and Dohme, Pierre Fabre, LEO, and Candela. JU is on the advisory board or has received honoraria and travel support from Amgen, Bristol Myers Squibb, GSK, LeoPharma, Merck Sharp and Dohme, Novartis, Pierre Fabre, Roche, Sanofi outside the submitted work. JH reports speakers honoraria from Bristol Myers Squibb, Novartis, Merck Sharp and Dohme, and Roche, advisory board honoraria from Merck Sharp and Dohme, Pierre Fabre, Sunpharma and Sanofi Genzyme, and travel support from Bristol Myers Squibb, and Pierre Fabre. CL declares speakers and advisory board honoraria and travel support from Bristol Myers Squibb, Merck Sharp and Dohme, Merck Serono, Novartis, Roche, Amgen, Pierre Fabre, and Sun Pharma. CP received speaker or consultant honoraria and travel support from Novartis, Bristol Myers Squibb, Roche, Merck Serono, Merck Sharp and Dohme, Celgene, AbbVie, and LEO. LH received grants from Novartis, and has received speaker or consultant fees personal fees from Amgen, Bristol Myers Squibb, Merck Sharp and Dohme, Roche, Curevac, Pierre Fabre, Roche, Novartis, and Sanofi. MK has received grants from Bristol Myers Squibb, Merck Sharp and Dohme, Leo, Novartis, and Roche. DG declares speakers and advisory honoraria as well as travel support from Bristol Myers Squibb, Novartis, Pierre Fabre, Sanofi Genzyme, Amgen, Galderma, Janssen, and Roche. DS declares advisory board and speakers honoraria from Roche, Novartis, Bristol-Myers-Squibb, MSD, Merck-Serono, Sanofi, Nektar, Amgen, Hexal, InFlaRx, Array, Pierre Fabre, Immunocore, Philogen Sun Pharma, Regeneron, and Ultimovacs, as well as grant and travel support from Roche, Novartis, Bristol-Myers-Squibb, MSD, Merck-Serono, and Sanofi. SU declares research support from Bristol Myers Squibb, and Merck Serono, speakers and advisory board honoraria from Bristol Myers Squibb, Merck Sharp and Dohme, Merck Serono, Novartis and Roche, and travel support from Bristol Myers Squibb, Merck Sharp, and Dohme. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Kähler, Gutzmer, Meier, Zimmer, Heppt, Gesierich, Thoms, Utikal, Hassel, Loquai, Pföhler, Heinzerling, Kaatz, Göppner, Pflugfelder, Bohne, Satzger, Reinhardt, Placke, Schadendorf and Ugurel.)

Therapy with immune checkpoint inhibitors (ICIs) has improved overall survival and cancer-related morbidity of cancer treatment even in cancer entities with poor prognosis. Since the approval of the first ICI, ipilimumab, for treatment of advanced melanoma by the Food and Drug Administration (FDA) in 2011, the spectrum of indications and approved ICIs has grown, rapidly. Up to now, seven different ICIs for more than 20 indications are available. However, their mechanisms of action can lead to immune-related adverse events (irAEs). In particular, neurological irAEs are clinically relevant. Although they are rare, an early and accurate diagnosis is challenging and neurological disease course and sequelae are potentially fatal. Between 08/2017 and 03/2020, 31 patients received ICI treatment at Hannover Medical School and presented with neurological adverse events (N-irAEs). Treated malignancies were metastatic melanoma, bronchial carcinoma, and urothelial cell carcinoma. All patients received comprehensive neurological diagnostics including clinical examination and magnetic resonance imaging (MRI). Cerebrospinal fluid (CSF) analysis was obtained in 21 patients and electroneurography was performed in 22 patients. Although N-irAEs were suspected in all 31 patients, 11 patients had other conditions leading to neurological symptoms including tumor metastases in seven patients and hemorrhagic or ischemic stroke in four patients. In the following, these patients are referred to as the differential diagnosis (DD) group. Patients with N-irAEs suffered from immune mediated neuropathy (9/20), myositis and/or myasthenic syndrome (6/20), or encephalitis/cerebellitis (5/20). Except for cell count, CSF results did not differ between the N-irAEs and the DD group. Symptoms related to N-irAEs are rather unspecific potentially mimicking other tumor-related symptoms such as metastases. Patients with malignancy are predominantly not treated by neurologists. Because of the complexity of neurological symptoms, detailed neurological investigations in specialized institutions are necessary in patients with new neurological symptoms and need to be critically discussed with treating oncologists., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2020 Nora Möhn et al.)

Background: The tumor burden within the sentinel lymph node (SLN) is not included in the 8th edition of the American Joint Committee of Cancer (AJCC) melanoma classification. Therefore, we analysed the prognostic relevance of the SLN tumor burden in the stage III subgroups., Patients and Methods: A total of 736 patients with melanoma with positive SLN and long-term follow-up (mean, 64.4 months; median, 59.0 months) were assessed. SLN tumor burden was evaluated by the maximum diameter of the largest deposit in all patients., Results: By univariate Kaplan-Meier analyses, melanoma-specific survival (MSS) of patients in stage IIIA, IIIB and IIIC and lower sentinel tumor burden (cut-offs ≤0.5 mm and ≤1 mm) was significantly better than that in patients with higher sentinel tumor load (>0.5 mm and >1 mm). By multivariate analysis using the Cox model, the maximum diameter of the largest deposit (cut-off ≤0.5 mm versus >0.5 mm and cut-off ≤1 mm as continuous variables) represented an independent prognostic parameter for MSS in stage III patients. Cut-off of 0.5 mm showed a slightly higher area under the receiver operating characteristic curve (AUC = 0.617) when than the cut-off of 1 mm (AUC = 0.599)., Conclusion: The prognosis of patients with stage III melanoma can be determined more precisely if the SLN tumor burden is considered, also within the existing AJCC subgroups. Thus, this parameter should be included in future classifications, and our study provides benchmarks in estimating prognosis and counselling patients with melanoma with positive sentinel nodes beyond the 8th AJCC Cancer Staging Manual. The optimal cut-off remains for SLN tumor burden remains to be determined, but our results suggest that a cut-off lower than 1 mm is preferable., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Immune-checkpoint blockade (ICB) has demonstrated efficacy in many tumor types, but predictors of responsiveness to anti-PD1 ICB are incompletely characterized. In this study, we analyzed a clinically annotated cohort of patients with melanoma (n = 144) treated with anti-PD1 ICB, with whole-exome and whole-transcriptome sequencing of pre-treatment tumors. We found that tumor mutational burden as a predictor of response was confounded by melanoma subtype, whereas multiple novel genomic and transcriptomic features predicted selective response, including features associated with MHC-I and MHC-II antigen presentation. Furthermore, previous anti-CTLA4 ICB exposure was associated with different predictors of response compared to tumors that were naive to ICB, suggesting selective immune effects of previous exposure to anti-CTLA4 ICB. Finally, we developed parsimonious models integrating clinical, genomic and transcriptomic features to predict intrinsic resistance to anti-PD1 ICB in individual tumors, with validation in smaller independent cohorts limited by the availability of comprehensive data. Broadly, we present a framework to discover predictive features and build models of ICB therapeutic response.

Immune checkpoint inhibitor (ICI) therapy has revolutionized the management of various cancers with previously poor prognosis. Despite its great efficacy, the therapy is associated with a wide spectrum of immune-related adverse events (irAE) including neurological symptoms which can affect all parts of the central and peripheral nervous system. Even though these events are rare, they are of high relevance as the rate of residual symptoms or even fatal outcomes is remarkable. To provide a detailed overview of neurological adverse events associated with immune checkpoint-inhibitor therapy we conducted a literature search. While focusing on ipilimumab, nivolumab, and pembrolizumab therapy, all available case reports as well as larger case series and clinical trials have been considered. Eighty-two case reports about checkpoint-inhibitor therapy induced symptoms of the peripheral nervous system have been published, while only 43 case reports addressed central nervous system abnormalities. The frequency of immune checkpoint-inhibitor therapy inducing neurological adverse events is about 1% in larger studies. Especially neuromuscular adverse events exhibit distinct clinical and diagnostic characteristics. Additionally, several affected patients presented with overlap-syndromes, which means that symptoms and diagnostic findings indicating myositis, myasthenia gravis, and neuropathy were present in one individual patient at the same time. Thus, neurological and particularly neuromuscular adverse events of immune checkpoint-inhibitor therapy may constitute a new disease entity., Competing Interests: N.M. declares no conflict of interest. G.B. received research support from the Bundesministerium für Bildung und Forschung (BMBF) and Deutsche Gesellschaft für internistitische Intensiv- und Notfallmedizin (DGIIN). He received travel support/honoraria from Deutsche Gesellschaft für internistitische Intensiv- und Notfallmedizin (DGIIN), Deutsche Gesellschaft für Hämatologie und Onkologie (DGHO), Jazz Pharmaceuticals, MSD, and NewConceptOncology. R.G. received research support (to institution) from Pfizer, Johnson&Johnson, Novartis, Amgen, and MerckSerono. He got honoraria (to person) from RochePharma, Bristol-Myers-Squibb, Novartis, Merck MSD, Almirall-Hermal, Amgen, Merck-Serono, SUN, Pierre-Fabre, Sanofi, and 4SC. P.I. received research support from BMS, Bayer, Calithera, Lilly, Merck, Novartis, EISAI, Pfizer, MSD, AstraZeneca, Roche, and Ipsen. He got lecture honoraria from AIM, AstraZeneca, BMS, Bayer, DKG-Onko, EISAI, EUSA, Ipsen, Merck, MedKom, MedWiss, Novartis, Pfizer, Roche, and StreamedUP! He had an advisory role for BMS, Bayer, Ipsen, Merck, Novartis, Pfizer, and Roche. I.S. received honoraria from BMS, Novartis, Roche, and Sanofi. T.S. received honoraria from Alexion, Bayer Vital GmbH, CSL Behring, Merck, Novartis, and Sanofi.

Objective: The American Joint Committee on Cancer (AJCC) 8th staging system introduced several revisions. To assess the impact of the 8th edition American Joint Committee on Cancer (AJCC8) staging system on subgrouping and survival, patients with melanoma from two tertiary skin cancer centres were classified according to both the 7th edition American Joint Committee on Cancer (AJCC7) and AJCC8., Methods: A total of 1948 patients aged ≥18 years with cutaneous melanoma stage II-IV were included. The impact of sex and age on reclassification was assessed by log binomial models. The inverse probability of censoring weighting method was used to compute ROC curves from time-to-event data to assess the discriminatory ability of AJCC7 and AJCC8. Melanoma-specific survival (MSS) and overall survival (OS) were calculated, and age- and sex-adjusted MSS hazard ratios were estimated using Cox proportional hazards models., Results: Of all, 23.5% of patients were assigned a different subgroup when classified according to AJCC8. Owing to upshifting to stage IIIC (AJCC7 24.8% vs. AJCC8 50.8%), patient numbers of stages IIIA and IIIB decreased from 28.7% to 16.2% and 46.5% to 28.3%. The prediction accuracy for AJCC7 and AJCC8 was comparable (integrated time-dependent area under the curve [AUC] of 0.75 and 0.74, respectively). Five-year MSS of IIB and IIC AJCC8 was poor and lower than that of IIIA AJCC8 (80%, 67% and 89%, respectively). Compared to results of the International Melanoma Database and Discovery Platform, 5-year MSS was 10-15% points lower for stages IIC, IIIB and IIIC., Conclusions: Upshifting affects primarily stage III subgroups, while effects in stage II are minor. Stage IIB/C (AJCC8) patients have 67-80% MSS and should be considered for adjuvant treatment, while in stage IIIA, the indication of adjuvant treatment is questionable., (Copyright © 2019 Elsevier Ltd. All rights reserved.)