Cutaneous SCC with orbital invasion: case series.

Cutaneous squamous cell carcinoma (cSCC) is the most common tumour entity that grows secondarily into the orbital area, while basal cell carcinoma (BCC) is the most common periocular and eyelid tumour. Diagnostic delays are common and may increase post-treatment complications. The therapy is challenging and must be discussed at an interdisciplinary tumour board. We discuss four cases of cSCC with orbital invasion treated with immune-checkpoint inhibitors with variable responses.

Delayed immune-related adverse events with anti-PD-1-based immunotherapy in melanoma.

BACKGROUND: Immune-related adverse events (irAEs) typically occur within 4 months of starting anti-programmed cell death protein 1 (PD-1)-based therapy [anti-PD-1 ± anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4)], but delayed irAEs (onset >12 months after commencement) can also occur. This study describes the incidence, nature and management of delayed irAEs in patients receiving anti-PD-1-based immunotherapy. PATIENTS AND METHODS: Patients with delayed irAEs from 20 centres were studied. The incidence of delayed irAEs was estimated as a proportion of melanoma patients treated with anti-PD-1-based therapy and surviving >1 year. Onset, clinical features, management and outcomes of irAEs were examined. RESULTS: One hundred and eighteen patients developed a total of 140 delayed irAEs (20 after initial combination with anti-CTLA4), with an estimated incidence of 5.3% (95% confidence interval 4.0-6.9, 53/999 patients at sites with available data). The median onset of delayed irAE was 16 months (range 12-53 months). Eighty-seven patients (74%) were on anti-PD-1 at irAE onset, 15 patients (12%) were <3 months from the last dose and 16 patients (14%) were >3 months from the last dose of anti-PD-1. The most common delayed irAEs were colitis, rash and pneumonitis; 55 of all irAEs (39%) were ≥grade 3. Steroids were required in 80 patients (68%), as well as an additional immunosuppressive agent in 27 patients (23%). There were two irAE-related deaths: encephalitis with onset during anti-PD-1 and a multiple-organ irAE with onset 11 months after ceasing anti-PD-1. Early irAEs (<12 months) had also occurred in 69 patients (58%), affecting a different organ from the delayed irAE in 59 patients (86%). CONCLUSIONS: Delayed irAEs occur in a small but relevant subset of patients. Delayed irAEs are often different from previous irAEs, may be high grade and can lead to death. They mostly occur in patients still receiving anti-PD-1. The risk of delayed irAE should be considered when deciding the duration of treatment in responding patients. However, patients who stop treatment may also rarely develop delayed irAE.

A multicentre study of naevus-associated melanoma vs. de novo melanoma, tumour thickness and body site differences.

BACKGROUND: Whether melanoma in histological contiguity with a naevus [naevus-associated melanoma (NAM)] is distinctly different from melanoma arising de novo remains unclear. OBJECTIVES: To determine whether the characteristics of de novo melanoma differ from NAM and are not due to naevus obliteration in thicker tumours. METHODS: We conducted a multicentre retrospective study of de novo melanoma and NAM in seven referral centres in Europe, Australia and the USA between 2006 and 2015. RESULTS: In a total of 9474 localized melanomas, de novo melanoma was associated with thicker tumours and body site differences compared with NAM. In the subset of T1 melanomas (n = 5307), similar body site differences were found in multivariate analysis by body site. When compared with NAM, de novo melanoma was more likely to affect older individuals (≥ 70 years) when located on the head/neck [odds ratio (OR) 4·65, 95% confidence interval (CI) 2·55-8·46], the trunk (OR 1·82, 95% CI 1·40-2·36) or the upper extremity (OR 1·69, 95% CI 1·14-2·50), was more likely to affect female patients when located on the lower extremities (OR 1·36, 95% CI 1·03-1·80), and was more likely to be of the nodular melanoma subtype (OR 2·23, 95% CI 1·14-4·35) when located on the trunk. De novo melanoma was less likely to have regression present compared with NAM. CONCLUSIONS: Clinicopathological and body site differences between de novo melanoma and NAM support the divergent pathway model of development. These differences were also found in thin melanomas, suggesting that de novo melanomas are different from NAM and their differences are not due to the obliteration of naevus remnants in thicker tumours.

Management of early melanoma recurrence despite adjuvant anti-PD-1 antibody therapy☆.

BACKGROUND: Anti-programmed cell death protein 1 (PD-1) antibodies (PD1) prolong recurrence-free survival in high-risk resected melanoma; however, approximately 25%-30% of patients recur within 1 year. This study describes the pattern of recurrence, management and outcomes of patients who recur with adjuvant PD1 therapy. PATIENTS AND METHODS: Consecutive patients from 16 centres who recurred having received adjuvant PD1 therapy for resected stage III/IV melanoma were studied. Recurrence characteristics, management and outcomes were examined; patients with mucosal melanoma were analysed separately. RESULTS: Melanoma recurrence occurred in 147 (17%) of ∼850 patients treated with adjuvant PD1. In those with cutaneous melanoma (n = 136), median time to recurrence was 4.6 months (range 0.3-35.7); 104 (76%) recurred during (ON) adjuvant PD1 after a median 3.2 months and 32 (24%) following (OFF) treatment cessation after a median 12.5 months, including in 21 (15%) who ceased early for toxicity. Fifty-nine (43%) recurred with locoregional disease only and 77 (57%) with distant disease. Of those who recurred locally, 22/59 (37%) subsequently recurred distantly. Eighty-nine (65%) patients received systemic therapy after recurrence. Of those who recurred ON adjuvant PD1, none (0/6) responded to PD1 alone; 8/33 assessable patients (24%) responded to ipilimumab (alone or in combination with PD1) and 18/23 (78%) responded to BRAF/MEK inhibitors. Of those who recurred OFF adjuvant PD1, two out of five (40%) responded to PD1 monotherapy, two out of five (40%) responded to ipilimumab-based therapy and 9/10 (90%) responded to BRAF/MEK inhibitors. CONCLUSIONS: Most patients who recur early despite adjuvant PD1 develop distant metastases. In those who recur ON adjuvant PD1, there is minimal activity of further PD1 monotherapy, but ipilimumab (alone or in combination with PD1) and BRAF/MEK inhibitors have clinical utility. Retreatment with PD1 may have activity in select patients who recur OFF PD1.

The spectrum of cutaneous adverse events during encorafenib and binimetinib treatment in B-rapidly accelerated fibrosarcoma-mutated advanced melanoma.

BACKGROUND: B-rapidly accelerated fibrosarcoma (BRAF) inhibitor encorafenib alone and in combination with MEK inhibitor binimetinib improves survival in BRAF-mutated melanoma patients. So far, the range of cutaneous adverse events has been characterized only for established BRAF inhibitors (vemurafenib, dabrafenib) and MEK inhibitors (trametinib, cobimetinib). OBJECTIVE: The aim of this study was to investigate cutaneous adverse events emerging in melanoma patients treated with encorafenib and binimetinib. METHODS: Patients treated with BRAF and MEK inhibitors in clinical trials at the University Hospital of Zurich were identified. Frequency and features of cutaneous adverse events as well as their management were assessed based on the prospectively collected clinical and histopathological data. The events emerging during encorafenib and/or binimetinib therapy were compared to other BRAF and MEK inhibitors at the institution and in the literature. RESULTS: The most frequent cutaneous adverse events observed in patients treated with encorafenib alone (n = 24) were palmoplantar hyperkeratosis (54%), palmoplantar erythrodysesthesia (58%) and alopecia (46%). Drug-induced papulopustular eruptions prevailed in patients with binimetinib monotherapy (n = 25). The most frequent cutaneous adverse events in patients treated with encorafenib/binimetinib (n = 49) were palmoplantar hyperkeratosis (10%). CONCLUSION: Compared to data published for established BRAFi, encorafenib monotherapy showed less hyperproliferative cutaneous adverse events. In contrast, palmoplantar hyperkeratosis and palmoplantar erythrodysesthesia seem to occur more often. The combination of encorafenib and binimetinib is well tolerated and induces few cutaneous adverse events.

Successful retreatment with combined BRAF/MEK inhibition in metastatic BRAFV600-mutated melanoma.

BACKGROUND: The combination treatment with BRAF and MEK inhibitors is amongst the current standard of care for stage IIIC/IV BRAF-mutated melanoma. However, therapeutic options are limited once patients have progressed upon both targeted and immunotherapy. OBJECTIVE: To investigate whether retreatment with BRAF and MEK inhibitor combination is an option for patients with metastatic BRAF-mutated melanoma upon previous progression on kinase inhibitors. METHODS: Two patients with metastatic BRAF-mutated melanoma were rechallenged with BRAF and MEK inhibitor combination after progression on targeted therapy and subsequent immunotherapy with anti-CTLA-4 and anti-PD-1 antibodies. RESULTS: Both patients responded to retreatment. Responses were limited to a few months and associated with a considerable increase in quality of life. CONCLUSION: Retreatment with BRAF and MEK inhibitors may present a feasible treatment option upon progression on both kinase inhibitors and immunotherapy, and should be considered when all other treatment options have been exhausted.

Prognostic relevance of lactate dehydrogenase and serum S100 levels in stage IV melanoma with known BRAF mutation status.

BACKGROUND: Activating mutations of BRAF provide an important treatment target in patients with melanoma. The prognostic role of several biochemical markers in relation to mutation status is not clear. OBJECTIVES: To analyse the prognostic significance of BRAF mutation in patients with melanoma and correlate it to different markers. METHODS: In total, 162 patients with stage IV melanoma and known BRAF mutation status were included. Clinical, histopathological and laboratory information was collected and compared between patients with BRAF mutant (BRAFm) and wild-type (BRAFwt) melanoma at the time of first distant metastasis. RESULTS: In total, 88 patients (54%) had BRAFm melanoma (V600E/V600K). At the first distant metastasis, S100B levels in BRAFm patients were more frequently elevated (P = 0·01) and significantly higher (P = 0·02). Median overall survival (mOS) was significantly longer in BRAFwt patients with normal compared with patients with elevated S100B levels (P < 0·01). In BRAFm melanoma, elevated S100B levels showed no prognostic influence (P = 0·18). Elevated lactate dehydrogenase (LDH) levels had a significantly negative impact on mOS in both groups. mOS was increased for BRAFm patients treated with a BRAF inhibitor (BRAFi) compared with BRAFm patients not receiving BRAFi (P = 0·01). No difference in mOS between BRAFm patients who did not receive BRAFi treatment and BRAFwt patients was observed. CONCLUSIONS: Better mOS was observed in BRAFm patients treated with BRAFi. BRAFm patients not treated with BRAFi show similar survival curves to BRAFwt patients. Elevated LDH is a BRAF-independent prognostic parameter; S100B has prognostic significance in BRAFwt melanoma only.

An exploratory study investigating the metabolic activity and local cytokine profile in patients with melanoma treated with pazopanib and paclitaxel.

BACKGROUND: There is a medical need for new drugs in patients with BRAF wild-type metastatic melanoma. Pazopanib is a multitarget tyrosine kinase inhibitor with antitumour and antiangiogenic activity. OBJECTIVES: The primary aim was to investigate the metabolic response to pazopanib monotherapy and pazopanib plus paclitaxel in patients with BRAF wild-type melanoma. Secondary end points were the early cytokine and chemokine profiles and histological findings. METHODS: Pazopanib (400 mg twice daily) was administered orally from days 1 to 10 and from days 14 to 70. An intravenous infusion with paclitaxel (150 mg m-2 body surface) was administered on days 14, 35 and 56. Metabolic response evaluation was performed before treatment, after treatment with pazopanib (day 10) and after treatment with pazopanib and paclitaxel (day 70). Skin biopsy of metastatic tissue for chemokine and cytokine expression analysis and histology and immunohistochemistry (CD68, CD163) evaluation, and blood samples were taken at the same time points. RESULTS: Two patients failed screening and 17 were dosed. Of 67 adverse events, nine (13%) were grade 3 or 4. Five of 14 evaluable patients had a partial metabolic response at day 10 under pazopanib monotherapy. The response rate at day 70 under combined pazopanib-paclitaxel treatment was 0%. Immunohistochemistry revealed an increase of M2-like macrophages in nonresponders compared with responders. We observed a significant upregulation of five cytokines (CXCL1, CXCL2, CXCL13, CCL22 and SPP1) in responding vs. nonresponding lesions. Overall, the median progression-free survival was 70 days (range 5-331), which did not differ significantly between responders (148 days) and nonresponders (70 days, P = 0·17). CONCLUSIONS: In this patient population pazopanib efficacy was limited. Response is associated with low M2-like macrophage density and increased expression of several chemokines.

Efficacy and safety of oral alitretinoin in severe oral lichen planus--results of a prospective pilot study.

BACKGROUND: Patients with severe oral lichen planus refractory to standard topical treatment currently have limited options of therapy suitable for long-term use. Oral alitretinoin (9-cis retinoic acid) was never systematically investigated in clinical trials, although case reports suggest its possible efficacy. OBJECTIVES: To assess the efficacy and safety of oral alitretinoin taken at 30 mg once daily for up to 24 weeks in the treatment of severe oral lichen planus refractory to standard topical therapy. METHODS: We conducted a prospective open-label single arm pilot study to test the efficacy and safety of 30 mg oral alitretinoin once daily for up to 24 weeks in severe oral lichen planus. Ten patients were included in the study. Primary end point was reduction in signs and symptoms measured by the Escudier severity score. Secondary parameters included pain and quality of life scores. Safety parameters were assessed during a follow-up period of 5 weeks. RESULTS: A substantial response at the end of treatment, i.e. >50% reduction in disease severity measured by the Escudier severity score, was apparent in 40% of patients. Therapy was well tolerated. Adverse events were mild and included headache, mucocutaneous dryness, musculoskeletal pain, increased thyroid-stimulating hormone and dyslipidaemia. CONCLUSIONS: Alitretinoin given at 30 mg daily reduced disease severity of severe oral lichen planus in a substantial proportion of patients refractory to standard treatment, was well tolerated and may thus represent one therapeutic option for this special group of patients.

Developments in targeted therapy in melanoma.

Melanomas are disease entities driven in part by the mitogen activated protein kinase (MAPK) pathway. The TCGA network recently defined four genetic subtypes based on the most prevalent significantly mutated genes, including mutant BRAF, mutant RAS (N/H/K), mutant NF1, and Triple wild-type melanoma (harboring none of the aforementioned mutations, but instead includes KIT, GNA and GNAQ mutations). The successful development of kinase inhibitors marked a milestone in the treatment of metastatic melanoma. Combination treatment with a BRAF- and MEK-inhibitor is the current standard of care for inoperable stage IIIC/IV BRAF-mutated melanoma. Recent data demonstrate excellent long-term outcome, especially in patients with normal baseline LDH levels, and confirm that there is a subset of BRAF inhibitor-naive patients who experience durable responses without progression on combination treatment. In the future, adding a third compound based on individual genetic alterations might further improve the outcome of targeted therapy.

A prospective clinical trial to assess lapatinib effects on cutaneous squamous cell carcinoma and actinic keratosis.

BACKGROUND: Antiepidermal growth factor receptor (EGFR)-targeted therapy is widely used in many epithelial cancer types. We investigated lapatinib effects on cutaneous squamous cell carcinoma (cSCC) scheduled for resection and in coexisting precursor lesions (actinic keratosis (AK) and Bowen's disease (BD)) in a phase 2 mode of action clinical trial including a histological workup of the cSCC. PATIENTS AND METHODS: We initiated a prospective single-centre, open-label, non-controlled clinical study with translational intentions to investigate changes in size and histopathological features in cSCC after a 14-day period of neoadjuvant lapatinib therapy at a dose of 1500 mg/day prior to surgery, to quantify the impact on AK and BD in the same patient after 56 days and to evaluate the tolerability in patients with cSCC and precursor lesions. RESULTS: 10 immunocompetent male patients were included with a mean age of 73 years (range 59-87). 8 patients were treated with the study medication lapatinib 1500 mg/day for a total duration of 56 days according to the protocol and were available for full analysis, whereas 2 patients had to discontinue treatment during the first 2 weeks because of adverse events (diarrhoea, pancreatitis). Tolerability was acceptable with only 1 related grade III adverse event. A reduction in tumour size of cSCC was documented in 2 of 8 evaluable patients after 14 days of treatment. The mean regression of captured precursor lesions was 30% after 56 days of treatment and 36% 28 days after therapy cessation. CONCLUSIONS: Short-term lapatinib resulted in a cSCC tumour reduction in 2 of 8 patients. In addition, there was a clinically documented reduction of AK in 7 of 8 patients encouraging larger clinical trials, especially in high-risk patients with cSCC such as organ transplant recipients. TRIAL REGISTRATION NUMBER: NCT0166431.