A phase 2 open-label study of cemiplimab in patients with advanced cutaneous squamous cell carcinoma (EMPOWER-CSCC-1): Final long-term analysis of Groups 1, 2, and 3, and primary analysis of fixed-dose treatment Group 6.

BACKGROUND: In the phase 2 EMPOWER-CSCC-1 study (NCT02760498), cemiplimab demonstrated antitumor activity against metastatic (mCSCC) and locally advanced cutaneous squamous cell carcinoma (laCSCC). OBJECTIVES: To report final analysis of weight-based cemiplimab in mCSCC and laCSCC (Groups 1 and 2), fixed-dose cemiplimab in mCSCC (Group 3), and primary analysis of fixed-dose cemiplimab in mCSCC/laCSCC (Group 6). METHODS: Patients received cemiplimab (3 mg/kg intravenously [IV] every 2 weeks [Groups 1 and 2]) or cemiplimab (350 mg IV [Groups 3 and 6]) every 3 weeks. The primary endpoint was objective response rate (ORR). Duration of response (DOR) and progression-free survival (PFS) are presented per protocol, according to post-hoc sensitivity analyses that only include the period of protocol-mandated imaging assessments. RESULTS: At 42.5 months, ORR for Groups 1-3 (n=193) was 47.2%, estimated 12-month DOR was 88.3%, and median PFS was 26.0 months. At 8.7 months, ORR for Group 6 (n=165 patients) was 44.8%; median DOR and median PFS were not reached. Serious treatment-emergent adverse event rates (grade ≥3) were Groups 1-3: 31.1% and Group 6: 34.5%. LIMITATIONS: Non-randomized study, non-survival primary endpoint. CONCLUSION: EMPOWER-CSCC-1 provides the largest prospective data on long-term efficacy and safety for anti-programmed cell death-1 therapy in advanced CSCC.

Avelumab as second-line or later treatment in patients with metastatic Merkel cell carcinoma: Analysis of real-world outcomes in France using the CARADERM database linked to the French national healthcare database.

AIM: Avelumab has been approved worldwide for treatment of metastatic Merkel cell carcinoma (mMCC), a rare and aggressive skin cancer. This study evaluated outcomes in patients with mMCC in France who received avelumab as second-line or later (2L+) treatment in routine clinical practice. METHODS: This retrospective, noninterventional study evaluated all patients diagnosed with mMCC using two databases: CARADERM (French national database of rare dermatological cancers) and SNDS (national healthcare database), identified via probabilistic linkage. Eligible patients initiated avelumab as 2L+ treatment between August 2016 and December 2019 and were followed for 24 months. The primary endpoint was overall survival (OS) at 24 months. RESULTS: Overall, 180 patients who received 2L+ avelumab were identified (112 from CARADERM, 68 after SNDS linkage). Median age at diagnosis was 74.0 years and 177 (98.3 %) had received chemotherapy alone as first-line treatment. Median follow-up was 13.1 months. Median OS from start of avelumab was 14.6 months (95 % CI, 9.9-21.3) in the overall population, 15.9 months (95 % CI, 8.6-28.3) in CARADERM patients, and 13.3 months (95 % CI, 6.7-19.1) in non-CARADERM patients. OS rates at 12 and 24 months were 53.8 % (95 % CI, 46.2 %-60.8 %) and 40.5 % (95 % CI, 33.2 %-47.6 %), respectively. In evaluable patients (CARADERM database), median progression-free survival was 3.6 months (95 % CI, 2.7-7.5) and the objective response rate was 55.3 % (95 % CI, 45.3-65.4), including complete response in 31.9 %. CONCLUSIONS: Real-world outcomes with 2L+ avelumab treatment for mMCC are consistent with clinical trial findings, supporting the recommendation of avelumab as a standard of care.

Plasmonic nanophotothermal therapy: Destruction of 500 mm3 subcutaneous human basal cell carcinoma with gold nanoparticles and near infrared laser.

SIGNIFICANCE: Multilesional basal cell carcinoma (BCC) are spread on sun exposed skin areas, including arms, face and back. The first-line treatment remains the surgical resection or Mohs surgery. Despite its high complexity, Mohs surgery is well practiced in USA and Germany and presents very good results both in esthetic and in carcinology point of view. Large lesions more than 2 cm remain challenging to remove by topical cream used in photodynamic therapy (PDT). If these larger lesions are not treated in less than 1 month, they could grow deeply in the skin, thus enhancing the risk of reoccurrence and the severity of the disease. Despite this model herein studied, that is non melanoma skin cancer is a good prognostic cancer, the therapy aims to be applied to more aggressive melanoma skin cancers. AIM: Total regression of large cutaneous lesions less than 1 month with no reoccurrence. APPROACH: Tumor induction on murine model bearing a 500 mm3 subcutaneous lesion. Increasing dose of gold nanoparticles at fixed initial concentration C0 = 0.3 mg/mL, infused into the tumor then exposition of the region of interest to NIR medical laser to assess the therapy. One or two intratumoral administration(s) were compared to surgery and control, that is no treatment, laser alone or nanoparticles alone. RESULTS: Gold nanoparticles alone or the NIR laser alone did not induce the tumor regression. The combination of laser and nanoparticles called plasmonic nanophotothermal therapy induced apoptosis. Derma and hypoderm do not show any visible gold nanoparticles and demonstrated a good cicatrization process. CONCLUSION: Plasmonic nanophotothermal therapy using two doses of gold nanoparticles was the only protocol that proved its efficacy on large lesions in 14 days, that is 500 mm3 on a murine model bearing human basal cell carcinoma.

Pustular mycosis fungoides has a poor outcome: a multicentric clinico-pathological and molecular case series study.

BACKGROUND: Mycosis fungoides (MF) has usually an indolent course. However, some patients develop a more aggressive disease and few prognostic parameters have been identified. Isolated cases of pustular MF (pMF) suggest an unfavourable prognosis. OBJECTIVES: We aim to describe the clinico-pathological characteristics and prognostic value of pMF. METHODS: We retrospectively collected data of all cases of MF with histological pustules diagnosed from 2009 to 2020. The outcomes and clinico-pathological characteristics of pMF at diagnosis (pMFD) were compared to those of a cohort of non-pustular MF (NpMF). RESULTS: 33 pMF (including 22 pMFD) and 86 NpMF cases were included. The median age at diagnosis of pMF was 61 years [IQR=50-75]. The median follow-up of pMFD was 32 months [IQR=14-49]. Clinically, 33% of pMF had pustules. Large-cell transformation (LCT) occurred in 17 cases. pMFD were at a significantly more advanced-stage and more showed LCT at diagnosis than NpMF (50% vs 7%, p<0.001 and 23% vs 0%, p<0.001, respectively). In multivariate Cox analysis, the presence of histological pustule at diagnostic was associated with shorter OS in all patients (HR=13.90, CI95%[2.43-79]; p=0.003), and in early-stage patients (HR=11.09, CI95%[1.56-78.82]; p=0.02). In multivariate Fine and Gray model analysis, pMFD was associated with a higher cumulative incidence of LCT (SHR=13.90, CI95% [2.43-79]; p=0.003) in all patients. Median OS after the occurrence of histological pustules during follow-up of all pMF patients was 37 months, with a five-year OS of 25% (CI95% [0.06-0.5]). CONCLUSION: pMF often follows an aggressive course, with a high risk of LCT and shorter survival, even for early-stage patients. Histological pustules at diagnostic of MF might represent an independent poor prognostic factor, to be confirmed by further studies. Because pustules are not always clinically identified, histological pustules should be mentioned in pathology reports of MF and prompt discussion of a closer follow-up.

Real-world outcomes of combined lenvatinib and anti-PD-1 in advanced melanoma: the Lenvamel study, a multicenter retrospective study of the French Group of Skin Cancers (Groupe de Cancérologie Cutanée).

BACKGROUND: Currently, treatment options for patients with advanced melanoma who experience failed immunotherapy or targeted therapy are lacking. Recent studies suggest the antitumor activity of combined pembrolizumab and lenvatinib in patients with advanced melanoma progressing on immunotherapy. Herein, we report the clinical outcomes of combined lenvatinib and a programmed cell death protein-1 inhibitor (PD-1) in this population. MATERIALS AND METHODS: This French multicenter real-world study was conducted between September 2020 and July 2023. The primary endpoint was the objective response rate (ORR) according to the Response Evaluation Criteria in Solid Tumours (version 1.1). Secondary variables were treatment-related adverse events (TRAEs), progression-free survival (PFS), overall survival (OS), and duration of response (DOR). RESULTS: Of the 67 patients included (median age, 69 years; median follow-up, 5.0 months), 85% had stage IV-M1c or M1d disease. The overall ORR was 28.4% (95% CI, 18%-41%), including 3 complete (4.5%) and 16 partial (23.9%) responses. Median DOR was 3.1 (interquartile range, 1.3-4.3) months. Median PFS and OS were 3.1 (95% CI, 2.5-3.7) and 9.8 (95% CI, 5.6-13.9) months, respectively. Grades 3-5 TRAEs occurred in 16 (24%) patients; common TRAEs were fatigue (43.3%), nausea/vomiting (26.8%), diarrhea (20.9%), and hypertension (20.9%). No treatment-related deaths occurred. CONCLUSION: Our real-world study demonstrates an interesting response rate and acceptable safety profile in a population with poor prognostic factors. Our data support this treatment option for refractory melanoma, as it is not approved by the Food and Drug Administration or European Medicines Agency, and highlight the need for new strategies.

Real-life efficacy of immunotherapy for Sézary syndrome: a multicenter observational cohort study.

Background: Sézary syndrome is an extremely rare and fatal cutaneous T-cell lymphoma (CTCL). Mogamulizumab, an anti-CCR4 monoclonal antibody, has recently been associated with increased progression-free survival in a randomized clinical trial in CTCL. We aimed to evaluate OS and prognostic factors in Sézary syndrome, including treatment with mogamulizumab, in a real-life setting. Methods: Data from patients with Sézary (ISCL/EORTC stage IV) and pre-Sézary (stage IIIB) syndrome diagnosed from 2000 to 2020 were obtained from 24 centers in Europe. Age, disease stage, plasma lactate dehydrogenases levels, blood eosinophilia at diagnosis, large-cell transformation and treatment received were analyzed in a multivariable Cox proportional hazard ratio model. This study has been registered in ClinicalTrials (SURPASSe01 study: NCT05206045). Findings: Three hundred and thirty-nine patients were included (58% men, median age at diagnosis of 70 years, Q1-Q3, 61-79): 33 pre-Sézary (9.7% of 339), 296 Sézary syndrome (87.3%), of whom 10 (2.9%) had large-cell transformation. One hundred and ten patients received mogamulizumab. Median follow-up was 58 months (95% confidence interval [CI], 53-68). OS was 46.5% (95% CI, 40.6%-53.3%) at 5 years. Multivariable analysis showed that age ≥ 80 versus <50 (HR: 4.9, 95% CI, 2.1-11.2, p = 0.001), and large-cell transformation (HR: 2.8, 95% CI, 1.6-5.1, p = 0.001) were independent and significant factors associated with reduced OS. Mogamulizumab treatment was significantly associated with decreased mortality (HR: 0.34, 95% CI, 0.15-0.80, p = 0.013). Interpretation: Treatment with mogamulizumab was significantly and independently associated with decreased mortality in Sézary syndrome. Funding: French Society of Dermatology, Swiss National Science Foundation (IZLIZ3_200253/1) and SKINTEGRITY.CH collaborative research program.

Final Results for Adjuvant Dabrafenib plus Trametinib in Stage III Melanoma.

BACKGROUND: The 5-year results of this trial showed that adjuvant therapy with dabrafenib plus trametinib resulted in longer relapse-free survival and distant metastasis-free survival than placebo among patients with BRAF V600-mutated stage III melanoma. Longer-term data were needed, including data regarding overall survival. METHODS: We randomly assigned 870 patients with resected stage III melanoma with BRAF V600 mutations to receive 12 months of dabrafenib (150 mg twice daily) plus trametinib (2 mg once daily) or two matched placebos. Here, we report the final results of this trial, including results for overall survival, melanoma-specific survival, relapse-free survival, and distant metastasis-free survival. RESULTS: The median duration of follow-up was 8.33 years for dabrafenib plus trametinib and 6.87 years for placebo. Kaplan-Meier estimates for overall survival favored dabrafenib plus trametinib over placebo, although the benefit was not significant (hazard ratio for death, 0.80; 95% confidence interval [CI], 0.62 to 1.01; P = 0.06 by stratified log-rank test). A consistent survival benefit was seen across several prespecified subgroups, including the 792 patients with melanoma with a BRAF V600E mutation (hazard ratio for death, 0.75; 95% CI, 0.58 to 0.96). Relapse-free survival favored dabrafenib plus trametinib over placebo (hazard ratio for relapse or death, 0.52; 95% CI, 0.43 to 0.63), as did distant metastasis-free survival (hazard ratio for distant metastasis or death, 0.56; 95% CI, 0.44 to 0.71). No new safety signals were reported, a finding consistent with previous trial reports. CONCLUSIONS: After nearly 10 years of follow-up, adjuvant therapy with dabrafenib plus trametinib was associated with better relapse-free survival and distant metastasis-free survival than placebo among patients with resected stage III melanoma. The analysis of overall survival showed that the risk of death was 20% lower with combination therapy than with placebo, but the benefit was not significant. Among patients with melanoma with a BRAF V600E mutation, the results suggest that the risk of death was 25% lower with combination therapy. (Funded by GlaxoSmithKline and Novartis; COMBI-AD ClinicalTrials.gov number, NCT01682083; EudraCT number, 2012-001266-15.).

Radiotherapy and prognostic factors in adnexal carcinomas: A retrospective study of 657 patients from the French CARADERM network.

BACKGROUND: Cutaneous adnexal carcinomas are a heterogeneous group of rare neoplasms. Surgical excision is the first-line treatment in localized stage. The use and effectiveness of radiotherapy have not been thoroughly evaluated in these neoplasms. OBJECTIVES: The present work analyses prognostic factors on outcomes in skin adnexal carcinomas, based on data from the CARADERM (CAncers RAres DERMatologiques) database. METHODS: Data were collected retrospectively including demographic data, tumour types and therapeutic characteristics of all patients included in the CARADERM database, with at least one informative follow-up visit. Analyses were performed on three populations: patients with complete resection of the primary tumour (ADJ/primary population), patients achieving complete remission after complete resection of a recurrent tumour (ADJ/recurrent population) and patients with unresectable locally advanced or metastatic tumours (ADV/MET population). Overall and recurrence/progression-free survivals at 3-year were analysed using Cox regression models. RESULTS: Radiotherapy did not affect overall survival (OS) in the ADJ/primary population. Adjusted recurrence-free survival (RFS) was significantly lower in the radiotherapy group in ADJ/primary group. Older patients had significantly poorer OS and RFS. Tumour size and immunosuppression were significantly associated with poorer RFS only. Radiotherapy had no effect on OS and RFS in the ADJ/recurrent population. Age was the only factor associated with a poorer OS. Radiotherapy was significantly associated with longer progression-free survival (PFS) in age-sex adjusted analysis in the ADV/MET population, without effect on OS. CONCLUSIONS: Our study shows that age, tumour size and immunosuppression are significantly associated with survival in localized adnexal carcinomas. Radiotherapy may improve PFS in the ADV/MET population but not in localized and recurrent carcinomas after complete excision.

Sequential combination of sonic hedgehog inhibitors followed by consolidation radiotherapy in locally advanced basal cell carcinoma.

BACKGROUND: Sonic hedgehog inhibitors (SHHis) are an effective treatment in locally advanced basal cell carcinoma (laBCC). However, the use of these drugs is limited by adverse events, and relapse at discontinuation in around one-half of patients. A few cases of patients treated concomitantly by radiotherapy (RT) and SHHis have been reported in the literature, suggesting that the combination results in an improved overall response. Maintaining complete response after stopping treatment is a concern, especially as resuming treatment in the case of relapse does not guarantee a new therapeutic response. The optimal combination and sequence of treatment to improve local control of laBCCs are not yet defined. OBJECTIVES: We hypothesized that consolidation RT after complete response to SHHis could reduce the risk of relapse at discontinuation. METHODS: We present a case series of patients with laBCCs who achieved complete response after SHHi treatment and were treated with consolidation RT. Patients were evaluated by a skin cancer board. The closure RT technique and dosage were refined by a radiotherapist. RESULTS: Eleven patients were included. SHHis were prescribed for a median 5 months (range 4-11). Consolidation RT was performed after complete response to SHHis and discontinuation. RT was delivered at a median dose of 45 Gy (range 40.5-66) in 10 fractions (range 9-33). With a median follow-up of 23 months, all patients maintained complete clinical response. This strategy was well tolerated with no grade 3 adverse events. CONCLUSIONS: SHHi treatment followed by consolidation RT after drug discontinuation seems effective and safe. Further studies are needed to develop a precise strategy for the management of laBCCs.

Genomic profiling of mycosis fungoides identifies patients at high risk of disease progression.

ABSTRACT: Mycosis fungoides (MF) is the most prevalent primary cutaneous T-cell lymphoma, with an indolent or aggressive course and poor survival. The pathogenesis of MF remains unclear, and prognostic factors in the early stages are not well established. Here, we characterized the most recurrent genomic alterations using whole-exome sequencing of 67 samples from 48 patients from Lille University Hospital (France), including 18 sequential samples drawn across stages of the malignancy. Genomic data were analyzed on the Broad Institute's Terra bioinformatics platform. We found that gain7q, gain10p15.1 (IL2RA and IL15RA), del10p11.22 (ZEB1), or mutations in JUNB and TET2 are associated with high-risk disease stages. Furthermore, gain7q, gain10p15.1 (IL2RA and IL15RA), del10p11.22 (ZEB1), and del6q16.3 (TNFAIP3) are coupled with shorter survival. Del6q16.3 (TNFAIP3) was a risk factor for progression in patients at low risk. By analyzing the clonal heterogeneity and the clonal evolution of the cohort, we defined different phylogenetic pathways of the disease with acquisition of JUNB, gain10p15.1 (IL2RA and IL15RA), or del12p13.1 (CDKN1B) at progression. These results establish the genomics and clonality of MF and identify potential patients at risk of progression, independent of their clinical stage.

Retrospective comparison of a weight-based dose every 2 weeks with a fixed dose every month: a real-life analysis of nivolumab in the treatment of advanced melanoma.

Nivolumab was first authorized at a weight-based dose (WBD) of 3 mg/kg every two weeks (Q2W). Since 2017, a fixed dose (FD) regimen [first 240 mg Q2W and then 480 mg per month (Q4W)] was allowed. The objective of the study was to compare a WBD regimen and an FD regimen with regard to effectiveness and safety. We conducted a single-center, retrospective, real-life study of consecutive adult patients who had received a WBD of nivolumab or an FD of 480 mg Q4W. The primary endpoint was the occurrence of grade ≥3 immune-related adverse events (irAEs). The secondary endpoints were overall survival and cost of the treatment. In all, 342 patients were included: 71 in the WBD cohort and 271 in the FD cohort. Of these patients, 201 patients (59.6%) experienced an irAE, and 24 of these events were graded as ≥3. At 12 months, there was no significant difference in irAE occurrence between the two cohorts [hazard ratio (95% confidence interval): 0.54 (0.21-1.36), P  = 0.19]. The 12-month overall survival rate was significantly lower in the WBD cohort ( P  < 0.001). Switching from a fortnightly weight dose to a fixed monthly dose halves the cost of hospitalization. Our results did not show a significant difference between WBD and FD cohort in the occurrence of severe irAEs. However overall survival appeared to be significantly higher in FD group. Some clinical trials are investigating a hybrid dosing regimen in which a WBD is capped by an FD. The present results need to be confirmed in prospective studies.

Stereotactic body radiotherapy as a viable treatment on extracranial oligometastases in melanoma patients: a retrospective multicentric study.

Introduction: Stereotactic radiotherapy (SBRT) potentially has a role in the management of oligometastatic melanoma. However, literature with data specific to this management is very limited. The objectives of this study were to evaluate the time to local control (LC) of extra-cranial melanoma metastases after SBRT treatment and to help establish if SBRT is a useful therapy for oligometastatic melanoma. Methods: A retrospective study was conducted with data collected from two referral centers in France between 2007 and 2020. The oligometastatic status of patients was reported based on the latest recommendations with a maximum of three lesions prior to treatment. Results: A total of 69 patients receiving SBRT for 88 oligometastatic melanoma metastases were included. The median follow-up time was 42.6 months. Most patients were treated for metachronous oligometastatic lesions. Occurrence of oligoprogression, oligorecurrence, and oligopersistence was reported in 42.0%, 39.1%, and 17.4% of cases, respectively. Treated lesions were mostly pulmonary (40.6%), followed by lymph node (34.8%) and hepatic sites (24.6%). Progression-free survival at 1, 2, and 3 years were 47.0% (35-59), 27.0% (16-39), and 25.0% (15.0-37.0), respectively. Time to LC rates at 1, 2, and 3 years were 94.2% (87.0-98.1), 90.3% (81.3-96.1), and 90.3% (81.3-96.1), respectively. Overall survival at 1, 2, and 3 years were 87% (76.0-93.0), 74.0% (76.0-93.0), and 61.0% (47.0-73.0), respectively. Only 17.4% of patients experienced acute, grade 1 or grade 2 toxicities with no reports of grade 3 or higher toxicities. Conclusion: SBRT demonstrated efficacy in managing melanoma patients with extracranial oligometastases and showed an overall low toxicity profile. Future randomized studies are needed to establish the role of SBRT in therapeutic approaches for patients with oligometastatic melanoma.

Relevance of detection of RAF fusion transcripts in pan-negative melanoma in routine practice.

Pan-negative melanomas account for 30% of melanomas. In case of immunotherapy failure, therapeutic options are limited. Oncogene fusions represent a target of interest in many solid cancers. In melanoma, the frequency of oncogene fusion is not well documented and not routinely investigated. We conducted a single-center retrospective study. The objective was to determine the frequency of oncogene fusion detected by RNA sequencing, in patients with advanced or metastatic pan-negative melanoma. In parallel, an extended molecular alteration search was performed using extended targeted next-generation sequencing. We identified 59 patients with advanced pan-negative melanoma between January 2021 and January 2023. It was a cutaneous melanoma in 71.1% of the cases, a mucous melanoma in 15.2% of the cases. We identified nine patients with a RAF fusion, including seven BRAF gene fusion and two RAF1 fusion. Of the other molecular alterations, NF1 mutation was the most frequent molecular alteration identified. Among the nine patients with RAF fusions, all the patients initially received treatment with anti-PD1 ± anti-CTLA4 immunotherapy. After immunotherapy failure, five patients benefited from second-line targeted therapy (two with BRAF and MEK inhibitors combination, three MEK inhibitors alone). The response rate was 20%. In a population of pan-negative melanoma, we detected 15.2% of RAF fusion. Fusion detection allowed the introduction of a second line of targeted therapy, in the absence of a validated therapeutic option in 55.5% of cases. This study suggests the relevance of detecting RAF fusion in a selected population.

Differential gradients of immunotherapy vs targeted therapy efficacy according to the sun-exposure pattern of the site of occurrence of primary melanoma: a multicenter prospective cohort study (MelBase).

Background: The tumor mutational burden (TMB) is high in melanomas owing to UV-induced oncogenesis. While a high TMB is a predictive biomarker of response to PD-1 inhibitors, it may be associated with the rise of resistant clones to targeted therapy over time. We hypothesized that survivals may depend on both the sun-exposure profile of the site of primary melanoma and the type of systemic treatment. Patients and methods: Patients were screened from MelBase, a multicenter biobank dedicated to the prospective follow-up of stage III/IV melanoma. All patients with a known cutaneous primary melanoma who received a 1st-line systemic treatment by immunotherapy or targeted therapy were included (2013-2019). Outcomes were progression-free survival (PFS) and overall survival (OS). Results: 973 patients received either anti PD-1(n=466), anti CTLA-4(n=143), a combination of both (n=118), or targeted therapies (n=246). Patients' characteristics at treatment initiation were: male (62%), median age of 62, AJCC stage IV (84%). Median follow-up was 15.5 months. The primary melanoma was located on chronically sun-exposed skin in 202 patients (G1: head neck), on intermittently sun-exposed skin in 699 patients (G2: trunk, arms, legs), and on sun-protected areas in 72 patients (G3: palms, soles). Median PFS was significantly higher in G1 under anti PD-1 treatment (8.7 months vs 3.3 and 3.4 months for G2 and G3, respectively) (p=0.011). PFS did not significantly differ in other groups. Similarly, median OS was significantly higher in G1 receiving 1st line anti PD-1 treatment (45.6 months vs 31.6 and 21.4 months for G2 and G3) (p=0.04), as opposed to 1st line targeted therapy (19.5 months vs 16.3 and 21.1 months for G1, G2 and G3 respectively). Conclusion: Our study confirms that immunotherapy with anti PD-1 is particularly recommended for melanomas originating from chronically sun-exposed areas, but this finding needs to be confirmed by further research.

Health-Related Quality of Life with Pembrolizumab in Patients with Locally Advanced or Recurrent or Metastatic Cutaneous Squamous Cell Carcinoma: KEYNOTE-629.

INTRODUCTION: At first interim analysis of KEYNOTE-629, health-related quality of life (HRQoL) with pembrolizumab was stable or improved over 48 weeks in recurrent or metastatic (R/M) cutaneous squamous cell carcinoma (cSCC). HRQoL results from the second interim analysis in R/M or locally advanced (LA) cSCC are presented. METHODS: Patients received pembrolizumab 200 mg every 3 weeks for ≤ 2 years. Change in EORTC Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and EQ-5D-5L scores were exploratory end points. Primary analysis was performed at week 12 to ensure adequate completion/compliance. Descriptive analyses were also conducted through weeks 48 and 75 for the LA and R/M cohorts, respectively. RESULTS: At data cutoff (29 July 2020), mean scores in the LA cohort (n = 47) were stable from baseline to week 12 for EORTC QLQ-C30 global health status (GHS)/quality of life (QoL) (-0.27 points [95% confidence interval (CI) -10.93 to 10.39]), physical functioning (-1.29 points [95% CI -8.77 to 6.19]), and EQ-5D-5L visual analog scale (2.06 [95% CI -7.70 to 11.82]). HRQoL remained stable through week 48 in the LA cohort; 76.6% and 74.5% of patients had improved or stable GHS/QoL and physical functioning scores, respectively. HRQoL continued to show stability or improvement through week 75 in the R/M cohort (n = 99); 71.7% and 64.6% of patients had improved or stable GHS/QoL and physical functioning scores, respectively. CONCLUSIONS: Pembrolizumab has demonstrated antitumor activity and manageable safety. The current analysis shows pembrolizumab treatment preserved HRQoL. Collectively, these results support pembrolizumab as standard of care for LA or R/M cSCC. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03284424-September 15, 2017.

Combined Nivolumab and Ipilimumab in Octogenarian and Nonagenarian Melanoma Patients.

Data regarding elderly melanoma patients treated with anti-PD-1 or anti-CTLA-4 antibodies are in favor of tolerability outcomes that are similar to those of younger counterparts. However, there are very few studies focusing on elderly patients receiving nivolumab combined with ipilimumab (NIVO + IPI). Here, we ask what are the current prescribing patterns of NIVO + IPI in the very elderly population and analyze the tolerance profile. This French multicenter retrospective study was conducted on 60 melanoma patients aged 80 years and older treated with NIVO + IPI between January 2011 and June 2022. The mean age at first NIVO + IPI administration was 83.7 years (range: 79.3-93.3 years). Fifty-five patients (92%) were in good general condition and lived at home. Two dosing regimens were used: NIVO 1 mg/kg + IPI 3 mg/kg Q3W (NIVO1 + IPI3) in 27 patients (45%) and NIVO 3 mg/kg + IPI 1 mg/kg Q3W (NIVO3 + IPI1) in 33 patients (55%). NIVO + IPI was a first-line treatment in 39 patients (65%). The global prevalence of immune-related adverse events was 63% (38/60), with 27% (16/60) being of grade 3 or higher. Grade ≥ 3 adverse events were less frequent in patients treated with NIVO3 + IPI1 compared with those treated with NIVO1 + IPI3 (12% versus 44%, p = 0.04). In conclusion, the prescribing patterns of NIVO + IPI in very elderly patients are heterogeneous in terms of the dosing regimen and line of treatment. The safety profile of NIVO + IPI is reassuring; whether or not the low-dose regimen NIVO3 + IPI1 should be preferred over NIVO1 + IPI3 in patients aged 80 years or older remains an open question.

Hyperprogression in advanced melanoma is not restricted to immunotherapy.

BACKGROUND: The definition of hyperprogressive disease (HPD) is controversial in the literature and has not been widely described in melanoma. The aim of this study was to determine whether the concept of HPD applies to patients treated for advanced melanoma, using a definition with a simple, reproducible criterion, and to determine whether it is possible to identify predictive factors for HPD. METHODS: This was a retrospective analysis on a prospective cohort. The data were extracted from MelBase, a French prospective, multicentre cohort of adult patients with advanced melanoma. The patients, following informed consent, were treated prospectively with anti-PD1, ipilimumab+nivolumab, BRAF/MEKi, or chemotherapy, 1st line or thereafter. HPD was defined, within 3 months following the start of the treatment, with the help of a clinical and biological criterion using Response Evaluation Criteria in Solid Tumours, Eastern Cooperative Oncology Group Performance Score, and lactate dehydrogenase. RESULTS: The occurrence of HPD in the 4 groups was as follows (numbers of patients out of the total number): anti-PD1 98/1004 (10%), ipilumumab +nivolumab 19/327 (6%), targeted therapy 31/751 (4%), and chemotherapy 40/397 (10%). In the anti programmed cell death protein 1 (APD1) group, the relevant risk factors for HPD were: more than 3 metastatic sites (p = 0.03) and liver metastasis (p < 0.001). CONCLUSION: This data, thanks to relevant clinical and biological criteria feasible in daily practice, supports the presence of a subgroup whose disease deteriorates rapidly during mono-immunotherapy. Also observed with other treatments, HPD could be the consequence of a natural and aggressive evolution of the disease, alleviated by strong-acting treatments.