PFS and OS by detection of BRAF V600 alterations in ctDNA at (A and B) baseline and (C and D) on treatment. Only patients with BRAF V600 alteration detections at baseline are shown in C and D. Bini, binimetinib; D, detectable; Enco, encorafenib; ND, nondetectable; Vemu, vemurafenib.

PURPOSE:Treatment with encorafenib ± binimetinib is associated with improved survival versus vemurafenib in patients with BRAF V600E/K-mutant advanced melanoma. We retrospectively analyzed genomic and transcriptomic data from the phase III COLUMBUS trial to identify molecular correlates of benefit with encorafenib ± binimetinib. EXPERIMENTAL DESIGN:In COLUMBUS, patients with BRAF V600E/K-mutant locally advanced, unresectable, or metastatic melanoma (n = 921) were randomized to receive encorafenib plus binimetinib, encorafenib, or vemurafenib. We used whole-exome sequencing (n = 666), whole-transcriptome sequencing (RNA sequencing; n = 514), and assessment of circulating tumor DNA (ctDNA) at baseline (n = 336) and on treatment (cycle 2 day 1, n = 184) to evaluate biomarker associations with progression-free and overall survival. RESULTS:Survival benefits with encorafenib plus binimetinib versus vemurafenib were greatest in patients with higher tumor mutational burden (TMB) and those with evidence of tumor immune infiltration (i.e., higher cytolytic score, PD-L1 expression, or IFNγ gene signature scores). Clustering of gene expression profiles identified three tumor subgroups, including an "immune" subgroup associated with improved survival. Detection of BRAF V600 alterations in baseline ctDNA was associated with shorter survival; clearance of BRAF V600 alterations at cycle 2 day 1 was associated with improved survival across arms. CONCLUSIONS:The greatest benefits of encorafenib plus binimetinib were observed in patients with evidence of high TMB and/or tumor-immune infiltration, suggesting potential immune contributions to efficacy, which were not observed with vemurafenib. BRAF V600 detectability in ctDNA seems to have utility as a marker of prognosis and response in this population.

PFS and OS for encorafenib plus binimetinib or encorafenib vs. vemurafenib by (A and B) TMB and (C and D) cytolytic score. E, Volcano plots of univariable gene expression associations with OS in each arm based on z-scored gene expression values. F, Gene-set enrichment analysis of gene expression associations against hallmark gene signatures; signatures with greatest average NES across arms shown. Bini, binimetinib; BM, biomarker; CYT, cytotoxic score; Enco, encorafenib; NES, normalized enrichment scores; Vemu, vemurafenib.

Background/Objectives: Treatment with immune checkpoint inhibitors (ICIs) in patients with advanced melanoma has greatly improved clinical outcomes but can induce immune-related adverse events (irAEs). ICI-induced immune-related (ir) colitis is one of the most common severe irAEs and is primarily managed by treatment with high-dose corticosteroids. Some patients are steroid-refractory and require additional immunosuppressants. Infliximab is commonly used as the additional treatment of choice, while data for other immunosuppressants such as mycophenolate mofetil (MMF) are sparse. Methods: We used MMF to treat ir colitis in a cohort of patients in Heidelberg and compared clinical data with patients who received standard irAE management with infliximab in the Cancer Centers of Heidelberg, Hannover, Mainz, and Kiel. Outcome measures included response rate, time to response, duration and amount of steroid intake, and recurrence of colitis, as well as progression-free survival (PFS) and overall survival (OS) measured from the start of steroid intake. Results: Out of 52 patients refractory to steroids, 31 were treated with additional MMF and 21 with additional infliximab. A total of 24 out of 31 patients (77.4%) experienced bowel habit normalization during treatment with MMF after a median of seven days. Seven patients required additional infliximab to achieve a resolution of symptoms. Twenty out of 21 patients (95.2%) showed a normalization of stool frequency with infliximab after a median of eleven days. One patient required additional MMF to achieve a normal bowel habit. Hence, resolution of symptoms was achieved during both treatment regimens (p = 0.081) in a comparable period of time (p = 0.858). Neither recurrence of colitis after additional immunosuppression (p = 0.760) nor rate of CMV positivity after recurrence of colitis (p = 0.898) differed between groups. We observed a tendency towards longer treatment duration (108 vs. 85 days, p = 0.052) and significantly higher cumulative corticosteroid intake (7585 mg vs. 3485 mg, p = 0.002) in the MMF group compared to the infliximab group. However, we observed significantly higher cumulative steroid intake and a longer duration of corticosteroid therapy in patients treated at the Heidelberg center compared with those treated at the other participating centers within the infliximab group. In contrast, no significant differences in corticosteroid duration or cumulative dose were observed in the center-internal comparison between MMF- and infliximab-treated patients at Heidelberg. These subgroup analyses may indicate that the observed differences in corticosteroid exposure are more likely related to center-specific management strategies rather than substance-specific effects. Neither median PFS nor OS differed between the groups (mPFS: MMF: 3.2 months; infliximab: 2.1 months (p = 0.978); mOS MMF: 12 months; infliximab: 9.5 months (p = 0.561)). Conclusions: The data point to MMF as a well-tolerated, oral treatment alternative for patients with ICI-induced ir colitis, especially in patients where infliximab is contra-indicated.

Characterization of tumor samples to identify candidate molecular subtypes by K-means clustering and distribution of subtypes by biopsy site. A, Heatmap showing K-means cluster and the expression of key marker genes (AXL and MITF) and cell type scores generated by xCell. B, Distribution of K-means subgroups across biopsy sites. C, OS by K-means subgroup and treatment arm. Bini, binimetinib; Vemu, vemurafenib.

PFS and OS for encorafenib plus binimetinib or encorafenib vs. vemurafenib by (A and B) ERBB2 expression level and (C and D) PI3K pathway mutation status. Bini, binimetinib; BM, biomarker; Enco, encorafenib; Vemu, vemurafenib.

BACKGROUND AND OBJECTIVES:Given the increasing incidence of cutaneous neoplasms, the nationwide skin cancer screening program was implemented in Germany in 2008. However, there are few studies evaluating its effectiveness. The aim of this analysis was to assess factors influencing participation and outcomes of skin cancer screening within the cohort of the Gutenberg Health Study (GHS). PATIENTS AND METHODS:The GHS is a retrospective cohort study conducted at the University Medical Center Mainz since 2007. Initially, 15,010 participants aged 35-74 years were recruited, with later inclusion of younger and older individuals. Data were collected through interviews on skin cancer screening participation and linked to participant-specific information such as cancer history and occupational background. RESULTS:In the GHS cohort, the participation rate in skin cancer screening was 62.1% (3,383 out of 5,452). Occupational UV exposure was associated with lower screening participation, whereas a history of cancer correlated with higher participation. Dermatologists were the preferred screening providers and demonstrated higher malignancy detection rates compared to general practitioners (36.7% compared to 20%). CONCLUSIONS:The participation rate in skin cancer screening within the GHS cohort was substantially higher than national averages. Nevertheless, risk-prone populations with outdoor occupations are currently not adequately reached by the screening program. Improved education and targeted interventions for high-risk groups are needed.

Baseline patient characteristics by biomarker status.

BACKGROUND:Melanoma is the main cause of skin cancer-related death. Treatment with immune checkpoint inhibitors (CPI) has improved the prognosis in recent years. However, subtypes of melanoma differ in their response. Acral lentiginous melanoma (ALM) has a worse prognosis compared to cutaneous melanoma other than ALM (CM) and is therefore of particular relevance. AIMS:To evaluate the efficacy of CPI in first-line treatment of patients with advanced ALM compared CM. METHODS:Retrospective analysis of patients with metastatic ALM (n = 45) or CM (n = 328) who received first-line CPI therapy from the multicenter prospective skin cancer registry ADOREG. Study endpoints were best overall response (BOR), progression-free survival (PFS) and overall survival (OS). RESULTS:ALM patients had significantly higher rates of ulcerated tumors, loco regional metastases and fewer BRAF-mutated tumors compared to CM patients. Combined CPI was administered in 48.9 % ALM patients and 39.3 % of CM patients, while the remaining patients received PD-1 monotherapy. OS trended to be shorter in patients with ALM (18.1 vs. 43.8 months, p = 0.10) with no significant differences in PFS (7.0 vs. 11.5 months, p = 0.21). In patients with CM, median OS with combined CPI was not reached, whereas the median OS after PD-1 monotherapy was 37.8 months (p = 0.22). Conversely, in patients with ALM, OS with combined CPI was 17.8 months, compared to 26 months with PD-1 monotherapy (p = 0.15). There were no significant differences in BOR between patients with ALM or CM. CONCLUSION:Analysis of this real-world cohort of patients with metastatic melanoma showed a trend towards poorer survival outcomes upon first-line treatment with CPI in ALM compared to cutaneous melanoma of other subtypes.

PURPOSE:Adjuvant treatment with immune checkpoint inhibition (PD-1) and targeted therapy (TT) with BRAF + MEK inhibitors significantly improved recurrence-free survival (RFS) of patients with stage III melanoma. We investigated efficacy of adjuvant therapy with PD-1 or TT under real-world conditions. MATERIALS AND METHODS:A total of 589 patients with stage III melanoma who started adjuvant PD-1 or TT between June 2018 and September 2019 from 11 major German Dermatologic Cooperative Oncology Group skin cancer centers were followed for 4 years. End points were RFS, overall survival (OS), and melanoma-specific survival. Survival analyses and adjusted hazard ratios (HRs) were estimated with Kaplan-Meier and Cox proportional hazards model, inverse probability treatment weighting, and propensity score matching. RESULTS:RFS at 48 months was 42.9% (95% CI, 38.5 to 47.8) for all PD-1 patients and 52.6% (95% CI, 43.6 to 63.3) for TT patients. Among patients with BRAF mutation, rate of recurrence was higher for PD-1 compared with TT (HR, 1.57 [95% CI, 1.09 to 2.26]). OS at 4 years was 80.8% (95% CI, 73.6 to 88.7) for PD-1-treated patients with BRAF mutation and 87.3% (95% CI, 81.0 to 94.0) for TT patients. Patients starting adjuvant PD-1 after resection of macroscopic lymph node metastases had a higher risk of rapid recurrence (1-year RFS all PD-1 58%) compared with 87% in TT patients. Rate of recurrence after premature discontinuation (≤6 v >6 months treatment) was higher in TT patients (HR, 1.47 [95% CI, 0.67 to 3.23]), but not in PD-1 patients (HR, 1.07 [95% CI, 0.73 to 1.55]). CONCLUSION:PD-1-treated patients with BRAF mutation had a markedly higher rate of relapse compared with TT patients. Rapid recurrences occurred particularly in PD-1-treated patients with previous macroscopic lymph node metastasis. Treatment duration shorter than 6 months did not negatively affect RFS in PD-1, but in TT patients.

BackgroundAlthough systemic therapies have improved considerably over the last decade, up to 50% of patients with metastatic melanoma still die due to disease progression. Oncological treatment at the end-of-life phase is challenging. The aim of this study was to investigate the frequency and type of systemic therapy received by melanoma patients in their end-of-life phase.MethodsPatients with metastatic melanoma who had died between January 1, 2018 and October 31, 2022 were identified from the prospective multicenter skin cancer registry ADOReg. Study endpoints were percentage of patients who had been treated with systemic therapy within the last three months of life, timepoint of initiation of the last-line therapy, overall survival, treatment benefit and the incidence of treatment-related adverse events.ResultsIn total, 1067 patients from 46 skin cancer centers were included. Most of the patients (63%) had received immune checkpoint inhibitors (ICI) as last-line therapy, 22% targeted therapies (TT) and 12% chemotherapy (CTX). Comparing last-line ICI and TT, patients with TT were significantly more likely to benefit from treatment and had significantly fewer and milder treatment-related AE than patients with ICI. Even though two thirds of patients had received ICI as a last-line therapy, the majority of these patients (61%) had stopped therapy within the last 30 days of life, whereas the majority of patients with TT (66%) still continued their treatment to the end of life. We found markedly fewer patients with initiation of ICI within 30 days before their death (19%) compared to a historic cohort including patients who died in 2016 or 2017 (39%).ConclusionTreatment approaches near the end of life have markedly changed in skin cancer centers in Germany over recent years, with ICI prescribed less frequently in the end-of-life phase. In contrast, TT are frequently administered, even within the last 30 days of life. It should also be considered that discontinuation of TT can result in rapid tumor progression. Due to the oral administration and a low rate of severe toxicity, TT appear to be a suitable treatment option, even in the end-of-life situation of melanoma patients.

PURPOSE:We investigated SAR441000 (mixture of four mRNAs encoding IL-12, single-chain IFN-α-2b, GM-CSF, and IL-15 sushi domain) alone or in combination with cemiplimab in patients with advanced solid tumors. PATIENTS AND METHODS:SAR441000 was intratumorally administered weekly in a 4-week cycle in monotherapy and in a 3-week cycle at a predefined dose level with 350 mg cemiplimab (intravenously) every 3 weeks in combination therapy. The primary objective was to determine MTD or maximum administered dose, overall safety, tolerability, and objective response rate of SAR441000. RESULTS:We enrolled 77 patients previously treated with anticancer therapies [escalation monotherapy: N = 21; escalation combination: N = 15; and expansion combination (PD-1-refractory melanoma): N = 41]. The maximum administered dose at dose level 8 was 4,000 µg. The most common grade ≥3 treatment-related adverse events was fatigue in the escalation phase (monotherapy: 28.6% and combination therapy: 66.7%) and injection-site pain (31.7%) in the expansion phase. In combination therapy, one patient in the escalation phase and two patients in the expansion phase achieved partial responses. At 4,000 μg (highest dose) across all cohorts, the maximum fold change in plasma cytokine concentration was the highest and lowest for IFN-α-2 (74.9-fold) and IL-15 (1.96-fold), respectively. Increased blood IFN-γ and inducible protein-10 levels were observed for most patients. CONCLUSIONS:Intratumoral administration of SAR441000 in combination with cemiplimab was generally well tolerated with antitumor activity in the locoregional disease setting. Anecdotal evidence of pharmacodynamic immunomodulatory effect and distant noninjected lesion antitumor response was observed, without significant effects in patients with advanced solid tumors previously treated with anti-PD-1 therapies.

PURPOSE:There are limited treatment options for advanced melanoma that have progressed during or after immune checkpoint inhibitor therapy. Intratumoral (IT) immunotherapy may improve tumor-specific immune activation by promoting local tumor antigen presentation while avoiding systemic toxicities. The phase 3 ILLUMINATE-301 study (ClinicalTrials.gov identifier: NCT03445533) evaluated tilsotolimod, a Toll-like receptor-9 agonist, with or without ipilimumab in patients with anti-PD-1 advanced refractory melanoma. METHODS:Patients with unresectable stage III-IV melanoma that progressed during or after anti-PD-1 therapy were randomly assigned 1:1 to receive 24 weeks of tilsotolimod plus ipilimumab or 10 weeks of ipilimumab alone. Nine IT injections of tilsotolimod were administered to a single designated lesion over 24 weeks. Intravenous ipilimumab 3 mg/kg was administered once every 3 weeks from week 2 in the tilsotolimod arm and week 1 in the ipilimumab arm. The primary end point was efficacy measured using objective response rate (ORR; independent review) and overall survival (OS). RESULTS:A total of 481 patients received tilsotolimod plus ipilimumab (n = 238) or ipilimumab alone (n = 243). ORRs were 8.8% in the tilsotolimod arm and 8.6% in the ipilimumab arm, with disease control rates of 34.5% and 27.2%, respectively. Median OS was 11.6 months in the tilsotolimod arm and 10 months in the ipilimumab arm (hazard ratio, 0.96 [95% CI, 0.77 to 1.19]; P = .7). Grade ≥3 treatment-emergent adverse events occurred in 61.1% and 55.5% of patients in the tilsotolimod and ipilimumab arms, respectively. CONCLUSION:Combining IT tilsotolimod with ipilimumab did not significantly improve the ORR or OS compared with ipilimumab alone in patients with anti-PD-1 advanced refractory melanoma.

Background: Cancer immunotherapy has revolutionized melanoma treatment, but the high number of non- responders still emphasizes the need for improvement of therapy. One potential avenue for enhancing antitumor treatment is through the modulation of coagulation and platelet activity. Both have been found to play an important role in the tumor microenvironment, tumor growth and metastasis. Preclinical studies indicate a beneficial effect, clinical data has been inconsistent. Methods: We examined a cohort of advanced, non-resectable melanoma patients (n = 2419) derived from the German prospective multicenter skin cancer registry ADOReg, who were treated with immune checkpoint inhibitors (ICI). The patients were classified based on whether it was documented that they received platelet aggregation inhibition (PAI) (n = 137) (acetylsalicylic acid (ASA) or clopidogrel), anticoagulation (AC) (n = 185) (direct oral anticoagulation (DOAC), phenprocoumon, heparins) at the start of ICI or no antithrombotic medication (n = 2097) at any point during ICI treatment. The study endpoints were best overall response (BOR), progression-free survival (PFS) and overall survival (OS). Results: A significantly improved PFS was observed in patients documented to receive ASA (15.1 vs 6.4 months, HR 0.67, 95 % CI: 0.5 to 0.88, p = 0.0047) as well as in patients to receive AC (15.1 vs. 6.4 months, HR 0.7, 95 % CI: 0.53 to 0.91, p = 0.01) compared to patients for whom no antithrombotic medication was documented. Multivariate analysis of OS showed significant risk reduction in patients who received DOAC (HR 0.68, 95 % CI: 0.49 to 0.92, p = 0.0170) or phenprocoumon (HR: 0.44, 95 % CI: 0.19 to 0.85, p = 0.0301). Conclusion: Our study indicates a positive prognostic effect of anticoagulant and antiplatelet concomitant medication in melanoma patients receiving ICI. Further studies are needed to confrim the cancer-related benefit of adding anticoagulation or platelet inhibition to ICI treatment.

BACKGROUND:Adjuvant treatment with anti-PD1 antibodies has been shown to effectively reduce the risk of recurrence in patients with resected metastatic melanoma. Whether a full 12-month duration of treatment is needed to achieve full clinical benefit is not known. This study investigated the survival outcome depending on the duration of adjuvant anti-PD1 therapy. METHODS:From the prospective multicentre real-world skin cancer registry ADOREG data of 620 patients who finished adjuvant treatment with nivolumab or pembrolizumab for AJCCv8 stage III/IV resected melanoma was analyzed. Recurrence-free survival (RFS) and overall survival (OS) were compared between patients with regular treatment duration (52 ± 4 weeks; n = 229) and no disease recurrence during therapy (A1) and patients with a premature end of treatment (<48 weeks; n = 214, B). Patients with disease recurrence during adjuvant treatment were included in cohort A2. RESULTS:The median duration of follow-up was 26.0 months [interquartile range (IQR) 18.0-34.0] in group A1 [median treatment duration 51.3 weeks (IQR 50.0-52.1) and 19.0 months (IQR 13.0-29.0)] in group B [median treatment duration 22.2 weeks (IQR 10.0-34.8)]. Reasons for early discontinuation were treatment-related side effects in 45.3% (n = 97) and other reasons than toxicity in 54.7% (n = 117). The 2-year rate of RFS was 72.4% (95% CI, 68.5-76.3) for patients in group B and 51.5% (95% CI, 48.8-54.2) in patients with regular and intended regular treatment duration (A1 plus A2). When analysing the patients who did not relapse during adjuvant treatment (A1), there was a significantly higher RFS rate of 84.1% (95% CI, 81.5-86.7). When only assessing patients with a recurrence after more than 12 months after initiation of therapy, there was a trend towards better RFS in patients with regular treatment duration. CONCLUSIONS:In patients with resected metastatic melanoma, shorter treatment duration with anti-PD1 antibodies is not associated with a worse outcome.

BACKGROUND:Females and males differ in their innate and acquired immune responses. Thus, it is hypothesized that the efficacy of anti-tumor immunotherapies may differ by sex. This study aimed to investigate sex-specific survival differences upon different therapy types in metastatic melanoma. PATIENTS AND METHODS:Patients with unresectable metastatic melanoma (stage IV, AJCCv8) of the skin or unknown primary, who had received first-line PD-1-based immune checkpoint inhibition (ICI) or BRAF/MEK-directed targeted therapy (TT) were identified from the prospective multicenter DeCOG skin cancer registry ADOREG. Study endpoints were progression-free survival (PFS) and overall survival (OS). RESULTS:A total of 2032 patients, 1274 males (62.7 %) and 758 females (37.3 %), received ICI (n = 1484) or TT (n = 548) between May 2010 and December 2020. At median follow-up of 28.6 months, no significant sex-specific differences in survival could be detected, neither in the total cohort nor by treatment type: PFS (total, p = 0.86; ICI, p = 0.46; TT, p = 0.21), OS (total, p = 0.60; ICI, p = 0.20; TT, p = 0.30). Multivariable Cox regression analyses also did not show a relevant prognostic influence by sex. Subgroup analyses were performed according to ICI therapy type. In n = 872 patients treated with PD-1 monotherapy, a survival advantage (PFS, p = 0.041; OS, p = 0.07) could be detected for males by univariable and multivariable analyses, whereas no sex-specific survival differences were found for n = 456 patients who received combination immunotherapy. CONCLUSION:No overall sex-specific survival differences were detected for metastatic melanoma patients in the first-line therapy setting. According to subgroup analyses males show a trend towards a survival advantage over females.

Plain Language SummaryWhat is this summary about?This summary presents the 7-year study results from COLUMBUS part 1, which tested encorafenib (BRAFTOVI®) and binimetinib (MEKTOVI®) combined (COMBO group) against encorafenib alone (ENCO group) or vemurafenib (ZELBORAF®) alone (VEMU group) as a treatment for a skin cancer called locally advanced or metastatic BRAF V600-mutant melanoma.What were the results?More participants in the COMBO group were alive for longer and without their disease getting worse after 7 years than those in the VEMU group.Among participants who switched to a new anticancer treatment, those in the COMBO group lived longer than those in the VEMU or ENCO groups.What do the results of the study mean?This confirms that people with BRAF V600-mutant melanoma treated with encorafenib plus binimetinib or encorafenib alone lived longer than those treated with vemurafenib.This is an abstract of the Plain Language Summary of Publication article.View the full Plain Language Summary PDF of this article to read the full-text AcknowledgementsPfizer would like to thank the participants and their families for participating in this study, as well as the investigators and the clinical teams for making this study possible.Disclosure statementDirk Schadendorf. Honoraria: Roche/Genentech, Novartis, Bristol Myers Squibb, MSD, Immunocore, Merck Serono, Array BioPharma, Pfizer, Pierre Fabre, Philogen,Regeneron, 4SC, Sanofi/Regeneron, NeraCare GmbH, Sun Pharma, Inflarx GmbH, Ultimovacs, Sandoz, Amgen, Daiichi Sankyo Japan, LabCorp, Nektar, Replimune.Consulting or Advisory Role: Roche/Genentech, Novartis, Bristol Myers Squibb, MSD, Merck Serono, 4SC, Pierre Fabre, Sanofi/Regeneron, Nektar. Speakers' Bureau:Bristol Myers Squibb, MSD, Novartis, Pierre Fabre, Sanofi/Regeneron, Merck KGaA. Research Funding: Bristol Myers Squibb (Inst), Novartis (Inst), Roche (Inst), MSD Oncology (Inst), Array BioPharma/Pfizer (Inst), Amgen (Inst). Travel, Accommodations, Expenses: Roche/Genentech, Bristol Myers Squibb, Merck Serono, Novartis,MSD, Pierre Fabre, Sanofi/Regeneron.Reinhard Dummer. Honoraria: Roche, Novartis, Bristol Myers Squibb, MSD, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, CatalYm, Second Genome, Regeneron,Alligator Bioscience, MaxiVAX, touchIME, T3 Pharmaceuticals, Pfizer. Consulting or Advisory Role: Roche, Bristol Myers Squibb, MSD, Novartis, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, CatalYm, Second Genome, Alligator Bioscience, touchIME, MaxiVAX, Regeneron, Pfizer, T3 Pharmaceuticals. Research Funding: Roche (Inst), Bristol Myers Squibb (Inst), Novartis (Inst), MSD (Inst), Amgen (Inst).Keith T. Flaherty. Stock and Other Ownership Interests: Clovis Oncology, Loxo, X4 Pharma, Strata Oncology, PIC Therapeutics, Apricity Health, Oncoceutics,FogPharma, Tvardi Therapeutics, Checkmate Pharmaceuticals, Kinnate Biopharma, Scorpion Therapeutics, ALX Oncology, xCures, Monopteros Therapeutics,Vibliome Therapeutics, Transcode Therapeutics, Soley Therapeutics, Nextech Invest. Consulting or Advisory Role: Novartis, Lilly, Oncoceutics, Tvardi Therapeutics,Takeda, Debiopharm Group.Caroline Robert. Stock and Other Ownership Interests: Ribonexus. Consulting or Advisory Role: Bristol Myers Squibb, Roche, Novartis, Pierre Fabre, MSD, Sanofi,AstraZeneca, Pfizer. Research Funding: Novartis (Inst).Ana Arance. Consulting or Advisory Role: Bristol Myers Squibb, Roche, Novartis, Pierre Fabre, MSD, Merck, Sanofi. Speakers' Bureau: Pierre Fabre, Novartis, MSD,Bristol Myers Squibb, Roche, Merck, Sanofi Research Funding: Pierre Fabre (Inst), Novartis (Inst), Roche (Inst), Bristol Myers Squibb (Inst), MSD (Inst), Merck (Inst),Sanofi (Inst). Travel, Accommodations, Expenses: Bristol Myers Squibb, MSD, Novartis, Pierre Fabre.Jan Willem B. de Groot. Consulting or Advisory Role: Bristol Myers Squibb, Pierre Fabre, Servier.Claus Garbe. Honoraria: CeCaVa, MSD Oncology, NeraCare GmbH, Philogen. Consulting or Advisory Role: CeCaVa, MSD Oncology, NeraCare GmbH, Philogen.Helen J. Gogas. Consulting or Advisory Role: Bristol Myers Squibb, MSD, Pierre Fabre, Sanofi. Speakers' Bureau: Bristol Myers Squibb, MSD, Novartis, Pierre Fabre,Sanofi.Steering Committee Member: Amgen, Replimune. Research Funding: Amgen (Inst), Bayer (Inst), Bristol Myers Squibb (Inst), Iovance (Inst), Lilly (Inst), MSD (Inst), Pfizer (Inst), Pierre Fabre (Inst).Ralf Gutzmer. Honoraria: Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Merck Serono, Almirall Hermal GmbH, Amgen, Sun Pharma, Pierre Fabre, Sanofi/Regeneron, Immunocore. Consulting or Advisory Role: Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Almirall Hermal GmbH, 4SC, Amgen, Pierre Fabre Merck Serono, Sun Pharma,Sanofi/Regeneron, Immunocore, Delcath. Research Funding: Amgen (Inst), Merck Serono (Inst), Sun Pharma (Inst), Sanofi/Regeneron (Inst),Kyowa Kirin (Inst), Almirall Hermal GmbH (Inst). Travel, Accommodations, Expenses: Pierre Fabre, Sun Pharma, Boehringer Ingelheim.Ivana Krajsová. No disclosures or conflicts of interest to report.Gabriella Liszkay. Consulting or Advisory Role: Roche, MSD, Novartis, Bristol Myers Squibb/Pfizer, Sanofi, Pfizer. Speakers' Bureau: Bristol Myers Squibb, MSD Oncology (Inst), Sanofi. Research Funding: Roche, Novartis (Inst), Incyte Corporation (Inst).Carmen Loquai. Consulting or Advisory Role: Bristol Myers Squibb (Inst), MSD (Inst), BioNTech (Inst), Novartis (Inst), Sanofi (Inst), Pierre Fabre (Inst), Almirall Hermal GmbH (Inst), Sun Pharma (Inst), Merck (Inst), Roche (Inst), Kyowa Kirin International (Inst). Travel, Accommodations, Expenses: Bristol Myers Squibb (Inst), MSD (Inst),BioNTech (Inst), Novartis (Inst), Sanofi (Inst), Pierre Fabre (Inst), Almirall Hermal GmbH (Inst), Sun Pharma (Inst), Merck (Inst), Roche (Inst), Kyowa Kirin International (Inst).Mario Mandalà. Honoraria: MSD Oncology, Novartis, Pierre Fabre, Sanofi/Aventis, Bristol Myers Squibb/Sanofi. Consulting or Advisory Role: Bristol Myers Squibb, MSD Oncology, Novartis, Pierre Fabre. Research Funding: Novartis (Inst).Naoya Yamazaki. Consulting or Advisory Role: Ono Pharmaceutical, Chugai Pharma, MSD. Speakers' Bureau: Ono Pharmaceutical, Bristol Myers Squibb Japan, Novartis, MSD. Research Funding: Ono Pharmaceutical (Inst), Bristol Myers Squibb Japan (Inst), Novartis (Inst), Astellas Amgen BioPharma (Inst), Merck Serono (Inst), Takara Bio (Inst).Paola Queirolo. Consulting or Advisory Role: Pierre Fabre, Roche, Novartis, MSD, Bristol Myers Squibb, Sun Pharma, Sanofi/Regeneron, Merck Serono.Carolin Guenzel. Stock and Other Ownership Interests: Pfizer. Honoraria: Pfizer.Anna Polli. Stock and Other Ownership Interests: Pfizer. Honoraria: Pfizer.Alessandra di Pietro. Stock and Other Ownership Interests: Pfizer. Honoraria: Pfizer.Paolo A. Ascierto. Stock and Other Ownership Interests: PrimeVAX. Consulting or Advisory Role: Bristol Myers Squibb, Roche/Genentech, MSD, Novartis, Array BioPharma,Merck Serono, Pierre Fabre, Incyte, MedImmune, AstraZeneca, Sun Pharma, Sanofi, Idera, Ultimovacs, Sandoz, Immunocore, 4SC, Alkermes, Italfarmaco, Nektar,Boehringer Ingelheim, Eisai, Regeneron, Daiichi Sankyo, Pfizer, OncoSec, Nouscom, Takis Biotech, Lunaphore Technologies, Seagen, ITeos Therapeutics, Medicenna,Bio-Al Health. Research Funding: Bristol Myers Squibb (Inst), Roche/Genentech (Inst), Array BioPharma (Inst), Sanofi (Inst). Travel, Accommodations, Expenses: MSD.The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.Writing support was provided by Blaise Low, PhD, of Nucleus Global, an Inizio company, and was funded by Pfizer.Patient reviewers on this PLSP have received honorarium from Future Oncology for their review work but have no other relevant financial relationships to disclose.FundingThis manuscript was funded by Pfizer.

BACKGROUND:PD-1 or BRAF + MEK inhibition is considered the current gold standard in adjuvant melanoma therapy. Little is known if, after the recurrence of the disease and surgery, a second course of adjuvant therapy might be beneficial. METHODS:A multicenter, retrospective study investigating a second course of adjuvant therapy after recurrence and surgery in stage III-IV melanoma patients. Patients received nivolumab (NIV), pembrolizumab (PEM) or dabrafenib plus trametinib (D + T) between 01/2017 and 10/2021. The primary endpoint was 12-month recurrence-free survival (RFS2). Further analyses included descriptive and correlative statistics. RESULTS:Sixty-six patients from 22 centers in Germany, Austria and Switzerland were included. Thirty-two patients received D + T as second-course adjuvant therapy, 9 patients received PEM and 25 patients received NIV. Recurrence-free survival for the second-course adjuvant treatment (RFS2) was assessed after 12 and 24 months and showed a superiority of adjuvant BRAF + MEK over PD-1 therapy (12-months RFS2: 90.6% vs. 70.6%, HR 4.226 [95% CI 1.154-15.48]; p = 0.030; 24-months RFS2 71.9% vs. 52.9%, HR 3.154 [95% CI 1.374-7.242]; p = 0.007). There was no significant decrease in OS with either BRAF + MEK or PD-1 treatment (12-months OS: 100% both, 24-months OS: 100% vs. 93.8%). Furthermore, therapy sequences were investigated. For better comparability, only BRAF V600 mutated patients were assessed: RFS2 was significantly better for patients with a class switch from PD-1 to BRAF + MEK compared to BRAF + MEK to PD-1 (HR 4.401 (1.04-18.63), p = 0.044). No new safety signals were detected. CONCLUSIONS:In the investigated cohort, a second course of adjuvant melanoma treatment is feasible and provides similar RFS compared to an initial course of adjuvant therapy using BRAF + MEK inhibitors; however, RFS2 is reduced for PD-1 antibodies. In addition, both treatments were convincing with a 24-month OS of almost 100%. Switching from adjuvant PD-1 to BRAF + MEK treatment provided better overall RFS compared to switching from adjuvant BRAF + MEK to PD-1 treatment.

BackgroundImmune checkpoint inhibitor (ICI)-induced myocarditis is a rare immune-related adverse event (irAE) with a fatality rate of 40%–46%. However, irMyocarditis can be asymptomatic. Thus, improved monitoring, detection and therapy are needed. This study aims to generate knowledge on pathogenesis and assess outcomes in cancer centers with intensified patient management.MethodsPatients with cardiac irAEs from the SERIO registry (www.serio-registry.org) were analyzed for demographics, ICI-related information (type of ICI, therapy line, combination with other drugs, onset of irAE, and tumor response), examination results, irAE treatment and outcome, as well as oncological endpoints. Cardiac biopsies of irMyocarditis cases (n = 12) were analyzed by Nanostring and compared to healthy heart muscle (n = 5) and longitudinal blood sampling was performed for immunophenotyping of irMyocarditis-patients (n = 4 baseline and n = 8 during irAE) in comparison to patients without toxicity under ICI-therapy (n = 4 baseline and n = 7 during ICI-therapy) using flow cytometry.ResultsA total of 51 patients with 53 cardiac irAEs induced by 4 different ICIs (anti-PD1, anti-PD-L1, anti-CTLA4) were included from 12 centers in 3 countries. Altogether, 83.0% of cardiac irAEs were graded as severe or life-threatening, and 11.3% were fatal (6/53). Thus, in centers with established consequent troponin monitoring, work-up upon the rise in troponin and consequent treatment of irMyocarditis with corticosteroids and –if required–second-line therapy mortality rate is much lower than previously reported. The median time to irMyocarditis was 36 days (range 4–1,074 days) after ICI initiation, whereas other cardiotoxicities, e.g. asystolia or myocardiopathy, occurred much later. The cytokine-mediated signaling pathway was differentially regulated in myocardial biopsies as compared to healthy heart based on enrichment Gene Ontology analysis. Additionally, longitudinal peripheral blood mononuclear cell (PBMC) samples from irMyocarditis-patients indicated ICI-driven enhanced CD4+ Treg cells and reduced CD4+ T cells. Immunophenotypes, particularly effector memory T cells of irMyocarditis-patients differed from those of ICI-treated patients without side effects. LAG3 expression on T cells and PD-L1 expression on dendritic cells could serve as predictive indicators for the development of irMyocarditis.ConclusionInterestingly, our cohort shows a very low mortality rate of irMyocarditis-patients. Our data indicate so far unknown local and systemic immunological patterns in cardiotoxicity.