Epidermal growth factor receptor inhibitors in advanced cutaneous squamous cell carcinoma: A systematic review and meta-analysis.

Patients with advanced cutaneous squamous cell carcinoma (cSCC) who are not eligible for or who fail to respond to anti-PD1 immunotherapy have few treatment options. Epidermal growth factor receptor (EGFR) inhibitors have been investigated as a therapeutic option for advanced cSCC; however, data are limited to small single-arm trials or retrospective studies. A systematic review and meta-analysis was conducted to PRISMA guidelines (CRD42023394300). Studies reporting on outcomes of EGFR inhibition in advanced cSCC were identified. Objective response rate (ORR), progression-free survival (PFS), overall survival (OS) and adverse event (AE) rate were pooled using a random effects model and the inverse variance method. Twelve studies (six prospective, six retrospective) were identified, representing 324 patients. Pooled ORR was 26% (95% confidence interval [CI] 18-36), median PFS was 4.8 months (95% CI 3.9-6.6) and median OS was 11.7 months (95% CI 9.2-14.1). Any grade AEs occurred in 93% of patients (95% CI 85-97) while grade 3 and higher AEs occurred in 30% (95% CI 14-54). These results were similar between anti-EGFR monoclonal antibodies (MAbs) and tyrosine kinase inhibitors (TKIs). EGFR inhibitors can be considered in patients with advanced cSCC who are contraindicated for or progress on first-line anti-PD1 immunotherapy. Future studies should evaluate their activity and safety following anti-PD1, identify predictive biomarkers for their efficacy and explore combination approaches.

Chemotherapy in Cutaneous Melanoma: Is There Still a Role?

PURPOSE OF REVIEW: In the preceding decade, the management of metastatic cutaneous melanoma has been revolutionised with the development of highly effective therapies including immune checkpoint inhibitors (specifically CTLA-4 and PD-1 inhibitors) and targeted therapies (BRAF and MEK inhibitors). The role of chemotherapy in the contemporary management of melanoma is undefined. RECENT FINDINGS: Extended analyses highlight substantially improved 5-year survival rates of approximately 50% in patients with metastatic melanoma treated with first-line therapies. However, most patients will progress on these first-line treatments. Sequencing of chemotherapy following failure of targeted and immunotherapies is associated with low objective response rates and short progression-free survival, and thus, meaningful benefits to patients are minimal. Chemotherapy has limited utility in the contemporary management of cutaneous melanoma (with a few exceptions, discussed herein) and should not be the standard treatment sequence following failure of first-line therapies. Instead, enrolment onto clinical trials should be standard-of-care in these patients.

Merkel cell carcinoma in situ: A systematic review of prognosis and management.

BACKGROUND: Merkel cell carcinoma (MCC) is a rare primary cutaneous neuroendocrine tumour. While dermally invasive MCC is known to have a five-year survival of only 30-40%, the prognosis and management of MCC in situ (MCCis) is not widely reported. OBJECTIVE: We present a systematic review to elucidate the prognosis and management of MCCis. METHODS: We performed a systematic review, searching three databases to 01 June 2021. Case reports, cohort studies, clinical trials and literature reviews were considered for inclusion. RESULTS: We identified 26 cases of MCCis published in the literature with a median age of 74 years and involving 19 males and 7 females. Most cases were on the face and neck (n = 17), followed by upper limb (n = 8) and lower limb (n = 1). Sentinel lymph node biopsy was performed in three patients, and all were negative. One subject underwent adjuvant radiotherapy. No MCCis-associated deaths were reported. CONCLUSION: This review suggests that MCCis has an excellent prognosis with minimal, if any, risk of mortality and a very low risk of dermal invasion and recurrence when treated with wide local excision alone. Sentinel lymph node biopsy is unlikely to be useful for MCCis.

Long-Term Response to Intermittent Binimetinib in Patients with NRAS-Mutant Melanoma.

Melanoma can be classified based on the detection of relevant oncogenic driver mutations. These mutations partially determine a patient's treatment options. MEK inhibitors have demonstrated little efficacy in patients with NRAS-mutated melanoma owing to primary and secondary resistance. We report two patients with NRAS-mutant metastatic melanoma with long-term response to intermittent MEK-inhibitor binimetinib therapy. Intermittent dosing schedules could play a key role in preventing resistance to targeted therapy. This article highlights the efficacy of an intermittent dosing schedule, toxicities associated with binimetinib, and possible mechanisms preventing resistance in targeted therapy. Intermittent MEK-inhibitor therapy may be considered in patients with NRAS-mutated melanoma that have failed all standard therapies. KEY POINTS: Melanomas harbor NRAS mutations in 10%-30% of the cases. These mutations promote hyperactivation of the MAPK pathway, leading to proliferation and prolonged survival of tumor cells. Currently, drugs directly targeting NRAS are not available. Downstream inhibition of the MAPK pathway can be considered as a therapeutic option after immunotherapeutic failure. Intermittent administration of kinase inhibitors might be the way to partially overcome the development of drug resistance by (a) inducing a fitness deficit for drug-resistant cells on treatment break, (b) increasing the immunogenicity, and (c) inducing apoptosis and cell cycle arrest. It also enhances expression of numerous immunomodulating molecules, and reduction of immunosuppressive factors, which suggests better access of the immune system to the tumor.

First-line therapy-stratified survival in BRAF-mutant melanoma: a retrospective multicenter analysis.

BACKGROUND: Inhibition of the mitogen-activated protein kinase (MAPK) pathway as well as programmed death 1 receptor (PD-1) blockade was shown to prolong overall survival (OS) in patients with advanced B-Raf proto-oncogene (BRAF)-mutant melanoma. However, due to the lack of head-to-head trials, it remains unclear if one of these therapeutic approaches should be preferred in first-line therapy. Here, we present a retrospective analysis comparing anti-PD-1 monotherapy with BRAF/MAPK/ERK kinase (MEK) combined inhibition used as first-line agents in a real-world clinical setting. PATIENTS AND METHODS: Clinical data, routine blood counts and lactate dehydrogenase (LDH) levels of 301 patients with unresectable or metastatic melanoma harboring an activating mutation in BRAF (V600E/K) were included. Of these, 106 received anti-PD-1 antibodies, while 195 patients were treated with a selective BRAF inhibitor combined with an MEK inhibitor as palliative first-line therapy. Patients were sub-grouped according to previously described predictive and prognostic markers. RESULTS: OS was significantly longer in patients receiving anti-PD-1 monotherapy compared to patients receiving combined MAPK inhibitors. Subsequent therapies were comparable among these groups. The difference in OS was less pronounced in patients with high LDH levels and visceral metastatic spread. CONCLUSION: First-line treatment with a PD-1 blocking antibody might be associated with longer OS than first-line inhibition of the MAPK pathway in patients with advanced melanoma harboring mutant BRAF. These hypothesis-generating data need to be confirmed or rejected in prospective, randomized trials.

Clinical outcome of concomitant vs interrupted BRAF inhibitor therapy during radiotherapy in melanoma patients.

This corrects the article DOI: 10.1038/bjc.2017.85.

The World of Melanoma: Epidemiologic, Genetic, and Anatomic Differences of Melanoma Across the Globe.

PURPOSE OF REVIEW: As cancer remains an increasing problem in industrial countries, the incidence of melanoma has risen rapidly in many populations during the last decades and still continues to rise. Current strategies aiming to control the disease have largely focused on improving the understanding of the interplay of causal factors for this cancer. RECENT FINDINGS: Cutaneous melanoma shows clear differences in incidence, mortality, genomic profile, and anatomic presentation, depending on the country of residence, ethnicity, and socioeconomic status. Known risk factors are multiple atypical nevi, positive family and/or personal history, immune suppressive diseases or treatments, and fair skin phenotype. Besides new adjuvant therapeutic options, changed attitude toward leisure and sun exposure, primary prevention, and early detection are major contributors to disease control. Melanoma is a disease of multifactorial causality and heterogeneous presentation. Its subtypes differ in origin, anatomical site, role of UV radiation, and mutational profile. Better understanding of these differences may improve prevention strategies and therapeutic developments.

Evaluation of clinicopathological factors in PD-1 response: derivation and validation of a prediction scale for response to PD-1 monotherapy.

BACKGROUND: Anti-PD-1 therapy has shown significant clinical activity in advanced melanoma. We developed and validated a clinical prediction scale for response to anti- PD-1 monotherapy. METHODS: A total of 315 patients with advanced melanoma treated with pembrolizumab (2 or 10 mg kg-1 Q2W or Q3W) or nivolumab (3 mg kg-1 Q2W) at four cancer centres between 2011 to 2013 served as the setting for the present cohort study. Variables with significant association to response on a univariate analysis were entered into a forward stepwise logistic regression model and were given a score based on ORs to calculate a clinical prediction scale. RESULTS: The developed clinical prediction scale included elevated LDH (1 point), age <65 years (1 point), female sex (1 point), history of ipilimumab treatment (2 points) and the presence of liver metastasis (2 points). The scale had an area under the receiver-operating curve (AUC) of 0.73 (95% CI 0.67, 0.80) in predicting response to therapy. The predictive performance of the score was maintained in the validation cohort (AUC 0.70 (95% CI 0.58, 0.81)) and the goodness-to-fit model demonstrated good calibration. CONCLUSIONS: Based on a large cohort of patients, we developed and validated a simple five-factor prediction scale for the clinical activity of PD-1 antibodies in advanced melanoma patients. This scale can be used to stratify patients participating in clinical trials.

Case Report: Encephalitis, with Brainstem Involvement, Following Checkpoint Inhibitor Therapy in Metastatic Melanoma.

Checkpoint inhibitors are increasingly being used in the treatment of malignant melanoma and other cancers. With the use of such therapies, autoimmune-mediated adverse events in the central and peripheral nervous system are likely to occur more frequently. We report a unique case of brainstem encephalitis with a sudden lethal outcome following ipilimumab and pembrolizumab therapy in a patient with malignant melanoma. The autopsy showed a diffuse nodular activation of microglia in the whole encephalon with prominent intraparenchymal and perivascular lymphocytic infiltration of the brainstem. Non-infectious brainstem encephalitis is a well-recognized subset of paraneoplastic encephalitis. Brainstem involvement is usually accompanied by a wide spectrum of signs and symptoms, which were not observed in this case. The timing of the clinical symptoms as well as the histopathological findings suggest an autoimmune-adverse event of ipilimumab and pembrolizumab administration rather than a paraneoplastic disorder. In the presence of neurological symptoms, immediate cessation of the immunotherapy and immunosuppressive therapy may lead to successful therapeutic intervention, as described in previous reports. Therefore, it is crucial that physicians are aware of the possible side effects of immunotherapies on the nervous system. IMPLICATIONS FOR PRACTICE: Metastatic melanoma patients treated with the anti-CTLA-4 inhibitor ipilimumab have a high utilization of various types of health care services, such as inpatient hospital stays or doctor visits. There are differences across countries regarding patterns of health care utilization and economic burden of the disease. Health care services are used more frequently after patients experience progression of their disease. The study highlights that better therapies leading to durable response in patients with metastatic melanoma have the potential to decrease health care costs and patient burden in terms of hospitalizations and other health care services.

A review of serious adverse effects under treatment with checkpoint inhibitors.

PURPOSE OF REVIEW: The aim of this article is to raise awareness of physicians for the serious side-effects of immune-checkpoint blocking antibodies. As checkpoint inhibitors can induce severe side-effects and are increasingly being used also in subspecialties besides dermatology and oncology, with less experience with these drugs available, knowledge has to be spread. Early recognition and adequate management is essential. RECENT FINDINGS: Recent reports on side-effects document cases of serious side-effects involving all organ systems. These include formerly little referenced and life-threatening side-effects such as cardiotoxicity and neurotoxicity. Furthermore, important additional findings are the inclusion of CMV reactivation in the differential diagnosis or the side-effect profile in special patient populations, that is, in transplant patients, patients with autoimmune disease or previous toxicity to ipilimumab. SUMMARY: Checkpoint inhibitor treatment induces a wide range of serious side-effects. However, with prompt diagnosis and adequate treatment these can mostly be safely managed. Documentation and reporting of serious side-effects remains important to share knowledge and thus ensure optimal patient care.

Critical aspects to achieve a high-quality melanoma clinic.

PURPOSE OF REVIEW: With incidence of melanoma growing worldwide and new therapies prolonging the survival of patients with advanced disease, complex medical care is needed. RECENT FINDINGS: Best care of complicated melanoma cases is achieved in specialized referral centers. Aims to provide optimized melanoma therapy, best patient-reported treatment outcome, and successful clinical and translational research, necessitate a dedicated interdisciplinary team. SUMMARY: We report on critical aspects of the interaction between patients, medical care givers, clinical trial and biobanking teams, and emphasize the importance of interdisciplinary tumor boards. Specialized skin cancer nurses and local patient advocacy groups should be involved in patient care and could be the binding link between the patients and the treatment team.

Treatment of melanoma brain metastases.

PURPOSE OF REVIEW: Melanoma has a tendency to metastasize to the brain. The development of brain metastasis is observed in all mutational subgroups. Overall, they are associated with poor prognosis. They are also associated with pain, neurological deterioration and thus, have a major impact on patients' quality of life. Historically, effective palliation by systemic therapy has been rare. The availability of new therapeutic agents, however, heralds a significant improvement in management options for these patients. RECENT FINDINGS: The development of targeted therapies and immune activating checkpoint inhibitors with durable benefit has led to a treatment paradigm change. Several clinical studies in patients with metastatic melanoma have demonstrated improved survival compared to chemotherapy. Many of these studies however excluded patients with brain involvement. Antitumor activity in brain metastasis has now been observed with some agents; further positive data are emerging. Surgery and stereotactic radiotherapy are also used for local control of oligometastatic disease. We discuss the usefulness of the available systemic treatments for management of brain metastases and how these are integrated with local treatments to enable optimal palliation. SUMMARY: Advances in the treatment of melanoma are providing significant palliative benefit for patients with brain metastases. Further investigations are needed to determine optimal treatment combinations and sequences.

Noncutaneous Melanomas: A Single-Center Analysis.

BACKGROUND: The optimal treatment algorithm for noncutaneous melanomas must yet be established. OBJECTIVE: To compare systemic treatment-relevant mutational status, metastatic pattern and response to systemic treatment in noncutaneous melanoma. METHODS: Retrospective single-center study analyzing 64 noncutaneous melanoma patients treated between January 2006 and September 2013. RESULTS: c-KIT mutations were found exclusively in vulvovaginal melanoma (4/7). Overall status for NRAS and BRAF mutations was low (1/7 and 0/21 detected mutations, respectively). Seven out of 7 vulvovaginal and 6/13 sinonasal melanomas first metastasized to lymph nodes, whereas 18/22 ocular melanomas first metastasized to the liver. Response to systemic treatment in vulvovaginal melanomas was best for imatinib with a disease control rate of 3/3 and overall for ipilimumab with a disease control rate of 3/10. Sorafenib was associated with adverse drug reactions (6/13) and poor results. CONCLUSION: Noncutaneous melanomas show few tumor-signaling pathway mutations and distinct metastasization patterns. Immunotherapy induces response rates in mucosal melanoma similar to those in cutaneous melanoma.

Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial.

BACKGROUND: Patients with melanoma that progresses on ipilimumab and, if BRAF(V600) mutant-positive, a BRAF or MEK inhibitor or both, have few treatment options. We assessed the efficacy and safety of two pembrolizumab doses versus investigator-choice chemotherapy in patients with ipilimumab-refractory melanoma. METHODS: We carried out a randomised phase 2 trial of patients aged 18 years or older from 73 hospitals, clinics, and academic medical centres in 12 countries who had confirmed progressive disease within 24 weeks after two or more ipilimumab doses and, if BRAF(V600) mutant-positive, previous treatment with a BRAF or MEK inhibitor or both. Patients had to have resolution of all ipilimumab-related adverse events to grade 0-1 and prednisone 10 mg/day or less for at least 2 weeks, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and at least one measurable lesion to be eligible. Using a centralised interactive voice response system, we randomly assigned (1:1:1) patients in a block size of six to receive intravenous pembrolizumab 2 mg/kg or 10 mg/kg every 3 weeks or investigator-choice chemotherapy (paclitaxel plus carboplatin, paclitaxel, carboplatin, dacarbazine, or oral temozolomide). Randomisation was stratified by ECOG performance status, lactate dehydrogenase concentration, and BRAF(V600) mutation status. Individual treatment assignment between pembrolizumab and chemotherapy was open label, but investigators and patients were masked to assignment of the dose of pembrolizumab. We present the primary endpoint at the prespecified second interim analysis of progression-free survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01704287. The study is closed to enrolment but continues to follow up and treat patients. FINDINGS: Between Nov 30, 2012, and Nov 13, 2013, we enrolled 540 patients: 180 patients were randomly assigned to receive pembrolizumab 2 mg/kg, 181 to receive pembrolizumab 10 mg/kg, and 179 to receive chemotherapy. Based on 410 progression-free survival events, progression-free survival was improved in patients assigned to pembrolizumab 2 mg/kg (HR 0·57, 95% CI 0·45-0·73; p<0·0001) and those assigned to pembrolizumab 10 mg/kg (0·50, 0·39-0·64; p<0·0001) compared with those assigned to chemotherapy. 6-month progression-free survival was 34% (95% CI 27-41) in the pembrolizumab 2 mg/kg group, 38% (31-45) in the 10 mg/kg group, and 16% (10-22) in the chemotherapy group. Treatment-related grade 3-4 adverse events occurred in 20 (11%) patients in the pembrolizumab 2 mg/kg group, 25 (14%) in the pembrolizumab 10 mg/kg group, and 45 (26%) in the chemotherapy group. The most common treatment-related grade 3-4 adverse event in the pembrolizumab groups was fatigue (two [1%] of 178 patients in the 2 mg/kg group and one [<1%] of 179 patients in the 10 mg/kg group, compared with eight [5%] of 171 in the chemotherapy group). Other treatment-related grade 3-4 adverse events include generalised oedema and myalgia (each in two [1%] patients) in those given pembrolizumab 2 mg/kg; hypopituitarism, colitis, diarrhoea, decreased appetite, hyponatremia, and pneumonitis (each in two [1%]) in those given pembrolizumab 10 mg/kg; and anaemia (nine [5%]), fatigue (eight [5%]), neutropenia (six [4%]), and leucopenia (six [4%]) in those assigned to chemotherapy. INTERPRETATION: These findings establish pembrolizumab as a new standard of care for the treatment of ipilimumab-refractory melanoma. FUNDING: Merck Sharp & Dohme.

Curing advanced melanoma by 2025.

PURPOSE OF REVIEW: To outline the most urgent challenges in the management of advanced melanoma. RECENT FINDINGS: Considerable progress in targeted and immunotherapy of advanced melanoma has opened a perspective for a cure if all molecular and medical information is integrated in a rational precision treatment algorithm. SUMMARY: Bioinformatics and system biology approaches will be needed to deal with omics databases. The support of patient advocacy groups may help to increase the acceptance of large scale, routine biobanking.

Nano-particle vaccination combined with TLR-7 and -9 ligands triggers memory and effector CD8⁺ T-cell responses in melanoma patients.

Optimal vaccine strategies must be identified for improving T-cell vaccination against infectious and malignant diseases. MelQbG10 is a virus-like nano-particle loaded with A-type CpG-oligonucleotides (CpG-ODN) and coupled to peptide(16-35) derived from Melan-A/MART-1. In this phase IIa clinical study, four groups of stage III-IV melanoma patients were vaccinated with MelQbG10, given (i) with IFA (Montanide) s.c.; (ii) with IFA s.c. and topical Imiquimod; (iii) i.d. with topical Imiquimod; or (iv) as intralymph node injection. In total, 16/21 (76%) patients generated ex vivo detectable Melan-A/MART-1-specific T-cell responses. T-cell frequencies were significantly higher when IFA was used as adjuvant, resulting in detectable T-cell responses in all (11/11) patients, with predominant generation of effector-memory-phenotype cells. In turn, Imiquimod induced higher proportions of central-memory-phenotype cells and increased percentages of CD127(+) (IL-7R) T cells. Direct injection of MelQbG10 into lymph nodes resulted in lower T-cell frequencies, associated with lower proportions of memory and effector-phenotype T cells. Swelling of vaccine site draining lymph nodes, and increased glucose uptake at PET/CT was observed in 13/15 (87%) of evaluable patients, reflecting vaccine triggered immune reactions in lymph nodes. We conclude that the simultaneous use of both Imiquimod and CpG-ODN induced combined memory and effector CD8(+) T-cell responses.

Targeted therapy in melanoma - the role of BRAF, RAS and KIT mutations.

Melanoma today is considered as a spectrum of melanocytic malignancies characterised by clinical and molecular features, including targetable mutations in several kinases such as BRAF or c-KIT. The successful development of therapies targeting these mutations has resulted in new specific treatment options. These include vemurafenib, dabrafenib, trametinib, imatinib and other kinase inhibitors that are selected when the respective mutation is present. The BRAF inhibitor vemurafenib has resulted in improved survival in patients with BRAF-mutated advanced melanoma. Dabrafenib has shown similar efficacy. The MEK inhibitor trametinib also improved overall survival. In addition, the MEK inhibitor MEK 162 was investigated in a phase II clinical trial and showed promising efficacy in terms of response rate and progression-free survival (PFS) in NRAS-mutated melanomas. After this first success in the treatment of advanced melanoma, there is expectation that combinations of kinase inhibitors will additionally improve overall survival rates and PFS in advanced melanoma.

Chemotherapy after immune checkpoint inhibitor failure in metastatic melanoma: a retrospective multicentre analysis.

INTRODUCTION: Despite remarkably improved outcomes with immune checkpoint inhibition, many patients with metastatic melanoma will eventually require further therapy. Chemotherapy has limited activity when used first-line but can alter the tumour microenvironment and does improve efficacy when used in combination with immunotherapy in lung cancer. Whether chemotherapy after checkpoint inhibitor failure has relevant activity in patients with metastatic melanoma is unknown. METHODS: Patients with metastatic melanoma treated with chemotherapy after progression on immunotherapy with checkpoint inhibitors were identified retrospectively from 24 melanoma centres. Objective response rate (ORR), progression-free survival (PFS), overall survival (OS) and safety were examined. RESULTS: In total, 463 patients were treated between 2007 and 2017. Fifty-six per cent had received PD-1-based therapy before chemotherapy. Chemotherapy regimens included carboplatin + paclitaxel (32%), dacarbazine (25%), temozolomide (15%), taxanes (9%, nab-paclitaxel 4%), fotemustine (6%) and others (13%). Median duration of therapy was 7.9 weeks (0-108). Responses included 0.4% complete response (CR), 12% partial response (PR), 21% stable disease (SD) and 67% progressive disease (PD). Median PFS was 2.6 months (2.2, 3.0), and median PFS in responders was 8.7 months (6.3, 16.3), respectively. Twelve-month PFS was 12% (95% CI 2-15%). In patients who had received anti-PD-1 before chemotherapy, the ORR was 11%, and median PFS was 2.5 months (2.1, 2.8). The highest activity was achieved with single-agent taxanes (N = 40), with ORR 25% and median PFS 3.9 months (2.1, 6.2). Median OS from chemotherapy start was 7.1 months (6.5, 8.0). Subsequent treatment with checkpoint inhibitors achieved a response rate of 16% with a median PFS of 19.1 months (2.0-43.1 months). No unexpected toxicities were observed. CONCLUSION: Chemotherapy has a low response rate and short PFS in patients with metastatic melanoma who have failed checkpoint inhibitor therapy, although activity varied between regimens. Chemotherapy has a limited role in the management of metastatic melanoma.

Outcome of melanoma patients with elevated LDH treated with first-line targeted therapy or PD-1-based immune checkpoint inhibition.

BACKGROUND: Elevated lactate dehydrogenase (LDH) is a known predictive and prognostic factor for a poor outcome in patients with metastatic melanoma. It is unclear whether first-line targeted therapy (TT) or immune checkpoint inhibition (ICI) is more beneficial in melanoma patients with elevated LDH because prospective studies in this area are lacking. METHODS: This multicentre retrospective cohort study was conducted at 25 melanoma centres worldwide to analyse progression-free survival (PFS) and overall survival (OS) among melanoma patients with elevated LDH. The role of confounders was addressed by using inverse probability of treatment weighting. RESULTS: Among 173 BRAFV600-mutant patients, PFS at 12 months in the TT group was 22% compared with 52% in the combined anti-PD-1 and anti-CTLA-4 group (HR 0.6, 95% CI 0.4-1.0, p = 0.07) and 18% in the anti-PD-1 monotherapy group (HR 1.8, 95% CI 1.2-2.8, p = 0.003). Twelve months' OS was 48% in the TT group compared with 83% in the combined anti-PD-1 and anti-CTLA-4 group (HR 0.5, 95% CI 0.3-1.0, p = 0.03) and 50% in the anti-PD-1 monotherapy group (HR 1.2, 95% CI 0.8-2.0, p = 0.37). The ORR in the TT group was 63%, compared with 55% and 20% in the combined anti-PD-1 and anti-CTLA-4 and anti-PD-1 monotherapy group, respectively. Among 314 patients receiving ICI first-line, PFS at 12 months was 33% in the anti-PD-1 group versus 38% in the combined anti-PD-1 and anti-CTLA-4 group (HR 0.8, 95% CI 0.6-1.0; p = 0.07). OS at 12 months was 54% in the anti-PD-1 group versus 66% in the combined ICI group (HR 0.7, 95% CI 0.5-1.0; p = 0.03). The ORR was 30% in the anti-PD-1 monotherapy group and 43% in the combined anti-PD-1 and anti-CTLA-4 group. Results from multivariate analysis confirmed the absence of qualitative confounding. CONCLUSIONS: Among BRAF-mutant patients with elevated LDH, combined anti-PD-1 and anti-CTLA-4 blockade seems to be associated with prolonged OS compared with first-line TT. Among patients receiving ICI as a first-line treatment, OS appears to be longer for the combination of anti-PD-1 and anti-CTLA-4 than for anti-PD-1 alone.