Background Randomised trials recently showed that sequencing of first-line (1L) immune checkpoint inhibitor (ICI) and second-line (2L) BRAF-MEK-inhibitor (BRAF/MEKi) combination therapy provides better clinical outcomes in BRAFV600-mutated, irresectable/metastatic melanoma than the inverse sequence. However, efficacy benchmark data for 2L BRAF/MEKi are limited as the combination was developed for 1L use, lacking estimates for the impact of prior ICI. Methods This retrospectively study analysed 2,343 patients from the EUMelaReg registry with BRAFV600-mutated melanoma who received BRAF/MEKi either as 2L after failing 1L ICI (n=654) or as 1L treatment (n=1,689). Patients with prior adjuvant ICI or BRAF/MEKi were excluded. Prognostic imbalances between the two groups were adjusted using 1:1 inverse propensity score matching. Key efficacy outcomes included overall survival (OS), progression-free survival (PFS), overall response rate (ORR), and time on treatment (TOT). Results Patients in the 2L cohort achieved outcomes from start of treatment at least equivalent to the matched 1L BRAF/MEKi cohort. Kaplan-Meier estimates demonstrated longer median PFS (8.4 vs 7.7 months; p=0.01) and longer median TOT (7.8 vs 6.2 months; p=0.002) for patients treated with 2L BRAF/MEKi compared to 1L. Median OS from start of 2L (17.2 months) or 1L (16.0 months) BRAF/MEKi was similar (p=0.73) despite inherent bias from differing index dates. ORR among both groups (56.4% vs 53.5%; p=0.32) was equal. Conclusion This study further supports the recommended sequencing of ICI as 1L and BRAF/MEKi as 2L therapy for patients with BRAFV600-mutated melanoma. It shows that prior failure of ICI does not compromise the efficacy of BRAF/MEKi treatment.

Acral melanoma (AM) is uncommon in non-Asian race. Limited data exist in non-Asian population. To analyze the activity of immunotherapy in patients diagnosed with AM in Spain. We analyzed clinical outcomes of AM in the nationwide Spanish Melanoma Group Registry. 69 AM (17 stage III; 52 stage IV) and 724 cutaneous melanoma (CM) (190 stage III; 534 stage IV), predominantly non-Hispanic white. Regarding stage IV, AM patients were older (median 73.6 vs. 66.6 years, p = 0.001) and less often BRAF mutant (9.6

PURPOSE:Patients with anti-PD-1-resistant melanoma (MEL) have no well-defined standard of care. BO-112 is a synthetic, double-stranded RNA (poly I:C) nanoplexed with polyethylenimine that when administered intratumorally has showed in patients with solid tumors potential to revert this resistance. We report efficacy and safety of the phase II clinical trial of intratumoral BO-112 plus intravenous pembrolizumab for patients with anti-PD-1-resistant MEL (ClinicalTrials.gov identifier: NCT04570332). METHODS:Forty-two patients were treated with intratumoral BO-112 once every week for 7 weeks and then once every 3 weeks (up to 2 mg and up to eight lesions per treatment) combined with 200 mg pembrolizumab once every 3 weeks until progressive disease, unacceptable toxicity, death, or up to 1 year. Primary end point was RECIST 1.1 objective response rate (ORR) by independent central radiology review in modified intention-to-treat population (mITT; patients evaluable for response) with 20% ORR positivity threshold. Secondary key end points were progression-free survival (PFS), overall survival (OS), duration of response (DOR), and safety. RESULTS:For mITT, there were 40 patients and the ORR was 25%, with 10% complete, 15% partial, and 40% stable disease, with nonachieved (NA) median DOR (95% CI, 8.3 to NA). For ITT, there were 42 patients, and the median PFS and OS were 3.7 months (95% CI, 2.2 to 9.2) and NA (95% CI, 9.9 to NA), respectively, with 54% patients alive at 24 months. The combination was well tolerated: 16 patients (38.1%) experiencing ≥G3-4 adverse events, four (9.5%) drug-related, and no deaths related to treatment. CONCLUSION:The clinical trial has met its primary end point (ORR) making BO-112 with pembrolizumab a potential strategy to revert anti-PD-1 resistance in patients with MEL. PFS results are in line with other clinical trials in anti-PD-1-resistant scenario, with promising OS data.

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.

Background: BRAF p.V600 mutation is the most frequent molecular driver alteration in melanoma. Detection of BRAF mutations in circulating-free DNA (cfDNA) reflects the shedding of tumor DNA and offers a potential noninvasive biomarker for disease monitoring and prognosis. However, the lack of standardized methodologies and inter-assay variability hinders its clinical implementation. Methods: The sensitivity, agreement and concordance of seven BRAF mutation detection assays were assessed across four laboratories. BRAF p.V600 mutation in pretreatment plasma samples was analyzed in 51 patients diagnosed with advanced stage melanoma using two digital PCR-based assays (droplet digital PCR-ddPCR-Bio-Rad and microfluidic digital PCR-Absolute Q, ThermoFisher Scientific-), three RT-PCR based assays (Idylla (R), Cobas (R), PNA-Q-PCR) and two NGS based assays (OncomineTM Pan-Cancer Cell-Free Assay and Illumina Platforms). Results: digital PCR-based assays and Cobas (R) exhibited the highest sensitivity (51.0 %), followed by NGS Illumina (R) (45.1 %), Oncomine NGS / PNA-Q-PCR (43.1 %) and Idylla (R) (37.2 %). Results of different techniques showed a moderate to strong agreement, except for the comparison of Cobas with Idylla that was poor (Kappa=0.57). There was near-perfect agreement on detection of BRAF mutation between both NGS platforms and the NGS Illumina (R) with PNA-Q-PCR (Kappa = 0.92). Concordance of the quantitative results in terms of mutant allele frequency was near-perfect between NGS Illumina and ddPCR Bio-Rad assays (ICC = 0.99). Conclusions: Our study demonstrates substantial agreement among multiple cfDNA BRAF mutation detection assays, particularly between NGS and digital PCR assays. These findings support the potential utility of different techniques for BRAF testing in cfDNA.

PURPOSE:Anti-PD-1-based immunotherapy and targeted therapies (TT) are the current standard of care for patients with advanced melanoma. However, some patients die in less than a year from diagnosis and others become long-survivors. An accurate description of systemic treatments and patients' characteristics of long-term survivors are needed to guide treatment decisions in clinical practice. METHODS:GEM-1801 is a multi-cohort prospective study from the Spanish Multidisciplinary Melanoma Group that includes patients with resectable stage III or unresectable stage III/IV melanoma. Patients surviving at least 5 years and patients surviving less than 1 year since diagnosis were selected. Baseline characteristics and first and second-line systemic treatments are described and compared between groups. RESULTS:From Aug 2018 to Dec 2023, 60 patients with long-term survival and 216 patients with short-term survival were included. Long-term survivors received immunotherapy (65%), including anti-PD-1 in 86% and combination of an anti-PD-1 and anti-CTLA-4 in 14%; and TT (35%). The Objective Response Rate (ORR) was 76% for anti-PD-1, 80% for combination immunotherapy and 83% for TT. Short-term survivors received immunotherapy (58%), including anti-PD-1 (70%), anti-CTLA-4 (1%), and anti-PD-1 plus anti-CTLA-4 (29%); TT (36%); and chemotherapy (2%). ORR was 7% for anti-PD-1, 0% for anti-CTLA-4, 14% for combination immunotherapy, 53% for TT and 0% for chemotherapy. CONCLUSIONS:Response to first or second-line systemic treatment may be a surrogate for long-term survival patients with advanced melanoma. CLINICAL TRIAL IDENTIFICATION:Clinicaltrials.gov: NCT03605771.

The phase III KEYNOTE-913 study was conducted to evaluate the efficacy and safety of pembrolizumab as first-line therapy in patients with advanced Merkel cell carcinoma (MCC). The aim was to report results from the primary analysis of KEYNOTE-913. Patients with recurrent locally advanced or metastatic MCC received pembrolizumab 200 mg intravenously every 3 weeks for up to 35 treatments ( 2 years). The primary end point was objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1) by blinded independent central review (BICR). Secondary end points were duration of response (DOR) and progression-free survival (PFS) per RECIST v1.1 by BICR, overall survival (OS), and safety and tolerability. Fifty-five patients were treated with pembrolizumab. The median time from first dose to data cutoff (February 15, 2024) was 50.3 months (range 38.7–59.4). The ORR was 49

Representativeness of Study Participants

BACKGROUND:There are gaps and unanswered questions in clinical guidelines regarding several aspects of the management of patients with cutaneous squamous cell carcinoma (cSCC). METHODS:A scientific committee of ten cSCC specialists in Spain (dermatology, medical oncology, oral and maxillofacial surgery, plastic surgery, and radiotherapy) used ADAPTE methodology to develop recommendations by: (i) identifying clinical questions not fully answered by clinical practice guidelines; (ii) systematically reviewing the literature (published between November 2017 and July 2023 in PubMed and the Cochrane database) and grading the evidence (using Oxford levels); (iii) developing recommendations and assessing those with no consensus among the scientific committee or with evidence level 3-5 or strength of recommendation under C or D in a two-round Delphi method; and (iv) developing the final recommendations in the form of answers to key clinical questions, grading the strength of recommendation. An external group of 32 experts plus the members of the committee participated in both Delphi rounds, evaluating the appropriateness and need of the recommendations. RESULTS:Initially, 33 recommendations were made for 26 questions; 19 recommendations were evaluated with the Delphi method. All 19 recommendations were deemed appropriate and necessary. A total of 27 final recommendations were made, concerning initial patient management, treatment of the primary tumour, management of advanced disease, specific populations, supportive and palliative care, and follow-up. CONCLUSION:We developed 27 recommendations that answer clinical questions on the management of patients with cSCC, providing guidance on aspects that are unclear in clinical guidelines or on which guidelines differ.

Cutaneous melanoma incidence is rising. Early diagnosis and treatment administration are key for increasing the chances of survival. For patients with locoregional advanced melanoma that can be treated with complete resection, adjuvant-and more recently neoadjuvant-with targeted therapy-BRAF and MEK inhibitors-and immunotherapy-anti-PD-1-based therapies-offer opportunities to reduce the risk of relapse and distant metastases. For patients with advanced disease not amenable to radical treatment, these treatments offer an unprecedented increase in overall survival. A group of medical oncologists from the Spanish Society of Medical Oncology (SEOM) and Spanish Multidisciplinary Melanoma Group (GEM) has designed these guidelines, based on a thorough review of the best evidence available. The following guidelines try to cover all the aspects from the diagnosis-clinical, pathological, and molecular-staging, risk stratification, adjuvant therapy, advanced disease therapy, and survivor follow-up, including special situations, such as brain metastases, refractory disease, and treatment sequencing. We aim help clinicians in the decision-making process.

BACKGROUND:Encorafenib plus binimetinib (EB) is a standard-of-care treatment for advanced BRAFV600-mutant melanoma. We assessed the efficacy and safety of encorafenib plus binimetinib in patients with BRAFV600-mutant melanoma and brain metastasis (BM) and explored if radiotherapy improves the duration of response. METHODS:E-BRAIN/GEM1802 was a prospective, multicenter, single-arm, phase II trial that enrolled patients with melanoma BRAFV600-mutant and BM. Patients received encorafenib 450 mg once daily plus binimetinib 45 mg BID, and those who achieved a partial response or stable disease at first tumor assessment were offered radiotherapy. Treatment continued until progression. Primary endpoint was intracranial response rate (icRR) after 2 months of EB, establishing a futility threshold of 60%. RESULTS:The study included 25 patients with no BM symptoms and 23 patients with BM symptoms regardless of using corticosteroids. Among them, 31 patients (64.6%) received sequential radiotherapy. After 2 months, icRR was 70.8% (95% CI: 55.9-83.1); 10.4% complete response. Median intracranial progression-free survival (PFS) and OS were 8.5 (95% CI: 6.4-11.8) and 15.9 (95% CI: 10.7-21.4) months, respectively (8.3 months for icPFS and 13.9 months OS for patients receiving RDT). Most common grades 3-4 treatment-related adverse event was alanine aminotransferase (ALT) increased (10.4%). CONCLUSIONS:Encorafenib plus binimetinib showed promising clinical benefit in terms of icRR, and tolerable safety profile with low frequency of high-grade TRAEs, in patients with BRAFV600-mutant melanoma and BM, including those with symptoms and need for steroids. Sequential radiotherapy is feasible but it does not seem to prolong response.

BACKGROUND:Novel and highly effective drugs for non-melanoma skin cancer (NMSC) improve patient outcomes, but their high cost strains healthcare systems. Spain's decentralized public health system, managed by 17 autonomous communities (AaCc), raises concerns about equitable access. METHODS:A cross-sectional survey (July-September 2023) was sent to Spanish Multidisciplinary Melanoma Group (GEM Group) members to assess access to new drugs. FINDINGS:Fifty physicians from 15 Spanish AaCc responded to the survey. Access for drug with approved public reimbursement, Hedgehog inhibitors in basal-cell carcinoma and anti PD-L1 antibody in Merkel carcinoma, was observed in 84% and 86% of centers, respectively. For other EMA-approved treatments, but without reimbursement in Spain access decreased to 78% of centers. Heterogeneity in access was mainly observed intra regions. CONCLUSION:Unequal financial support for drugs for NMSC with creates a patchwork of access across Spanish hospitals, with variations even within the same AaCc.

BACKGROUND:The development of highly active drugs has improved the survival of melanoma patients, but elevated drug prices place a significant burden on health care systems. In Spain, the public health care system is transferred to the 17 autonomous communities (AACC). The objective of this study is to describe the situation of drug access for melanoma patients in Spain and how this decentralized system is affecting equity. METHODS:From July to September 2023, a cross-sectional survey was sent to members of the Spanish Multidisciplinary Melanoma Group (GEM Group). The questionnaire consulted about the real access to new drugs in each hospital. The responses were collected anonymously and analyzed according to several variables, including the AACC. RESULTS:The survey was answered by 50 physicians in 15 AACC. No major differences on access between AACC were observed for indications that are reimbursed by the Spanish Health Care System (adjuvant immunotherapy for stage IIIC-IIID and resected stage IV melanoma). Important differences in drug access were observed among AACC and among centers within the same AACC, for most of the EMA indications that are not reimbursed (adjuvant immunotherapy for stages IIB-IIC-IIIA-IIIB) or that are not fully reimbursed (ipilimumab plus nivolumab in advanced stage). Homogeneously, access to adjuvant targeted drugs, TIL therapy and T-VEC, is extremely low or non-existing in all AACC. CONCLUSIONS:For most indications that reimbursement is restricted out of the EMA indication, a great diversity on access was found throughout the different hospitals in Spain, including heterogeneity intra-AACC.

9559 Background: PD-1 inhibitors such as pembro are a standard-of-care option for advanced melanoma, and effective treatments are needed for disease that progresses on anti–PD-(L)1–based therapy. Previous results from the single-arm, open-label, phase 2 LEAP-004 study (NCT03776136) showed that len + pembro had antitumor activity in patients (pts) with advanced melanoma that progressed on prior anti–PD-(L)1–based therapy. With a median follow-up of 15.3 mo, the ORR was 21.4% and median DOR was 8.3 mo. Results from LEAP-004 led to the inclusion of len + pembro in treatment guidelines for pts with advanced melanoma and confirmed progression on a PD-(L)1 inhibitor. Here, we present results from LEAP-004 with over 4 years of follow-up. Methods: Eligible pts were aged ≥18 years, had unresectable stage III or IV melanoma, had ≥1 measurable lesion, had an Eastern Cooperative Oncology Group performance status of 0 or 1, and had confirmed disease progression within 12 weeks of the last dose of anti–PD-(L)1 therapy given alone or in combination for ≥2 doses. All pts received len 20 mg PO QD + ≤35 doses of pembro 200 mg IV Q3W. The primary end point was ORR per RECIST v1.1 by BICR. Secondary end points included DOR and PFS per RECIST v1.1 by BICR, OS, and safety. Results: 103 pts were enrolled and received treatment. Median time from first dose to data cutoff (Oct 11, 2023) was 52.0 months (range, 48.8-55.7). ORR in the overall population was 24.3% (95% CI, 16.4-33.7), with 5 pts (4.9%) having a complete response and 20 (19.4%) a partial response. In key subgroups, ORR was 33.3% (10/30; 95% CI, 17.3-52.8) in pts with progression on prior anti–PD-1 + anti–CTLA-4 therapy and 10.7% (3/28; 95% CI, 2.3-28.2) in pts with BRAF-mutant tumors who received prior BRAF/MEK-directed therapy for metastatic disease. Median DOR in the overall population was 8.5 mo (range, 3.2-40.8) and an estimated 35% of responders remained in response at ≥12 mo. Median PFS was 4.2 mo (95% CI, 3.5-6.3); 24-mo PFS rate was 10.1%. Median OS was 14.0 mo (95% CI, 10.8-18.3); 24-mo OS rate was 29.7%. Efficacy outcomes in pts with mucosal (n = 11) and acral lentiginous (n = 8) melanoma were consistent with the overall population. Any-grade treatment-related AEs occurred in 99 pts (96.1%). Grade 3-5 treatment-related AEs occurred in 51 pts (49.5%). No new treatment-related deaths occurred since prior analysis (1 pt had died because of treatment-related decreased platelet count). Conclusions: With over 4 years of follow up, len + pembrocontinued to show antitumor activity in pts with advanced melanoma and confirmed progression after ≥2 doses of anti–PD-(L)1-based therapy. Safety remained consistent with previous reports, with no new or unexpected safety signals. These results support len + pembro as a potential treatment option for advanced melanoma after anti–PD-(L)1-based therapy. Clinical trial information: NCT03776136 .

Introduction:Advanced malignant melanoma is a very aggressive disease, historically with poor prognosis before the new advances with immunotherapy and targeted therapies that have changed the standard of care, especially in cutaneous melanoma. Peru has aggressive features such as higher rates of acral lentiginous melanoma (ALM) subtype with historically shorter survival. Methods:This study describes Peruvian patients with advanced melanoma treated with immunotherapy (nivolumab) in two oncological institutions (public and private), including the discussion of the impact on overall survival (OS) divided by subtype (with incidence in ALM histology) and potential biomarkers that could be related to prognosis. Results:We found that immunotherapy is safe, and improves progression-free survival (PFS), OS and objective response rate (ORR) in our patients, with lower benefit in ALM histology. No prognostic blood inflammatory biomarkers were detected. Discussion:There is very limited data of Peruvian patients with metastatic melanoma treated with immunotherapy, especially the outcomes in ALM histology. Our goal is to share an example of the impact of immunotherapy in a Latin American (LATAM) population considered as an unsatisfied group with an enormous need of novel treatments and biomarkers.

Representativeness of Study Participants