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.

Background: Covid-19 pandemic by the new coronavirus SARS-Cov-2 has produced devastating effects on the health care system, affecting also cancer patient care. Data about COVID-19 infection in cancer patients are scarce, and they point out a higher risk of complications due to the viral infection in this population. Moreover, cancer treatments could increase viral complications, specially those treatments based on the use of immunotherapy with checkpoints antibodies. There are no clinical data about the safety of immune check point antibodies in cancer patients when they become infected by SARS-CoV-2. As checkpoint inhibitors, mainly anti PD-1 and anti CTLA-4 antibodies, are an effective treatment for most melanoma patients, avoiding their use during the pandemic could lead to a decrease in the chances of curing melanoma. Methods: In Spain we have started a national registry of melanoma patients infected by SARS-Cov-2 since April 1st, 2020. A retrospective analysis of patients included in the Spanish registery has been performed weekly since the activation of the study. Interim analysis shows unexpected findings about cancer treatment safety in SARS-Cov-2 infected melanoma patients, so a rapid communication to the scientific community is mandatory Results: Fifty patients have been included as of May 17th, 2020. Median age is 69 years (range 6 to 94 years), 27 (54%) patients are males and 36 (70%) patients have stage IV melanoma. Twenty-two (44%) patients were on active anticancer treatment with anti PD-1 antibodies, 16 (32%) patients were on treatment with BRAF plus MEK inhibitors and 12 (24%) patients were not on active cancer treatment. COVID-19 episode has been resolved in 43 cases, including 30 (70%) patients cured, four (9%) patients that have died due to melanoma progression, and nine (21%) patients that have died from COVID-19. Mortality rates from COVID-19 according to melanoma treatment type were 16%, 15% and 36% for patients on immunotherapy, targeted drugs, and for those that were not undergoing active cancer treatment, respectively. Conclusion: These preliminary findings show that the risk of death in those patients undergoing treatment with anti PD-1 antibodies does not exceed the global risk of death in this population. These results could be relevant in order to select melanoma therapy during the COVID-19 pandemic

Purpose: Combined BRAF/MEK inhibition with encorafenib (E) plus binimetinib (B) has demonstrated efficacy and tolerability in phase III clinical trials, and is the standard of care for advanced/metastatic BRAF^V600-mutant melanoma. However, real-life evidence is limited, particularly in patients pre-treated with immune checkpoint inhibitors (ICI).Patients and methods: BECARE GEM 2002 was a retrospective, non-interventional study aimed at investigating the real-world effectiveness and tolerability of EB in patients with unresectable or metastatic BRAF^V600-mutant melanoma conducted at 21 sites in Spain. The primary objective of this study was to characterise the population of patients receiving EB and assess the efficacy and tolerability of EB in real life. The study included patients treated according to standard clinical practice with EB as the 1^st line or 2^nd line after progression to ICI for an unresectable or metastatic stage. Patients who previously received treatment with BRAF and/or MEK inhibitor, other than as adjuvants, that ended ≥ 6 m before EB were not eligibleResults: From September 2021 to March 2023, 117 patients were included; 89 (76.1%) and 28 (23.9%) patients received EB as 1^st line and 2^nd line, respectively. The median follow-up was 13.8 months (95% CI: 12.0-17.4). In patients with EB as 1^st line treatment, ORR and median PFS were 75% and 12 months (95% CI: 9.4-18.6), respectively. In patients with EB as 2^nd line treatment after ICI, ORR and median PFS were 77.8% and 12.5 months (95% CI: 6.6-NA), respectively. In patients with brain metastasis ORR and median PFS were 70.8% and 6.3 months (95% CI: 6.1-10.3). Treatment-related adverse events of grade ≥3 were reported in 17 (14.5%) patients; transaminitis (9.4%) and diarrhoea (2.6%) were the most frequent adverse events.Conclusion: In this real-world study, EB treatment demonstrated effectiveness and a consistent safety profile in patients with BRAF^V600-mutant melanoma treated according to standard clinical practice, including in those with prior ICI treatment and of brain metastasis; therefore, EB is a feasible treatment option for unresectable and metastatic melanoma.Clinical trial identification: REec: 0004-2021-OBSClinical trial identification: REec: 0004-2021-OBS.

With ever-increasing incidence and high metastatic potential, cutaneous melanoma is the deadliest skin cancer. Risk prediction based on the Tumor-Node-Metastasis (TNM) staging system has medium accuracy with intermediate IIB-IIIB stages, as roughly 25% of patients with low-medium-grade TNM, and hence a favorable prognostic, undergo an aggressive disease with short survival and around 15% of deaths arise from metastases of thin, low-risk lesions. Therefore, reliable prognostic biomarkers are required. We used genomic and clinical information of melanoma patients from the TCGA-SKCM cohort and two GEO studies for discovery and validation of potential biomarkers, respectively. Neither mutation nor overexpression of major melanoma driver genes provided significant prognostic information. Conversely, expression of MGRN1 and the melanocyte-specific genes MLANA, PMEL, and TYRP1 provided a simple 4-gene signature identifying with high-sensitivity (>80%), low-medium TNM patients with adverse outcomes. Transcriptomic analysis of tumors with this signature, or from low-medium-grade TNM patients with poor outcomes, revealed comparable dysregulation of an inflammatory response, cell cycle progression, and DNA damage/repair programs. A functional analysis of MGRN1-knockout cells confirmed these molecular features. Therefore, the simple MGRN1-MLANA-PMEL-TYRP1 combination of biomarkers complemented TNM staging prognostic accuracy and pointed to the dysregulation of immunological responses and genomic stability as determinants of a melanoma outcome.

Background: Venous thromboembolism (VTE) is one of the leading causes of death in patients with cancer. Currently, there is a need to develop an easily applicable risk model that can identify patients who will benefit from receiving primary thromboprophylaxis to reduce the incidence of VTE. Patients and methods: This was a non-interventional, multicenter, observational, prospective study carried out in 62 Oncology and Hematology services in Spain and Portugal between January 2018 and December 2019. The main objective of the CARTAGO study was to develop a predictive model within a competitive risk framework to assess the risk of VTE in patients with cancer undergoing chemotherapy, biological, or hormonal treatment. Results: A total of 1596 patients were analyzed. VTE events occurred in 124 (8%) during the 6-month follow-up period (42% of deep vein thrombosis [DVT], 48% of pulmonary embolism [PE], and 10% of both DVT and PE). Four variables were selected for the multivariate predictive model to determine the risk of VTE (tumor type, D-dimer, compression of a vessel by the tumor, and leukocyte count). The 4 variables were associated with an increased risk of VTE (C-statistic, 0.646 [95%CI, 0.620-0.673]). The most significant variables in the internal validation with bootstrapping were the “very high risk” tumors (hazard ratio [HR] 2.032; 95%CI, 1.287-3.211). Conclusion: The CARTAGO model predicts the VTE risk in patients with cancer receiving anticancer therapy in an outpatient setting. This model can easily aid in identifying ambulatory patients who would probably benefit from primary thromboprophylaxis.