Future perspectives in melanoma research: meeting report from the “Melanoma Bridge”, Napoli, December 5th-8th 2013

The fourth “Melanoma Bridge Meeting” took place in Naples, December 5 to 8th, 2013. The four topics discussed at this meeting were: Diagnosis and New Procedures, Molecular Advances and Combination Therapies, News in Immunotherapy, and Tumor Microenvironment and Biomarkers. Until recently systemic therapy for metastatic melanoma patients was ineffective, but recent research in tumor biology and immunology has led to the development of new targeted and immunotherapeutic agents that prolong progression-free survival (PFS) and overall survival (OS). New therapies, such as mitogen-activated protein kinase (MAPK) pathway inhibitors, like BRAF and MEK inhibitors, as well as other signaling pathways inhibitors, are being tested in metastatic melanoma either as monotherapy or in combination, and have yielded promising results. Improved survival rates have also been observed with immune therapy for patients with metastatic melanoma. Immune-modulating antibodies came to the forefront with anti-CTLA-4, programmed cell death-1 (PD-1) and PD-1 ligand 1 (PD-L1) pathway blocking antibodies that result in durable responses in a subset of melanoma patients. Agents targeting other immune inhibitory (e.g., Tim-3) or immune stimulating (e.g., CD137) receptors and other approaches such as adoptive cell transfer demonstrate clinical benefit in melanoma as well. This meeting’s specific focus was on advances in targeted therapy and immunotherapy. Both combination targeted therapy approaches and different immunotherapies were discussed. Similarly to the previous meetings, the importance of biomarkers for clinical application as markers for diagnosis, prognosis and prediction of treatment response was an integral part of the meeting. Significant consideration was given to issues surrounding the development of novel therapeutic targets as further study of patterns of resistance to both immunologic and targeted drugs are paramount to future drug development to guide existing and future therapies. The overall emphasis on biomarkers supports novel concepts toward integrating biomarkers into contemporary clinical management of patients with melanoma across the entire spectrum of disease stage. Translation of the knowledge gained from the biology of tumor microenvironment across different tumors represents a bridge to impact on prognosis and response to therapy in melanoma

Kernel Penalized K-means: A feature selection method based on Kernel K-means

Artículo de publicación ISIWe present an unsupervised method that selects the most relevant features using an embedded strategy while maintaining the cluster structure found with the initial feature set. It is based on the idea of simultaneously minimizing the violation of the initial cluster structure and penalizing the use of features via scaling factors. As the base method we use Kernel K-means which works similarly to K-means, one of the most popular clustering algorithms, but it provides more flexibility due to the use of kernel functions for distance calculation, thus allowing the detection of more complex cluster structures. We present an algorithm to solve the respective minimization problem iteratively, and perform experiments with several data sets demonstrating the superior performance of the proposed method compared to alternative approaches.FONDECYT project 11121196 1140831 Complex Engineering Systems Institute ICM: P-05-004-F CONICYT: FB016 Ministerio de Economia y Competitividad MTM2012-36163-C06-03 Junta de Andalucia P11-FQM-7603 FQM 32

Palbociclib (P) in patients (pts) with head and neck cancer (HNC) with CDKN2A loss or mutation: Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) study

6043 Background: TAPUR is a phase II basket study evaluating anti-tumor activity of commercially available targeted agents in pts with advanced cancers with genomic alterations. Results in a cohort of HNC pts with CDKN2A loss or mutation treated with P are reported. Methods: Eligible pts had advanced HNC, no standard treatment options, measurable disease, ECOG PS 0-2, and adequate organ function. Genomic testing was performed in CLIA-certified, CAP-accredited site selected labs. Pts received P at 125 mg orally once daily for 21 days, followed by 7 days off until disease progression. Pts matched to P had CDKN2A loss or mutation and no RB mutations. Simon 2-stage design tested the null disease control (DC) - defined as partial (PR), complete response (CR) or stable disease at 16+ weeks (SD 16+) - rate of 15% vs. 35% (power = 0.85; α = 0.10). If ≥2 of 10 pts in stage 1 have DC, 18 more pts are enrolled. If ≥7 of 28 pts have DC, the null DC rate is rejected. Secondary endpoints are progression-free survival (PFS), overall survival (OS) and safety. Results: 28 pts (64% male) with HNC with CDKN2A loss (20 pts) or mutation (8 pts) were enrolled from June 2016 to Sept 2019. All were eligible for efficacy and toxicity. Demographics and outcomes are summarized in Table. No objective response (OR) and 10 pts with SD16+ (9 with CDKN2A loss, 1 with mutation) were observed for a DC rate of 37% (95% CI: 21%, 50%); the null DC rate of 15% was rejected (p=0.005). 14 pts had at least one grade 3-5 adverse or serious adverse event (AE/SAE) at least possibly related to P with the most common being low WBC/platelets. Other grade 3-4 AEs included anemia, fatigue, hypocalcemia, and syncope. There was one pt with grade 5 respiratory failure likely due to extensive lung metastases and aspiration but P-related pneumonitis could not be ruled out. Conclusions: Monotherapy P demonstrated modest anti-tumor activity and clinically significant AEs in heavily pre-treated pts with HNC with CDKN2A loss or mutation. Additional study is warranted to confirm the efficacy of P in pts with HNC with CDKN2A loss or mutation. Clinical trial information: NCT02693535. [Table: see text