It is uncertain whether drugs approved by the US Food and Drug Administration (FDA) have clinically meaningful benefit as determined by validated scales such as the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS). We searched the Drugs@FDA website for applications of anticancer drugs from January 2006 to December 2016. Study characteristics, outcomes, and regulatory pathways were collected from drug labels and reports of registration trials. For randomized controlled trials (RCTs), ESMO-MCBS grades were applied. Meaningful benefit was defined as a grade of A or B for (neo)adjuvant intent and 4 or 5 for palliative intent. All statistical tests were two-sided. We identified 63 individual drugs for 118 indications. These were supported by 135 studies, among which were 105 RCTs for which ESMO-MCBS could be applied. Only 46 (43.8%) met the ESMO-MCBS meaningful benefit threshold (100% of (neo)adjuvant trials and 38.8% of palliative trials). In palliative therapy trials, meaningful ESMO-MCBS grades were associated with phase III trials (compared with phase II; odds ratio [OR] = 38.45, 95% confidence interval [CI] = 3.27 to 452.00, P = .004), those with overall survival as their primary end point (compared with intermediate end points; OR = 8.28, 95% CI = 2.49 to 27.50, P = .001) and trials of targeted drugs with companion diagnostics (OR = 11.62, 95% CI = 2.95 to 45.78, P < .001). Over time, there has been an increase in the number of trials meeting the ESMO-MCBS threshold (P_trend = .04). There were insufficient (neo)adjuvant studies to perform statistical analysis. The number of trials meeting the ESMO-MCBS threshold for clinical benefit has improved over time. However, fewer than half of RCTs supporting FDA approval meet the threshold for clinically meaningful benefit.

Background: Immune-related adverse events (irAEs) have been associated with improved efficacy in advanced non-small cell lung cancer (NSCLC) patients receiving anti-PD-(L)1 blockade agents, while the concurrent use of corticosteroids seems to worsen it. We evaluated outcomes in advanced NSCLC patients treated with anti-PD-(L)1 blockade agents in relation to the presence of irAEs and the reasons for using corticosteroids: whether for palliative cancer-related reasons or for the management of irAEs.

Uveal melanoma (UM) is a malignant tumor that arises in the melanocytes of the uveal tract. It is the most frequent eye cancer, and despite new therapeutic approaches, prognosis is still poor, with up to 50% of patients developing metastasis with no efficient treatment options available. In contrast to cutaneous melanoma, UM is considered an “immune-cold” tumor due to the low mutational burden and the unique immunosuppressive microenvironment. To gain insight into the role of the UM microenvironment in regard to prognosis and metastatic progression, we have performed a pool analysis characterizing the UM microenvironment by using a bioinformatic approach. A variety of scores based on gene expression measuring stromal infiltration were calculated and used to assess association with prognosis. As a result, the highest immune and stromal scores were associated with poor prognosis. Specifically, stromal cells (fibroblasts and endothelial cells), T cells CD8+, natural killer (NK) cells, and macrophages M1 and M2 infiltration were associated with poor prognosis. Contrary to other tumors, lymphocytic infiltration is related to poor prognosis. Only B cells were associated with more favorable prognosis. UM samples scoring high in both angiogenesis (Angio) and antigen presentation (AP) pathways showed a poor prognosis suggesting an additive role of both functions. Almost all these tumors exhibited a chromosome 3 monosomy. Finally, an enrichment analysis showed that tumors classified as high Angio-high AP also activated metabolic pathways such as glycolysis or PI3K-AKT-MTOR. In summary, our pool analysis identified a cluster of samples with angiogenic and inflammatory phenotypes exhibiting poor prognosis and metabolic activation. Our analysis showed robust results replicated in a pool analysis merging different datasets from different analytic platforms.

3064Background: ICIs are associated with irAEs. We describe the incidence of irAEs in patients with solid tumors receiving ICIs and its correlation with efficacy. Methods: We retrospectively analyzed all patients with solid tumors receiving ICIs in our center. IrAEs were graded according CTCAE v4.0. Kaplan Meier and log-rank tests were used to evaluate progression-free (PFS) and overall survivals (OS). Analyses were performed using SPSS v24 package. Results: From March 2014 to January 2018, 178 patients received ICIs. Median age was 64.1 [33-88] years, 72% were male. Most frequent tumors were lung (63.5%), bladder (14.6%) and melanoma (11.8%). 96% presented advanced disease. Most common used ICIs were nivolumab (38.2%), pembrolizumab (28.7%) and atezolizumab (17.4%). ICIs were used as monotherapy (74.7%) or in combination with ICI (3.4%), chemotherapy (17.4%) or targeted therapies (4.5%). Median duration of immunotherapy was 6.9 [0.7-46.3] months. 95 (53.4%) patients developed 158 irAEs with a median numb...

Uveal melanoma (UM) is the most common intraocular cancer in adults, with metastatic disease (mUM) occurring in approximately half of the patients. Tebentafusp, an immune-mobilizing monoclonal T cell receptor against cancer (ImmTAC), is a therapeutic shown to improve overall survival (OS) in HLA-A*02:01⁺ adult patients with mUM. Here we investigate the impact of tumor-associated macrophages (TAM) on ImmTAC activity. In vitro, M2 macrophages inhibit ImmTAC-mediated tumor-killing in a dose-dependent and contact-dependent manner. Accordingly, high baseline intratumoral TAM-to-T cell ratios correlate with shorter OS (HR = 2.09, 95% CI, 1.31–3.33, p = 0.002) in tebentafusp-treated mUM patients from a phase 2 trial. By contrast, IL-2 conditioning of T cells overcomes M2 macrophage-mediated suppression in vitro, while ImmTAC treatment leads to M2-to-M1 macrophage reprogramming both in vitro and in tebentafusp-treated mUM patients. Overall, we show that tebentafusp reshapes the tumor microenvironment to enhance anti-tumor T cell activity, whilst combining tebentafusp with IL-2 may enhance benefit in patients with high levels of TAM.