Background: Uveal melanoma is a disease that is distinct from cutaneous melanoma, with a low tumor mutational burden and a 1-year overall survival of approximately 50% in patients with metastatic uveal melanoma. Data showing a proven overall survival benefit with a systemic treatment are lacking. Tebentafusp is a bispecific protein consisting of an affinity-enhanced T-cell receptor fused to an anti-CD3 effector that can redirect T cells to target glycoprotein 100-positive cells. Methods: In this open-label, phase 3 trial, we randomly assigned previously untreated HLA-A*02:01-positive patients with metastatic uveal melanoma in a 2:1 ratio to receive tebentafusp (tebentafusp group) or the investigator's choice of therapy with single-agent pembrolizumab, ipilimumab, or dacarbazine (control group), stratified according to the lactate dehydrogenase level. The primary end point was overall survival. Results: A total of 378 patients were randomly assigned to either the tebentafusp group (252 patients) or the control group (126 patients). Overall survival at 1 year was 73% in the tebentafusp group and 59% in the control group (hazard ratio for death, 0.51; 95% confidence interval [CI], 0.37 to 0.71; P<0.001) in the intentionto-treat population. Progression-free survival was also significantly higher in the tebentafusp group than in the control group (31% vs. 19% at 6 months; hazard ratio for disease progression or death, 0.73; 95% CI, 0.58 to 0.94; P = 0.01). The most common treatment-related adverse events in the tebentafusp group were cytokine-mediated events (due to T-cell activation) and skin-related events (due to glycoprotein 100-positive melanocytes), including rash (83%), pyrexia (76%), and pruritus (69%). These adverse events decreased in incidence and severity after the first three or four doses and infrequently led to discontinuation of the trial treatment (2%). No treatment-related deaths were reported. Conclusions: Treatment with tebentafusp resulted in longer overall survival than the control therapy among previously untreated patients with metastatic uveal melanoma. (Funded by Immunocore; ClinicalTrials.gov number, NCT03070392; EudraCT number, 2015-003153-18.).

The utility of circulating tumor DNA (ctDNA) as a biomarker in patients with advanced cancers receiving immunotherapy is uncertain. We therefore analyzed pretreatment (n=978) and on-treatment (n=171) ctDNA samples across 16 advanced stage tumor types from three phase I/II trials of durvalumab (± anti-CTLA-4 therapy tremelimumab).Higher pretreatment variant allele frequencies (VAF) were associated with poorer overall survival and other known prognostic factors, but not objective response, suggesting a prognostic role for patient outcomes. On-treatment reductions in VAF and lower on-treatment VAF were independently associated with longer PFS and OS, and increased ORR, but not prognostic variables, suggesting that on-treatment ctDNA dynamics are predictive of benefit from immune checkpoint blockade. Accordingly, we propose a concept of "molecular response" using ctDNA, incorporating both pretreatment and on-treatment VAF that predicted long-term survival similarly to initial radiological response, while also permitting early differentiation of responders among patients with initially radiologically stable disease. SignificanceIn a pan-cancer analysis of immune checkpoint blockade, pretreatment ctDNA levels appeared prognostic and on-treatment dynamics predictive. A "molecular response" metric identified long-term responders and adjudicated benefit among patients with initial radiologically stable disease. Changes in ctDNA may be more dynamic than radiographic changes and could complement existing trial endpoints.

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Introduction: Durvalumab is a selective, high-affinity human immunoglobulin G1 monoclonal antibody that blocks programmed cell death ligand 1 (PD-L1) binding to programmed death 1. Here we report safety and clinical activity in the NSCLC cohort of a phase I/II trial that included multiple tumor types (Study 1108; NCT01693562).

Angiogenesis is essential for the growth of primary tumors and for their metastasis. This process is induced by factors, such as vascular endothelial growth factors (VEGFs), that bind to transmembrane VEGF receptors (VEGFRs). VEGF‐A is the primary factor involved with angiogenesis; it binds to both VEGFR‐1 and VEGFR‐2. The inhibition of angiogenesis by obstructing VEGF‐A signaling has been investigated as a method to treat solid tumors, but the development of resistance to this blockade has complicated treatment. The major mechanisms of this resistance to VEGF‐A blockade include signaling by redundant receptors, such as the fibroblast growth factors, angiopoietin‐1, ephrins, and other forms of VEGF. Other major mechanisms of resistance are increased metastasis of hypoxia‐resistant tumor cells, recruitment of cell types capable of promoting VEGF‐independent angiogenesis, and increased circulation of nontumor proangiogenic factors. Additional mechanisms of resistance to VEGF‐A blockade include heterogeneity of responsiveness among tumor cells, use of anti‐VEGF‐A agents at insufficient doses or for insufficient duration, altered sensitivity to anti‐VEGF‐A agents by mutations in endothelial cells or vascular remodeling, maintenance of vascular sleeves that allow for easy regrowth of tumor vasculature upon discontinuation of therapy, vascular cooption, and intussusceptive angiogenesis. An understanding of these mechanisms may lead to the development of targeted therapies that overcome this resistance. Some of these approaches include the combined inhibition of redundant angiogenic pathways, proper patient selection for various therapies based on gene expression profiles, blockade of cellular migration by inhibition of colony‐stimulating factor, or the use of agents to disrupt vascular architecture. Cancer 2012;3455–3467. © 2011 American Cancer Society.