KEYNOTE-030 (ClinicalTrials.gov ID, NCT02083484) was a global expanded access program that allowed access to pembrolizumab, an antiprogrammed death 1 antibody, for patients with advanced melanoma before its regulatory approval. Patients with unresectable stage III/IV melanoma that progressed after standard-of-care therapy, including ipilimumab and, if BRAFV600 mutant, a BRAF inhibitor, were eligible to receive pembrolizumab 2 mg/kg every 3 weeks. Response was assessed by immune-related response criteria by investigator review. Adverse events (AEs) were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. In the United States, 979 patients enrolled between April and September 2014. Of the 947 evaluable patients, 621 (65.6%) remained on treatment and transitioned to receive commercial pembrolizumab following approval by the Food and Drug Administration, whereas 326 (34.4%) discontinued, most commonly for disease progression (39.6%) or death (26.4%). Objective response rate was 14.5% (95% confidence interval, 12.2%–16.8%) in the treated population (n=947) and 22.1% (95% confidence interval, 18.8%–25.5%) in patients who had ≥1 response assessment reported (n=619). Twelve patients achieved complete response. One hundred eighty-one (19.1%) patients experienced ≥1 treatment-related AE, most commonly general disorders (8.0%), skin/subcutaneous tissue disorders (7.3%), and gastrointestinal disorders (6.4%); 29 (3.1%) patients experienced ≥1 grade 3/4 treatment-related AE. Immune-mediated AEs were also reported. There were no treatment-related deaths. The safety and efficacy observed in this expanded access program were consistent with those previously reported for similar populations and support the use of pembrolizumab for patients with advanced melanoma.

Background: Breast cancer (BRCA) is the leading cause of cancer death among females. Studies suggested that β-adrenoceptors involved in tumor progression by regulating immune system. However, how ADRB2 affects the immune infiltration in BRCA is still being unraveled.Methods: Expressions of ADRB2 in multiple tissues, cancers and blood cells were analyzed by using the Human Protein Atlas and UALCAN database. Expression differentiation of ADRB2 in tumor microenvironment (TME) of BRCA was detected in TISCH database. Correlations between ADRB2 and immune cell infiltration were analyzed by TIMER 2.0, and co-expression genes of ADRB2 were obtained from the cBioPortal website. Functional enrichment analyses and protein-protein interactions were constructed as well. Finally, the potential mechanisms of ADRB2 and candidate drugs targeting BRCA were discussed by using the Metascape, STITCH and Cmap tools.Results: ADRB2 was significantly down-regulated in BRCA, and lower ADRB2 expression often resulted in worse prognosis in BRCA patients. ADRB2 was mainly expressed in breast tissue and blood. Among blood cell subtypes and TME of BRCA, ADRB2 was specifically expressed in T cell subtypes. Also, ADRB2 expression level was positively correlated with the infiltration levels of immune cells such as CD4+ T cell, CD8+ T cell, Tγδ and myeloid DC while negatively correlated with Treg, Tfh and myeloid-derived suppressor cell. Furthermore, functional enrichment analyses revealed that most enriched pathways were immune-related, especially in T cell-related pathways. Also, transcription factors (TFs) analyses showed that most downstream TFs regulated by ADRB2 were immune-related, and most candidate drugs had promising anti-tumor effects.Conclusions: In conclusion, ADRB2 was a potential protective gene in BRCA, and it might play a vital role in regulating immune responses. The expression level of ADRB2 was positively correlated with immune cells infiltration in BRCA, especially for T cells. Therefore, ADRB2 would be a target for boosting immunotherapy effects in BRCA.

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