This is not surprising given the emerging evidence that supports the use of PD-1Ctargeted therapies to treat both HPV-associated and nonCHPV-associated HNSCC.18,29 Although HPV-associated and nonCHPV-associated HNSCC differ in several ways, and the mechanisms that lead to PD-L1 expression may differ between the two, PD-L1 has been shown to be overexpressed in both settings. years (range, 25 to 84 years), 83% were male, and 57% received two or more lines of therapy for R/M disease. ORR was 18% (95% CI, 12 to 26) by central imaging merchant and 20% (95% CI, 13 to 28) by investigator Apigenin-7-O-beta-D-glucopyranoside review. Median duration of response was not reached (range, 2 to 11 weeks). Six-month progression-free survival and overall survival rates were 23% and 59%, respectively. By using tumor and immune cells, a statistically significant increase in ORR was observed for PD-L1Cpositive versus Cnegative individuals (22% 4%; = .021). Treatment-related adverse events of any grade and grade 3 events occurred in 62% and 9% of individuals, respectively. Summary Fixed-dose pembrolizumab 200 mg given once every 3 weeks was well tolerated and yielded a clinically meaningful ORR with evidence of durable reactions, which supports further development of this regimen in individuals with advanced HNSCC. Intro Head and neck squamous cell carcinoma (HNSCC) is the seventh most common cancer worldwide.1 In the United States, it is estimated there will be approximately 61,760 new instances of HNSCC and 13,190 deaths in 2016.2 Main risk factors include tobacco cigarette smoking and alcohol usage.3 Another risk element for a growing subset of head Apigenin-7-O-beta-D-glucopyranoside and neck cancers is human being papillomavirus (HPV) infection.4 Several differences among smoking- and alcohol-related versus HPV-associated HNSCC have been reported, including different patient characteristics, genomic profiles, and prognoses; for example, individuals with HPV-associated HNSCC often have better results than those with HPV-unrelated disease.5 A common first-line treatment regimen for recurrent and/or metastatic (R/M) HNSCC is the combination of cetuximab, platinum, and fluorouracil (Great regimen), which has demonstrated a median overall survival (OS) of 10 months.6 Although this regimen has shown promising efficacy, individuals who experience disease progression on first-line therapy or who are platinum refractory are seldom responsive to treatment, with response rates to second-line therapiestypically methotrexate, cetuximab, or taxanesthat range from 3% to 13%.4,7 HNSCC is generally associated with deficiencies of the immune system8,9; patients show impaired natural killer cell activity, poor antigen-presenting function, low complete lymphocyte counts,10 and mutations in genes that regulate swelling.9,11 In the healthy immune system, programmed death-1 (PD-1) receptor functions as an immune checkpoint and is expressed primarily on the surface of activated CD4+ and CD8+ T cells.12,13 Engagement of PD-1 by either of its ligands, programmed death-ligand 1 or 2 2 (PD-L1 or PD-L2) results in inhibition of T-cell activation and limits the response to swelling.14,15 In HNSCC and other solid tumors, tumor-infiltrating lymphocytes, and especially T helper 1 cells, activate interferon-mediated signaling and induce expression of PD-L1 on cells in the tumor environment, which shields tumor cells from tumor-directed immunity.16,17 Moreover, HNSCC tumor cells Apigenin-7-O-beta-D-glucopyranoside are known to show high levels of PD-L1 manifestation.17,18 Preclinical studies indicate that blockade of the PD-1 and PD-L1 interaction enhances T-cell activation and inhibits tumor growth.16,17,19 Pembrolizumab, a highly selective humanized monoclonal immunoglobulin G4 antibody that blocks the interaction between PD-1 and its ligands, has shown antitumor activity in multiple tumor types.20-23 Support for pembrolizumab in the treatment of R/M HNSCC Rabbit Polyclonal to NSG2 has been described in the initial HNSCC cohort of the KEYNOTE-012 trial, which proven medical activity of pembrolizumab 10 mg/kg administered intravenously once every 2 weeks in individuals with PD-L1Cpositive R/M HNSCC.24 Overall response rate (ORR) to this body weightCbased dosing regimen was 18% (central imaging vendor evaluate), with responses in 25% of individuals who have been HPV positive and 14% in those who were HPV negative. In that study, responses were durable (median, 53 weeks); median (95% CI) progression-free survival (PFS) and OS were 2 weeks (2 to 4 weeks) and 13 weeks (5 weeks to not-reached), respectively. Recent studies that have used human population pharmacokinetics and exposure-response models suggest that a lower, fixed dose of pembrolizumab (200 mg) and a less frequent administration routine (once every 3 weeks) may be adequate for target engagement and medical activity.25,26 A fixed-dose regimen confers several advantages over body weightCbased dosing, including safety, convenience, reduction of waste, and adherence. The aim of the current study was to statement the security and effectiveness of a fixed-dose routine.
This is not surprising given the emerging evidence that supports the use of PD-1Ctargeted therapies to treat both HPV-associated and nonCHPV-associated HNSCC
