Pembrolizumab For First-line Treatment Research Articles

Abstract CT047: A phase 2 study of ipatasertib in combination with pembrolizumab for first line treatment of recurrent or metastatic squamous cell cancer of the head and neck

Abstract Background: Single agent pembrolizumab in relapsed/metastatic head and neck squamous cell carcinoma (R/M HNSCC) has an ORR of 19% and mOS of 13.6 months. There are many factors which may influence which patients respond to antibodies targeting the PD-1 axis. Regulatory T cells (Tregs) play a significant role in an immunosuppressive tumor microenvironment (TME). Low Tregs in the TME have been correlated with clinical efficacy with PD-1 blockade in various solid tumors. Tregs play an active role in HNSCC. Anti-PD-1 antibodies induce Treg activation in part through AKT pathway activation, which may contribute to low response rates to checkpoint inhibitor therapy. AKT blockade selectively inhibits the proliferation of human Tregs. Additionally, inhibition of the PI3K-AKT-mTOR pathway limits myeloid-derived suppressor cells (MDSC) infiltration and differentiation, and boosts CD8+ T cell memory and effector function. Ipatasertib is an oral highly selective small-molecule inhibitor of all three isoforms of AKT. In the Ice-CAP phase I solid tumor trial, combination PD-L1 antibody and Ipatasertib demonstrated reduction of Tregs and increased CD8+ effector T cells in paired biopsy specimens. This trial is designed to compare the efficacy of combination ipatasertib plus pembrolizumab compared to pembrolizumab monotherapy in R/M HNSCC. Methods: In this prospective, two-arm, phase II, multicenter trial, patients with R/M HNSCC will be treated with pembrolizumab 200mg on day 1 with or without ipatasertib 400mg QD days 1-14 of 21-day cycles. Patients must have PD-L1 CPS score ≥ 1, have measurable disease per RECIST 1.1, and consent to on-treatment biopsy. Patients will be excluded if they have received prior systemic therapy for R/M HNSCC, cannot swallow a pill, or require insulin for diabetes. The primary objective is to compare the PFS between the two arms. We will estimate the relative hazard ratio associated with Ipatasertib plus pembrolizumab compared to pembrolizumab using the Cox Model where randomized treatment assignment is the only variable in the model. A total of 48 patients will be enrolled, with 24 patients in each cohort. Secondary objectives include ORR, safety and tolerability of the combination, and changes in tumor immune cell infiltration, AKT signaling, and changes in peripheral blood immune cells. Accrual is ongoing (NCT05172258). Citation Format: Jacob S. Thomas, Robert Hsu, Victoria Villaflor, Jonathan Riess, Jorge Nieva, Mark Krailo, Silvio Gutkind, Dimitri Colevas. A phase 2 study of ipatasertib in combination with pembrolizumab for first line treatment of recurrent or metastatic squamous cell cancer of the head and neck [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT047.

FDA approves pembrolizumab for first-line treatment of head and neck squamous cell carcinoma

FDA approves pembrolizumab for first-line treatment of head and neck squamous cell carcinoma

Immunotherapy for Bladder Cancer

Urothelial carcinoma is the most common urological malignancy. Nonspecific immunotherapy using the Bacillus Calmette-Guerin vaccine has long been the mainstay for the treatment of high-risk superficial bladder carcinoma in an adjuvant setting after transurethral endoscopic resection. In metastatic disease, cisplatin-based chemotherapy remains the main therapeutic modality. In Europe, the standard second-line chemotherapy for patients with cisplatin-refractory tumours is vinflunine. Other systemic treatments with a lower level of evidence include paclitaxel and docetaxel. Studies of tumour microenvironment indicate a significant role for the immune system in the pathogenesis of urothelial tumours and the presence of a CD8 lymphocyte infiltrate is associated with better survival. In urothelial tumours, the correlation between PD-L1 expression in the tumour and the response to PD-1/PD-L1 inhibitors has been repeatedly demonstrated in clinical studies. Several inhibitors of PD-1/PD-L1 pathway are undergoing advanced-phase clinical trials and atezolizumab, nivolumab, pembrolizumab, durvalumab, and avelumab have already have received permanent or temporary registration status in the United States, mostly as second-line treatments for patients progressing on cisplatin-based chemotherapy. Three of these agents are currently registered in Europe: nivolumab for second line treatment and atezolizumab and pembrolizumab for first line treatment in patients not eligible for cisplatin as well as and for second line treatment. These novel immunotherapeutic agents for bladder cancer are relatively well tolerated and therefore potentially useful for patients with contraindications or intolerance to platinum regimens. The main toxicities include asthenia/fatigue, lymphopenia, anaemia, musculoskeletal pain, decreased appetite, and nausea.Key words: bladder cancer - imunotherapy - PD-1 receptor - antibodies - monoclonal This work was supported by the Czech Ministry of Health CR - RVO Thomayer Hospital - TN 0064190. The author declare he has no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.Submitted: 29. 8. 2017Accepted: 3. 10. 2017.