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Overview of Therapeutic Biomarkers in Cancer
Published in Sherry X. Yang, Janet E. Dancey, Handbook of Therapeutic Biomarkers in Cancer, 2021
Sherry X. Yang, Janet E. Dancey Treatment
A significant breakthrough in the treatment of cancer across multiple cancer types is immunotherapy with monoclonal antibodies that target the immune checkpoints such as cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) pathway (Chapter 14). Currently, this class of antibodies that activate the immune system, but not limited to, include ipilimumab that blocks CTLA-4, tremelimumab, pembrolizumab and nivolumab that inhibit PD-1, as well as avelumab, atezolizumab, and durvalumab that target the PD ligand 1 (PD-L1). The three PDL1 antibodies are approved for the treatment of metastatic Merkel-cell carcinoma, advanced bladder cancer or NSCLC. Ipilimumab and pembrolizumab are indicated in the treatment of a range of cancer types including metastatic melanoma, NSCLC, small cell lung cancer, and HNSCC, hormone-refractory prostate cancer and advanced cervical cancer. Nivolumab is indicated for both BRAF wildtype and BRAF V600 mutation-positive unresectable or metastatic NSCLC progressed on or after platinum-based chemotherapy. It is also used for advanced renal cell carcinoma, classical Hodgkin’s lymphoma, and hepatocellular carcinoma in patients previously treated with sorafenib. In June 2020, it was approved for patients with recurrent or metastatic esophageal squamous cell carcinoma after prior platinum- and fluoropyrimidine-based chemotherapy.
Drug-induced hypopigmentation
Published in Electra Nicolaidou, Clio Dessinioti, Andreas D. Katsambas, Hypopigmentation, 2019
Katerina Damevska, Suzana Nikolovska, Razvigor Darlenski, Ljubica Suturkova, Torello Lotti
Pembrolizumab is a selective humanized monoclonal IgG4 antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1. Vitiligo-like depigmentation is a well-described side effect of pembrolizumab. Of 67 patients with MM who received pembrolizumab, 17 (25%) developed hypopigmentation. The time to onset of hypopigmentation ranged from 52 to 453 days. Complete or partial response to treatment was associated with a higher occurrence of hypopigmentation (71% vs 28%; P = 0.002).The authors concluded that these visible irAEs could be associated with the clinical benefit to pembrolizumab.18 In contrast to ordinary vitiligo, patients did not report any personal or family history of vitiligo, thyroiditis, or other autoimmune disorders.19 The most common involved skin sites in post anti-PD1 depigmentation are sun-exposed areas (Figure 23.1).
Biologically Targeted Agents in Head and Neck Cancers
Published in John C Watkinson, Raymond W Clarke, Terry M Jones, Vinidh Paleri, Nicholas White, Tim Woolford, Head & Neck Surgery Plastic Surgery, 2018
Kevin J. Harrington, Magnus T. Dillon
In the context of SCCHN, there have been initial reports of single-agent activity in patients with relapsed/metastatic disease. The largest experience has accrued with single-agent therapy with the anti-PD1 monoclonal antibody, pembrolizumab. In the KEYNOTE-012 (NCT01848834) study, patients with PD-L1-positive (> 1% staining of tumour cells) tumours were divided into HPV+ve and HPV−ve cohorts and treated with 10 mg/kg of pembrolizumab every 2 weeks. Treatment beyond disease progression was permitted, as long as the patient was judged to be deriving clinical benefit from therapy. Overall, 26 of 51 patients had a reduction in tumour burden and 20% satisfied standard radiological criteria (RECIST v1.1) for response.104 In a subsequent study, a larger group of 132 patients was treated with a fixed dose of pembrolizumab (200 mg) every 3 weeks. Patients were included irrespective of PD-L1 status. The treatment was well tolerated with only 7.6% of patients experiencing a grade 3 or greater adverse effect. Of 99 patients who were evaluable for preliminary analysis, 18.2% showed a response (all partial responses) and 31.3% of patients had stable disease.105 There are a number of ongoing randomized phase II and III clinical trials with both anti-PD1 and anti-PD-L1 agents (pembrolizumab [KEYNOTE-040 NCT02252042, KEYNOTE-048 NCT02358031], nivolumab [CHECKMATE-141 NCT02105636], durvalumab/MEDI4736 [HAWK NCT02207530, EAGLE NCT02369874] in patients with relapsed/metastatic disease that are likely to be reported in the next 2–3 years.
Pembrolizumab-Induced Giant Cell Arteritis in the Setting of Urothelial Carcinoma
Published in Neuro-Ophthalmology, 2023
Deanna Ingrassia Miano, Ryan Cosgrove, Joshua Sherman, Savitha Balaraman, Michael Sherman
Pembrolizumab is an intravenous (IV) anti-neoplastic agent used in a variety of oncological treatment regimens including unresectable melanoma, lymphomas, gastrointestinal and urogenital carcinomas. It is a monoclonal antibody (MAB) that functions through antagonistic effects on the humanised programmed-death-receptor-1 (PD1).1,2 As noted with other anti-PD1 agents, the side effects of pembrolizumab are thought to be immune-mediated and affect a multitude of organ systems such as cardiovascular, respiratory, ocular, integumentary, endocrine, connective tissue and haematological.2,3 Of particular interest, the ocular manifestations of pembrolizumab are thought to be inflammatory in nature. Potential ophthalmological side effects listed by the manufacturer include iritis, uveitis, varying grades of retinal detachment, and symptoms consistent with Vogt-Koyanagi-Harada (VKH) disease.1 Though giant cell arteritis (GCA) is not denoted as an aftereffect by the manufacturers, recent reports have shed light on the probable association between pembrolizumab and GCA.4–6 Herein we report a patient with urothelial carcinoma who experienced pembrolizumab-induced vision changes within 2 weeks of treatment initiation. Despite an absence of traditional nuances, such as laboratory findings and cranial pain noted in previous cases, our patient’s atypical presentation was confirmed to be GCA following temporal artery biopsy.
Pembrolizumab as a single agent for patients with MSI-H advanced endometrial carcinoma
Published in Expert Review of Anticancer Therapy, 2022
Margherita Turinetto, Valentina Lombardo, Carmela Pisano, Lucia Musacchio, Sandro Pignata
Before the recent approval of immunotherapy by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA), there had been no standard of care for women after failing front-line carboplatin and paclitaxel [8]. In May 2017, the FDA approved single-agent pembrolizumab (Keytruda, Merck) in patients with metastatic, MSI-H, or mismatch-repair deficient (dMMR) solid tumors after progression to prior treatment and who have no satisfactory alternative treatment options [8]. On 21 March 2022, the FDA approved pembrolizumab as a single agent for patients with advanced dMMR or MSI-H EC who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation [9]. Well-defined second-line treatments for advanced EC include immunotherapy with pembrolizumab, which has demonstrated efficacy in several solid tumor types, and a combination of lenvatinib (Lenvima) and pembrolizumab. Another drug developed for the same population is the immune checkpoint inhibitor (ICI) dostarlimab (Jemperli), which received accelerated FDA approval in 2021 for recurrent or advanced EC with dMMR that has progressed on or after a platinum-containing regimen. This is particularly important as it can be offered to the same patients as pembrolizumab [8].
Pembrolizumab for the treatment of renal cell carcinoma
Published in Expert Opinion on Biological Therapy, 2021
Carlo Di Bona, Viktoria Stühler, Steffen Rausch, Arnulf Stenzl, Jens Bedke
The promising results in combination therapy and the lack of data in monotherapy led to the study of pembrolizumab in first-line monotherapy in patients with advanced clear (arm A) and non-clear cell RCC (arm B) in the phase II open-label study KEYNOTE-427 (NCT02853344) [12]. Pembrolizumab was administered intravenously 200 mg every 3 weeks for two years or until disease progression, unacceptable toxicity or patient’s refusal to continue treatment. Temporary analyses show, in the 110 enrolled patients of cohort A, an ORR of 33.6% (n = 36; 95% CI 24.8–43.4) with 1 complete response (0.9%) and 35 (32.7%) partial responses. ORR for patients with favorable, intermediate/poor risk IMDC was 27.5% and 37.3%, respectively. In terms of safety, 73.6% of patients developed treatment-related AEs, with 18.2% of them being grade 3–5 and one patient developing grade 5 pneumonia.