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Antibody-Based Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
A number of examples of PD-1-targeted antibodies are described below. Nivolumab (Opdivo™), pembrolizumab (KeytrudaTM), and cemiplimab (LibtayoTM) are approved by the FDA and many other other Western countries, while toripalimab (TuoyiTM), tislelizumab, sintilimab (Tyvyt™), and camrelizumab have been approved (conditionally in some cases at the time of writing) by the Chinese FDA. Several other PD-1-targeted antibodies are at various stages of clinical development for a wide range of hematological and solid tumor indications but are not discussed any further here. These include spartalizumab (PDR001; Novartis), dostarlimab (TSR-042, WBP-285; GlaxoSmithKline), retifanlimab (INCMGA00012, MGA012; Incyte and MacroGenics), AMP-224 (AstraZeneca/MedImmune and GlaxoSmithKline), and AMP-514 (MEDI0680; AstraZeneca).
Systemic Therapy (Targeted Therapy and Immunotherapy) for Thyroid Cancers
Published in Madan Laxman Kapre, Thyroid Surgery, 2020
Many malignancies are often associated with suppression of the immune response. The malignant cells that survive the immune system surveillance may have an over-expression of programmed death-ligand 1 and 2 (PD-L1/2), which in turn binds to its receptor, programmed cell death protein 1 (PD-1), on T-cells. This causes a weakened T-cell immune response. PD-L1 is expressed in DTC and ATC and may even be a prognostic marker in ATC. Subsequent to the successful application of immunotherapy in melanoma and other solid tumors leading to FDA approval of several immunotherapies, this approach is also being tried in thyroid cancer. A phase I basket trial (NCT02054806) with pembrolizumab, an anti-PD1 drug, included a small group of DTC patients, where two of 22 (9%) patients achieved a PR to pembrolizumab monotherapy. Spartalizumab, an anti-PD1 drug, was studied in an expansion trial in ATC patients. Of 30 evaluated patients, five (17%) achieved a PR.
Evaluating new treatments for anaplastic thyroid cancer
Published in Expert Review of Anticancer Therapy, 2022
Andrés Coca-Pelaz, Juan P. Rodrigo, Fernando Lopez, Jatin P. Shah, Carl E. Silver, Abir Al Ghuzlan, C.Willemien Menke-van der Houven van Oordt, Robert C. Smallridge, Ashok R. Shaha, Peter Angelos, William M. Mendenhall, Cesare Piazza, Kerry D. Olsen, June Corry, Ralph P. Tufano, Alvaro Sanabria, Sandra Nuyts, Cherie-Ann Nathan, Vincent Vander Poorten, Fernando Luiz Dias, Carlos Suarez, Nabil F. Saba, Pim de Graaf, Michelle D. Williams, Alessandra Rinaldo, Alfio Ferlito
Spartalizumab is a humanized immunoglobulin 4 monoclonal antibody that binds PD-1 with sub-nanomolar activity, blocking interaction with PDL1 and PD-L2 [42]. In 2020, Capdevila et al. published a phase II study on 42 patients with ATC, 2 of them without tumor tissue available for central pathology review [43]. The commonest AEs were diarrhea (12%), pruritus (12%), fatigue (7%), and pyrexia (7%). The overall response rate was 19%, including 3 patients with a complete response and 5 with a partial response. Twenty-eight of the 40 patients with available biopsy material showed tumors that expressed PD-L1, and response rates were higher in PD-L1–positive (29%) versus PD-L1–negative (0%) patients. The highest rate of response (35%) was observed in patients with PD-L1 ≥ 50%. Responses were seen in both BRAF-nonmutant and BRAF-mutant patients and were durable, with a 1-year survival of 52.1% in the PD-L1–positive population. This study demonstrated the responsiveness of ATC to PD-1 blockade.
Antibodies to watch in 2021
Published in mAbs, 2021
Hélène Kaplon, Janice M. Reichert
Developed by Novartis, spartalizumab (PDR001) is a humanized IgG4 antibody that targets PD-1. The antibody has been or is being evaluated in over 50 clinical studies involving patients with various types of cancers. Novartis had planned to file for approval of spartalizumab in combination with Tafinlar® (dabrafenib) and Mekinist® (trametinib) for the treatment of unresectable or metastatic BRAF V600 mutation-positive cutaneous melanoma if results of the Phase 3 COMBI-i study (NCT02967692) were positive. On August 22, 2020, however, Novartis announced that the COMBI-i study did not meet its primary endpoint of investigator-assessed PFS.120 The company indicated that the development of spartalizumab will continue. As of November 2020, spartalizumab is undergoing evaluation in numerous Phase 2 studies that are recruiting cancer patients.
The potential of BRAF-targeted therapy combined with immunotherapy in melanoma
Published in Expert Review of Anticancer Therapy, 2020
Sheida Naderi-Azad, Ryan Sullivan
A new study has been conducted with the anti-PD1 antibody spartalizumab in combination with dabrafenib and trametinib in advanced BRAF v600-mutant melanoma patients [38]. Remarkably, more than 40% (15 of 36) patients treated with spartalizumab + dabrafenib + trametinib had a confirmed complete response. Furthermore, the median PFS was 23.7 months (95% CI, 12mo-NE) overall and 10.7 months (95% CI, 4.6 mo-NE) in patients with elevated baseline LDH levels. Similar to the KEYNOTE-022 cohorts, grade 3 toxicities were common, 78%, and dose adjustment or interruption was required for every patient. These findings demonstrate the potential efficacy of combination therapy with anti-PD1 antibodies, which will be further corroborated by the ongoing global, placebo-controlled, randomized part 3 of COMBI–i trial (NCT02967692).