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Antibody-Based Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Avelumab is currently being evaluated in Phase III trials for breast, gastric, head and neck, non-small-cell lung and ovarian cancers, and also diffuse large B-cell lymphoma. A number of Phase II studies are also underway in several hematological and solid cancers.
External Control Using RWE and Historical Data in Clinical Development
Published in Harry Yang, Binbing Yu, Real-World Evidence in Drug Development and Evaluation, 2021
Qing Li, Guang Chen, Jianchang Lin, Andy Chi, Simon Davies
In 2017, the FDA approved Bavencio® (avelumab) as a treatment for adults and pediatric patients 12 years and older with metastatic MCC under the Accelerated Approval regulations (FDA 2017b). The primary analysis supporting the clinical efficacy and safety evidence of Bavencio® in patients with metastatic MCC comes from Study 003, a single-arm trial with 88 patients. For the primary efficacy endpoint, confirmed best ORR was 33%, with 95% confidence interval (CI) (23%, 44%). Further details are shown in Table 4.11 The secondary efficacy endpoint is duration of response (DOR), which ranges from 2.8 months to 23.3 months (ongoing). The Kaplan-Meier estimate for the percentage of patients with a 6-month DOR is 93% (95% CI: 74%, 98%), and the estimate for the percentage of patients with a 12-month DOR is 75% (95% CI: 53%, 87%).
Non-Melanoma Skin Cancer
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Irene De Francesco, Sean Whittaker, Stephen L. Morris
MCCs are chemosensitive but rarely curable in patients with metastasis or locally advanced tumors. A high incidence of mortality directly related to chemotherapy has been reported.316 Widely used chemotherapy regimens are those developed for other small cell cancers: cyclophosphamide, doxorubicin (or epirubicin), and vincristine (CAV or CEV), and carboplatin (or cisplatin) and etoposide (EP). Response rates around 29e75% and CR rates of between 13% and 35% have been reported.317–320 There is current interest in immunotherapy and check point inhibitors with ongoing clinical trials. The PD-L1 inhibitor monoclonal antibody avelumab has been shown in a Phase 2 study to have a response rate of 62%, with 80% of responses ongoing at 6 months.332 In a trial for patients who had progressed on previous chemotherapy, including 41% with more than one line of previous treatment, the overall response rate to avelumab was 33%, durable (>6 months) response rate 29%, and CR rate 9%. Three-quarters of responses lasted more than 1 year. The response was not clearly associated with tumor viral or PD-L1 status.313 Immunotherapy trials may help to shape the optimal management of MCC in the future, but surgery and radiotherapy continue to be the prime modalities in achieving loco-regional control.
10th antibody industrial symposium: new developments in antibody and adoptive cell therapies
Published in mAbs, 2023
Ana Antunes, Luis Alvarez-Vallina, Federico Bertoglio, Nicolas Bouquin, Stéphanie Cornen, Francis Duffieux, Pierre Ferré, Raphaëlle Gillet, Christian Jorgensen, Mark B Leick, Bernard Maillère, Hélène Negre, Mireia Pelegrin, Nicolas Poirier, Dietmar Reusch, Bruno Robert, Guy Serre, Alain Vicari, Martin Villalba, Christoph Volpers, Gavin Vuddamalay, Hervé Watier, Thierry Wurch, Lennart Zabeau, Stefan Zielonka, Baolin Zhang, Alain Beck, Pierre Martineau
Dr. Hulin Jin and Dr. Berend Neuteboom (Merck KGaA, Germany) described the mechanisms of the faster clearance and shorter half-life of avelumab compared to other anti – PD-L1 monoclonal antibodies (~4 days vs ~21 days for atezolizumab). Avelumab is an IgG1 approved as monotherapy for metastatic Merkel cell carcinoma and advanced urothelial carcinoma. They compared avelumab and atezolizumab. Both antibodies recognize PD-L1 with comparable affinities (~0.2–0.4 nM) and cross-react with cynomolgus monkey and mouse targets. In both antibodies, a series of mutations abrogating antigen or FcγR binding were also compared. In cynomolgus monkeys and mice, they demonstrated that avelumab internalization is essentially due to CD64 (FcγRI) binding in vitro, but that both PD-L1 and FcγRs are involved. Interestingly, atezolizumab harboring wild-type Fc was not internalized by FcγRs in vitro, and was eliminated slightly faster in vivo compared with the FcγR binding – deficient (N297A) variant. Concerning clearance in the mouse, avelumab with a functional Fc was the fastest eliminated molecule and the PD-L1 binding-deficient variant the slowest. Avelumab harboring a FcγR binding-deficient Fc presented an intermediate clearance rate. These data clearly show the effect of both antigen and FcγR binding on the half-life of these monoclonal antibodies in animal models.5
Avelumab in locally advanced or metastatic urothelial carcinoma
Published in Expert Review of Anticancer Therapy, 2022
Francesca Jackson-Spence, Bernadett Szabados, Charlotte Toms, Yu-Hsuen Yang, Christopher Sng, Thomas Powles
It binds selectively and with high affinity to PD-L1 and competitively blocks its interaction with both PD-1 and CD80, removing the immune suppressive effects of PD-L1 on antitumor CD8 + T cells, resulting in restoration of a cytotoxic T cell response [12]. Furthermore, the efficacy component of avelumab is distinct. Unlike some other mAbs directed at PD-1/PD-L1, avelumab possesses a Fc region, which can bind to immune effector cells and appears to have an effect on antibody-dependent cytotoxicity (ADCC) lysis of tumor cells [25,26]. While other mAbs against PD-1/PD-L1 show clinical benefits, they intentionally lack this specific property. ADCC activity may also have other effects on the immune repertoire, which are not fully understood, but may be potentially beneficial to the antitumor response. Biomarker data from the JAVELIN Bladder 100 study [NCT02603432] support this. The fully humanized mAbs are either of the IgG4 subtype, which lacks ADCC potential, or of the IgG1 subtype, which has been specifically engineered to eliminate ADCC activity. This was due to concerns regarding potential toxicity resulting from ADCC-mediated lysis of some immune cells, which may express PD-L1. It has since been found that ADCC plays an important role in immune-mediated antitumor responses in preclinical studies [16]. A phase I study conducted on over 100 subjects showed no additional toxicity observed with avelumab compared to that observed with other mAbs against PD-1/PD-L1, which lack the ADCC potential [27].
Avelumab: is it time to get excited?
Published in Expert Review of Anticancer Therapy, 2018
Ariel E. Marciscano, James L. Gulley, Howard L. Kaufman
We are in the midst of the cancer immunotherapy revolution. Several therapies targeting the PD-1/PD-L1 axis have now demonstrated clinical efficacy leading to multiple FDA approvals which has generated tremendous excitement but also urgency to best define their optimal application. Whether there is cross-resistance among PD-1- and PD-L1-directed agents is not clear. The ongoing JAVELIN Solid Tumor trials will provide efficacy and safety data across diverse cohorts of patients and begin to define the therapeutic landscape for avelumab. Because other Fc-unmodified IgG1 isotype antibodies (i.e. cetuximab) have demonstrated clinically relevant ADCC, avelumab may hold a distinct advantage over other FDA-approved agents in this class given the potential for both innate and adaptive immune activation via ADCC and PD-L1 targeting, respectively. This consideration may be particularly important for combination therapies involving avelumab; however, progress in biomarker development and patient selection will be needed to fully realize the potential of avelumab. Avelumab has demonstrated therapeutic responses across different tumors with an acceptable safety profile. Thus, we are excited about this agent and eagerly look forward to results from ongoing clinical trials and biomarker investigations.