Role of Engineered Proteins as Therapeutic Formulations
Peter Grunwald in Pharmaceutical Biocatalysis, 2019
Ado-trastuzumab emtansine (Kadcyla) and brentuximab vedotin (Adcetris) are two ADCs that are being used for the treatment of hematological malignancies (Hodgkin lymphoma) and solid tumor (breast cancer), respectively (Beck and Reichert, 2014; Scott, 2017a). Brentuximab vedotin is a conjugate of a monoclonal antibody targeting CD30, which is expressed only during Hodgkin lymphoma. It is connected via cathepsin to anti-mitotic drug monomethyl auristatin E (Beck and Reichert, 2014; Scott, 2017a). Ado-trastuzumab emtansine is composed of anti-Her2-mAb Trastuzumab antibody linked to cytotoxic drug mertansine via thioether linkage (Beck and Reichert, 2014; Lambert and Chari, 2014). Variety of drugs can be conjugated at multiple locations in monoclonal antibody to further enhance their actions (Tobin et al., 2014).
Hodgkin Lymphoma
Pat Price, Karol Sikora in Treatment of Cancer, 2020
Brentuximab vedotin is an antibody-drug conjugate targeting CD30. After the phase I study had indicated significant single-agent activity, a pivotal phase II study including 102 patients with HL recurrence after high-dose chemotherapy and ASCT was conducted.43 Patients received brentuximab vedotin at a dose of 1.8 mg/kg every 3 weeks for up to 16 cycles. The overall response rate was 75%. The median PFS was 5.6 months. However, the group of patients that achieved a complete remission had median PFS of 20.5 months.44 A recent follow-up analysis of the study revealed 5-year PFS and OS estimates of 22% and 41%, respectively. Of note, some patients had a durable remission without any additional therapy after the end of study treatment.45 Given the excellent activity in patients failing high-dose chemotherapy and ASCT, brentuximab vedotin either alone in combination with conventional chemotherapy was subsequently evaluated in patients who had disease recurrence after first-line treatment and in individuals with newly diagnosed HL.24,36,46,47 Final analyses of these studies are in part pending so that final conclusions with regard to the possible role of brentuximab vedotin in these situations cannot yet be drawn.
Real-World Evidence for Coverage and Payment Decisions
Harry Yang, Binbing Yu in Real-World Evidence in Drug Development and Evaluation, 2021
More payers and other stakeholders are increasingly demanding evidence for a product's effectiveness in their coverage populations. Studies to generate this evidence can be conducted either by the product manufacturer, or payer, or as a joint collaboration from multiple stakeholders. A real-world study by Takeda Pharmaceuticals in Germany and the United Kingdom showed that brentuximab vedotin is effective in autologous stem cell transplant (ASCT)-ineligible patients with relapsed/refractory Hodgkin lymphoma (rrHL)21. Kaiser Permanente Northern California has a viral hepatitis registry that includes administrative and clinical data for all patients with chronic hepatitis C22. Recently, many new joint collaborations between a product manufacturer and a payer/HTA were announced to align reimbursement to real-world outcomes in the payer/HTA's target population. For example, Merck and United Health's Optum have an initiative that involves the use of real-world data to co-develop and test advanced predictive models and co-design an outcome-based risk sharing agreement to reduce clinical and financial uncertainty23.
Relapse localization in Danish pediatric patients with Hodgkin lymphoma
Published in Acta Oncologica, 2021
Anni Young Lundgaard, Lisa Lyngsie Hjalgrim, Danijela Dejanovic, Anne Kiil Berthelsen, Eckhard Schomerus, Pernille Wendtland, Lena Specht, Maja Vestmoe Maraldo
Response assessment with PET/CT is now considered standard of care in HL treatment [15] and its ability to identify responders and non-responders is used to direct further treatment in pHL clinical trials. However, it has not been established that a CR after two series chemotherapy can predict EFS in low-risk patients [9], nor after three series, but a very early PET-response after one series may possibly do so [21]. Likewise, for adult patients with early stage HL, a negative response assessment PET/CT has not identified the patients for whom consolidating radiotherapy can be omitted without increasing the risk of relapse [22–24]. In our study, time to relapse or site of relapse did not seem to be associated with the outcome of the response assessment or the metabolic response on PET. A recent study in adult patients with early stage HL did not find a correlation between initial lymph node characteristics (nodal size, 2-[18F]FDG-uptake, or CT abnormalities after chemotherapy) and the risk of relapse [25]. Hence, irradiating metabolically active sites or bulky tumor sites only does not seem optimal and can only be recommended within clinical trials (currently investigated in AHOD1331 [NCT02166463], EuroNet-PHL C2 [NCT02684708] [11]). In patients with advanced disease, ISRT or INRT would still lead to large treatment volumes and other treatment strategies should be explored. Brentuximab vedotin is currently investigated in the high-risk group as first line treatment in the Children’s Oncology Group AHOD1331 trial (NCT02166463).
Cost-effectiveness of brentuximab vedotin for relapsed or refractory systemic anaplastic large-cell lymphoma in China
Published in Journal of Medical Economics, 2022
Jia Liu, Lei Zheng, Ling-Hsiang Chuang
Brentuximab vedotin is an antibody-drug conjugate that targets CD30-expressing malignant cells by binding CD30 on the surface. Targeted delivery of monomethyl auristatin E, the microtubule-disrupting agent, to CD30-expressing tumor cells is the primary mechanism of action9,10. A single-arm, open-label, multicenter, phase II trial evaluating the efficacy and safety of brentuximab vedotin in 58 patients with RRsALCL demonstrated an overall response rate of 86% with 66% of patients achieving a complete response (CR), a median of progression-free survival of 13 months, and a median overall survival not being reached (a median observation time of 33.4 months)11. Based on this evidence, brentuximab vedotin has been approved by the U.S. Food and Drug Administration (FDA) and by the European Medicines Agency (EMA) for the treatment of patients with sALCL after the failure of at least one prior multiagent chemotherapy regimen and is since then recommended in several treatments guidelines12–14. Furthermore, the 5-year follow-up of the original trial was published in 2017 to provide the long-term outcomes of brentuximab vedotin1. In China, the market authorization of brentuximab vedotin for recommendation on the treatment of RRsALCL, as well as relapsed/refractory Hodgkin lymphoma, was granted by the National Medical Products Administration (NMPA) in May 2020.
Current treatment of lymphoma in pregnancy
Published in Expert Review of Hematology, 2019
Anna Gurevich - Shapiro, Irit Avivi
Nivolumab and pembrolizumab, anti PD1 antibodies used in refractory or relapsed HL, have not been examined with respect to pregnancy, but have been associated with an increased risk of fetal loss [89,90]. The PD-1/PD-L1 pathway plays an important role in maintaining maternal immune tolerance to the fetus during pregnancy [91]. Inhibition of this pathway could cause an immune-mediated response to the fetus with detrimental effects. Nivolumab administration resulted in a non–dose-related increase in spontaneous abortion and increased neonatal death in monkeys [92]. A single case report exists of treatment with nivolumab and ipilimumab during the first trimester with a normal progression of the pregnancy until week 32, when a healthy preterm newborn was delivered due to signs of placental insufficiency [91]. As mentioned earlier, brentuximab vedotin, approved for relapsed and refractory HL outside pregnancy, is contraindicated during the gestational period.
Related Knowledge Centers
- Cathepsin
- Fusion Protein
- Monoclonal Antibody
- Valine
- Hodgkin Lymphoma
- T Cell
- Antibody–Drug Conjugate
- Anaplastic Large-Cell Lymphoma
- NON-Hodgkin Lymphoma
- Indication