ABSTRACT
BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is an aggressive non-Hodgkin lymphoma subtype with a significant relapse rate and poor prognosis in relapsed/refractory (R/R) patients. Polatuzumab vedotin in combination with bendamustine and rituximab (Pola-BR) has demonstrated promising efficacy and safety as salvage therapy for R/R DLBCL. This systematic review protocol aims to comprehensively evaluate the efficacy of Pola-BR for the treatment of R/R DLBCL by synthesizing data from relevant randomized controlled trials. METHODS: This protocol details the eligibility criteria, search strategy, study selection, data extraction, and analysis methods for the systematic review. Randomized controlled trials comparing Pola-BR with other interventions for R/R DLBCL will be included. The primary endpoint is overall survival, with secondary endpoints being progression-free survival and incidence of adverse events. A comprehensive search will be conducted across databases such as Medline/PubMed, Cochrane Library, Web of Science, Scopus, EMBASE, ProQuest, EU Clinical Trials Register, WHO International Clinical Trials Registry Platform (ICTRP), and ClinicalTrials.gov from the January 2000 to April 2024. To assess the potential risk of bias, the Cochrane Risk of Bias 1 tool will be used. Data synthesis will utilize fixed-effect or random-effects models, and subgroup and meta-regression analyses will examine heterogeneity. Additionally, publication bias and sensitivity analyses will be performed, and the GRADE approach will be applied to assess the certainty of the evidence. CONCLUSION: This systematic review and meta-analysis protocol provides a rigorous framework for evaluating the efficacy of Pola-BR in the treatment of R/R DLBCL. The results will inform clinical decision-making and guideline development, addressing the unmet need for effective and tolerable treatments for this challenging patient population. Potential limitations and biases will be acknowledged, and future research directions will be discussed.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Bendamustine Hydrochloride , Lymphoma, Large B-Cell, Diffuse , Rituximab , Systematic Reviews as Topic , Humans , Lymphoma, Large B-Cell, Diffuse/drug therapy , Lymphoma, Large B-Cell, Diffuse/pathology , Rituximab/administration & dosage , Rituximab/therapeutic use , Bendamustine Hydrochloride/administration & dosage , Bendamustine Hydrochloride/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Neoplasm Recurrence, Local/drug therapy , Immunoconjugates/therapeutic use , Immunoconjugates/administration & dosage , Immunoconjugates/adverse effects , Randomized Controlled Trials as Topic , Antibodies, MonoclonalABSTRACT
PURPOSE: Human trophoblast cell surface antigen 2 (Trop-2) is a protein highly expressed in urothelial cancer (UC). Sacituzumab govitecan (SG) is a Trop-2-directed antibody drug conjugate with a hydrolysable linker and a potent SN-38 payload. This study explored Trop-2 expression in tumors treated with SG in cohorts 1 to 3 (C1-3) from the TROPHY-U-01 study and evaluated whether efficacy was associated with Trop-2 expression. PATIENTS AND METHODS: TROPHY-U-01 (NCT03547973) is an open-label phase II study that assessed the efficacy and safety of SG (alone or in combinations) in patients with unresectable locally advanced or metastatic UC (mUC). Archival tumor samples collected at enrollment for C1-3 were analyzed for Trop-2 membrane expression by considering histological scores (H-scores; scale 0-300) and the percentage of membrane positive tumor cells at low magnification (4×). The association of Trop-2 with clinical endpoints [objective response rate (ORR), progression-free survival (PFS), and overall survival (OS)] was evaluated. RESULTS: In C1-3, tissue was collected from 158 (82%) of 192 treated patients, and 146 (76%) had evaluable Trop-2 data. Trop-2 was highly expressed in tumor samples. The median [interquartile range (IQR)] Trop-2 H-score was 215 (180-246), and the median (IQR) percentage of membrane positive tumor cells was 91% (80-98). Trop-2 expression at any level was observed in 98% of patients. Furthermore, ORR, PFS, and OS benefits were observed across all Trop-2 expression levels. CONCLUSIONS: Trop-2 protein is highly expressed in UC, as confirmed by examining tumors from patients enrolled in the TROPHY-U-01 trial. The results indicate that SG demonstrates efficacy in mUC across Trop-2 expression levels.
Subject(s)
Antibodies, Monoclonal, Humanized , Antigens, Neoplasm , Camptothecin , Cell Adhesion Molecules , Immunoconjugates , Humans , Cell Adhesion Molecules/metabolism , Antibodies, Monoclonal, Humanized/therapeutic use , Female , Male , Aged , Middle Aged , Camptothecin/analogs & derivatives , Camptothecin/therapeutic use , Immunoconjugates/therapeutic use , Aged, 80 and over , Adult , Biomarkers, Tumor/metabolism , Urologic Neoplasms/drug therapy , Urologic Neoplasms/pathology , Urologic Neoplasms/mortality , Urologic Neoplasms/metabolism , Treatment Outcome , Neoplasm StagingABSTRACT
Ovarian cancer stands as the deadliest gynecologic malignancy, responsible for nearly 65% of all gynecologic cancer-related deaths. The challenges in early detection and diagnosis, coupled with the widespread intraperitoneal spread of cancer cells and resistance to chemotherapy, contribute significantly to the high mortality rate of this disease. Due to the absence of specific symptoms and the lack of effective screening methods, most ovarian cancer cases are diagnosed at advanced stages. While chemotherapy is a common treatment, it often leads to tumor recurrence, necessitating further interventions. In recent years, antibody-drug conjugates (ADCs) have emerged as a valuable tool in targeted cancer therapy. These complex biotherapeutics combine an antibody that specifically targets tumor specific/associated antigen(s) with a high potency anti-cancer drug through a linker, offering a promising approach for ovarian cancer treatment. The identification of molecular targets in various human tumors has paved the way for the development of targeted therapies, with ADCs being at the forefront of this innovation. By delivering cytotoxic agents directly to tumors and metastatic lesions, ADCs show potential in managing chemo-resistant ovarian cancers. Mucins such as MUC16, MUC13, and MUC1 have shown significantly higher expression in ovarian tumors as compared to normal and/or benign samples, thus have become promising targets for ADC generation. While traditional markers are limited by their elevated levels in non-cancerous conditions, mucins offer a new possibility for targeted treatment in ovarian cancer. This review comprehensively described the potential of mucins for the generation of ADC therapy, highlighting their importance in the quest to improve the outcome of ovarian cancer patients.
Subject(s)
Immunoconjugates , Mucins , Ovarian Neoplasms , Humans , Female , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/metabolism , Immunoconjugates/therapeutic use , Immunoconjugates/pharmacology , Mucins/metabolism , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/pharmacology , AnimalsABSTRACT
Trastuzumab deruxtecan (T-DXd) is a novel anti-HER2 antibody-drug conjugate formed by the combination of trastuzumab and deruxtecan. It is used in human epidermal growth factor 2 receptor (HER2) mutant breast, stomach and colorectal cancers as well as non-small cell lung cancer (NSCLC). The 58-year-old denovo metastatic NSCLC patient we will discuss here progressed with newly developing brain metastasis under first-line carboplatin/paclitaxel treatment. After next generation sequencing revealed a mutation in the ERBB2 gene located in exon 20, we administered T-DXd to our patient. While a significant improvement was observed in the clinical condition of the patient after one course of treatment, brain metastases were found to be in complete response in control screening after four courses of treatment. Systemic screening with PET/computed tomography showed nearly complete regression of the primary lesion, metastatic lymphadenopathies, and surrenal metastases. T-DXd may be successfully used in HER2 mutant metastatic NSCLC patients. In addition, it can also be successfully used in patients with central nervous system metastases with or without cranial radiotherapy.
Subject(s)
Brain Neoplasms , Camptothecin , Carcinoma, Non-Small-Cell Lung , Exons , Lung Neoplasms , Receptor, ErbB-2 , Trastuzumab , Humans , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Trastuzumab/therapeutic use , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Middle Aged , Brain Neoplasms/secondary , Brain Neoplasms/drug therapy , Brain Neoplasms/genetics , Receptor, ErbB-2/genetics , Camptothecin/analogs & derivatives , Camptothecin/therapeutic use , Immunoconjugates/therapeutic use , Mutation , Female , Male , Antineoplastic Agents, Immunological/therapeutic useABSTRACT
Antibody-drug conjugates (ADCs), which combine the precise targeting capabilities of antibodies with the powerful cytotoxicity of small-molecule drugs, have evolved into a promising approach for tumor treatment. However, the traditional covalent coupling method requires the design of a specific linker tailored to the properties of the small-molecule drugs, which greatly limits the development of ADCs and the range of drugs that can be used. Herein, a novel type of antibody-calixarene drug conjugates (ACDCs) that function similarly to ADCs by delivering drugs to their targets using antibodies but without the requirement of covalent conjugation of the drugs with antibodies is presented. By replacement of conventional linkers with supramolecular linkers, the ACDCs can load various chemotherapeutic drugs through host-guest interactions. Furthermore, ACDCs are readily reduced upon reaching the hypoxic microenvironment, resulting in rapid release of the drugs. With this precise drug encapsulation and controlled release mechanism, ACDCs deliver drugs to tumor tissues effectively and achieve a significantly enhanced antitumor effect. Considering that the ACDCs can be easily prepared by combining antibody-calixarene conjugates derived from tumor-targeting antibodies with various small-molecule drugs, ACDCs may provide a promising platform technology to accelerate ADC development and thus improve the therapeutic efficacy of chemotherapy.
Subject(s)
Antineoplastic Agents , Calixarenes , Immunoconjugates , Calixarenes/chemistry , Immunoconjugates/chemistry , Immunoconjugates/pharmacology , Immunoconjugates/therapeutic use , Humans , Animals , Mice , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Neoplasms/drug therapy , Drug Delivery Systems , Mice, Inbred BALB C , Drug Carriers/chemistry , Female , Drug LiberationABSTRACT
Sacituzumab Govitecan (SG) is an antibody-drug conjugate that has demonstrated efficacy in patients with TROP-2 expressing epithelial cancers. In a xenograft model of intracranial breast cancer, SG inhibited tumor growth and increased mouse survival. We conducted a prospective window-of-opportunity trial (NCT03995706) at the University of Texas Health Science Center at San Antonio to examine the intra-tumoral concentrations and intracranial activity of SG in patients undergoing craniotomy for breast cancer with brain metastases (BCBM) or recurrent glioblastoma (rGBM). We enrolled 25 patients aged ≥18 years diagnosed with BCBM and rGBM to receive a single intravenous dose of SG at 10 mg/kg given one day before resection and continued on days 1 and 8 of 21-day cycles following recovery. The PFS was 8 months and 2 months for BCBM and rGBM cohorts, respectively. The OS was 35.2 months and 9.5 months, respectively. Grade≥3 AE included neutropenia (28%), hypokalemia (8%), seizure (8%), thromboembolic event (8%), urinary tract infection (8%) and muscle weakness of the lower limb (8%). In post-surgical tissue, the median total SN-38 was 249.8 ng/g for BCBM and 104.5 ng/g for rGBM, thus fulfilling the primary endpoint. Biomarker analysis suggests delivery of payload by direct release at target site and that hypoxic changes do not drive indirect release. Secondary endpoint of OS was 35.2 months for the BCBM cohort and 9.5 months for rGBM. Non-planned exploratory endpoint of ORR was 38% for BCBM and 29%, respectively. Exploratory endpoint of Trop-2 expression was observed in 100% of BCBM and 78% of rGBM tumors. In conclusion, SG was found to be well tolerated with adequate penetration into intracranial tumors and promising preliminary activity within the CNS. Trial Registration: Trial (NCT03995706) enrolled at Clinical Trials.gov as Neuro/Sacituzumab Govitecan/Breast Brain Metastasis/Glioblastoma/Ph 0: https://clinicaltrials.gov/study/NCT03995706?cond=NCT03995706 .
Subject(s)
Antibodies, Monoclonal, Humanized , Brain Neoplasms , Breast Neoplasms , Glioblastoma , Immunoconjugates , Neoplasm Recurrence, Local , Humans , Female , Glioblastoma/drug therapy , Glioblastoma/pathology , Brain Neoplasms/secondary , Brain Neoplasms/drug therapy , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Middle Aged , Antibodies, Monoclonal, Humanized/therapeutic use , Antibodies, Monoclonal, Humanized/administration & dosage , Adult , Aged , Immunoconjugates/therapeutic use , Camptothecin/analogs & derivatives , Camptothecin/therapeutic use , Prospective Studies , Bridged Bicyclo Compounds, Heterocyclic/therapeutic use , Antigens, Neoplasm/metabolism , Cell Adhesion Molecules/metabolismABSTRACT
Antibody-drug conjugates (ADCs) have demonstrated effectiveness in treating various cancers, particularly exhibiting specificity in targeting human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Recent advancements in phase 3 clinical trials have broadened current understanding of ADCs, especially trastuzumab deruxtecan, in treating other HER2-expressing malignancies. This expansion of knowledge has led to the US Food and Drug Administration's approval of trastuzumab deruxtecan for HER2-positive and HER2-low breast cancer, HER2-positive gastric cancer, and HER2-mutant nonsmall cell lung cancer. Concurrent with the increasing use of ADCs in oncology, there is growing concern among health care professionals regarding the rise in the incidence of interstitial lung disease or pneumonitis (ILD/p), which is associated with anti-HER2 ADC therapy. Studies on anti-HER2 ADCs have reported varying ILD/p mortality rates. Consequently, it is crucial to establish guidelines for the diagnosis and management of ILD/p in patients receiving anti-HER2 ADC therapy. To this end, a panel of Chinese experts was convened to formulate a strategic approach for the identification and management of ILD/p in patients treated with anti-HER2 ADC therapy. This report presents the expert panel's opinions and recommendations, which are intended to guide the management of ILD/p induced by anti-HER2 ADC therapy in clinical practice.
Subject(s)
Immunoconjugates , Lung Diseases, Interstitial , Receptor, ErbB-2 , Humans , Lung Diseases, Interstitial/drug therapy , Lung Diseases, Interstitial/chemically induced , China , Immunoconjugates/therapeutic use , Immunoconjugates/adverse effects , Pneumonia/drug therapy , Female , Consensus , Trastuzumab/therapeutic use , Trastuzumab/adverse effects , Breast Neoplasms/drug therapy , Camptothecin/analogs & derivativesABSTRACT
BACKGROUND: Delta-like ligand 3 (DLL3) is highly expressed on the cell surface of small cell lung cancer (SCLC), one of the most lethal malignancies, but minimally or not in normal tissues, making it an attractive target for SCLC. However, none of the DLL3-targeting antibody-drug conjugates (ADCs) have been approved for SCLC therapy yet. We developed DB-1314, the new anti-DLL3 ADC composed of a novel humanized anti-DLL3 monoclonal antibody (DB131401) conjugated with eight molecules of P1021 (topoisomerase I inhibitor), and described its preclinical profiles. METHODS: The binding epitope for DB131401 and Rovalpituzumab was tested by biolayer interferometry. The binding affinity and specificity of DB-1314 to DLL3 and other homologous proteins were respectively measured by surface plasmon resonance and enzyme-linked immunosorbent assay. Internalization, bystander effects, and antibody-dependent cell-mediated cytotoxicity (ADCC) were assessed by respective assay. DLL3 was quantified by antibodies bound per cell assay and immunohistochemistry. In vitro and in vivo growth inhibition studies were evaluated in SCLC cell lines, and cell line/patient-derived xenograft models. The safety profile was measured in cynomolgus monkeys. RESULTS: DB-1314 induces potent, durable, and dose-dependent antitumor effects in cells in vitro and in cell/patient-derived xenograft models in vivo. The killing activity of DB-1314 mechanically arises from P1021-induced DNA damage, whereby P1021 is delivered and released within tumor cells through DLL3-specific binding and efficient internalization. Bystander effects and ADCC also contribute to the antitumor activity of DB-1314. DB-1314 displays favorable pharmacokinetic and toxicokinetic profiles in rats and cynomolgus monkeys; besides, DB-1314 is well-tolerated at a dose of up to 60 mg/kg in monkeys. CONCLUSIONS: These results suggest that DB-1314 may be a candidate ADC targeting DLL3 for the treatment of DLL3-positive SCLC, supporting further evaluation in the clinical setting.
Subject(s)
Immunoconjugates , Lung Neoplasms , Membrane Proteins , Small Cell Lung Carcinoma , Topoisomerase I Inhibitors , Small Cell Lung Carcinoma/drug therapy , Small Cell Lung Carcinoma/pathology , Animals , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Humans , Topoisomerase I Inhibitors/pharmacology , Topoisomerase I Inhibitors/therapeutic use , Cell Line, Tumor , Immunoconjugates/pharmacology , Immunoconjugates/therapeutic use , Membrane Proteins/metabolism , Membrane Proteins/antagonists & inhibitors , Macaca fascicularis , Xenograft Model Antitumor Assays , Rats , Intracellular Signaling Peptides and Proteins/metabolism , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Female , Antibodies, Monoclonal, Humanized/therapeutic use , Antibodies, Monoclonal, Humanized/pharmacology , Mice , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal/pharmacology , BenzodiazepinonesABSTRACT
Trophoblast cell surface antigen 2 (Trop2) is overexpressed in a range of solid tumors and participants in multiple oncogenic signaling pathways, making it an attractive therapeutic target. In the past decade, the rapid development of various Trop2-targeted therapies, notably marked by the advent of the antibody-drug conjugate (ADC), revolutionized the outcome for patients facing Trop2-positive tumors with limited treatment opinions, such as triple-negative breast cancer (TNBC). This review provides a comprehensive summary of advances in Trop2-targeted therapies, including ADCs, antibodies, multispecific agents, immunotherapy, cancer vaccines, and small molecular inhibitors, along with in-depth discussions on their designs, mechanisms of action (MOAs), and limitations. Additionally, we emphasize the clinical research progress of these emerging Trop2-targeted agents, focusing on their clinical application and therapeutic efficacy against tumors. Furthermore, we propose directions for future research, such as enhancing our understanding of Trop2's structure and biology, exploring the best combination strategies, and tailoring precision treatment based on Trop2 testing methodologies.
Subject(s)
Antigens, Neoplasm , Cell Adhesion Molecules , Immunoconjugates , Molecular Targeted Therapy , Neoplasms , Humans , Antigens, Neoplasm/immunology , Cell Adhesion Molecules/antagonists & inhibitors , Cell Adhesion Molecules/metabolism , Immunoconjugates/therapeutic use , Immunoconjugates/pharmacology , Molecular Targeted Therapy/methods , Neoplasms/drug therapy , Neoplasms/therapy , Immunotherapy/methods , Animals , Cancer Vaccines/therapeutic useABSTRACT
BACKGROUND: Ductal Adenocarcinoma (DAC) and Intraductal Carcinoma of the Prostate (IDC-P) respond poorly to all the currently available conventional therapies. Given their accurate and efficient elimination of cancer cells, Antibody-Drug Conjugates (ADCs) have become one of the most promising anticancer treatments. However, no ADCs have so far been approved for Prostate Cancer (PCa) treatment. This study investigated TROP-2, HER2, and CD46 expression in DAC/IDC-P samples, indirectly analyzing their preliminary feasibility as therapeutic targets for future treatment of the two conditions. PATIENTS AND METHODS: We conducted a retrospective study involving 184 participants (87 DAC/IDC-P patients and 97 Prostatic Acinar Adenocarcinoma (PAC) patients with a Gleason score ≥ 8) without prior treatment between August 2017 and August 2022. Immunohistochemical staining was employed to detect the differential protein expressions of TROP-2, HER2, and CD46 in DAC/IDC-P, PAC, and normal prostate tissues. RESULTS: Compared to pure PAC tissues, TROP-2 expression was significantly higher in DAC/IDC-P and DAC/IDC-P-adjacent PAC tissues (H-score 68.8 vs. 43.8, p < 0.001, and 59.8 vs. 43.8, p = 0.022, respectively). No significant differences in HER2 expression were observed across different cancer tissues. Compared to both DAC/IDC-P-adjacent PAC and pure PAC tissues, CD46 expression was significantly higher in DAC/IDC-P tissues (42.3 vs. 28.6, p = 0.041, and 42.3 vs. 24.3, p = 0.0035, respectively). CONCLUSIONS: Herein, TROP-2 and CD46 expression was higher in DAC/IDC-P tissues than in pure PAC and normal prostate tissues. This finding implies that ADCs targeting the two proteins hold significant promise as potential future treatments for DAC/IDC-P.
Subject(s)
Antigens, Neoplasm , Cell Adhesion Molecules , Feasibility Studies , Immunoconjugates , Membrane Cofactor Protein , Prostatic Neoplasms , Receptor, ErbB-2 , Humans , Male , Prostatic Neoplasms/pathology , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/drug therapy , Cell Adhesion Molecules/metabolism , Retrospective Studies , Receptor, ErbB-2/metabolism , Aged , Immunoconjugates/therapeutic use , Middle Aged , Antigens, Neoplasm/metabolism , Membrane Cofactor Protein/metabolism , Carcinoma, Ductal/metabolism , Carcinoma, Ductal/pathology , Carcinoma, Ductal/drug therapy , Aged, 80 and overABSTRACT
To observe the clinical outcomes of patients diagnosed with metastatic breast cancer undergoing Trastuzumab Deruxtecan (T-DXd) therapy in a real-world setting. The study retrospectively reviewed and collected medical data from 13 patients at Shin Kong Wu Ho-Su Memorial Hospital who underwent T-DXd treatment over a period from April 2022 to June 2023. Demographics, pathological characteristics, treatment patterns, and outcomes were descriptively analyzed. Thirteen patients diagnosed with metastatic breast cancer underwent T-DXd treatment between April 2022 and June 2023. This study observed that T-DXd was effective in patients with high human epidermal growth factor receptor 2 (HER2) levels. In patients with low HER2, the majority also experienced favorable responses. Only 2 patients exhibited poor or no response: one was a BRCA2 carrier with unmanageable disease progression, and the other had a HER2 1â +â status with multiorgan metastases whose cancer was not controlled by T-DXd. Additionally, 2 patients with no HER2 expression responded well to T-DXd treatment. T-DXd is a valuable treatment alternative for patients with breast cancer, including those with HER2-high, HER2-low, and HER2-negative statuses. In this study, the majority of patients experienced positive therapeutic effects. However, this evaluation relied on a limited sample size and short-term observations. Additional studies involving larger and more diverse patient groups and long follow-up durations are required.
Subject(s)
Antineoplastic Agents, Immunological , Breast Neoplasms , Camptothecin , Receptor, ErbB-2 , Trastuzumab , Humans , Trastuzumab/therapeutic use , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Breast Neoplasms/genetics , Female , Receptor, ErbB-2/metabolism , Middle Aged , Retrospective Studies , Taiwan , Antineoplastic Agents, Immunological/therapeutic use , Camptothecin/analogs & derivatives , Camptothecin/therapeutic use , Adult , Aged , Immunoconjugates/therapeutic use , Neoplasm Metastasis , Treatment OutcomeABSTRACT
Antineoplastic therapy is one of the main research themes of this century. Modern approaches have been implemented to target and heighten the effect of cytostatic drugs on tumors and diminish their general/unspecific toxicity. In this context, antibody-drug conjugates (ADCs) represent a promising and successful strategy. The aim of this review was to assess different aspects regarding ADCs. They were presented from a chemical and a pharmacological perspective and aspects like structure, conjugation and development particularities alongside effects, clinical trials, safety issues and perspectives and challenges for future use of these drugs were discussed. Representative examples include but are not limited to the following main structural components of ADCs: monoclonal antibodies (trastuzumab, brentuximab), linkers (pH-sensitive, reduction-sensitive, peptide-based, phosphate-based, and others), and payloads (doxorubicin, emtansine, ravtansine, calicheamicin). Regarding pharmacotherapy success, the high effectiveness expectation associated with ADC treatment is supported by the large number of ongoing clinical trials. Major aspects such as development strategies are first discussed, advantages and disadvantages, safety and efficacy, offering a retrospective insight on the subject. The second part of the review is prospective, focusing on various plans to overcome the previously identified difficulties.
Subject(s)
Immunoconjugates , Neoplasms , Humans , Immunoconjugates/therapeutic use , Immunoconjugates/chemistry , Neoplasms/drug therapy , Animals , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/chemistry , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal/chemistryABSTRACT
Platinum-resistant ovarian cancer (PROC) refers to disease progression within 6 months after the completion of platinum-based chemotherapy. Historically, treatment options for PROC were limited with a poor prognosis and non-platinum single agent plus bevacizumab has been the mainstay of treatment. Fortunately, there have been notable advancements in recent years, leading to an advance in treatment paradigms for this challenging disease. Various combinations of chemotherapy, targeted agents such as poly (ADP-ribose) polymerase (PARP) inhibitors, and immunotherapy are being explored for an improved treatment outcome. Antibody-drug conjugates targeting folate receptor alpha, which deliver a cytotoxic payload directly to cancer cells, have emerged as a promising therapeutic approach for PROC. WEE1 inhibitors, such as adavosertib, function by inhibiting the WEE1 kinase activity, leading to premature entry of a cell into mitosis phase and thus increased DNA damage. It has been observed that cancer cells with TP53 mutations may be more sensitive to WEE1 inhibitors. Biomarker testing such as analysis of the expression level of folate receptor alpha or mutation in TP53 may be applicable for identifying patients who are more likely to respond to the specific therapy, enabling a more personalized treatment approach. This overview summarizes key clinical findings on the efficacy and safety of theses novel biomarker-driven therapeutic approaches.
Subject(s)
Drug Resistance, Neoplasm , Ovarian Neoplasms , Humans , Female , Ovarian Neoplasms/drug therapy , Protein-Tyrosine Kinases/antagonists & inhibitors , Antineoplastic Agents/therapeutic use , Folate Receptor 1/antagonists & inhibitors , Cell Cycle Proteins/antagonists & inhibitors , Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Immunotherapy/methods , Immunoconjugates/therapeutic use , Pyrazoles/therapeutic use , Tumor Suppressor Protein p53 , Pyrimidinones/therapeutic useABSTRACT
Traditional therapeutic approaches such as chemotherapy and radiation therapy have burdened cancer patients with onerous physical and psychological challenges. Encouragingly, the landscape of tumor treatment has undergone a comprehensive and remarkable transformation. Emerging as fervently pursued modalities are small molecule targeted agents, antibody-drug conjugates (ADCs), cell-based therapies, and gene therapy. These cutting-edge treatment modalities not only afford personalized and precise tumor targeting, but also provide patients with enhanced therapeutic comfort and the potential to impede disease progression. Nonetheless, it is acknowledged that these therapeutic strategies still harbour untapped potential for further advancement. Gaining a comprehensive understanding of the merits and limitations of these treatment modalities holds the promise of offering novel perspectives for clinical practice and foundational research endeavours. In this review, we discussed the different treatment modalities, including small molecule targeted drugs, peptide drugs, antibody drugs, cell therapy, and gene therapy. It will provide a detailed explanation of each method, addressing their status of development, clinical challenges, and potential solutions. The aim is to assist clinicians and researchers in gaining a deeper understanding of these diverse treatment options, enabling them to carry out effective treatment and advance their research more efficiently.
Subject(s)
Genetic Therapy , Neoplasms , Humans , Neoplasms/therapy , Neoplasms/genetics , Neoplasms/drug therapy , Immunoconjugates/therapeutic use , Molecular Targeted Therapy , Cell- and Tissue-Based Therapy , Antineoplastic Agents/therapeutic useABSTRACT
Lung cancer is the most common malignant tumor and the second most common malignant tumor in terms of mortality in the world. Non-small cell lung cancer (NSCLC) is the most common pathological type of lung cancer. Currently, the first-line standard treatment for advanced NSCLC is immunotherapy and targeted therapy. Although these treatments prolong the survival of patients, acquired drug resistance is still inevitable. Antibody-drug conjugates (ADCs) are a new type of anti-tumor drug made by coupling cytotoxic payloads to specific monoclonal antibodies via linkers. Compared with chemotherapy drugs, ADCs have the advantages of accurate recognition, local release, and high patient tolerance. In recent years, they have shown good clinical benefits in the treatment of NSCLC. This article provides an overview of the mechanism of action of ADCs, clinical studies progress in advanced NSCLC, and existing problems and challenges.â©.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Immunoconjugates , Lung Neoplasms , Humans , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/immunology , Lung Neoplasms/drug therapy , Lung Neoplasms/immunology , Immunoconjugates/therapeutic use , Antineoplastic Agents/therapeutic use , Animals , Antibodies, Monoclonal/therapeutic useABSTRACT
Antibody-drug conjugates (ADCs) represent a novel type of targeted cancer therapy combining the specificity of monoclonal antibodies with the cytotoxicity of conventional chemotherapy. Recently, ADCs have demonstrated practice-changing efficacy across diverse solid cancers. The anti-NECTIN-4 ADC enfortumab vedotin (EV) has just been approved for patients with urothelial cancer and is currently under investigation for patients with castration-resistant prostate cancer (CRPC e.g. Phase II ENCORE trial). Our objective was to evaluate the efficacy of EV in established prostate cancer (PCa) cell lines and to examine the membranous NECTIN-4 expression in primary tumours (PRIM) and distant metastases (MET). NECTIN-4 was heterogeneously expressed in the panel of PCa cell lines. EV led to growth inhibition in NECTIN-4 expressing PCa cells (22Rv1 and LNCaP), whereas the NECTIN-4-negative PC-3 cells were significantly less responsive to EV, emphasizing the dependence of EV response on its target expression. Immunohistochemical staining revealed moderate membranous NECTIN-4 expression only in a small subgroup of CRPC patients with lung and peritoneal MET [n = 3/22 with H-score ≥100, median H-score 140 (IQR 130-150)], while 100% of PRIM (n = 48/48) and 86.4% of common MET sites (n = 19/22), including lymph node, bone and liver MET, were NECTIN-4 negative. In summary, EV may be effective in NECTIN-4-positive PCa. However, our findings demonstrate that the tumoural NECTIN-4 expression is predominantly low in metastatic PCa, which suggests that EV may only be effective in a biomarker-stratified subgroup.
Subject(s)
Antibodies, Monoclonal , Cell Adhesion Molecules , Prostatic Neoplasms , Humans , Male , Cell Adhesion Molecules/metabolism , Cell Adhesion Molecules/genetics , Antibodies, Monoclonal/pharmacology , Antibodies, Monoclonal/therapeutic use , Cell Line, Tumor , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/pathology , Prostatic Neoplasms/genetics , Gene Expression Regulation, Neoplastic/drug effects , Immunoconjugates/pharmacology , Immunoconjugates/therapeutic use , Prostatic Neoplasms, Castration-Resistant/drug therapy , Prostatic Neoplasms, Castration-Resistant/metabolism , Prostatic Neoplasms, Castration-Resistant/pathology , Cell Proliferation/drug effects , NectinsABSTRACT
Cost-effectiveness analyses are required for therapies within Canada's universal healthcare system, leading to delays relative to U.S. healthcare. Patients with Hodgkin lymphoma (HL) generally have an excellent prognosis, but those who relapse after or are ineligible for transplant benefit from novel therapies, including brentuximab vedotin (BV). BV was FDA-approved in 2011 but not Canadian-funded until 2014. To assess the impact of access delays, we compared changes in survival for U.S. (by insurer) and Canadian patients in periods pre/post-U.S. approval. Patients were 16-64 years, diagnosed with HL in 2007-2010 (Period 1) and 2011-2014 (Period 2) from the U.S. SEER and Canadian Cancer Registries. Approval date (surrogate) was utilized as therapy was unavailable in registries. Kaplan-Meier survival curves and adjusted Cox regression models compared survival between periods by insurance category. Among 12,003 U.S. and 4210 Canadian patients, survival was better in U.S. patients (adjusted hazard ratio (aHR) 0.87 (95%CI 0.77-0.98)) between periods; improvement in Canadian patients (aHR 0.84 (95%CI 0.69-1.03) was similar but non-significant. Comparisons between insurers showed survival was significantly worse for U.S. uninsured and Medicaid vs. U.S. privately insured and Canadian patients. Given the increasingly complex nature of oncologic funding, this merits further investigation to ensure equity in access to therapy developments.
Subject(s)
Brentuximab Vedotin , Hodgkin Disease , Immunoconjugates , Humans , Hodgkin Disease/drug therapy , Hodgkin Disease/mortality , Canada , Brentuximab Vedotin/therapeutic use , United States , Adult , Female , Male , Middle Aged , Retrospective Studies , Adolescent , Young Adult , Immunoconjugates/therapeutic useSubject(s)
Folate Receptor 1 , Immunoconjugates , Ovarian Neoplasms , Precision Medicine , Humans , Female , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/pathology , Precision Medicine/methods , Immunoconjugates/therapeutic use , Immunoconjugates/administration & dosage , Folate Receptor 1/antagonists & inhibitors , Cystadenocarcinoma, Serous/drug therapy , Cystadenocarcinoma, Serous/pathologyABSTRACT
On August 11, 2022, FDA granted accelerated approval to fam-trastuzumab deruxtecan-nxki (DS-8201a, T-DXd, ENHERTU, Daiichi Sankyo) for adult patients with unresectable or metastatic non-small cell lung cancer (NSCLC) whose tumors have activating human epidermal growth factor receptor 2 (HER2) mutations, as detected by an FDA-approved test, and who have received a prior systemic therapy. The approval was based on a prespecified interim analysis of DESTINY-Lung02 (Study U206), a multi-center, randomized, dose-optimization trial in patients with NSCLC harboring activating HER2-mutations. At the approved dose of 5.4 mg/kg given intravenously every 3 weeks, the overall response rate (ORR) was 58% (95% confidence interval [CI]: 43, 71). The median duration of response was 8.7 months (95% CI: 7.1, not estimable). These results were consistent with response rates observed at the 6.4 mg/kg dose level. The most common (≥â 20%) adverse reactions were nausea, constipation, decreased appetite, vomiting, fatigue, and alopecia. The rate of interstitial lung disease (ILD) or pneumonitis was 6% at the 5.4 mg/kg dose level and 14% at the 6.4 mg/kg dose level. In the setting of similar efficacy and reduced toxicity, approval was granted for the 5.4 mg/kg dose level. The applicant conducted a randomized, dose-optimization study with guidance from the FDA Oncology Center of Excellence's Project Optimus. This is the first approval of a targeted therapy for HER2-mutated NSCLC.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Mutation , Receptor, ErbB-2 , Trastuzumab , Humans , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Receptor, ErbB-2/genetics , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Female , Trastuzumab/therapeutic use , Trastuzumab/pharmacology , Male , Middle Aged , United States , United States Food and Drug Administration , Drug Approval , Aged , Immunoconjugates/therapeutic use , Immunoconjugates/pharmacology , Immunoconjugates/adverse effects , Camptothecin/analogs & derivatives , Camptothecin/therapeutic use , Camptothecin/pharmacology , Camptothecin/adverse effects , Adult , Antibodies, Monoclonal, Humanized/therapeutic use , Antibodies, Monoclonal, Humanized/pharmacologyABSTRACT
PURPOSE OF REVIEW: Antibody-drug conjugates (ADCs) are designed to carry cytotoxic payloads and deliver them to specific molecular targets within tumor cells. Several ADCs are already approved with many more in development across several disease types. In this review, we will provide an overview of the ADCs currently approved and those under investigation in solid tumors. RECENT FINDINGS: Currently there are dozens of ADCs under clinical study evaluation of a variety of solid tumors, and preliminary results are promising. Multiple ADCs have received regulatory approval in disease such as breast cancer, non-small cell lung cancer, and bladder cancer. While some are approved in biomarker selected settings with disease specific indication (e.g. breast cancer), others have been approved irrespective of biomarker expression (urothelial carcinoma) and pan-cancer indications in biomarker selected patients (HER2 3+ expression). SUMMARY: Cytotoxic chemotherapy has been the mainstay of systemic treatment for patients with various solid tumors. ADCs offer the advantage of carrying the cytotoxic payload onto a specific molecular receptor, thereby inducing a more selective response. Optimizing selection of target antigen, payload delivery and investigating biomarkers of response will be crucial for further expanding the therapeutic benefit of ADCs across solid tumors.