Emerging Toxicities of Antibody-Drug Conjugates for Breast Cancer: Clinical Prioritization of Adverse Events from the FDA Adverse Event Reporting System.

BACKGROUND: Antibody-drug conjugates (ADCs) are gaining widespread use in the treatment of breast cancer, although toxicity remains an underexplored issue in the real-world clinical setting. Individual case safety reports collected in large pharmacovigilance databases can advance our knowledge on their safety profile in routine clinical practice. OBJECTIVE: We prioritized adverse events (AEs) reported with ADCs approved for breast cancer using the Food and Drug Administration Adverse Event Reporting System (FAERS). METHODS: We assessed clinical priority of AEs reported in FAERS (February 2013-March 2022) for trastuzumab emtansine (T-DM1), trastuzumab deruxtecan (T-DXd), and sacituzumab govitecan (SG) by attributing a score to each AE disproportionally reported with ADCs. Four criteria were assessed: clinical relevance, reporting rate, reported case fatality rate, and stability of disproportionality signals (consistency of the reporting odds ratio across multiple analyses using three different comparators). RESULTS: We retained 6589 reports (77.4% referring to T-DM1 as suspect), and 572 AEs generated a disproportionality signal in at least one analysis. The majority of these AEs (62%) were classified as moderate clinical priorities (e.g., interstitial lung disease with T-DXd, thrombocytopenia, peripheral neuropathy with T-DM1, febrile neutropenia, and large intestine perforation with SG). Three AEs emerged as high clinical priorities (6 points): septic shock and neutropenic colitis with SG (N = 8 and 13, with median onset 13 and 10 days, respectively), without co-reported immunosuppressive agents; and pulmonary embolism with T-DM1 (N = 31, median onset 109 days, 52% with reported metastasis). CONCLUSION: The heterogeneous spectrum of post-marketing toxicities for ADCs used in breast cancer, as emerging from the FAERS, is largely in line with preapproval evidence. Although causality cannot be proved, we call for increased awareness by oncologists on potential serious unexpected reactions, including early onset of septic shock and neutropenic colitis with SG, and late emergence of pulmonary embolism with T-DM1.

Trastuzumab deruxtecan in patients with solid tumours harbouring specific activating HER2 mutations (DESTINY-PanTumor01): an international, phase 2 study.

BACKGROUND: Trastuzumab deruxtecan is a HER2-directed antibody-drug conjugate approved by the US Food and Drug Administration and the European Medicines Agency for HER2-mutant non-small-cell lung cancer. Few treatment options exist for patients with HER2-mutant solid tumours beyond lung cancers. We investigated trastuzumab deruxtecan in metastatic solid tumours with specific activating HER2 mutations. METHODS: In this open-label, phase 2, basket study done in 29 centres in Asia, Europe, and North America, we investigated trastuzumab deruxtecan (5·4 mg/kg every 3 weeks by intravenous infusion) in patients aged 18 years or older with unresectable or metastatic solid tumours with specific activating HER2 mutations, an Eastern Cooperative Oncology Group performance status of 0 or 1, and disease progression following previous treatment (previous HER2-targeted therapy was permitted) or with no satisfactory alternative treatment options. The primary endpoint was confirmed objective response rate by independent central review. Anti-tumour activity and safety were analysed in all patients who received at least one dose of trastuzumab deruxtecan. This trial is registered with ClinicalTrials.gov, NCT04639219, and is active but no longer recruiting. FINDINGS: Between Dec 30, 2020, and Jan 25, 2023, 102 patients (62 [61%] female and 40 [39%] male; median age 66·5 years [IQR 58-72]; 51 [50%] White, two [2%] Black or African American, 38 [37%] Asian, and 11 [11%] did not have race information reported) with solid tumours with activating HER2 mutations received trastuzumab deruxtecan and were included in the anti-tumour activity and safety analyses sets. Patients had a median of three (IQR 2-4) previous treatment regimens. The median duration of follow-up was 8·61 months (IQR 3·71-12·68). The objective response rate by independent central review was 29·4% (95% CI 20·8-39·3; 30 of 102 patients). 52 (51%) patients had a treatment-emergent adverse event of grade 3 or worse; the most common events (in ≥5% of patients) were anaemia (16 [16%]) and neutrophil count decreased (eight [8%]). Drug-related treatment-emergent serious adverse events occurred in ten (10%) patients. Adjudicated drug-related interstitial lung disease or pneumonitis of any grade occurred in 11 patients (11%; three grade 1, five grade 2, one grade 3, and two grade 5); there were two (2%) cases of fatal adjudicated drug-related interstitial lung disease or pneumonitis. INTERPRETATION: Trastuzumab deruxtecan showed anti-tumour activity and durable responses in heavily pretreated patients across multiple tumour types with activating HER2 mutations, with no new safety signals. Prespecified HER2 mutations might be targeted by HER2-directed antibody-drug conjugates and our findings support further investigation of trastuzumab deruxtecan in the pan-tumour setting. FUNDING: AstraZeneca and Daiichi Sankyo.

Mirvetuximab soravtansine: A breakthrough in targeted therapy for platinum-resistant ovarian cancer.

Ovarian cancer, ranked as the second leading cause of gynecologic malignancy-related deaths globally, poses a formidable challenge despite advances in early detection and treatment modalities. This paper explores the efficacy and safety of mirvetuximab soravtansine, the first folate receptor alpha (FRα)-targeting antibody-drug conjugate, in platinum-resistant ovarian cancer expressing FRα. A review of 4 key studies involving 453 participants consistently demonstrates mirvetuximab soravtansine's clinically meaningful antitumor activity and favorable safety profile. Clinical implications emphasize mirvetuximab soravtansine's pivotal role in targeted therapy, especially for high FRα-expressing tumors, potentially reshaping platinum-resistant ovarian cancer management. The combination therapy approach introduces a novel dimension, suggesting enhanced therapeutic outcomes. Even in heavily pretreated patients, mirvetuximab soravtansine's favorable tolerability positions it as a viable option. The reliability of archival tissue for FRα assessment simplifies patient selection, streamlining accessibility to targeted therapies. However, identified gaps, including limited diversity in patient populations, sparse quality of life data, and the need for long-term safety information, indicate areas for future research. Exploration of additional biomarkers predicting mirvetuximab soravtansine responsiveness is essential for personalized treatment.

RC48-Antibody-Drug Conjugate in Metastatic Urothelial Carcinoma: A Multicenter Real-World Study in China.

OBJECTIVES: RC48 is an antibody-drug conjugate (ADC) that targets HER2. In China, RC48 is approved for patients with HER-2-positive metastatic urothelial carcinoma (mUC) who have failed at least platinum-based chemotherapy. This study aimed to evaluate RC48 for mUC in a cohort of real-world patients. MATERIALS AND METHODS: We retrospectively collected data from 103 mUC patients from 12 centers between July 2021 and August 2023 in China. RC48 alone or with immunotherapy was administered until disease progression, intolerable toxicity, death, or other reasons. The objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and incidence of treatment-related adverse events (TRAEs) were evaluated. RESULTS: The median age of the patients was 68 years, and 68.0% were men. Twenty-nine (28.2%) patients received RC48 alone; 73 (70.9%) received RC48 combination therapy. The response rates were as follows: complete response in 2 (1.9%) patients, partial response in 50 (48.5%) patients, stable disease in 30 (29.1%) patients. The ORR was 50.5%. In patients with ≥80 years, Eastern Cooperative Oncology Group (ECOG) performance status ≥2 and creatinine clearance rate (CCr) <30 mL/min, the ORR was 75%, 48.6%, and 40.0%, respectively. The median PFS was 6 (3.9-8.1) months, and the median OS was not reached. The most reported TRAEs were peripheral sensory neuropathy (53.4%), alopecia (42.7%), asthenia (38.8%), decreased appetite (35.9%) and weight loss (35.9%) and TRAE did not increase in patients with poor condition or impaired renal function. CONCLUSION: Administration of RC48 for real-world patients is both effective and safe. mUC patients can benefit from RC48-based therapy, regardless of their poor condition or impaired renal function.

Comparison of infectious complications with BCMA-directed therapies in multiple myeloma.

B-cell-maturation-antigen (BCMA)-directed therapies are highly active for multiple myeloma, but infections are emerging as a major challenge. In this retrospective, single-center analysis we evaluated infectious complications after BCMA-targeted chimeric-antigen-receptor T-cell therapy (CAR-T), bispecific-antibodies (BsAb) and antibody-drug-conjugates (ADC). The primary endpoint was severe (grade ≥3) infection incidence. Amongst 256 patients, 92 received CAR-T, 55 BsAb and 109 ADC. The incidence of severe infections was higher with BsAb (40%) than CAR-T (26%) or ADC (8%), including grade 5 infections (7% vs 0% vs 0%, respectively). Comparing T-cell redirecting therapies, the incidence rate of severe infections was significantly lower with CAR-T compared to BsAb at 1-year (incidence-rate-ratio [IRR] = 0.43, 95%CI 0.25-0.76, P = 0.004). During periods of treatment-emergent hypogammaglobulinemia, BsAb recipients had higher infection rates (IRR:2.27, 1.31-3.98, P = 0.004) and time to severe infection (HR 2.04, 1.05-3.96, P = 0.036) than their CAR-T counterparts. During periods of non-neutropenia, CAR-T recipients had a lower risk (HR 0.44, 95%CI 0.21-0.93, P = 0.032) and incidence rate (IRR:0.32, 95% 0.17-0.59, P < 0.001) of severe infections than BsAb. In conclusion, we observed an overall higher and more persistent risk of severe infections with BsAb. Our results also suggest a higher infection risk during periods of hypogammaglobulinemia with BsAb, and with neutropenia in CAR-T recipients.

[Chinese expert consensus on the management of clinical pathway and adverse events of trastuzumab deruxtecan (2024 edition)].

Trastuzumab deruxtecan (T-DXd) is one of the new generation antibody-drug conjugates (ADCs) targeting human epidermal growth factor receptor 2 (HER-2) with bystander effect. T-DXd can not only significantly improve the survival of HER-2-positive advanced breast cancer patients, but also enable advanced breast cancer patients with low HER-2 expression to benefit from HER-2-targeted therapy. T-DXd has been approved by the National Medical Products Administration (NMPA) for the treatment of HER-2-positive or HER-2-low breast cancer patients. It is foreseeable that T-DXd will be widely used in clinical practice in the future. However, T-DXd has also shown different safety characteristics compared to previous HER-2 targeted drugs in clinical trials. How to manage T-DXd adverse events more reasonably and fully utilize the efficacy of T-DXd is an urgent clinical problem. Based on the existing clinical evidence and guideline consensus, combined with clinical practice experience, the expert group finally reached the consensus of clinical care pathway and adverse reaction management of trastuzumab deruxtecan after many discussions. This consensus content includes the clinical use method of T-DXd, pre-treatment patient education, and management of common or noteworthy adverse events of T-DXd. The adverse events include infusion related adverse events, digestive system adverse events (nausea/vomiting, constipation, diarrhea, and decreased appetite), hematological adverse events (neutropenia, febrile neutropenia, anemia, thrombocytopenia), respiratory adverse events (interstitial lung disease/pneumonia), cardiovascular adverse events (decreased left ventricular ejection fraction), adverse events in liver function (elevated transaminases) and other common adverse events (alopecia, fatigue, etc). This consensus focuses on the prevention of adverse events, dose adjustment and treatment when adverse events occur, and recommendations for patients' lifestyle, aiming to improve clinicians' understanding of T-DXd and provide practical guidance for clinical oncologists on T-DXd clinical management.

Clinical Pharmacology of the Antibody-Drug Conjugate Enfortumab Vedotin in Advanced Urothelial Carcinoma and Other Malignant Solid Tumors.

Enfortumab vedotin is an antibody-drug conjugate comprised of a human monoclonal antibody directed to Nectin-4 and monomethyl auristatin E (MMAE), a microtubule-disrupting agent. The objectives of this review are to summarize the clinical pharmacology of enfortumab vedotin monotherapy and demonstrate that the appropriate dose has been selected for clinical use. Pharmacokinetics (PK) of enfortumab vedotin (antibody-drug conjugate and total antibody) and free MMAE were evaluated in five clinical trials of patients with locally advanced or metastatic urothelial carcinoma (n = 748). Intravenous enfortumab vedotin 0.5-1.25 mg/kg on days 1, 8, and 15 of a 28-day cycle showed linear, dose-proportional PK. No significant differences in exposure or safety of enfortumab vedotin and free MMAE were observed in mild, moderate, or severe renal impairment versus normal renal function. Patients with mildly impaired versus normal hepatic function had a 37% increase in area under the concentration-time curve (0-28 days), a 31% increase in maximum concentration of free MMAE, and a similar adverse event profile. No clinically significant PK differences were observed based on race/ethnicity with weight-based dosing, and no clinically meaningful QT prolongation was observed. Concomitant use with dual P-glycoprotein and strong cytochrome P450 3A4 inhibitors may increase MMAE exposure and the risk of adverse events. Approximately 3% of patients developed antitherapeutic antibodies against enfortumab vedotin 1.25 mg/kg. These findings support enfortumab vedotin 1.25 mg/kg monotherapy on days 1, 8, and 15 of a 28-day cycle. No dose adjustments are required for patients with renal impairment or mild hepatic impairment, or by race/ethnicity.

Side effects of drug-antibody conjugates enfortumab-vedotin and sacituzumab-govitecan in targeted therapy in cancer.

OBJECTIVE: Antibody-drug conjugates (ADC), enfortumab-vedotin (EV) and sacituzumab-govitecan are new drugs in the treatment of urologic tumors, whose safety profile has not been fully investigated. Therefore, the aim of our study was to evaluate adverse events related to both agents reported to VigiBase, the World Health Organization's global pharmacovigilance database. METHODS: We employed Bayesian disproportionality analysis based on the information component (IC) to explore the safety profile associated with both therapies. Additionally, we used the proportional reporting ratio approach to examine the safety profile further. RESULTS: We identified 41,752 reports connected to ADC therapy (EV: n=5359; SG: n=36,393). In the EV subgroup, most reports were associated with dermatologic (38.6%), neurologic adverse events (16.5%), or adverse laboratory assessments (19.4%). In contrast, reports in the SG subgroup were mainly associated with gastrointestinal adverse events (24.2%) and adverse laboratory assessments (39.0%). Adverse laboratory assessments in both cohorts were often based on haematotoxic adverse events. CONCLUSION: We could provide a comprehensive real-world safety profile of EV and SG using a global pharmacovigilance database. Based on the safety signals explored in this study, further research regarding the impact of these side effects on patient outcomes is justified.

Racial Differences in Cutaneous Events Among Patients Receiving Enfortumab Vedotin.

INTRODUCTION: Enfortumab vedotin (EV) is an antibody-drug conjugate approved alone and in combination with pembrolizumab for advanced urothelial cancer (UC). EV-related-cutaneous-events (EVCEs) are common and rarely life-threatening. Black patients are frequently under-represented in oncology trials, and dermatologic conditions may vary with race. METHODS: Therefore, this retrospective analysis investigated differences in EVCE frequency between Black and White patients in an urban cohort (Johns Hopkins [JH]) and a US-based, nationwide electronic health record (EHR)-derived deidentified database (Flatiron Health [FH]) with sub-group analysis of those who had received prior pembrolizumab. RESULTS: The study included 12 Black patients in the JH Cohort (17.1%) and 24 Black patients in the FH Cohort (7.6%). In both cohorts, the frequency of EVCEs among Black patients was higher compared to White patients (JH: 66.7% vs. 33.3%; FH: 25.0% vs. 15.8%), though not statistically significant. In the larger FH Cohort EVCEs were significantly more common among Black compared to White patients treated with prior pembrolizumab (Odds Ratio [OR]: 4.76 [95%CI: 1.42, 15.95]) and recent pembrolizumab (within 90 days of EV initiation) (OR 9.00 [95%CI: 1.94, 41.66]). CONCLUSION: This hypothesis-generating retrospective study, comprising the largest population of EV-treated Black patients reported to date, emphasizes the importance of attentiveness to EVCEs among Black patients, particularly with receipt of pembrolizumab.

Trastuzumab deruxtecan in patients with metastatic non-small-cell lung cancer (DESTINY-Lung01): primary results of the HER2-overexpressing cohorts from a single-arm, phase 2 trial.

BACKGROUND: DESTINY-Lung01 is a multicentre, open-label, phase 2 study evaluating the antitumour activity and safety of trastuzumab deruxtecan, a HER2-directed antibody-drug conjugate, in patients with HER2-overexpressing or HER2 (ERBB2)-mutant unresectable or metastatic non-small-cell lung cancer (NSCLC). The results of the HER2-mutant cohort (cohort 2) have been reported elsewhere. Herein, we report the primary analysis of cohorts 1 and 1A, which aimed to evaluate the activity and safety of trastuzumab deruxtecan 5·4 mg/kg and 6·4 mg/kg in patients with HER2-overexpressing NSCLC. METHODS: Patients aged 18 years or older with unresectable or metastatic (or both unresectable and metastatic) non-squamous NSCLC who had relapsed following or were refractory to standard treatment or for whom no standard treatment was available, with an HER2 immunohistochemistry score of 3+ or 2+ (without known HER2 mutations) and an Eastern Cooperative Oncology Group performance status score of 0 or 1, were enrolled at 20 specialist hospitals in France, Japan, the Netherlands, Spain, and the USA. Patients were assigned to cohorts sequentially, first to cohort 1, to receive trastuzumab deruxtecan 6·4 mg/kg (cohort 1), then to cohort 1A, to receive trastuzumab deruxtecan 5·4 mg/kg, both administered intravenously once every 3 weeks. The primary endpoint was confirmed objective response rate by independent central review and was assessed in the full analysis set, which included all patients who signed an informed consent form and were enrolled in the study. Safety was assessed in all enrolled patients who received at least one dose of trastuzumab deruxtecan. This trial is registered with ClinicalTrials.gov, NCT03505710, and is ongoing (closed to recruitment). FINDINGS: Between Aug 27, 2018, and Jan 28, 2020, 49 patients were enrolled in cohort 1 (median age 63·0 years [IQR 58·0-68·0], 30 [61%] male, 19 [39%] female, and 31 [63%] White), and from June 16 to Dec 9, 2020, 41 patients were enrolled in cohort 1A (median age 62·0 years [IQR 56·0-66·0], 22 [54%] male, 19 [46%] female, and 31 [76%] White). As of data cutoff (Dec 3, 2021), the median treatment duration was 4·1 months (IQR 1·4-7·1) in cohort 1 and 5·5 months (1·4-8·7) in cohort 1A, and median follow-up was 12·0 months (5·4-22·4) in cohort 1 and 10·6 months (4·5-13·5) in cohort 1A. Confirmed objective response rate by independent central review was 26·5% (95% CI 15·0-41·1; 13 of 49, all partial responses) in cohort 1 and 34·1% (20·1-50·6; 14 of 41; two complete responses and 12 partial responses) in cohort 1A. The most common treatment-emergent adverse events of grade 3 or worse were neutropenia (12 [24%] of 49 in cohort 1, none in cohort 1A), pneumonia (six [12%] and two [5%], respectively), fatigue (six [12%] and three [7%], respectively), and disease progression (six [12%] and four [10%], respectively). Drug-related treatment-emergent adverse events of grade 3 or worse occurred in 26 (53%) of 41 patients in cohort 1 and nine (22%) of 49 patients in cohort 1A. Drug-related serious adverse events were reported in ten (20%) patients and three (7%) patients, respectively. Deaths due to treatment-emergent adverse events occurred in ten (20%) patients in cohort 1 (disease progression in six (12%) patients and bronchospasm, hydrocephalus, respiratory failure, and pneumonitis in one [2%] patient each), and in seven (17%) patients in cohort 1A (due to disease progression in four (10%) patients and dyspnoea, malignant neoplasm, and sepsis in one (2%) patient each). One death due to a treatment-emergent adverse event was determined to be due to study treatment by the investigator, which was in cohort 1 (pneumonitis). Independent adjudication of interstitial lung disease or pneumonitis found that drug-related interstitial lung disease or pneumonitis occurred in ten (20%) patients in cohort 1 (two [4%] grade 1, five [10%] grade 2, and three [6%] grade 5) and two (5%) patients in cohort 1A (one [2%] grade 2 and one [2%] grade 5). An additional patient in cohort 1A had grade 4 pneumonitis after the data cutoff, which was subsequently adjudicated as drug-related grade 5 interstitial lung disease or pneumonitis. INTERPRETATION: Given the low antitumour activity of existing treatment options in this patient population, trastuzumab deruxtecan might have the potential to fill a large unmet need in HER2-overexpressing NSCLC. Our findings support further investigation of trastuzumab deruxtecan in patients with HER2-overexpressing NSCLC. FUNDING: Daiichi Sankyo and AstraZeneca.

Clinical management, monitoring, and prophylaxis of adverse events of special interest associated with datopotamab deruxtecan.

Antibody drug conjugates (ADCs) are an emerging class of treatments designed to improve efficacy and decrease toxicity compared with other systemic therapies through the selective delivery of cytotoxic agents to tumor cells. Datopotamab deruxtecan (Dato-DXd) is a novel ADC comprising a topoisomerase I inhibitor payload and a monoclonal antibody directed to trophoblast cell-surface antigen 2 (TROP2), a protein that is broadly expressed in several types of solid tumors. Dato-DXd is being investigated across multiple solid tumor indications. In the ongoing, first-in-human TROPION-PanTumor01 phase I study (ClinicalTrials.gov: NCT03401385), encouraging and durable antitumor activity and a manageable safety profile was demonstrated in patients with advanced/metastatic hormone receptor-positive/human epidermal growth factor receptor2-negative breast cancer (HR+/HER2- BC), triple-negative breast cancer (TNBC), and non-small cell lung cancer (NSCLC). Improved understanding of the adverse events (AEs) that are associated with Dato-DXd and their optimal management is essential to ensure safe and successful administration. Interstitial lung disease/pneumonitis, infusion-related reactions, oral mucositis/stomatitis, and ocular surface events have been identified as AEs of special interest (AESIs) for which appropriate prevention, monitoring, and management is essential. This article summarizes the incidence of AESIs among patients with HR+/HER2- BC, TNBC, and NSCLC reported in TROPION-PanTumor01. We report our recommendations for AESI prophylaxis, early detection, and management, using experience gained from treating AESIs that occur with Dato-DXd in clinical trials.

Efficacy and safety of trastuzumab deruxtecan in treating human epidermal growth factor receptor 2-low/positive advanced breast cancer:A meta-analysis of randomized controlled trials.

BACKGROUND: A novel antibody-drug conjugate, trastuzumab deruxtecan is a combination of a human epidermal growth factor receptor 2 (HER2)-targeting antibody and DNA topoisomerase I inhibitor used to treat HER2-low/positive advanced breast cancer. To determine its safety and efficacy in treating HER2-low/positive advanced breast cancer, we performed a meta-analysis of several randomized clinical trials (RCTs) including DESTINY-Breast02 (NCT03523585), DESTINY-Breast03 (NCT03529110), and DESTINY-Breast04 (NCT03734029). METHODS: We searched PubMed, Embase, and the Cochrane Library for RCTs on the efficacy and safety of trastuzumab deruxtecan that were published before May 2023. The efficacy endpoints included median progressive-free survival (PFS), overall survival (OS), duration of response (DOR), overall response rate (ORR), and clinical benefit rate (CBR). The safety endpoints included treatment-related adverse events. Statistical analyses were performed using RevMan 5.4 software. To ensure transparency, this study was registered on the International Prospective Register of Systematic Reviews website (CRD42023414170). RESULTS: Three RCTs involving 1689 patients were included. Compared with physician-recommended and conventional treatments, trastuzumab deruxtecan exhibited statistically significant improvements in PFS, ORR, and CBR. The median OS and DOR failed to be combined; however, the analyzed studies showed that they were longer. The incidence of adverse events was generally higher with trastuzumab deruxtecan than with physician-recommended or conventional treatments. CONCLUSION: The results of this study suggest that trastuzumab deruxtecan is more effective in treating HER2-low/positive advanced breast cancer than physician-recommended or conventional treatments. However, trastuzumab deruxtecan-related adverse drug reactions should be closely monitored because of its higher incidence of adverse events.

Antibody-Drug Conjugates and Ocular Toxicity: Nursing, Patient, and Organizational Implications for Care.

BACKGROUND: Antibody-drug conjugates (ADCs) are a novel class of drugs with rapidly expanding oncology indications across solid and hematologic malignancies. OBJECTIVES: This article provides an overview of ADCs with a high risk of ocular reactions and guidance for oncology nurses to help mitigate risk and identify toxicities for prompt management. METHODS: This review presents updated evidence, manufacturer recommendations, and clinical guidance about three ADCs with a risk of overall ocular reactions exceeding 40%, as well as strategies to prepare patients for treatment, prevent reactions, and respond to presenting ocular toxicities. FINDINGS: ADCs can cause a range of ocular reactions from mild dry eye to severe and dose- limiting corneal adverse reactions and vision loss. Oncology nurses and other members of the interprofessional team can perform focused clinical assessment, provide patient education about self-management and prevention, and coordinate surrounding eye care for patients receiving treatment with ADCs.

A multicenter phase Ia study of AbGn-107, a novel antibody-drug conjugate, in patients with advanced gastrointestinal cancer.

AbGn-107 is an antibody-drug conjugate directed against AG-7 antigen, a Lewis A-like glycol-epitope expressed in a variety of gastrointestinal (GI) malignancies. Based on promising antitumor activity of AbGn-107 in both in vitro and in vivo preclinical studies, we performed a GI cancer-specific Phase I trial. Standard 3 + 3 dose escalation was used evaluating intravenous doses ranging from 0.1 mg/kg every 4 weeks to 1.0 mg/kg every 2 weeks. Key eligibility included chemo-refractory locally advanced, recurrent, or metastatic gastric, colorectal, pancreatic, or biliary cancer, with ECOG PS 0-1; positive AG-7 expression was not required during dose escalation phase. Patients were treated until disease progression or unacceptable toxicity, with tumor assessments every 8 weeks. Primary objectives included safety and determination of maximum tolerated dose; secondary objectives included efficacy defined by objective response rate. Thirty-nine patients were enrolled across seven dose levels during dose escalation phase. Based on safety profile and pharmacokinetic data, 1.0 mg/kg Q2W was selected as the dose schedule for cohort expansion phase, in which an additional seven patients were enrolled. Median number of lines of prior therapy was 3 (range 1-7). AbGn-107 was generally well-tolerated, with infections, cytopenias, hyponatremia, fatigue, abdominal pain, and diarrhea representing the most common grade 3 or higher treatment-emergent adverse events. One subject achieved a partial response, while 18 (46.2%) achieved a best response of stable disease. Disease control lasting > 6 months was observed in 6 subjects (13.0%), including 4 of 15 (26.7%) treated at the highest dose level. AbGn-107 showed a reasonable safety profile and modest clinical activity in this highly pretreated patient population. Further evaluation is required to assess the clinical validity of AG-7 as a suitable antigen for therapeutic targeting. Clinical Trial information: NCT02908451.

Unveiling the Untapped Potential of Antibody Drug Conjugates in Precision Oncology.

This Viewpoint discusses cancer antigen expression and antibody drug conjugates.

Loss of or decrease in CD30 expression in four patients with anaplastic large cell lymphoma after brentuximab vedotin-containing therapy.

Brentuximab vedotin (BV), CD30 specific antibody drug conjugate, has been used to treat anaplastic large cell lymphoma (ALCL) and classic Hodgkin lymphoma (CHL); it is also used in the treatment of other CD30-positive peripheral T-cell lymphomas. We aimed to investigate the incidence and clinicopathological characteristics of patients with ALCL or CHL with loss of or decrease in CD30 expression after BV-containing therapy. Twelve and nine patients with refractory/relapsed CHL and ALCL, respectively, were analyzed after receiving BV-containing therapy. In four ALCL patients (44%), CD30 expression was lost/decreased in re-biopsy materials, including one with complete loss and three with a reduction of less than 20%. All 12 CHL patients showed consistent CD30 expression levels after BV treatment. Compared with five ALCL patients with consistent CD30 expression, four ALCL patients with a loss of/decrease in CD30 expression received a higher cumulative dose of BV (P = 0.014) and revealed a lower intensity of CD30 expression in initial biopsy materials (P = 0.017). The subtypes of ALCL (ALK positive, ALK negative, and primary cutaneous) were not related to the loss of/decrease in CD30 expression. In conclusion, 44% of ALCL patients, regardless of histological subtypes, showed a loss of/decrease in CD30 expression after receiving BV-containing therapy, but this phenomenon was not observed in CHL patients. A higher cumulative dose of BV and a lower amount of CD30 antigen in tumor cells in the initial biopsy materials might be predictors of a loss of/decrease in CD30 expression in ALCL patients.

Incidence of antibody-drug conjugate-related fatigue in patients with breast cancer: A systematic review and meta-analysis.

BACKGROUND: Numerous studies have reported the efficacy of antibody-drug conjugates (ADCs) for treating breast cancer. However, during cytotoxic drug treatment, long-term disabling fatigue is common. Moreover, studies in the relevant literature have indicated that fatigue can significantly increase the incidence of depression and sleep disorders. Therefore, this meta-analysis aims to evaluate the incidence of fatigue in breast cancer survivors treated with ADCs. METHODS: PubMed, EMBASE, Web of Science, and Cochrane Library databases were systematically searched for articles and conference abstracts published before March 16, 2023. Further, two authors independently extracted data from the included studies. The primary outcome of this study was the incidence of all-grade fatigue caused by the use of ADCs in patients with breast cancer. Finally, a random-effects model was used to calculate the incidence and 95% confidence intervals (CIs) of the outcome. RESULTS: Overall, 7963 patients from 31 studies were included in this meta-analysis to assess the incidence of fatigue caused by the use of approved and marketed ADCs in patients with breast cancer. Notably, the incidence of all-grade fatigue during ADC monotherapy was 39.84% (95% CI, 35.09%-44.69%). In subgroup analyses, among ADCs, the incidence of trastuzumab deruxtecan-induced fatigue was the highest, with an all-grade fatigue incidence of 47.05% (95% CI, 42.38%-51.75%). Meanwhile, the incidence of trastuzumab emtansine (T-DM1)-induced all-grade fatigue was 35.17% (95% CI, 28.87%-41.74%), which was the lowest among ADCs. Further, the incidence of all-grade fatigue due to sacituzumab govitecan was 42.82% (95% CI, 34.54%-51.32%), which was higher than that due to T-DM1. Moreover, the incidence of fatigue was higher with T-DM1 combination therapy than with monotherapy. CONCLUSIONS: Clinicians have highlighted the high incidence of ADC-related fatigue and its negative impact on patients' physical and mental health, making fatigue an important research variable. The results of this study will further contribute to a comprehensive understanding of ADCs, which have some clinical importance and are of great benefit to patients with breast cancer.

UGT1A1 Testing in Breast Cancer: should it become routine practice in patients treated with antibody-drug conjugates?

The use of genetic testing to personalize therapeutic strategies in cancer is rapidly evolving and thus changing the landscape of treatment of oncologic patients. The UGT1A1 gene is an important component for the metabolism and glucoronidation of certain drugs, including irinotecan and sacituzumab govitecan (SG); therefore, various UGT1A1 polymorphisms leading to decreased function of the UGT1A1 enzyme may lead to increased risk of treatment-related side effects. Testing for UGT1A1 polymorphism is not routinely adopted in clinical practice; that is due to the lack of concise studies and recommendations concerning the clinical relevance of this test and its impact on the quality of life of cancer patients. The knowledge regarding UGT1A1 polymorphism and its clinical relevance will be reviewed in this article, as well as the published literature on the association between UGT1A1 polymorphism and the toxicity risk of irinotecan as well as sacituzumab govitecan. The current recommendations and guidelines on UGT1A1 testing will be discussed in detail in the hopes of providing guidance to oncologists in their clinical practice.