Antibody-drug Conjugate In Patients Research Articles

Current Status and Future Prospects of TROP-2 ADCs in Lung Cancer Treatment.

Lung cancer is the leading cause of mortality worldwide, and non-small cell lung cancer accounts for the majority of lung cancer cases. Chemotherapy and radiotherapy constitute the mainstays of lung cancer treatment; however, their associated side effects involving the kidneys, nervous system,gastrointestinal tract, and liver further add to dismal outcomes. The advent of antibody‒drug conjugates (ADCs) could change this situation. Trophoblast surface antigen 2 (TROP-2), a human trophoblast surface antigen, is a tumor-associated antigen that is expressed at low levels in normal tissues and is overexpressed in a variety of malignant tumors. The differential expression of the TROP-2 protein in a variety of tumors makes tumor immunotherapy with ADCs targeting TROP-2 a promising approach. Previous studies have shown that the expression of TROP-2 is related to the prognosis of patients with lung cancer and that TROP-2 expression is different across different histological types; however, research on TROP-2 and TROP-2 ADCs in patients with lung cancer is not comprehensive. The aims of this study were to review the mechanism of action and clinical efficacy of TROP-2 and related drugs in the treatment of lung cancer, to elucidate the prognostic value of TROP-2 in lung cancer, and to discuss the future prospects of TROP-2 ADCs to provide a reference for the precise treatment of lung cancer.

Assessment of mirvetuximab soravtansine immunogenicity in patients with folate receptor alpha-positive ovarian cancer.

Aim: The aim of this research was to evaluate the immunogenicity of mirvetuximab soravtansine (MIRV), an antibody-drug conjugate in patients with folate receptor alpha-positive ovarian cancer across four clinical studies.Materials & methods: An assay was developed and validated for the detection of antidrug antibodies (ADAs) against MIRV. A cell-based method was also developed and validated for the detection of neutralizing anti-MIRV antibodies (NAbs). Both ADAs and NAbs were assessed across four clinical studies in 734 patients.Results: Across studies, MIRV demonstrated low immunogenicity with 7.8% of patients with treatment-emergent ADAs, 7.2% with treatment-unaffected ADAs, and 0.5% with treatment-enhanced ADAs. MIRV trough concentrations were comparable in ADA-negative and ADA-positive individuals. Limited data suggest that MIRV ADAs may be associated with decreased efficacy. Due to the very limited number of NAb-positive individuals, no conclusions could be drawn on the effect of NAb on efficacy.Conclusion: Both the validation tests and the data from the MIRV clinical studies demonstrated that these assays were suitable and reliable for the detection of MIRV ADAs and NAbs. These validated assays will continue to be used to monitor MIRV immunogenicity in future clinical trials.

First-in-human study of DP303c, a HER2-targeted antibody-drug conjugate in patients with HER2 positive solid tumors

DP303c is a HER2-targeted ADC with a cleavable linker-MMAE payload. Previous in vitro studies demonstrated that DP303c showed similar or better antitumor activity than T-DM1 in xenograft models. This was a multicenter, dose escalation and dose expansion phase 1 study in China. Eligible patients were 18-75 years old with HER2-positive advanced solid tumors who were unable to benefit from standard therapy. DP303c was administered intravenously every 3 weeks, with accelerated titration at lower dose of 0.5 mg/kg and 3 + 3 design with dose levels of 1.0, 2.0, 3.0 or 4.0 mg/kg at dose escalation part, followed by the selected dose level at dose expansion part. The primary endpoints were safety and tolerability, as well as identification of recommended phase 2 dose. As of Feb 28, 2023, 94 patients were enrolled and received DP303c (dose escalation: n = 22; dose expansion: n = 72), of whom 68 patients had breast cancer. One dose limiting toxicity (Grade 3 eye pain) was observed at 4.0 mg/kg dose, and the maximum tolerated dose was not reached. The most common treatment-related adverse events at grade 3 or higher were blurred vison (16.0%), dry eye (6.4%), and peripheral neuropathy (5.3%). No treatment-related death occurred. Overall, among 91 efficacy evaluable patients, 39 patients (42.9%) achieved an objective response. Disease control was observed in 62 patients (68.1%). In 66 efficacy evaluable patients with breast cancer, 34 patients achieved an objective response (51.5%). Disease control was achieved in 51 patients (77.3%). Median PFS was 6.4 months. On a molar basis, DP303c Cmax at 3.0 mg/kg doses was 132-folder higher than that for free MMAE. DP303c demonstrated promising anti-tumor activity with acceptable safety in patients with pre-treated advanced HER2 positive solid tumors, especially in breast cancer. Based on safety and efficacy results, 3.0 mg/kg Q3W was determined as recommended phase 2 dose for DP303c. (Trial registration: ClinicalTrials.gov Identifier: NCT04146610).

Updated clinical evidence and molecular features of antibody-drug conjugates for advanced urothelial carcinoma

Platinum-based chemotherapy and immunotherapy are the primary systemic treatments for patients with advanced urothelial carcinoma (UC). However, the efficacy of these systemic therapies has yet to be optimized. Antibody-drug conjugates (ADCs), which combine the specificity of monoclonal antibodies with the cytotoxic potency of small-molecule drugs, have emerged as a promising new class of targeted therapies for UC. Currently, the Food and Drug Administration has approved 2 ADCs, namely Padcev and Trodelvy, for the treatment of advanced UC. This review provides an overview of the clinical evidence supporting the use of ADCs in patients with UC and summarizes the molecular features underlying these ADCs, which could be essential for understanding resistance mechanisms and minimizing treatment-related adverse events.

Preclinical studies of BB-1701, a HER2-targeting eribulin-containing ADC with potent bystander effect and ICD activity.

Several HER2-targeting antibody-drug conjugates (ADC) have gained market approval for the treatment of HER2-expressing metastasis. Promising responses have been reported with the new generation of ADCs in patients who do not respond well to other HER2-targeting therapeutics. However, these ADCs still face challenges of resistance and/or severe adverse effects associated with their particular payload toxins. Eribulin, a therapeutic agent for the treatment of metastatic breast cancer and liposarcoma, is a new choice of ADC payload with a distinct mechanism of action and safety profile. We've generated a novel HER2-tageting eribulin-containing ADC, BB-1701. The potency of BB-1701 was tested in vitro and in vivo against cancer cells where HER2-expressing levels vary in a large range. Bystander killing effect and toxin-induced immunogenic cell death (ICD) of BB-1701 were also tested. In comparison with HER2-targeting ADCs with DM1 and Dxd payload, eribulin-containing ADC demonstrated higher in vitro cytotoxicity in HER2-low cancer cell lines. BB-1701 also effectively suppressed tumors in models resistant to DM1 or Dxd containing ADCs. Mode of action studies showed that BB-1701 had a significant bystander effect on HER2-null cells adjacent to HER2-high cells. In addition, BB-1701 treatment induced ICD. Repeated doses of BB-1701 in nonhuman primates showed favorable pharmacokinetics and safety profiles at the intended clinical dosage, route of administration, and schedule. The preclinical data support the test of BB-1701 in patients with various HER2-expressing cancers, including those resistant to other HER2-targeting ADCs. A phase I clinical trial of BB-1701 (NCT04257110) in patients is currently underway.

Antibody-drug conjugates (ADC) in patients with advanced/metastatic HER2-low expressing breast cancer: A systematic review and meta-analysis.

e13174 Background: Historically, HER2-targeted therapies failed to improve survival of patients with HER2-low-expressing tumors. Recently, trastuzumab deruxtecan (T-DXd), an antibody-drug conjugate (ADC), demonstrated superior outcomes compared with treatment of physician´s choice (TPC) in this population. Other ADCs have also shown encouraging results, including sacituzumab govitecan (SG), MRG002, and RC48-ADC. Hence, we performed a systematic review and meta-analysis to assess the effectiveness of ADCs in patients with HER2-low advanced/metastatic (a/m) breast cancer (BC). Methods: We searched PubMed, Embase, and Cochrane databases and ASCO, ESMO, and SABCS websites for studies evaluating ADCs on patients with HER2-low a/mBC. Outcomes of interest were objective response rate (ORR); disease control rate (DCR); clinical benefit rate (CBR); progression-free survival (PFS); and overall survival (OS). We used R software (v.4.2.2) and random effects models for all analyses. Heterogeneity was assessed using I2 test. Results: Overall, 12 studies were included (3 real-world studies and 9 clinical trials), with 1,292 HER2-low a/mBC patients, 378 received TPC, and 914 received ADCs. Most were treated with T-DXd (63%, n=572), SG (29%, n=268), MRG002 (6%, n=56), and RC48-ADC (2%, n=18). Median age ranged from 48.1 to 58 years, and follow-up from 9.5 to 18.4 months. Patients treated with T-DXd achieved a significantly higher ORR and DCR compared to those who received SG, RC48-ADC, and MRG002 (Table). CBR was numerically higher in patients on T-DXd than those on SG but did not reach a significant difference. Patients with HR-positive tumors treated with SG had an ORR of 45% (95% CI 23 – 67%), and patients with pure HER2-low treated with any ADC, had an ORR of 38% (95% CI 30 – 45%). In the pooled analysis of 3 RCTs, ADCs significantly prolonged PFS compared with TPC (n=963, HR: 0.44, 95% CI 0.32 – 0.61, I2 = 66%, p<0.001), and OS (n= 680, HR: 0.56, 95% CI 0.36 – 0.89, I2 = 73%, p=0.015). Patients on ADCs also achieved a greater anti-tumor response than TPC, including better ORR (OR: 4.18, 95% CI 2.40 - 7.28, I2 = 52%, p<0.001), DCR (OR: 2.82, 95% CI 2.06 - 3.85, I2 = 7%, p<0.001), and CBR (OR: 3.41, 95% CI 2.36 - 4.93, I2 = 25%, p<0.001). Conclusions: Our systematic review and meta-analysis supports the efficacy of ADCs in HER2-low a/mBC patients over TPC. Future studies should focus on bringing ADCs into earlier lines of therapy in this population.Anti-tumor activity of ADCs presented as overall % (95% CI). [Table: see text]

SV-BR-1-GM after progression on ADC in patients with metastatic breast cancer.

1087 Background: Antibody-drug conjugate (ADC) sequencing raises concerns of cross-resistance due to their shared targets and cytotoxic payloads. Consequently, treatments after ADCs in heavily pretreated MBC is uncertain. SV-BR-1-GM, a GM-CSF secreting, antigen-presenting immortalized breast cancer cell line, has emerged as a post ADC solution (1) based on a different MOA. We now report the results of SV-BR-1-GM in ADC treated patients. Methods: Post-hoc analysis of an ongoing randomized Phase 2 censored to the data-cut date prior to data lock. Bria-IMT (~20x106 SV-BR-1-GM cells, intradermally 48-72 hours after ctx (300 mg/m2), followed by interferon-alpha 2 days later) administered q3wks with a checkpoint inhibitor (CPI). Adverse events were classified according to their severity and relationship to treatment regimen. Results: Among 54 advanced MBC patients randomized, 23 who failed prior ADC therapy were identified. All were heavily pretreated (median 6 prior lines, range 3 – 13). Median age 62 (41-83). 14 pts had HR+/HER2-, 5 TNBC, and 2 HR+/HER2+ MBC. The remaining were HR-/HER2+ or HR-/HER2 low. 8 pts received > 1 ADC. Prior ADCs included: 4 ado-trastuzumab emtansine, 14 trastuzumab deruxtecan, 13 sacituzumab govitecan. 7 pts had also received ≥ 1 prior CPI line. To date, pts received a median 3 cycles of Bria-IMT™ + CPI (2-8). Kaplan-Meier analysis revealed a median OS of 42 weeks with survival of 69% at 6 months. The subset experienced a median PFS of 74 days with 40% of pts demonstrating a Bria-IMT PFS (PFS2) similar to or > their prior line PFS (PFS1). 39% of pts experienced a PFS2 ≥ their most recent line of ADC PFS. The disease control rate was 40% among evaluable pts. 43% of pts had a reduction in cancer-associated macrophage-like cell (CAML) levels; median reduction was 36% (22-98%) after 1 cycle. There were no toxicity-related treatment discontinuations. 43% (10/23) reported grade 3 or 4 AEs, independent of study drug causality. AEs included injection site reaction (39%), fatigue (26%), and nausea/vomiting (43%), mostly mild to moderate. One case of elevated lipase was the most clinically significant grade 4 AE. No interstitial lung disease (ILD) was reported. Conclusions: This subset analysis of the Bria-IMT regimen in ADC refractory MBC patients suggests a potential clinical benefit and treatment option for this patient population. The absence of serious AEs, notably interstitial lung disease (ILD), and no toxicity-related treatment discontinuations, underscores the regimen's favorable safety profile. Future studies are warranted to confirm these results and explore the potential of Bria-IMT™ in broad clinical settings of heavily pretreated contemporary MBC patients. 1. Kamaraju 2024 AACR. Clinical trial information: NCT03328026 .

A phase 1/2 study of LM-302, an anti-claudin 18.2 (CLDN18.2) antibody-drug conjugate in patients with advanced gastric/gastroesophageal junction cancer.

3028 Background: LM-302 is a novel and potent MMAE antibody-drug conjugate (ADC) targeting CLDN18.2, which is highly expressed in gastric/gastroesophageal junction (GEJ), pancreatic, and biliary tract cancers. Preclinical studies of LM-302 have demonstrated compelling anti-tumor activity in multiple CLDN18.2-positive cell-lines and xenograft models. Methods: This phase 1/2 study included dose escalation phase and dose expansion phase. In the dose escalation phase, eligible patients received LM-302 once every three weeks (0.2-2.8 mg/kg Q3W), and once every two weeks (1.8-2.0 mg/kg Q2W) to evaluate the safety, tolerability, and pharmacokinetics. In the dose expansion phase, CLDN18.2-positive patients received LM-302 at recommended phase 2 doses of 2.4 mg/kg Q3W or 1.8 mg/kg Q2W to evaluate the efficacy and safety. The primary endpoints included dose-limiting toxicity (DLT) and adverse events (AEs) in phase 1, and objective response rate (ORR) in phase 2. Here we report the results from safety analysis of LM-302 and efficacy data in gastric/GEJ cancer. Results: As of September 23, 2023, 135 patients received LM-302 treatment and the median prior lines of systemic therapy were 2 (range 1-4). In phase 1 and 2, most common TRAEs were white blood cell decreased (51.9%), neutrophil count decreased (51.1%), anaemia (38.5%), vomiting (36.3%), and nausea (34.1%). The most frequent grade ≥3 TRAEs were neutrophil count decreased (22.2%) and white blood cell decreased (17.8%). In phase 2 dose expansion, 52 CLDN18.2-positive (TC ≥ 50%, IHC ≥ 2+) gastric/GEJ cancer patients were enrolled (4 pts at 2.4mg/kg Q3W, 48 pts at 1.8mg/kg Q2W). 1.8mg/kg Q2W was selected for further evaluation based on PK, safety, and efficacy data analysis. Of 36 evaluable gastric/GEJ cancer patients who received at least two or more prior therapies, 11 partial response (PR) and 16 stable disease (SD) were observed. The ORR was 30.6% (11/36), and DCR was 75.0% (27/36). The median PFS was 7.16 months (95% CI 2.72-NA). The median overall survival (OS) was not reached, with an OS rate of 95.0% at the 6-month (as of November 15, 2023). Conclusions: LM-302 was well-tolerated with a manageable safety profile and demonstrated promising anti-tumor activity in CLDN18.2-positive patients with third-line and beyond gastric/GEJ cancer. The results support further investigation of LM-302 as a new therapeutic approach to treat CLDN18.2-positive gastric/GEJ cancer. Clinical trial information: NCT05161390 .

Abstract 6438: Subcutaneous fat mass predicts progression-free survival in patients treated with antibody-drug-conjugates in early-phase clinical trials

Abstract Background: Antibody drug conjugates (ADCs) have revolutionized the treatment of many solid tumours and hematological diseases. Little is known about the influence of body composition on efficacy and safety of ADCs. Methods: All patients treated with ADCs in early phase clinical trials between 03/2015 and 03/2023 at the Drug Development Department at Gustave Roussy were retrospectively included in the analysis. A deep learning software (Anthropometer3DNet) automatically measured anthropometric parameters in 3D on pretreatment scans, allowing multi-slice measurements of muscle body mass (MBM), fat body mass (FBM), subcutaneous fat mass (SFM) and visceral fat mass (VFM). Other clinical and biological parameters were also retrieved and evaluated. Primary endpoints were progression-free survival (PFS) and overall survival (OS). Survival analysis was performed using Cox regression models and Kaplan-Meier (KM) estimator. Cut-offs were determined using the maxstat method. Anthropometric parameters’ effect on toxicity was also evaluated using a ROC analysis. Results: A total of 136 patients were treated with ADCs. The most frequent tumor types were non-small cell lung cancer (56 patients, 41%) and colorectal cancer (31 patients, 23%). Median age, ECOG PS, albumin and number of previous lines of treatment were 60.8 years (30 to 85), 1, 42 g/L and 3 respectively. In the overall cohort, median PFS and OS were 2.8 and 8.6 months respectively, 90 (66%) patients had experienced toxicity, of which 46 were grade 3-4. The Royal Marsden Hospital (RMH) prognostic score of 2 or more was significantly associated with worse PFS (HR=2.13, p=0.007) and OS (HR=2.12, p=0.008). The number of treatment lines was significantly associated with worse OS (HR=1.21, p<0.001). For the anthropometric parameters, SFM (HR=0.89, p=0.013) and FBM (HR=0.89, p=0.02) were significantly associated to PFS. Higher SFM (cutoff: 3.3 kg/m2) and FBM (cutoff: 3.6 kg/m2) were significantly associated with longer PFS (mPFS=3.8 vs 2.3 months and 3.7 vs 1.9 respectively). Patients with higher SFM and FBM had numerically but non-significantly longer (mOS=8.5 vs 7.7 months and 8.6 vs 6.4 months respectively). All anthropometric parameters were significantly associated with all-grade toxicity in the univariate but not in the multivariate analysis. None of the parameters were associated with grade 3-4 toxicity. Conclusions: In this large monocenter cohort, 3D measured high SFM and FBM were significantly associated with PFS. Automatic extraction of body composition parameters using AI may help in anticipating the benefits of ADCs in patients included in early-phase clinical trials. Citation Format: Matthieu Delaye, Littisha Lawrance, Younes Belkouchi, Felix Wirth, Pierre Decazes, Alexandre Bône, Kaïssa Ouali, Antoine Hollebecque, Cristina Smolenschi, Rastislav Bahleda, Anas Gazzah, Stéphane Champiat, François-Xavier Danlos, Clémence Hénon, Kristi Beshiri, Madona Sakkal, Aurélien Marabelle, Jean-Marie Michot, Vincent Ribrag, Claudia Parisi, Christophe Massard, Vincent Goldschmidt, Pierre Vera, Santiago Ponce-Aix, Nathalie Lassau, Samy Ammari, Capucine Baldini. Subcutaneous fat mass predicts progression-free survival in patients treated with antibody-drug-conjugates in early-phase clinical trials [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6438.

Prevalence and Therapeutic Targeting of High-Level ERBB2 Amplification in NSCLC

IntroductionERBB2 amplification in lung cancer remains poorly characterized. HER2 (encoded by ERBB2) is a transmembrane tyrosine kinase capable of ligand-independent dimerization and signaling when overexpressed, and a common cause of HER2 overexpression is ERBB2 amplification. Here, we evaluated the clinicopathologic and genomic characteristics of ERBB2-amplified NSCLC and explored a HER2 antibody–drug conjugate (ADC) therapeutic strategy. MethodsOur institutional next-generation DNA sequencing data (OncoPanel) from 5769 NSCLC samples (5075 patients) were queried for cases having high-level ERBB2 amplification (≥6 copies). Clinical and demographic characteristics were extracted from the electronic medical records. Efficacy of the pan-ERBB inhibitor afatinib or HER2 ADCs (trastuzumab deruxtecan and trastuzumab emtansine) was evaluated in NSCLC preclinical models and patients with ERBB2 amplification. ResultsHigh-level ERBB2 amplification was identified in 0.9% of lung adenocarcinomas and reliably predicted overexpression of HER2. ERBB2 amplification events are detected in two distinct clinicopathologic and genomic subsets of NSCLC: as the sole mitogenic driver in tumors arising in patients with a smoking history or as a concomitant alteration with other mitogenic drivers in patients with a light or never smoking history. We further reveal that trastuzumab deruxtecan is effective therapy in in vitro and in vivo preclinical models of NSCLC harboring ERBB2 amplification and report two cases of clinical activity of an anti-HER2 ADC in patients who acquired ERBB2 amplification after previous targeted therapy. ConclusionsHigh-level ERBB2 amplification reliably predicts HER2 overexpression in patients with NSCLC, and HER2 ADC is effective therapy in this population.

Preliminary Results of a Phase 1, First-in-Human Study of INA03, an Anti-CD71 Antibody-Drug Conjugate in Patients with Relapsed or Refractory (R/R) Acute Leukemias

Background: Relapsed or refractory (R/R) acute leukemias (AL) represent major therapeutic challenges. Several reports have highlighted the deregulation of iron metabolism in various proliferative tumor models (and notably AL) which includes the over-expression of the transferrin receptor (TfR1/CD71). Our strategy is thus to harness CD71 overexpression to specifically target cytotoxic agents to leukemic cells. INA03 is an antibody drug conjugate (ADC) constituted of a humanized monoclonal IgG 4 against CD71 and MMAE. We herein report the preliminary safety and efficacy data of a phase 1 trial INA03 (NCT03957915) evaluating INA03 in R/R AL. Methods: INA03 is given as 30 minutes IV infusion on days 1 (Loading dose,LD) followed by maintenance injections on D15 for cycle 1 and on D1 and D15 of cycle 2 and beyond. Eligibility criteria are age >18y, ECOG<2, R/R AL after at least one line of treatment with high dose chemotherapy and/or Vidaza and Venetoclax (VEN), LVEF>50%, Creatinine Clearance >30ml/min, normal liver function. The study design is based on a continuous reassessment method and includes 2 parts: a Loading Dose (LD) Titration study (Part 1, completed), followed by a Dose Escalation Part 2. During Part 1, sequential cohorts of 2 pts were included to receive ascending LD of INA03 followed by repeated fixed doses of INA03 to deal with a potential sink effect related to the high expression of CD71 in normal erythroblasts. During Part 2, sequential cohorts of 3 pts received escalating doses of INA03 Q2 weeks in 28-day cycles. The objectives were to establish the maximal tolerated dose (MTD) for subsequent administration and both safety/tolerability and anti-leukemic activity. Results: With a cutoff date of July 05, 2023, 27 patients (pts) across 10 cohorts were included in the study. The median age was 73 (range: 39 - 83), 25 (93%) pts had AML and two (7%) had ALL. Four (14.8%) pts had a prior allogeneic stem cell transplantation and 18 (66.6%) had prior VEN exposure. Pts received escalating doses of INA03 of 0.02 mg/kg to 3 mg/kg. Two patients in the 3 mg/kg loading dose cohort presented a dose limiting toxicity (DLT), one with grade 3 toxic erythema, grade 3 hepatitis and grade 3 mucositis and one with grade 4 colonic perforation. Up to the 2.5 mg/kg dose, no grade 2-4 treatment emerging adverse events (TEAE) were observed among the 19 evaluable pts and only one related grade 1 TEAE (hyperkalemia/phosphatemia) was reported. Transient decrease of reticulocyte count and erythroblasts percentage were observed at 0.5 mg/kg and above. Blasts reductions were seen in 6/20 (30%) evaluable pts at dose > 1 mg/kg including two partial responses according to ELN 2022 classification. MMAE pharmacokinetics (PK) appears dose-proportional with a small accumulation after repeated IV, while INA03 PK exhibits target-mediated drug disposition without accumulation. Conclusions: The preliminary results of this phase 1 study indicate that INA03 is well tolerated for doses up to 2.5 mg/kg. Induction of transient erythroblastopenia indicates effective targeting of CD71 in vivo and early signs of antileukemic efficacy have been observed in patients with refractory AL. Inclusion in the trial are continuing and additional data will be presented.

Antibody-Drug Conjugates for the Treatment of Renal Cancer: A Scoping Review on Current Evidence and Clinical Perspectives.

Antibody-drug conjugates (ADCs) are complex chemical structures composed of a monoclonal antibody, serving as a link to target cells, which is conjugated with a potent cytotoxic drug (i.e., payload) through a chemical linker. Inspired by Paul Ehrlich's concept of the ideal anticancer drug as a "magic bullet", ADCs are also highly specific anticancer agents, as they have been demonstrated to recognize, bind, and neutralize cancer cells, limiting injuries to normal cells. ADCs are among the newest pharmacologic breakthroughs in treating solid and hematologic malignancies. Indeed, in recent years, various ADCs have been approved by the Food and Drug Administration and European Medicines Agency for the treatment of several cancers, resulting in a "practice-changing" approach. However, despite these successes, no ADC is approved for treating patients affected by renal cell carcinoma (RCC). In the present paper, we thoroughly reviewed the current literature and summarized preclinical studies and clinical trials that evaluated the activity and toxicity profile of ADCs in RCC patients. Moreover, we scrutinized the potential causes that, until now, hampered the therapeutical success of ADCs in those patients. Finally, we discussed novel strategies that would improve the development of ADCs and their efficacy in treating RCC patients.

Low and Ultra-Low HER2 in Human Breast Cancer: An Effort to Define New Neoplastic Subtypes.

HER2-low and ultra-low breast cancer (BC) have been recently proposed as new subcategories of HER2 BC, supporting a re-consideration of immunohistochemical negative scores of 0, 1+ and the 2+/in situ hybridization (ISH) negative phenotype. In the present review, we outline the criteria needed to exactly distinguish HER2-low and ultra-low BC. Recent clinical trials have demonstrated significant clinical benefits of novel HER2 directing antibody-drug conjugates (ADCs) in treating these groups of tumors. In particular, trastuzumab-deruxtecan (T-Dxd), a HER2-directing ADC, has been recently approved by the US Food and Drug Administration as the first targeted therapy to treat HER2-low BC. Furthermore, ongoing trials, such as the DESTINY-Breast06 trial, are currently evaluating ADCs in patients with HER2-ultra low BC. Finally, we hope that new guidelines may help to codify HER2-low and ultra-low BC, increasing our knowledge of tumor biology and improving a targetable new therapeutical treatment.

Optimizing the safety of antibody-drug conjugates for patients with solid tumours.

Over the past 5 years, improvements in the design of antibody-drug conjugates (ADCs) have enabled major advances that have reshaped the treatment of several advanced-stage solid tumours. Considering the intended rationale behind the design of ADCs, which is to achieve targeted delivery of cytotoxic molecules by linking them to antibodies targeting tumour-specific antigens, ADCs would be expected to be less toxic than conventional chemotherapy. However, most ADCs are still burdened by off-target toxicities that resemble those of the cytotoxic payload as well as on-target toxicities and other poorly understood and potentially life-threatening adverse effects. Given the rapid expansion in the clinical indications of ADCs, including use in curative settings and various combinations, extensive efforts are ongoing to improve their safety. Approaches currently being pursued include clinical trials optimizing the dose and treatment schedule, modifications of each ADC component, identification of predictive biomarkers for toxicities, and the development of innovative diagnostic tools. In this Review, we describe the determinants of the toxicities of ADCs in patients with solid tumours, highlighting key strategies that are expected to improve tolerability and enable improvements in the treatment outcomes of patients with advanced-stage and those with earlystage cancers in the years to come.

Abstract CT056: A multicenter, open-label phase 1/2 trial evaluating the safety, tolerability, and efficacy of MORAb-202, a folate-receptor-alpha-targeting antibody-drug conjugate in patients with selected tumor types

Abstract Background: MORAb-202 (farletuzumab ecteribulin) is an antibody-drug conjugate (ADC) comprised of the humanized antifolate receptor-alpha (FRα) monoclonal antibody, farletuzumab, and the cytotoxic microtubule inhibitor, eribulin, conjugated by a cathepsin B-cleavable linker. MORAb-202 targets the eribulin payload to tumor cells expressing FRα, where internalization leads to lysosomal cleavage of the ADC and intracellular release of eribulin, causing apoptosis, cell-cycle arrest, and bystander effects in adjacent cells. A previous phase 1 study in Japan of MORAb-202 (NCT03386942) demonstrated antitumor activity across multiple tumor types and identified interstitial lung disease (ILD) as an adverse event of interest (Shimizu CCR 2021). An expansion cohort (doses: 0.9, 1.2 mg/kg) in patients with platinum-resistant ovarian cancer (OC) found meaningful efficacy across FRα-expression levels and ILD/pneumonitis (mainly low grade) was the most common adverse event (Nishio ASCO 2022). Methods: This multicenter phase 1/2 study (NCT04300556) consists of Dose-Escalation and Dose-Confirmation cohorts. In the Dose-Escalation phase, the primary objectives were to evaluate safety/tolerability and determine the recommended phase 2 dose of MORAb-202 in patients with OC, endometrial cancer (EC), non-small cell lung cancer (NSCLC), or triple-negative breast cancer (TNBC). In the ongoing Dose-Confirmation phase, the primary objectives are (1) to further evaluate safety/tolerability and (2) to evaluate preliminary efficacy (Objective Response Rate) in patients with OC or EC. Based on a population pharmacokinetics model (Hayato ASCO 2022), body-surface-area-based dosing is utilized. The initial cohort has enrolled 7 patients at a MORAb-202 25 mg/m2 IV Q3W dose and is ongoing; further enrollment of patients at 25 mg/m2 and 33 mg/m2 will occur following ILD safety evaluation. Tumor assessments will be conducted by investigators using RECIST v1.1 at screening, every 6 weeks for 24 weeks, then every 12 weeks or as needed. Assessments of computed tomography scans for ILD will be conducted by a central expert review board. Citation Format: Robert Wenham, Sharad Ghamande, Vicky Makker, June Hou, Linda Duska, Daniela Matei, Manali Bhave, Rachael Scott, Natalyn Hawk, Tingting Song, Deborah K. Armstrong. A multicenter, open-label phase 1/2 trial evaluating the safety, tolerability, and efficacy of MORAb-202, a folate-receptor-alpha-targeting antibody-drug conjugate in patients with selected tumor types [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT056.

Abstract 559: Expression of molecular targets for antibody-drug conjugates in patients with NSCLC and RET fusions

Abstract Background RET fusions are found in 1-2% of patients (pts) with advanced non-small cell lung cancer (NSCLC). RET inhibitors are highly effective, but resistance eventually occurs. Antibody-drug conjugates (ADC) are promising treatments in NSCLC, that could be employed at time of resistance. Data on the membranous expression of ADC targets, such as EGFR/HER2/HER3 and the possible impact of novel therapeutic agents in RET+ NSCLC are lacking. Methods We conducted a single-center observational study, collecting tissue specimens from 19 patients (pts) affected by RET+ NSCLC. The expression of EGFR/HER2/HER3 proteins on the cellular membrane was evaluated by immunohistochemistry (IHC). EGFR expression was assessed by using the DAKO EGFR pharmDx kit (Dako, Glostrup, Denmark); HER2 staining (4B5 clone by Roche clone) was evaluated using ASCO/CAP guidelines in scale from 0 to 3+; HER3 staining (D22C5 clone by Cell Signaling) was categorized by intensity as 0, 1+, 2+, and 3+, according to the same criteria used for HER2 evaluation. All IHC analyses were performed at Gustave Roussy. Results Out of 19 pts, 18 were evaluable for EGFR expression, 18 for HER2, 17 for HER3. All analyses were conducted on archival tissue samples from tumor biopsies performed predominantly in treatment-naïve pts (17/19). Pts had adenocarcinoma in 5/19 cases, KIF5B fusion partner in 13/19 cases. Median PD-L1 expression in evaluable pts was 15% (IQR 1- 60.00). EGFR expression was high, moderate, and low in 4 (22%), 2 (11%) and 5 (27%) cases, respectively. HER3 expression was 2+ in 4 (24%) cases, 1+ in 5 (29%) pts and 0 in the other 47%. None had HER2 membranous expression. EGFR expression was more frequently found in pts with uncommon fusion partners (6/11 vs 0/7, p=0.038) and non-adenocarcinoma histology (5/11 vs 0/7, p=0.10). HER3 expression evaluated at 2+ were identified in 3 cases with KIF5B-RET fusion and adenocarcinoma and 1 case with ANKRD26-RET fusion and undifferentiated histology. PD-L1 expression did not show significant difference between pts with positive vs negative EGFR or HER3 staining (p=1). Conclusions EGFR and HER3 had variable expression in RET+ NSCLC, deserving further exploration for novel treatment strategies. HER2 expression was not found in our RET cohort. Citation Format: Arianna Marinello, Maria Rosa Ghigna, Anas Gazzah, Karine Godefroy, Ludovic Lacroix, Damien Vasseur, Jordi Remon-Masip, Fabrice Barlesi, David Planchard, Jean-Yves Scoazec, Benjamin Besse, Mihaela Aldea. Expression of molecular targets for antibody-drug conjugates in patients with NSCLC and RET fusions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 559.

Abstract 1538: Revisiting the dogma of antibody drug conjugates (ADCs): Emerging data challenge the benefit of linker stability and the primacy of payload delivery

Abstract Antibody drug conjugates (ADCs) are an effective class of cancer therapeutics which have become more prominent after eight FDA approvals in the past three years. ADCs are envisioned to enable the selective delivery of a potent drug to cells that express the antibody target while sparing normal tissues, and thus to improve the therapeutic window by both increasing the maximum tolerated dose (MTD) and decreasing the minimum efficacious dose (MED) of the conjugated drug. Mounting clinical evidence does not support this simplified paradigm [1]. Herein we focus on three prominent issues in ADC development: 1. Alternative mechanisms over and above direct tumor targeting are likely to contribute to ADC therapeutic benefits in the clinic [2]. The responses to certain ADCs in patients with different levels of target antigen expression reveal some target-independent antitumor effects, suggesting the possibility that circulating payload may contribute to efficacy. 2. The preclinical optimization of ADCs is based on efficacy and tolerability in non-human animal studies. Fundamental differences in biology and translatability between species potentially overemphasize the importance of linker stability. 3. Clinical data, although limited, does not support the idea that increased ADC stability drives substantial therapeutic benefit. None of the 13 approved ADCs are completely ‘stable’ in circulation, and more stable drug-linkers have been associated with alternative toxicity profiles and no significant improvement in MTD. Novel meta-analyses and case studies assembled and integrated from >40 approved or clinically active ADCs and >70 discontinued ADCs will be presented in support of these three perspectives. The ADCs included in the analysis differ in terms of payload class, linker type, conjugation chemistry, drug-to-antibody ratio, and antibody target. Gaining a better understanding of the mechanism(s) of action of effective ADCs and the interrelationship between ADC structural components and their pharmacokinetics and pharmacodynamics is critical to inform the next generation of ADCs.

First-in-human study of OBI-999: A globo H-targeting antibody-drug conjugate in patients with advanced solid tumors.

3029 Background: OBI-999 is a novel antibody-drug conjugate, composed of a humanized monoclonal IgG1 antibody which targets the tumor-associated carbohydrate antigen Globo H, conjugated with monomethyl auristatin E (MMAE, vedotin). Upon binding to Globo H, OBI-999 is internalized into the tumor cell, and the linker (Thiobridge) connecting MMAE (an ultrapotent antimitotic agent) to the monoclonal antibody is cleaved by cathepsin B to release MMAE, thereby causing cell cycle arrest by inhibiting tubulin polymerization. We conducted a first-in-human, phase 1, dose-escalation study of OBI-999 monotherapy in patients with advanced cancer (NTC04084366). Methods: OBI-999 was administered intravenously at doses of 0.4, 0.8, 1.2, and 1.6 mg/kg on Day 1 of a 21-day cycle. Patients received study treatment until disease progression, unacceptable toxicity, or up to 2 years of treatment. Results: Overall, 15 adult patients were treated. OBI-999 administered on Day 1 of each 21-day cycle was well tolerated up to 1.2 mg/kg, the maximum tolerated dose (MTD). Treatment-related AEs (TRAEs) were noted in 40% (6/15) of patients. TRAEs ≥Grade 3 were noted in 27% (4/15) of patients; of whom 3 had neutropenia and 2 had anemia. OBI-999 exhibited non-linear pharmacokinetics from 0.4 mg/kg to 1.6 mg/kg, with lower clearance at higher doses. A retrospective validated automated immunohistochemistry assessment indicated 50% of patients with advanced solid tumors had high Globo H staining (H-score cutoff ≥100). Of 3 patients treated at the 1.6 mg/kg dose level; 2 developed Grade 4 neutropenia during Cycle 1 and the third developed Grade 4 neutropenia on Cycle 2 Day 15. One patient (1.6 mg/kg) with Grade 4 neutropenia also developed Grade 4 renal insufficiency and died from progressive disease (direct bilirubin, 3.5 mg/dL). Five (33.3%) patients had stable disease (SD), including 1 patient with adenoid cystic carcinoma of the oropharynx (SD for 13 cycles); 1 patient with gastroesophageal junction adenocarcinoma (SD for 8 cycles), and 3 patients with other tumor types (SD for 4, 2, and 2 cycles). Conclusions: We completed the dose-escalation portion of the study. OBI-999 was well tolerated. The recommended phase 2 dose was determined to be 1.2 mg/kg once every 3 weeks. Dose-dependent, non-cumulative neutropenia was dose limiting. We are currently enrolling patients with high Globo H expressing solid tumors (H-score ≥100) in the expansion phase of the study, which includes pancreatic, colorectal, and cancers of other histologic subtypes. Clinical trial information: NTC04084366.

Targeting HER2-positive metastatic breast cancer with ARX788, a novel anti-HER2 antibody-drug conjugate in patients whose disease is resistant or refractory to T-DM1, and/or T-DXd, and/or tucatinib-containing regimens.

TPS1112 Background: The overexpression and/or amplification of human epidermal growth factor receptor 2 (HER2) occurs in approximately 20% of breast cancers (BC) and is a major driver of tumor development and progression. This HER2 subtype confers aggressive tumor behavior and the HER2 receptor remains a valuable target for antibodies, bi-specifics, and antibody drug conjugates (ADC). With advances in targeted therapy, patients with HER2-positive breast cancer (HER2+ BC) may experience an improved prognosis, including survival. Novel HER2-targeted therapies are being investigated to overcome drug resistance and to help mitigate adverse events (e.g., cardiotoxicity). ARX788 is a next-generation ADC using a technology platform whereby a HER2 specific monoclonal antibody is conjugated with Amberstatin269 (AS269), a potent cytotoxic tubulin inhibitor. Site-specificity, high homogeneity, and stable covalent conjugation of ARX788 leads to its slow release and prolonged peak of serum pAF-AS269, which may contribute to the lower systemic toxicity and increased targeted delivery of payload to tumor cells at a lower effective dose compared to other HER2 ADCs. Clinical activity has been seen in Phase I HER2 breast and pan-tumor studies. Methods: Trial Design: ACE-Breast-03 (NCT04829604) is a global, phase 2 study designed to assess anticancer activity and safety of ARX788 in patients with metastatic HER2 positive breast cancer. Patients whose disease is resistant or refractory to T-DM1, and/or T-DXd, and/or tucatinib-containing regimens are eligible. Patients must have adequate organ function. Any brain metastases must be radiographically stable without steroid dependence. Efficacy will be assessed using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 by imaging every 6 weeks on study. Endpoints include objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), best overall response (BOR), duration of response (DOR), and time to response (TTR). The safety and tolerability profile will be evaluated. Blood samples will be collected at specified time points to determine serum concentrations of ARX788, total antibody, and metabolite pAF-AS269. Potential predictive and/or prognostic biomarkers at baseline and on-treatment will be analyzed for exploratory purposes. Descriptive statistics will be used to evaluate anticancer activity, safety, and tolerability. The study is currently recruiting patients. Please contact breast03trialinquiry@ambrx.com for additional information. Clinical trial information: NCT04829604.

A Phase 1 Study of a CDH6-Targeting Antibody-Drug Conjugate in Patients with Advanced Solid Tumors with Evaluation of Inflammatory and Neurological Adverse Events

Purpose: This first-in-human study (NCT02947152) evaluated the safety, tolerability, pharmacokinetics, and preliminary efficacy of HKT288, a first-in-class CDH6-targeting antibody-drug conjugate (ADC). Experimental Design: HKT288 was administered intravenously (IV) every 3 weeks until patients experienced unacceptable toxicity or progressive disease (PD). The starting dose of 0.3 mg/kg was determined based on the highest nonseverely toxic dose in monkeys, which was 2 mg/kg IV weekly. Based on preclinical toxicology, skin, eyes, bone marrow, and liver were expected targets of toxicity. Results: Nine patients were enrolled: 5 with renal cell carcinoma and 4 with epithelial ovarian cancer. The best overall response on the 0.3 mg/kg cohort in patients with measurable disease was RECIST v1.1 stable disease in 3 patients and PD in 2 patients. The most frequent adverse events (AEs) regardless of causality were pyrexia (44.4%), constipation (44.4%), fatigue (33.3%), and vomiting (33.3%). Three suspected-related neurologic AEs (Grade 2) were reported on the 0.75 mg/kg cohort: seizure in 1 patient and another patient with aphasia and encephalopathy. Further studies were unable to identify the underlying mechanism of the neurologic AEs, and the study was terminated early. Conclusions: Preclinical toxicology did not predict the neurotoxicity observed with HKT288, and a comprehensive assessment performed post hoc did not identify the mechanism of toxicity. The development of further CDH6-targeting ADCs should be pursued with caution.