Antibody-drug Conjugate Targeting Research Articles

A DXd/TLR7-agonist dual-conjugate anti-HER2 ADC exerts robust anti-tumor activity through tumor cell killing and immune activation.

The emergence of trastuzumab deruxtecan (T-DXd), a new-generation antibody-drug conjugate (ADC), has profoundly altered the therapeutic paradigm for HER2-positive solid tumors, demonstrating remarkable clinical benefits. However, the combined outcomes of T-DXd with immunotherapy agents remain ambiguous. In this study, we introduce Tras-DXd-MTL1, an innovative HER2 targeting ADC that integrates the topoisomerase inhibitor DXd and a toll-like receptor 7 (TLR7) agonist MTT-5, linked to trastuzumab via a GGFG tetrapeptide linker. Mechanistically, Tras-DXd-MTL1 retains the DNA-damaging and cell-killing properties of topoisomerase inhibitors while simultaneously enhancing the immune response within the tumor microenvironment (TME). This is achieved by promoting immune cell infiltration and activating dendritic cells and CD8+T cells via MTT-5. In vivo evaluation of Tras-DXd-MTL1's anti-tumor potency revealed a notably superior performance compared to the T-DXd (Tras-DXd) or Tras-MTL1 in immunocompetent mice with trastuzumab-resistant EMT6-HER2 tumor and immunodeficient mice with JIMT-1 tumor. This improved efficacy is primarily attributed to its dual functions of immune stimulation and cytotoxicity. Our findings highlight the potential of incorporating immunostimulatory agents into ADC design to potentiate antitumor effects and establish durable immune memory, thereby reducing tumor recurrence risks. Therefore, our study offers a novel strategy for the design of immune-activating ADCs and provides a potential approach for targeting solid tumors with different levels of HER2 expression.

Antitumor Activity of a Pyrrolobenzodiazepine Antibody-Drug Conjugate Targeting LGR5 in Preclinical Models of Neuroblastoma.

Neuroblastoma (NB) is a cancer of the peripheral nervous system found in children under 15 years of age. It is the most frequently diagnosed cancer during infancy, accounting for ~12% of all cancer-related deaths in children. Leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5) is a membrane receptor that is associated with the primary tumor formation and metastasis of cancers in the gastrointestinal system. Remarkably, high levels of LGR5 are found in NB tumor cells, and high LGR5 expression is strongly correlated with poor survival. Antibody-drug conjugates (ADCs) are monoclonal antibodies that are covalently linked to cell-killing cytotoxins to deliver the payloads into cancer cells. We generated an ADC with an anti-LGR5 antibody and pyrrolobenzodiazepine (PBD) dimer-based payload SG3199 using a chemoenzymatic conjugation method. The resulting anti-LGR5 ADC was able to inhibit the growth of NB cells expressing LGR5 with high potency and specificity. Importantly, the ADC was able to completely inhibit the growth of NB xenograft tumors in vivo at a clinically relevant dose for the PBD class of ADCs. The findings support the potential of targeting LGR5 using the PBD class of payload for the treatment of high-risk NBs.

Trastuzumab-Deruxtecan: Redefining HER2 as a Tumor Agnostic Biomarker.

Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate (ADC) targeting HER2-positive malignancies across various tumor types. Through its unique composition, T-DXd achieves selective payload delivery, inducing cell death and halting tumor progression. Clinical trials initially investigated T-DXd's efficacy in HER2-positive advanced or metastatic breast, gastric, lung, and colorectal cancers; however, recent results from the DESTINY-PanTumor02 trial further underscore T-DXd's versatility, prompting T-DXd's US FDA approval for HER2-positive (immunohistochemistry [IHC] 3+) solid tumors. Moreover, in addition to T-DXd's efficacy against brain metastasis, T-DXd is showing promising results in HER2-low and HER2-ultra-low metastatic breast cancer, indicating a broader population of patients who may benefit.

Therapeutic Targeting Tongue Squamous Cell Carcinoma via ICAM1 Antibody‐Drug Conjugates in Preclinical Models

AbstractTo date, the treatment options for metastatic and recurrent tongue squamous cell carcinoma (TSCC) remain limited due to the lack of effective drug targets and therapeutics. Here the identification of ICAM1 is reported as a TSCC target candidate for the development of antibody‐drug conjugate (ADC), an emerging class of targeted therapeutics. An unbiased and quantitative screening of a panel of 69 TSCC cell surface antigens is first performed that identifies ICAM1 as the most abundant hit. The overexpression level of ICAM1 is validated in 26 TSCC clinical specimens and four cell lines along with genomic information of 127 TSCC patients from the TCGA database. Based on this new target, the anti‐TSCC efficacy of ICAM1‐targeted ADCs featuring two payloads is evaluated of different mechanisms of action: MMAE and DXd. Both ADCs selectively and potently ablate TSCC tumors in the established SAS cell line and patient‐derived xenograft (PDX) models. The findings strongly support ICAM1 as a promising ADC target candidate for TSCC therapy.

A real-world pharmacovigilance study of polatuzumab vedotin based on the FDA adverse event reporting system (FAERS).

Polatuzumab vedotin, the first FDA-approved antibody-drug conjugate (ADC) targeting CD79b, is utilized in the treatment of previously untreated diffuse large B-cell lymphoma (DLBCL) or high-grade B-cell lymphoma (HGBL), as well as relapsed or refractory (R/R) DLBCL. Despite its approval, concerns persist regarding the long-term safety profile of polatuzumab vedotin. This study aims to evaluate the adverse events (AEs) associated with polatuzumab vedotin since its approval in 2019, utilizing data mining strategies applied to the FDA Adverse Event Reporting System (FAERS). Signal detection employed four methodologies, including reporting odds ratio (ROR), proportional reporting ratio (PRR), bayesian confidence propagation neural network (BCPNN), and multi-item gamma poisson shrinker (MGPS), to evaluate and quantify the signals of polatuzumab vedotin-associated AEs. Additionally, subgroup analyses based on patients age, gender, and fatal cases were conducted to investigate AEs occurrences in specific subpopulations. A total of 1,521 reports listing polatuzumab vedotin as a "principal suspect (PS)" drug were collected from the FAERS database. Through concurrent compliance with four algorithms, 19 significant Standardized MedDRA Query (SMQ) AEs and 92 significant Preferred Term (PT) AEs were detected. Subgroup analyses revealed a higher incidence of PTs in male patients compared to female patients, increased likelihood of polatuzumab vedotin-associated AEs in elder patients (>65years), and AEs with a high risk of fatal cases include: blood lactate dehydrogenase increased, cytopenia, and hydronephrosis. The median time to AEs occurrence following polatuzumab vedotin initiation was 18.5 (5∼57.75) days, with 95% of AEs occurred within 162days. This study identified various AEs associated with polatuzumab vedotin, offering critical insights for clinical monitoring and risk identification in patients receiving polatuzumab vedotin therapy.

Mechanistic Characterization of Cancer-associated Fibroblast Depletion via an Antibody-Drug Conjugate Targeting Fibroblast Activation Protein.

The direct elimination of FAP-expressing CAFs disrupts the cross-talk with cancer cells leading to a proinflammatory response and alterations in the immune microenvironment and antitumor immune response.

MYTX-011: a pH-dependent anti-cMET antibody-drug conjugate designed for enhanced payload delivery to cMET expressing tumor cells.

Advances in linker payload technology and target selection have been at the forefront of recent improvements in antibody-drug conjugate (ADC) design, leading to several approvals over the last decade. In contrast, the potential of novel ADC technologies to enhance payload delivery to tumors is relatively underexplored. We demonstrate that incorporation of pH-dependent binding in the antibody component of a cMET targeting ADC (MYTX-011) can overcome the requirement for high cMET expression on tumors, an innovation that has the potential to benefit a broader population of patients with lower cMET levels. MYTX-011 drove four-fold higher net internalization than a non-pH engineered parent ADC in non-small cell lung cancer (NSCLC) cells and showed increased cytotoxicity against a panel of cell lines from various solid tumors. A single dose of MYTX-011 showed at least three-fold higher efficacy than a benchmark ADC in mouse xenograft models of NSCLC ranging from low to high cMET expression. Moreover, MYTX-011 showed improved pharmacokinetics over parent and benchmark ADCs. In a repeat dose toxicology study, MYTX-011 exhibited a toxicity profile similar to other MMAE-based ADCs. These results highlight the potential of MYTX-011 for treating a broader range of NSCLC patients with cMET expression than other cMET targeting ADCs. A first in human study is ongoing to determine the safety, tolerability, and preliminary efficacy of MYTX-011 in patients with NSCLC (NCT05652868).

The role of TROP-2 in the progression and target therapy in penile squamous cell carcinoma.

e17023 Background: Penile squamous cell carcinoma(PSCC) is a devastating malignancy of urogenitary system. However, current chemotherapy treatments including TIP regimen has showed limited effects but strong side effects in advanced PSCC. Trophoblast cell-surface antigen-2 (Trop-2) is a novel target for Antibody-drug conjugates (ADC) drugs and is proved to be effective in several human cancers, but its role in PSCC has not been clearly certified. Methods: 198 PSCC tumor tissue specimens and clinicopathological data were collected. TROP-2 expression was detected by IHC experiments and the correlation between TROP-2 expression and clinicopathological data of patients was analyzed through statistical methods. Then a series of in vivo and in vitro experiments were conducted to investigate the mechanism that how TROP-2 promote PSCC cell proliferation. Results: IHC results showed that TROP-2 was highly expressed in 60.2% of tumor specimens, and statistical analysis revealed a positive association of TROP-2 expression with advanced pT, pN stages and extranodal extension (ENE), as well as poor prognosis. Knockdown of TROP-2 expression inhibited the proliferation of PSCC cells both in vivo and in vitro. Further experiments identified that TROP-2 promoted PSCC cell proliferation via AKT-mediated PKCα signaling pathway. TROP-2 ADC drugs could inhibited PSCC cell proliferation both in vitro and in vivo. Conclusions: TROP-2 promotes PSCC cell proliferation, and TROP-2 targeted ADC-drug is a promising agent for PSCC treatment in future.

Population pharmacokinetics of trastuzumab deruxtecan (T-DXd) in subjects with HER2-mutant and HER2-overexpressing non-small cell lung cancer (NSCLC).

e20537 Background: T-DXd is a novel human epidermal growth factor receptor 2 (HER2) targeting antibody drug conjugate, approved globally at the dose of 5.4 mg/kg in HER2-positive or HER2-low breast cancer (BC) and HER2-mutant (HER2m) NSCLC1,2. The aim of the analysis was to characterize the populaton pharmacokinetics (PopPK) of T-DXd and its released payload, deruxtecan (DXd), in HER2m or HER2-overexpressing (HER2-OE) NSCLC subjects using data across tumor types (BC, NSCLC and others) from 12 Phase 1 to 3 studies with T-DXd doses ranging from 0.8-8.0 mg/kg. Methods: Analysis wasperformed using nonlinear mixed-effects modeling methods in NONMEM (version 7.4.3), similar to the previous analysis in HER2-positive BC1. Covariate effects were explored on the PK parameters of T-DXd and DXd. Results: Analysis included data across 1822 subjects, including 346, 1128, and 348 subjects with NSCLC, BC, and other cancers, respectively. The PK of T-DXd and DXd were adequately described by a PopPK model, judging by standard model diagnostics3. Covariate effects on T-DXd and DXd steady-state area under the concentration-time curve (AUC) were not clinically meaningful (within 0.8 to 1.25 AUC ratio interval for tested covariate level versus reference), except for subjects with high body weight (e.g., 90 kg; 95th percentile) showing a 31% and 37% higher T-DXd and DXd AUC, respectively, relative to typical subject with 58 kg body weight (median).The T-DXd and DXd AUC were also similar across subjects with BC, HER2m or HER2-OE NSCLC, with the same T-DXd dose. T-DXd and DXd AUC in NSCLC subjects were similar across subjects with mild hepatic or mild or moderate renal impairment (vs. normal counterparts), region (Asia, North America, Europe, and rest of the world), and race-country (Asian-Japan, Asian-Non-Japan, and Non-Asian) groups. Conclusions: T-DXd and DXd exposures were similar across subjects with BC and HER2m or HER2-OE NSCLC, as well as across hepatic function, renal function, region, and race-country groups within NSCLC supporting the use of 5.4 mg/kg dose (approved dose in BC) in HER2m or HER2-OE NSCLC from PK perspective. Reference: Enhertu [package insert]. Basking Ridge, NJ: Daiichi Sankyo, Inc.; 2022. Enhertu [summary of product characteristics]. Daiichi Sankyo Europe GmbH, Munich; 2022 Yin O et al. Clin Pharmacol Ther. 2021;109(5):1314-1325. Clinical trial information: NCT04644237 , NCT03505710 .

Exposure-response (ER) analyses of efficacy and safety of trastuzumab deruxtecan (T-DXd) to inform dosing recommendation in HER2-mutant non-small cell lung cancer (NSCLC).

e20545 Background: T-DXd, a novel human epidermal growth factor receptor 2 (HER2) targeting antibody drug conjugate, was evaluated at doses of 5.4 and 6.4 mg/kg every three weeks in Phase 1 or 2 trials in HER2 mutant (HER2m) NSCLC subjects, including Destiny-Lung01 (DL-01) and DL-02 trials1,2. ER analyses of key efficacy and safety endpoints were conducted to support the dosing recommendation of T-DXd in HER2m NSCLC. Methods: Exposure-efficacy (EE) analysis was performed using confirmed objective response (cORR) data from HER2m NSCLC in Phase 1-2 trials (N = 181). The dataset included primary analysis data cut from DL-011 and interim analysis data cut from DL-02. Exposure-safety (ES) analyses of T-DXd were performed, using pooled data from 11 Phase 1-3 trials (N = 1850) across tumor types, including DL-01 and DL-02, for safety endpoints of adverse events (AEs) associated with dose reduction or discontinuation, Grade3+ (G3+) AEs, serious AEs, G3+Anemia, G3+neutropenia, G3+thrombocytopenia, adjudicated any grade interstitial lung disease (ILD), and G3+ ILD. cORR and all safety endpoints, except ILD were analyzed by logistic regression; any grade ILD was analyzed by parametric time-to-event analysis. The T-DXd or DXd exposure metric and numerous patient-specific covariates were tested in the analysis. Results: T-DXd exposure had a positive but shallow relationship with cORR. The predicted cORR varied from 57% (95% credible interval (CrI): [36, 77]) to 65% (95% CrI: [41, 84]) across 5th and 95th percentile of T-DXd exposure respectively. No clinically meaningful difference in cORR was estimated across 5.4 and 6.4 mg/kg doses with predicted cORR values of 53% (95% CrI: [44, 60]) and 55% (95% CrI: [47, 62]) at T-DXd doses of 5.4 mg/kg and 6.4 mg/kg, respectively. ES relationships were consistent with previous T-DXd ES analyses in breast cancer (BC). Model-predicted AE rates were lower (up to 9%) in 5.4 mg/kg compared to the 6.4 mg/kg dose. Model-predicted safety at 5.4 mg/kg dose in HER2m NSCLC was similar to the approved dose of 5.4 mg/kg in BC. Conclusions: The ER analyses showed no clinically meaningful difference in efficacy between 5.4 and 6.4 mg/kg doses of T-DXd; and safety events were lower in 5.4 mg/kg, thus supporting the 5.4 mg/kg recommended dose for HER2m NSCLC. These findings were later confirmed based on primary analysis in DL-022 and support the utility of ER analyses in dosing recommendation. Reference: Li BT et al. N Engl J Med 2022;386:241-51 Goto K et al. J Clin Oncol 41:4852-4863. Clinical trial information: NCT03505710 , NCT04644237 .

Increased risk of hyperglycemia in patients with advanced urothelial cancer treated with enfortumab vedotin: A systematic review and meta-analysis.

e15001 Background: Enfortumab vedotin (EV), an antibody-drug conjugate targeting anti-nectin-4, which is highly expressed in urothelial cancers, has emerged as an effective therapy in the management of previously treated advanced urothelial cancer. urothelial cancer. Severe hyperglycemia has been recognized as an unexpectedly adverse effect, and can lead to discontinuation of EV or fatal event. To assess the overall risk of hyperglycemia associated with the use of EV, a systematic review and meta-analysis of published clinical trials was performed. Methods: A comprehensive review through 2023 of PubMed and American Society of Clinical Oncology conferences was performed to identify relevant clinical trials and abstracts. Eligible studies were clinical trials of patients with urothelial cancer receiving EV at the standard dose with data on hyperglycemia available. Incidence rates, relative risks, and 95% confidence intervals were calculated using random-effects or fixed-effects models. Results: Our search culminated in the inclusion of 1,150 patients from four trials, with 859 of them receiving EV. The summary incidences for all-grade and high-grade hyperglycemia were 9.9% (95% CI: 7.8-12.5%) and 6.0% (95% CI: 4.6-7.8%) respectively. Patients treated with EV had an increased risk of developing hyperglycemia in comparison with chemotherapy with an RR of 19.66 (95% CI: 2.66-145.55, P=0.004) for all-grade and 26.54 (95% CI: 1.59-444.48, P=0.023). In comparison with single-agent EV, its combination with pembrolizumab did not significantly increase the risk of all-grade hyperglycemia (P=0.148). Conclusions: EV is associated with a significantly increased risk of all-grade and high-grade hyperglycemia.

First-in-human study of ABBV-706, a seizure-related homolog protein 6 (SEZ6)–targeting antibody-drug conjugate (ADC), in patients (pts) with advanced solid tumors.

3001 Background: SEZ6 is a transmembrane protein expressed in small cell lung cancer (SCLC) and other neuroendocrine neoplasms (NENs), and central nervous system (CNS) tumors. These malignancies have a high unmet need for novel effective therapies. ABBV-706 is an ADC targeting SEZ6 conjugated to a topoisomerase 1 inhibitor payload at a drug-to-antibody ratio of 6, and is highly efficacious in preclinical models of SCLC, NENs, and CNS tumors. Here, results from ABBV-706 monotherapy dose escalation (DE) are presented. Methods: Phase 1, open-label, multicenter, DE and dose-expansion study (NCT05599984) of ABBV-706 as monotherapy or in combination with budigalimab (a programmed cell death 1 inhibitor), carboplatin, or cisplatin. Primary objectives are to determine the safety, PK, preliminary efficacy, and recommended phase 2 dose of ABBV-706. Exploratory objectives are to assess SEZ6 expression retrospectively and its association with safety, PK, and efficacy. DE enrolled adults (≥18 yr) with relapsed/refractory SCLC, high-grade CNS tumors, and high-grade NENs, following the Bayesian optimal interval design. ABBV-706 was administered IV at 1.3–3.5 mg/kg doses Q3W in 21-d cycles. Results: As of data cutoff on Nov 15, 2023, 49 pts (SCLC: n=22 [45%]; CNS tumors: n=5 [10%]; NEN: n=22 [45%]) were enrolled and treated with ABBV-706 in DE and backfill cohorts. Median age was 64 yr (range 32–81) and median prior lines of therapy was 2.5 (range 1–6). 2 pts had a dose-limiting toxicity: 1 G4 leukopenia and neutropenia lasting >7 d at 3.0 mg/kg and 1 G4 thrombocytopenia at 3.5 mg/kg. TEAEs occurred in 45 (92%) pts, the most frequent being anemia (51%), fatigue (41%), neutropenia (31%), and leukopenia (31%). G≥3 TEAEs occurred in 28 (57%) pts and were mainly hematologic: neutropenia (29%), anemia (27%), and leukopenia (25%). No pneumonitis/interstitial lung disease was observed. Gastrointestinal TEAEs (all G1/2) were seen in 55% of pts, with the most common being nausea (27%) and vomiting (18%). There were no ABBV-706–related deaths. The maximum tolerated dose was 3 mg/kg IV Q3W. ABBV-706 ADC showed an approximate dose-proportional increase in exposure with an elimination half-life of approximately 7 d across doses. For 33 RECIST-evaluable pts, the confirmed (c) objective response rate was overall 21% (7 partial responses [PRs]); 40% (6/15) for SCLC and 6% (1/18) for NEN. The overall response (c and unconfirmed [u]) rate without confirmation was 45% (7 cPRs/8 uPRs); 73% (6 cPRs/5 uPRs) for SCLC, and 22% (1 cPR/3 uPRs) for NEN. 8 uPRs are pending confirmation and will be reported in the final presentation. The clinical benefit rate was 91% (7 PR, 23 stable disease). No activity was observed in 3/3 pts with high-grade gliomas. Conclusions: ABBV-706 demonstrated a manageable safety profile with promising efficacy in SCLC and NENs. Further evaluation of ABBV-706 is ongoing. Clinical trial information: NCT05599984 .

A phase II multicenter study of enfortumab vedotin with or without pembrolizumab in rare genitourinary tumors (E-VIRTUE).

TPS4628 Background: Enfortumab vedotin (EV) is an antibody-drug conjugate (ADC) targeting nectin-4 with a monomethyl auristatin E (MMAE) payload, a potent microtubule inhibitor. It is standard of care (SOC) in metastatic urothelial carcinoma in combination with pembrolizumab in untreated patients and as monotherapy in post-chemotherapy, post-immune checkpoint blockade (ICB) patients. Nectin-4 expression has been retrospectively observed in 66.7-100% of urinary tract adenocarcinoma, 70-100% of urinary tract squamous cell carcinoma (SCC) (Case et al., 2022; Hoffman-Censits et al., 2021) and 36% of testicular germ cell tumors (GCTs) (The Human Protein Atlas). Metastatic urinary tract adenocarcinoma and SCC, and treatment refractory GCTs do not have an established SOC. Given the known nectin-4 expression, we hypothesize that EV with or without pembrolizumab will be active in these rare GU tumors. Methods: E-VIRTUE is an open-label, non-randomized, Phase 2 multicenter study. Eligible patients must have locally advanced or metastatic urinary tract pure adenocarcinoma, urinary tract pure SCC or refractory GCTs and have measurable disease by RECIST 1.1. Patients may have received any number of lines of prior systemic therapy except EV or other MMAE-based ADCs, and GCT patients must be refractory to all curative SOC treatments. Each histology will have an ICB-naïve and post anti-PD-1/PD-L1 ICB cohort: ICB-naïve patients will be given EV 1.25 mg/kg (maximum 125 mg) on Days 1 and 8 and pembrolizumab 200 mg on Day 1 of 21-day cycles, and post ICB patients will be given EV 1.25 mg/kg (maximum 125 mg) on Days 1, 8 and 15 of 28-day cycles. EV will be given for up to 5 years and pembrolizumab will be given for up to 2 years, or until progressive disease (PD) or unacceptable toxicity. Patients who stop pembrolizumab after achieving a complete response may resume it for 1 year after developing PD. The primary objective is to evaluate the objective response rate (ORR) in all cohorts. Secondary objectives include safety, progression-free survival (PFS) and overall survival (OS). The initial 6 cohorts will each be evaluated with exploratory intent. With 10 patients in each cohort, an exact binomial test with a 10% one-sided significance level will have 85.3% power to detect the difference between a very low (5%) ORR and a higher (30%) ORR. If there are ≥2/10 objective responses in any cohort, activity will be demonstrated. Additional histologies may be added after nectin-4 data emerges to justify their inclusion. Exploratory objectives include estimating the level of nectin-4 expression for each histology, performing DNA and RNA sequencing of tumor and blood samples, and observing changes in levels of circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) with treatment and disease status. Clinical trial registration NCT06041503. Clinical trial information: NCT06041503 .

ARTEMIS-002: Phase 2 study of HS-20093 in patients with relapsed or refractory osteosarcoma.

11507 Background: Patients (pts) with relapsed and refractory (R/R) osteosarcoma have a poor prognosis with limited therapeutic options. HS-20093 is a novel antibody-drug conjugate (ADC) targeting B7-H3, which showed preliminary anti-tumor activity in phase 1 ARTEMIS-001 study (NCT05276609). Here we report results in R/R osteosarcoma pts treated with HS-20093 from ARTEMIS-002 study (NCT05830123). Methods: ARTEMIS-002 trial is an open label, two-arm phase 2 trial in pts with R/R osteosarcoma or other sarcomas progressed upon standard systemic treatment. Based on the results of the phase 1 trial that the maximum tolerated dose was 12 mg/kg once every 3 weeks (Q3W) intravenous infusion, the osteosarcoma pts in the phase 2 trial were randomized to receiving HS-20093 either at 8 mg/kg or 12 mg/kg Q3W at a ratio of 1:1. The primary endpoint was objective response rate (ORR) according to RECIST1.1. B7-H3 expression was retrospectively evaluated by IHC in osteosarcoma FFPE tissue. Results: A total of 34 pts with R/R osteosarcoma were enrolled from June to December in 2023, receiving HS-20093 at the dose of either 8.0 mg/kg (N = 15) or 12.0 mg/kg (N = 19). Median age was 21.5 years (range: 18~65). At baseline, most pts were evaluated with clinical stage IV disease (32/34, 94.1%) and pulmonary metastasis (28/34, 82.4%). Twenty-two pts (64.7%) had received ≥3 prior lines therapy. Twenty-six pts (76.5%) had received 4 types of standard chemotherapies consisting of platinum, anthracyclines, ifosfamide and methotrexate. Treatment emergent adverse event (TEAEs) occurred in 33 pts (97.1%). The common grade 3/4 TEAEs (≥5%) were: neutropenia, leukopenia, thrombocytopenia, lymphopenia and anemia. The incidences of discontinuations, dose withhold and dose reductions were 2.9%, 11.8% and 23.5%, respectively. There was no TEAE leading to death. As of cut-off date (25 December, 2023), the median follow-up time was 4.1 months (95% CI: 1.4~5.5) among 21 response-evaluable pts (11 treated with 8 mg/kg and 10 with 12.0 mg/kg). The ORR of 12.0 mg/kg HS-20093 was 20.0%. Two confirmed partial responses were observed in pts with 12.0 mg/kg and remained on response until last follow-up, of which the longest duration of response was 4.0 months. The disease control rate was 81.8% (9/11) and 100% (10/10) in pts with 8 mg/kg and 12.0 mg/kg. The median progression-free survival of all 21 pts was not mature. B7-H3 is highly expressed in osteosarcoma with median H-score 185 (0~260). No correlation was observed between tumor response and B7-H3 expression level. The PK exposure of HS-20093 ADC, total Ab and payload increased with dose, approximately proportional to dose, with a half-life of 4 to 6 days, and no or minor accumulation after multiple doses of Q3W. Conclusions: The data has demonstrated that HS-20093 exhibited promising antitumor activity with acceptable toxicity in pts of heavily-pretreated R/R osteosarcoma. The enrollment of ARTEMIS-002 is continuing. Clinical trial information: NCT05830123 .

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 .

Preliminary results from a first-in-human trial of AMT-116, a topoisomerase I inhibitor containing antibody-drug conjugate (ADC), in patients with advanced solid tumors.

e15010 Background: CD44v9 is a tumor-associated antigen highly expressed in various solid tumor types including head and neck, lung, esophageal, pancreatic, colorectal, breast, bladder, hepatic, cervical, and gastric cancers. AMT-116 is a first-in-class antibody-drug conjugate (ADC) targeting CD44v9, by conjugating a novel topoisomerase I inhibitor, belotecan derivative named KL610023 (Sichuan Kelun-Biotech) to a humanized anti-CD44v9 immunoglobulin G1 (IgG1) antibody via a hydrolysable linker with an average drug-to-antibody ratio of 7-8. Methods: This is an ongoing first-in-human, non-randomized, open-label, multicenter, Phase 1 study designed to evaluate the safety, tolerability, pharmacokinetics, and preliminary anti-tumor activity of AMT-116 in patients (pts) with advanced solid tumors, unselected for target expression. Pts received escalating doses of AMT-116 Q2W starting from 1.5 mg/kg guided by the Bayesian logistic regression model (BLRM) following escalation with overdose control (EWOC) principle. Results: As of Feb 1, 2024, eight pts (4 pts at 1.5 mg/kg, 3 pts at 3 mg/kg and 1 pt at 5 mg/kg) have been treated in Australia and pts at 1.5 mg/kg and 3 mg/kg completed the 28-day dose-limiting toxicity (DLT) evaluation period. No DLT events were observed, and the maximum tolerated dose (MTD) has not been reached. Treatment related adverse events (TRAEs) were reported in 5 pts out of 8. The most common TRAEs were fatigue (n=3) and nausea (n=3). Only one Grade 3 TRAE (leukopenia) was reported. There were no Grade 4 or 5 TRAEs or treatment-related SAEs. Seven pts have completed at least one post-treatment tumor assessment. At dose level 3 mg/kg, one pt with anal squamous cell carcinoma achieved unconfirmed PR with a 31% tumor shrinkage and one pt with hepatocellular carcinoma achieved SD with a 23% tumor shrinkage from baseline. Subject enrollment in 5 mg/kg is underway. Conclusions: These preliminary data indicate that AMT-116 is well tolerated at the first two dose levels in patients with heavily pretreated advanced solid tumors. Dose escalation is ongoing. Clinical trial information: NCT05725291 .

Dose escalation and expansion results from the phase I study of F0024, a trophoblast cell-surface antigen 2 (TROP2) antibody-drug conjugate (ADC), in patients (pts) with advanced solid tumors.

e13131 Background: F0024 is an antibody-drug conjugate (ADC) targeting Trop-2, an intracellular calcium signaling transducer overexpressed on many epithelial tumors, for delivery of SN-38, the active metabolite of irinotecan. We assessed its safety and efficacy in patients with advanced solid tumors, mainly in triple negative breast cancer (TNBC). Methods: PTs with unresectable solid tumors refractory to/relapsed from standard treatment received F0024 on days 1 and 8 of 21-day treatment cycles. Primary objectives include maximum tolerated dose (MTD) identification, safety, and tolerability and secondary objectives include efficacy, pharmacokinetics, and incidence of anti-drug antibodies against F0024. Pts were eligible regardless of TROP2 level. Results: As of October 8, 2023, 62 pts were treated with≥1 dose of F0024. 21 pts were treated during dose escalation at 2.5 (n = 1), 5.0 (n = 3), 7.5 (n = 3), 10 (n = 4), 12 (n = 8), and 15 (n = 2) mg/kg and 41 pts with TNBC were treated in dose expansion at 10.0 (n = 30) and 12.0 (n = 11) mg/kg. 32 pts (51.6%) discontinued (20 (32.2%) due to disease progression per RECIST v1.1). Treatment emergent adverse events (TEAEs) regardless of causality were reported in 61 of 62 pts (98.4%; 34 pts [54.8%] experienced ≥grade 3, 9 pts [14.5%] had serious adverse events). Treatment related adverse events (TRAEs) were reported in 61 of 62 pts (98.4%; 32 pts [51.6%] experienced ≥grade 3, 4 pts [6.5%] had serious adverse events). The most common grade 3 TRAE were neutropenia (45.2%), leukopenia (33.9%), febrile neutropenia (4.8%), anemia (4.8%), and maculo-papular rash (4.8%). A total of 17 responses have been observed at the dose of 5.0 mg/kg or greater. 34 TNBC pts were dosed at 10 and 19 were dosed at 12 mg/kg with exposure to a median of 11.5 (1.0-26.0) and 4.0 (1.0-21.0) doses. 11 partial responses were achieved in 29 efficacy-evaluable TNBC pts at 10 mg/kg leading to an overall response rate (ORR) of 37.9% (95% CI 20.7% - 57.7%). The disease control rate of 10 mg/kg is 79.3% (95% CI 60.3%-92.0%). 5 escalation pts and 25 expansion pts remain on trial. Updated trial details/results will be presented. Conclusions: In this first-in-human study of F0024, treatment was generally well tolerated and MTD was not yet reached up to 12 mg/kg. F0024 demonstrated encouraging preliminary antitumor activity in heavily pretreated TNBC pts, especially in 10 and 12 mg/kg. Clinical trial information: NCT05174637 .

SMART: A phase II study of sacituzumab govitecan (SG) with or without atezolizumab immunotherapy in rare genitourinary (GU) tumors such as small cell, adenocarcinoma, and squamous cell bladder/urinary tract cancer, renal medullary carcinoma (RMC) and penile cancer.

TPS4627 Background: Rare tumors of the GU tract often exhibit aggressive clinical behavior, yet lack effective standard of care treatment options. SG is an antibody-drug conjugate (ADC) targeting trophoblastic cell surface antigen 2 (Trop2) with a payload of SN-38, a topoisomerase inhibitor. SG monotherapy gained accelerated approval in pts with metastatic urothelial carcinoma (mUC) post platinum and immune-checkpoint inhibitor (ICI) therapy based on the TROPHY-U-01 trial (Tagawa S et al., JCO 2021). Atezolizumab is an anti-PD-L1 ICI approved for use in multiple solid tumors. SMART will evaluate the efficacy and safety of SG monotherapy or SG plus atezolizumab in select rare GU tumors. Methods: SMART is an open-label, non-randomized, Phase 2 trial. Pts must have locally advanced (unresectable) or metastatic GU tumors of the following histologies: small cell carcinoma, squamous cell carcinoma, or primary adenocarcinoma of the bladder or urinary tract, RMC, or squamous cell carcinoma of the penis. Pts may be treatment-naïve or have received any number of prior therapies; pts with small cell carcinoma must have received a platinum-based regimen. Pts treated with a PD-1/PD-L1 ICI will be assigned to Cohort A/Treatment Arm 1 and will receive SG monotherapy (10mg/kg IV, D1 and D8 of 21 day cycles). Pts without prior ICI treatment will be assigned to Cohort B/Treatment Arm 2 and will receive SG (10mg/kg IV, D1 and D8 of 21 day cycles) with concomitant atezolizumab (1200mg IV, D1 of 21 day cycles). Treatment will continue until disease progression (max duration of treatment 5 years) or intolerable side effects. The primary endpoint is objective response rate (ORR) (RECIST v1.1) for each Cohort, with restaging every 3 cycles. Secondary endpoints include safety, clinical benefit rate (CR+PR+SD), median PFS/OS for each Cohort, and ORR for each histology. Exploratory analyses include determination of baseline tumor mutation and transcriptional profile, Trop2 expression, ctDNA/CTCs, peripheral blood immune subsets and cytokine profile correlation with response, and correlation of UGT1A1 allele genotype with response and safety. This study utilizes a Simon minimax two-stage design, with enrollment of up to 43 evaluable pts (accrual ceiling of 60 pts). Cohort A will enroll 11 pts in Stage 1; if 1 or more of the first 11 pts has a response (unacceptably low rate of 5%, p0=0.05; alpha 0.10, beta=0.20), accrual will continue into Stage 2 up to 18 evaluable pts. Cohort B will enroll 16 evaluable pts in Stage 1; if 2 or more pts have a response (unacceptably low rate of 10%, p0=0.10; alpha 0.10, beta=0.10), accrual will continue in Stage 2 up to a total of 25 evaluable pts. This study is open at the NIH Clinical Center (CC); enrollment may open at 1-2 additional centers. Clinical trial information: NCT06161532 .

Clinical update related to the first-in-human trial of SYS6002 (CRB-701), a next-generation nectin-4 targeting antibody drug conjugate.

3151 Background: SYS6002 (CRB-701) is a novel, nectin-4 targeting antibody drug conjugate (ADC) that take advantage of a third generation, site-specific cleavable linker with novel conjugation chemistry. This technology is designed to establish a stable linker across antibody and payload, to produce an ADC with a homogenous drug antibody ratio of 2.0, with the additional aim to reduce the concentration of free-MMAE and thereby improve known payload related toxicities. SYS6002 (CRB-701) also contains a novel monoclonal antibody with a prolonged half-life that can support Q3W dosing. Methods: This is a multicenter, open-label, single-arm, phase I study using Bayesian optimal interval design. Eligible patients were aged ≥18 years with histologically confirmed Nectin-4 positive solid tumors (no Nectin-4 testing was required for urothelial carcinoma [UC]) who had failed or were intolerant to standard of care options. In the dose escalation, patients were given SYS6002 (dose level 0.2, 0.6, 1.2, 1.8, 2.7, 3.6, and 4.5 mg/kg) administered Q3W by intravenous infusion. The primary endpoints were safety, tolerability, and the recommended phase 2 dose. Results: As of January 2024, SYS6002 (CRB-701) has established a differentiated safety profile across a broad dose range (0.2-3.6 mg/kg) with no dose limiting toxicities and the majority of adverse events representing grade 1 or 2. No low-grade peripheral neuropathy, skin rash or fatigue, known toxicities that rate limit the usage of enfortumab vedotin (EV) have occurred. Herein, we report the anti-tumor activity of SYS6002 (CRB-701) in patients with nectin-4 positive solid tumors with a median of 4 prior therapies. The first confirmed stable disease was observed at 0.6 mg/kg and the first confirmed partial response was at 1.2 mg/kg. Anti-tumor activity in nectin-4 positive patients at doses ≥ 2.7 mg/kg ( n=6) would suggest an overall unconfirmed objective response rate of 50%, and among them, the ORR of patients with UC was 50% (1/2), and that of patients with cervical cancer reached 67% (2/3). Across this group of patients, 4/6 had moderate to high nectin-4 expression (H-score ≥ 150) and 3 achieved a partial response, suggesting SYS6002 (CRB-701) could achieve a highly differentiated ORR of 75% in patients with moderate to high Nectin-4 expression. After single IV infusion of SYS6002 0.2-3.6 mg/kg, the exposure of TAb, ADC and MMAE generally increased in a dose proportional manner. The half-lives of TAb, ADC and MMAE were 4-6 days, 4-5 days and 5-10 days, respectively. SYS6002 (CRB-701) exhibited a longer ADC half-life and lower free-MMAE exposures relative to EV at comparable dose levels. Conclusions: SYS6002 (CRB-701) demonstrates promising anti-tumor activity with a well-tolerated safety profile in patients with advanced nectin-4 positive solid tumors. Dose escalation at 4.5 mg/kg Q3W and dose expansion at 3.6 mg/kg Q3W are ongoing. Clinical trial information: ChiCTR2200066256.

Open-label, single-arm phase Ib/II study of immune combination therapy with elotuzumab and belantamab mafodotin in patients with relapsed refractory multiple myeloma.

7559 Background: The B cell maturation antigen (BCMA)-targeted antibody drug conjugate belantamab mafodotin enhances cell-mediated antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis. Elotuzumab, a signaling lymphocytic activation molecule family member 7 (SLAMF7) checkpoint inhibitor, activates NK cells and induces antibody-dependent cellular cytotoxicity. Bela-Elo (NCT05002816) is an ongoing phase Ib/II trial evaluating the safety, tolerability and preliminary efficacy of the unique combination of these two agents in patients with relapsed/refractory myeloma (RRMM). We report data from phase I part of this trial. Methods: This single-arm phase Ib/II study is enrolling patients with triple-class refractory RRMM. Patients with progression after prior BCMA-targeted therapy are eligible. Elotuzumab is administered via intravenous (IV) infusion at an established dose of 10 mg/kg on days 1, 8, 15, 22 every 28 days for cycles 1 and 2; followed by 20mg/kg on day 1 of each 28-day cycle. Belantamab mafodotin is administered via IV infusion with the starting dose of 1.9 mg/kg IV at every 4-week interval, with subsequent dose-reduction based on toxicity. Descriptive statistics were used to summarize patient demographics and safety and efficacy outcomes. Results: As of data cut-off (January 20, 2024) 12 subjects have been enrolled; and 10 subjects received treatment on study. Median age of patients was 66.5 years (range 59-79). The patient population was heavily pretreated with 5 prior median lines of therapy (range 2-8); 40% (4/10) of patients were refractory to prior BCMA-targeted therapy (2 post-BCMA bispecific antibody, 2 post-BCMA chimeric antigen receptor T-cell therapy [CART]). Phase I part of the study has completed. Median duration of treatment was 4 months (range 2-19). No dose-limiting toxicities were observed. Four severe adverse events were observed possibly related to the study treatment in 3 patients, including grade 3 pulmonary infection (n=1) and lymphopenia (n=3). Ocular keratopathy developed in 40% of patients, all were grades 1-2 and resolved after discontinuation or dose-reduction of belantamab. Preliminary activity is noted with partial responses (PR) in 4/10 (40%) and stable disease (SD) in additional 3/10 (30%) of patients. Among the four patients who were refractory to prior BCMA therapy, 2 (50%) achieved PR, with duration of response (DOR) of 19 months and 9 months, respectively. Conclusions: This novel combination immune therapy with belantamab mafodotin and elotuzumab appears to have an encouraging safety profile and a promising preliminary efficacy in patients with heavily pretreated RRMM, including in those with prior failure of BCMA-targeted therapy. Clinical trial information: NCT05002816 .