Antibody-drug Conjugate Targeting Research Articles

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.

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.

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.

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 .

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 .

Dose optimization and exposure-response analyses to support optimal dose of ABBV-400, a novel C-met–targeting antibody drug conjugate, in patients with metastatic colorectal cancer (mCRC).

3030 Background: ABBV-400 is an antibody drug conjugate (ADC) consisting of a c-Met targeting antibody conjugated to a potent inhibitor of topoisomerase 1 (Top1) payload. ABBV-400 has shown encouraging activity and demonstrated tolerability of dosages up to 3.0 mg/kg Q3W as monotherapy in patients with advanced solid tumors in an ongoing phase 1 study (1). Dosage optimization is a critical aspect of oncology drug development and FDA Project Optimus has focused on reformulating the dosage selection paradigm for oncology products. The phase 1 study included a dose optimization phase in mCRC patients in which 3 doses were evaluated (1.6, 2.4 and 3.0 mg/kg Q3W) to determine the optimal dose for further development. Herein, exposure-response analyses are reported to determine optimal monotherapy dose in mCRC patients. Methods: Data across a range of doses (1.6 – 6.0 mg/kg Q3W) from the phase 1 study (NCT05029882) were used. Population pharmacokinetics (PK) and exposure-response (E-R) analyses were conducted to characterize ABBV-400 conjugate and unconjugated payload PK and the relationship between exposures and efficacy (objective response rate [ORR]) and safety (Grade (Gr) ≥ 3 neutropenia, anemia and thrombocytopenia) endpoints. Relative dose intensity (RDI) analysis was performed. Results: ABBV-400 conjugate and payload PK were adequately described by a combined multi-analyte population PK model with first order kinetics (n=204). ABBV-400 conjugate average concentration was a better predictor of response and showed that higher exposure correlated with higher probability of response (n=122 CRC, ORR, p < 0.05) and safety events (n=204, Gr ≥ 3 neutropenia, anemia and thrombocytopenia, p < 0.001). Dose intensity analyses showed greater number of dose reductions for 3 mg/kg Q3W with effective (actual) dose received of 2.6 mg/kg Q3W in mCRC patients. E-R analyses for safety and efficacy and dose intensity analyses in mCRC 3L+ patients indicate that both 2.4 and 3.0 mg/kg doses provided meaningful efficacy (ORR); while the 3.0 mg/kg dose may provide higher response rates, the 2.4 mg/kg Q3W dosing regimen provides an optimal balance of safety and efficacy compared to 3.0 mg/kg Q3W. Conclusions: Population PK, E-R for efficacy and safety and RDI analyses and totality of clinical data supported the selection of 2.4 mg/kg Q3W as optimal ABBV-400 monotherapy dose for further study in mCRC patients. 1. Sharma M, et al. ASCO 2023. Abstract 3015. Clinical trial information: NCT05029882 .

BC3195, a novel ADC targeting CDH3: Preliminary results of a first-in-human phase I study in patients with advanced solid malignancies.

e15008 Background: Cadherin-3 (CDH3), a calcium-dependent cell-cell adhesion glycoprotein, is overexpressed on lung, breast, ovarian, colorectal, pancreatic, head and neck and other malignancies, but with negligible expression on nonmalignant tissues, and associated with cancer aggressiveness, invasiveness, and poor prognosis. BC3195 is known as the only antibody drug conjugate (ADC) in clinical stage, targeting CDH3 with payload of monomethyl auristatin E (MMAE). Methods: A phase I, open-label, first in human study to evaluate the safety, tolerability, PK, and preliminary antitumor activity of BC3195 is being performed in subjects with advanced solid malignancies. Disease assessments are performed every 6 weeks using RECIST v1.1. BC3195 is administered as 1 hour (h) IV infusion every 3 weeks. An evaluation of seven dose levels is planned: 0.3, 0.6, 1.2, 2.4, 3.0 and 3.6 mg/kg with a BOIN design guiding dose escalation. Results: Up to January 1st, 2024, nine patients (median age, 59; male, 56%) have been enrolled and treated with BC3195, with 3 patients each in the 0.3, 0.6 and 1.2 mg/kg dose cohorts. No DLT was observed across all the 3 dose cohorts. Treatment emergent adverse events (TEAEs) occurring in ≥3 patients included: aspartate aminotransferase increased (5/9, 55.6%), conjugated bilirubin increased (5/9, 55.6%), triglycerides increased (4/9, 44%), uric acid increased (3/9, 33.3%), heart rate increased (3/9, 33%), and hypoalbuminemia (5/9, 55.6%), cough (4/9, 44.4%), hyponatraemia (4/9, 44.4%), anemia (4/9, 44.4%), asthenia (3/9, 33.3%), rash (3/9, 33.3%), vomiting (3/9, 33.3%) and back pain (3/9, 33.3%). Two subjects experienced ≥ Grade 3 TEAEs unrelated to study drug. Six subjects were evaluable for tumor assessment, and 3 subjects (3/6, 50%) show stable disease (SD) as the best response (2 subjects with target lesion reduction). PK results demonstrated that exposure for the ADC and total antibody (TA) increased with dose, the relationship between AUC0-last and dose was greater than dose-proportional, while Cmax was linear. Free MMAE was highest at the 1.2 mg/kg dose level. Median Tmax values for ADC and TA were 1 h (end of infusion), and median Tmax for free MMAE was 25-169 h. In addition, elimination t1/2 values averaged 27-48 h, 31-68 h and 63-76 h for the ADC, TA, and MMAE, respectively. Conclusions: BC3195 exhibited favorable safety profile and PK characteristics up to 1.2mg/kg. Given BC31095’s safety and PK behavior, as well as preliminary activity at the 0.6 mg/kg dose level, patient enrollment at higher dose levels is ongoing. Clinical trial information: NCT05957471 .

Two stage, multi-center trial of cadonilimab and LM-302 for patients with CLDN18.2+ biliary tract cancer (BTC) that failed chemotherapy and PD-(L)1 antibody (ZSAB-Calm).

e16152 Background: BTC is a lethal disease with limited effective treatments, especially for those who have failed immune checkpoint inhibitors (ICIs) plus chemotherapy. Cadonilimab, a tetrameric bispecific antibody targeting PD-1 and CTLA-4, showed promising safety profile and efficacy in several malignant tumors. LM-302 is a novel antibody-drug conjugate targeting CLDN18.2, a tight junction protein expressed on the cell surface of many solid tumors, including BTC. Here, we present preliminary data on the safety and efficacy of cadonilimab plus LM-302 in CLDN18.2+ BTC patients (pts) with prior treatment of ICI and chemotherapy. Methods: This ongoing study is a multicenter, two-stage, randomized phase Ib/II clinical trial. In the dose-escalation phase, 6 pts (no requirement for CLDN18.2) are enrolled, using "3+3" design to determine the RP2D. Pts will receive LM302 (1.6mg/kg or 1.8mg/kg Q2W) and cadonilimab (6mg/kg Q2W). The expansion stage is expected to enroll 90 pts (CLDN18.2 + staining in ≥40% of tumor cells), randomized into 3 arms with 30 patients each. Arm 1: cadonilimab (6mg/kg Q2W), Arm 2: LM-302 (1.8mg/kg, Q2W), Arm 3: cadonilimab (6mg/kg Q2W) and LM-302 (RP2D). The primary endpoints are the safety (CTCAE 5.0) in phase 1b and ORR (RECIST1.1) in phase 2. The secondary endpoints include DCR, PFS, OS and safety. Results: A total of 18 pts were enrolled from Aug 4, 2023 to Jan 15, 2024. Median age was 62 (range: 42-79), 44% were male. 61% have intrahepatic cholangiocarcinoma. 78% pts with distant metastasis were diagnosed as stage IV. In the dose-escalation phase, 7 pts were enrolled. The first pt was discontinued after only one dose due to percutaneous transhepatic cholangiography and drainage catheter infection and gastrointestinal bleeding (unrelated to treatment). No DLTs were observed. 7 (100%) pts experienced TRAEs. The most common TRAEs were bilirubin increase (71.4%) thrombocytopenia (57.1%), neutropenia (57.1%), infusion reactions (rash) (42.9%), leukopenia (42.9%), anemia (28.6%). Only 2 pts had grade 3 TRAEs including anemia(1pt), neutropenia, leukopenia and rash (1pt). There was no grade≥4 TRAE. Of the 6 efficacy-evaluable pts, 3 pts(CLDN18.2 expression in 30%, 40%, 80%)achieved PR resulting in a BOR of 50% in Phase Ib. The RP2D for LM-302 was 1.8mg/kg. In expansion phase, 11 pts with CLDN18.2+ BTC were randomly enrolled. The median number of treatment cycles was 2 (range 1-8), with 4 pts each in Arm 1 and Arm 2, and 3 pts in Arm 3. Among the 11 pts, 5 (45.5%) occurred TRAEs, with 3 pts in Arm 3 and 2 pts in Arm 1. The most common TRAEs were neutropenia (18.2%), neutropenia (18.2%). Only 1 pt in Arm 3 experienced grade 3 neutropenia. One pt had a SAE of myocardial infarction (unrelated to treatment). Conclusions: Cadonilimab combined with LM-302 has manageable safety and promising antitumor activity in CLDN18.2+ BTC. Clinical trial information: NCT05994001 .

First-in-human study of ABBV-400, a novel c-Met–targeting antibody-drug conjugate, in advanced solid tumors: Results in colorectal cancer.

3515 Background: c-Met (MET protein) is frequently overexpressed in several advanced solid tumors including colorectal cancer (CRC). There are no approved therapies specific for c-Met–overexpressing tumors in CRC. The antibody-drug conjugate ABBV-400 comprises c-Met–targeting antibody telisotuzumab conjugated to a novel topoisomerase 1 inhibitor payload. A phase 1 study of ABBV-400 was initiated for adults with advanced solid tumors and progression on standard therapies (NCT05029882); results from dose escalation (ESC) at doses 1.6–6.0 mg/kg once every 3 weeks (Q3W) were previously presented and showed preliminary efficacy (Sharma et al. ASCO 2023. Abstract 3015). We present data from dose ESC and expansion (EXP) cohorts in CRC. Methods: During EXP, patients (pts) with CRC were randomized to receive ABBV-400 at 1.6, 2.4, or 3.0 mg/kg Q3W. Primary objectives were to evaluate the safety, tolerability, pharmacokinetics, preliminary efficacy, and the recommended phase 2 dose of ABBV-400. Results: As of Oct 2023, 122 pts (ESC: 29; EXP: 93) were included. Median age: 56 years; 65 (53%) males. Median prior treatments was 4. Follow-up was longer in ESC vs EXP (14.8 vs 3.8 months). Seventy-eight (64%) pts had a grade (G)≥3 treatment-emergent adverse event (TEAE); 41% had a serious TEAE. Most frequent hematologic TEAEs were anemia (52%; G≥3: 30%), neutropenia (37%; G≥3: 25%), leukopenia (25%; G≥3: 12%), and thrombocytopenia (23%; G≥3: 12%); nonhematologic TEAEs were nausea (57%, G≥3: 3%), fatigue (43%; G≥3: 2%), and vomiting (39%, G≥3: 4%). G≥3 diarrhea was < 1%. Unadjudicated interstitial lung disease/pneumonitis rate was 7% (G≥3: 2%). Treatment-related AEs leading to discontinuation occurred in 11 (9%) pts. Preliminary efficacy outcomes are shown in the Table. The majority of tissues expressed c-Met. In pts with higher c-Met expression, an increased ORR of > 30% was observed at efficacious doses (≥2.4 mg/kg). Activity was also seen at lower c-Met expression levels (10–15% ORR). Conclusions: ABBV-400 at 2.4 and 3.0 mg/kg Q3W has a tolerable and manageable safety profile, with promising antitumor activity. Long-term tolerability appears improved at 2.4 relative to 3.0 mg/kg, with higher relative dose intensity and generally lower TEAEs. The study is also evaluating ABBV-400 with bevacizumab in pts with CRC. Clinical trial information: NCT05029882 . [Table: see text]

Development of novel MUC1-C targeting antibody-drug conjugate for pancreatic cancer treatment.

e15025 Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive forms of cancers, which is usually diagnosed in advanced stages and presents an abysmal 5-year survival rate of 3-10%. With late detection of metastasized/advanced disease, curative surgery is not an option for most patients. Accordingly, there is an urgent unmet need for development of therapeutics targeting the pancreatic cancer cells. MUC1 is one such cell surface antigen that is aberrantly overexpressed in most solid tumors including pancreatic cancer. In this study we report preclinical efficacy of pharmacological inhibition of MUC1 signaling by GO-203 and targeted delivery of toxin conjugated to novel MUC1-C antibodies (7B8 and 3D1) binding to the extra cellular domain (ECD) to the PDAC xenografts. Methods: Subjects from TCGA-PAAD were stratified into high (75th percentile) and low (25th percentile) MUC1-expressing cohorts. Differential expression was performed using DESeq2, followed by GSEA, and signaling network analysis using partial correlation networks, ARACNE, and BC3NET. Anti-MUC1 antibody-drug conjugates (ADCs) were generated by coupling monomethyl auristatin E (3D1-MMAE, 7B8-MMAE) via V-C-PAB linker and characterized for anti-tumor activity against pancreatic cancer cells including MIA PaCa-1, CAPAN2 and HAPF-II. Paired-end RNA-seq (50bp) was aligned and quantified to the Human Ensembl GRC38 reference using STAR aligner. Subcutaneous xenografts were obtained in nude mice by injecting 5X106 HPAF-II tumor cells. Results: Differential expression, pathway, and network analyses revealed consistent dysregulation of cancer survival-related processes, and P53-related pathways in the cohort with increased MUC1 expression. The ADCs (DAR of ~3.5) exhibited efficient internalization in cancer cells and associated apoptotic cell death (Kds = 2 - 5nM). Pharmacological inhibition of MUC1 signaling by GO-203 demonstrated reduction in canonical pathways including P53 and EMT. Treatment with 3D1-MMAE compared to both vehicle and GO-203 showed dysregulation of cellular metabolism pathways (cholesterol homeostasis, glycolysis) and exhibited several strong indicators of cellular stress including activation of unfolded protein response processes and mTorc1 signaling. Excellent tumor-suppressive effects of ADCs were observed in HPAF-II xenografts in nude mice. The 7.5 mg/kg (i.v., q7dx3), treatment showed complete tumor regression from 14th day (end of treatment) till the date of termination (Day 50). Doses up to 40 mg/kg were well tolerated by the mice and this anti-tumor efficacy was observed without any appreciable loss in body weight or adverse effects on tissues. Conclusions: Targeted delivery of MMAE toxin to the pancreatic cancer cells presents an exciting opportunity for a novel therapeutic intervention for the treatment of pancreatic cancer patients with MUC1 over expression in tumors.

Adverse events of patients treated with antibody-drug conjugates in phase 1 clinical trials at the Royal Marsden Drug Development Unit from 2014 to 2024.

e15020 Background: Antibody-drug conjugates (ADCs) are designed to improve therapeutic indices of cytotoxic agents. Nevertheless, they may induce unexpected toxicities not observed with parent payloads. This study aimed to characterize the adverse events (AEs) seen in patients treated with ADCs in Phase 1 trials at The Royal Marsden Drug Development Unit (DDU). Methods: This is a retrospective cohort analysis of consecutive patients who received at least one dose of an ADC in a phase I trial from January 2014 to January 2024 at The Royal Marsden DDU. Descriptive statistics of patient characteristics, ADCs, and treatment-related AEs were performed. Univariate and multivariate logistic regression will be utilized to assess correlations among patient and ADC characteristics and adverse events. P values of < 0.05 will be considered significant. Results: A total of 131 patients who participated in twelve ADC trials were included. The median age of participants was 63 years (range: 31-84) and 61% were females. Patients received a median of three prior lines of systemic treatment. The most common type of ADC target, antibody, linker and payload were receptor tyrosine kinase (51%), humanized IgG monoclonal antibody (69%), valine-citrulline (VC) cleavable linker (85%), and a tubulin-binding payload (59%), respectively. Most patients received an ADC dose of 1-3 mg/kg (76%) with each cycle given once every 3 weeks (64%). The median number of cycles was 3 with an average treatment duration of 63 days. Within the cohort, 89% of patients developed any grade AE and 17% experienced grade 3 or higher AEs. The major treatment-related AEs were fatigue (48%), nausea/vomiting (27%), ocular toxicity (26%), neuropathy (26%), skin rash (20%) and pneumonitis (8%). The median time to first onset of treatment-related adverse events were 37 days for ocular toxicity, 46 days for pneumonitis, and 54 days for neuropathy. ADC-related AEs led to treatment interruptions (51%), dose reductions (13%), and treatment discontinuations (28%). Two treatment-related grade 5 events occurred. The objective response rate was 18%, with 1 complete response and 22 partial responses. Conclusions: Despite being designed to minimize side effects, ADCs were associated with significant toxicities, including unexpected adverse events unrelated to target, antibodies or the payloads, limiting their therapeutic indices. Further analysis of the relationship between different components of the wide range of ADCs and AEs are warranted to better understand the potential mechanisms of ADC toxicity.

Nectin-4 expression in primary breast cancer and associated clinical outcomes.

570 Background: Antibody-drug conjugates (ADC) selectively deliver chemotherapy to tumor cells expressing a target antigen. Currently approved ADCs in breast cancer target HER2 or Trop-2. Enfortumab vedotin, an ADC targeting Nectin-4, a cell adhesion molecule, is approved in advanced/metastatic urothelial cancer. This study evaluated the expression landscape of Nectin-4 in breast cancer and its association with clinical outcomes. Methods: Processed mRNAseq data was assessed for expression of the gene encoding Nectin-4 in primary breast cancer tissue and adjacent normal breast tissue from The Cancer Genome Atlas (TCGA), and normal tissue from the Genotype-Tissue Expression (GTEx) Project. Low gene expression was determined as <100 transcripts per million (TPM). TCGA samples had been annotated for putative copy-number alterations using GISTIC 2.0; genes with a score of 2 were marked as amplified. Multivariable Cox regression analysis was used to analyze the association of low vs medium/high gene expression with disease-free survival (DFS) and overall survival (OS), adjusting for age, stage, and subtype. Results: RNA-Seq data was available for 1086 patients with primary breast cancer, including known hormone receptor positive (HR+)/HER2- (n=530), HER2+ (n=112), and triple negative breast cancer (TNBC) (n=120). NECTIN4was amplified in 15% of cases (n=165): 15% (n=78) in HR+, 15% (n=17) in HER2+ and 21% (n=25) in TNBC. NECTIN4 expression was medium/high in 356 (33%) patients: 149 (28%) HR+/HER2- (median 77.8 TPM, IQR 50.1-116.5), 32 (29%) HER2+ (median 73.7 TPM, IQR 51.9-107.8), and 59 (49%) TNBC (median 99.7 TPM, IQR 57.8-148.3). Median expression in normal breast tissue was 47 TPM (TCGA) & 16.74 TPM (GTEx), and highest in normal skin at 205 TPM. In multivariable analysis, medium/high NECTIN4 expression was associated with worse OS (HR 1.96, 95% CI 1.32-2.99, p<0.001). As a continuous variable, increasing NECTIN4 expression levels were associated with worse OS. After correcting for age, stage and subtype, for each 10-unit increase in NECTIN4TPM, the risk of death increased by 5% (HR 1.0050, 95% CI 1.0028 - 1.0072, p < 0.001). Conclusions: NECTIN4 expression was higher in TNBC and associated with worse overall survival. The high expression level in normal skin possibly contributes to the cutaneous toxicity associated with enfortumab vedotin approval and requires careful consideration as ADCs targeting Nectin-4 are developed to target breast cancer.

9MW2821, a nectin-4 antibody-drug conjugate (ADC), in patients with advanced solid tumor: Results from a phase 1/2a study.

3013 Background: 9MW2821 is a monoclonal ADC that delivers monomethyl auristatin E to cells expressing Nectin-4. Nectin-4 is an adhesion molecule that highly expressed in variety of solid tumors, especially urothelial cancer (UC), cervical cancer (CC), esophageal cancer (EC) and breast cancer. Here we report the updated safety and efficacy data of 9MW2821. Methods: 9MW2821 was administered by intravenous infusion at doses of 0.33-1.5mg/kg on days 1, 8 and 15 of each 28-day cycle. The study included dose escalation, dose expansion and cohort expansion period which included UC, CC, EC, triple negative breast cancer (TNBC) and other Nectin-4 positive solid tumors that progressed after ≥1 systemic treatments (Tx). Primary objectives were assessment of safety and preliminary efficacy. Results: As of Jan 15, 2024, 260 patients (pts) were enrolled with doses ranging from 0.33 to 1.5mg/kg. Only 1 out of 6 pts in 1.5mg/kg group had dose limiting toxicity (grade 4 neutropenia lasted more than 5 days). The maximum tolerated dose was not reached up to 1.5mg/kg and the RP2D was selected as 1.25mg/kg for tolerance. 240 pts were enrolled at dose of 1.25mg/kg. The most common TRAEs of 1.25mg/kg dose group (≥20%, all grade/≥5%, ≥G3) were white blood cell (WBC) count decreased (50.8%, 23.3%), neutrophil count decreased (46.3%, 27.9%), anemia (43.8%, 8.3%), aspartate aminotransferase increased (42.1%, 2.9%), alanine aminotransferase increased (35.4%, 2.1%), asthenia (32.1%, 2.9%), rash (30.0%, 5.0%), decreased appetite (28.8%, 1.3%), nausea (26.7%, 0%), hyperglycemia (25.4%, 2.1%), platelet count decreased (24.2%, 4.6%), alopecia (24.2%, 0%), hypoaesthesia (22.5%, 1.7%), constipation (21.3%, 0%), vomiting (20.9%, 1.3%), hypertriglyceridemia (20.4%, 2.1%), gamma-glutamyltransferase increased (15.8%, 5.4%). Among 190 pts treated with 9MW2821 at 1.25mg/kg or above and reached tumor assessment, objective response rate (ORR) and disease control rate (DCR) was 35.3% and 78.4%, respectively. 37 UC pts, 45 CC pts, 27 EC pts and 16 TNBC pts were enrolled at 1.25mg/kg and evaluable for tumor assessment. Median prior lines of Tx were 2 (range, 1-4). All UC, 51% CC and 93% EC pts progressed after platinum-based chemotherapy and immune checkpoint inhibitors, respectively. Objective responses were also observed in pts with other solid tumor types. Conclusions: The data indicated encouraging efficacy of 9MW2821 in advanced UC, CC, EC and TNBC. 9MW2821 is the first Nectin-4 targeting ADC showed antitumor activity in patients with CC, EC and TNBC. The safety profile showed adequate tolerability. Clinical trial information: NCT05216965 . [Table: see text]

Targeting CD19-positive lymphomas with the antibody-drug conjugate loncastuximab tesirine: preclinical evidence as single agent and in combination therapy.

Antibody-drug conjugates (ADCs) represent one of the most successful therapeutic approaches introduced in clinical practice in the last few years. Loncastuximab tesirine (ADCT-402) is a CD19 targeting ADC, in which the antibody is conjugated through a protease cleavable dipeptide linker to a pyrrolobenzodiazepine (PBD) dimer warhead (SG3199). Based on the results of a phase 2 study, loncastuximab tesirine was recently approved for adult patients with relapsed/refractory large B-cell lymphoma. We assessed the activity of loncastuximab tesirine using in vitro and in vivo models of lymphomas, correlated its activity with CD19 expression levels, and identified combination partners providing synergy with loncastuximab tesirine. Loncastuximab tesirine was tested across 60 lymphoma cell lines. Loncastuximab tesirine had strong cytotoxic activity in B-cell lymphoma cell lines. The in vitro activity was correlated with CD19 expression level and intrinsic sensitivity of cell lines to the ADC's warhead. Loncastuximab tesirine was more potent than other anti-CD19 ADCs (coltuximab ravtansine, huB4-DGN462), albeit the pattern of activity across cell lines was correlated. Loncastuximab tesirine activity was also largely correlated with cell line sensitivity to R-CHOP. Combinatorial in vitro and in vivo experiments identified the benefit of adding loncastuximab tesirine to other agents, especially BCL2 and PI3K inhibitors. Our data support the further development of loncastuximab tesirine as a single agent and in combination for patients affected by mature B-cell neoplasms. The results also highlight the importance of CD19 expression and the existence of lymphoma populations characterized by resistance to multiple therapies.