With an increasing number of antibody-drug conjugates (ADC) being approved and commercially available for the treatment of patients with cancer and hematological malignancies, the interest in advancing, even more, ADCs is rapidly increasing. This year, during the virtual meeting of the virtual annual meeting of the American Society of Clinical Oncology (ASCO), investigators presented major updates. An overview.
Researchers at BrickBio (Woburn, MA) investigated the feasibility of efficiently incorporating an azide-containing unnatural amino acids (UAAs) into full-length antibody at different sites and facilitate site-specific functionalization. UAAs can add to the chemical diversity of a protein, allowing scientists to create proteins with novel functions. The purpose of this approach is to develop a facile scale-up compatible route to generate precise antibody-drug conjugates with fine-tuned therapeutic properties. In their study, the investigators specifically engineered multiple variants of trastuzumab to contain UAAs, enabling site-specific attachment of cytotoxic payloads, such as MMAE/MMAF, via click chemistry to generate ADCs with homogeneous DARs. 
Using this approach, BrickBio’s ADCs exhibit high therapeutic efficacy against HER2+ cell lines in vitro as well as in mouse xenograft models. Furthermore, the resulting homogenous ADCs outperform traditional antibody-conjugation technologies that lack site-specificity or site-selectivity.
The investigators concluded that the ability to systematically vary the attachment topology between the drug and the antibody is a major advantage of this approach. Preliminary data seems to suggest that such variation affects the performance of the ADC.
ADCs using BrickBio’s proprietary technology are currently in the preclinical development
First-in-human study of MGC018
Investigators at MacroGenics presented updated results from MG018, the company’s investigational ADC with a duocarmycin payload linked to an anti-B7-H3 mAb. The study, designed to evaluates safety, dose-limiting toxicities (DLT), and maximum tolerated dose (MTD) of MGC018 in a dose-escalation 3+3+3 design as well as pharmacokinetics, immunogenicity, and tumor response using RECIST v1.1 enrolled 20 patients.
The investigators observed one 1 treatment-related adverse event (TRAE) in 16 participating patients (80.0%). The most common TRAEs were neutropenia/decreased neutrophil count (35%); fatigue, lymphopenia/decreased lymphocyte count (30.0%); palmar plantar erythrodysaesthesia (PPE), skin hyperpigmentation (25.0%); pruritis, nausea, chills, infusion-related reaction (20.0%); and vomiting, pyrexia, maculopapular rash (15.0%).
A total of eleven patients (55.0%) experienced TRAEs ≥ Grade 3 which included decreased lymphocyte count/lymphopenia (n = 6), decreased neutrophil count/neutropenia (n = 3), PPE (n = 2), and maculopapular rash (n = 2). Furthermore, the investigators observed serious adverse events in patients (pneumonitis in a patient with concurrent bacterial pneumonia, non-infectious gastroenteritis, and stasis dermatitis in a patient with chronic venous insufficiency and one DLT (Grade 4 neutropenia). However, no febrile neutropenia was observed.
Target lesion decrease was noted in 1 patient each with small cell lung cancer (-6.3%), non-small cell lung cancer (-23.8%), and metastatic castrate-resistant prostate cancer (mCRPC) (-29.4%) with PSA change from 82.8 ng/ml to 57.1 ng/ml. One patient diagnosed with mCRPC with bone-only disease had substantial improvement in bone scans and a PSA decrease from 60 ng/ml to 4.7 ng/ml.
The observed results demonstrated an overall manageable safety profile with early evidence of clinical activity. Continued dose escalation and clinical investigation of MGC018 is ongoing. 
ALT-P7 is an antibody-drug conjugate that conjugates monomethyl auristatin E (MMAE) site-specifically to a cysteine-containing peptide motif of trastuzumab variant. Investigators studied this novel ADC in a first-in-human, open-label, 3+3 dose-escalation phase I trial to evaluate the safety and pharmacokinetics of the drug in patients with HER2-positive advanced breast cancer who had at least received two kinds of prior anti-HER2 treatment.
ALT-P7, being developed by South Korean based Alteogen, was administered at doses 0.3mg/kg to 4.8mg/kg once every 3 weeks (Q3W). The investigators evaluated dose-limiting toxicities over the first cycle of 21 days. The primary objective of the study was to define the maximum tolerated dose (MTD).
Between January 2018 and February 2020 the study enrolled 27 patients (n=4 at 0.3mg/kg, n=3 at each of 0.6, 1.2, 2.4, 3.6, 4.2, 4.5 mg/kg, n=5 at 4.8mg/kg). Patients had received, on average six previous lines of systemic therapy, including median four prior anti-HER2 agents. The most commonly observed adverse events included grade 3/4 neutropenia (n=4). Other common drug-related AEs of all grades were myalgia (n=9), fatigue (n=7), sensory neuropathy (n=6), alopecia (n=6), pruritus (n=6), and neutropenia (n=6). Dose-limiting toxicities were observed in three patients at 4.8mg/kg (febrile neutropenia, thrombocytopenia, hyperbilirubinemia, myalgia, hyponatremia). However, the investigators did not observe DLTs up to 4.2mg/kg, and safety evaluation at 4.5mg/kg is currently ongoing.
After 6 weeks of treatment, the investigators observed a disease control rate of 77.3% (17/22). A partial response was achieved in two out of fifteen patients with measurable lesions. The median PFS at doses from 2.4 to 4.8mg/kg was 6.2 months (95% CI 2.5-9.9 months).
Based on these results, the investigators demonstrated that ALT-P7 to be well tolerated at a dose of 4.2mg/kg in heavily pretreated HER2-positive advanced breast cancer, warranting further evaluation in a phase II trial.
AbGn-107, being developed by AltruBio (Abgenomics), is an ADC directed against AG-7 antigen, a Lewis A-like glycol-epitope expressed in 24-61% of gastric, colorectal, pancreatic, and biliary cancers hs demonstrated promising antitumor activity in both in vitro and in vivo preclinical studies. Based on these results, the investigators performed a Phase Ia trial using a standard 3+3 dose escalation in heavily pretreated patients with GI malignancies with ECOG PS 0-1. The investigators tested 2 dosing intervals in which the trial drug was dosed Q4W (at doses ranging from 0.1-1.2 mg/kg) and Q2W (at doses from 0.8-1.0 mg/kg). In this study, dose-limiting toxicities (DLTs) were based on grade 3/4 hematologic and non-hematological adverse events occurring during the initial 4-week treatment window.
The participating patients were treated until disease progression or unacceptable toxicity, with tumor assessments Q8W. The study, which included 35 patients enrolled across 6 dose levels, demonstrated that that appears well-tolerated with encouraging prelim signs of efficacy in unselected patients with heavily pre-treated advanced GI cancers.
The study results presented at the 2020 virtual ASCO meeting demonstrated that AbGn-107 to be well-tolerated with encouraging preliminary signs of efficacy in unselected patients with heavily pre-treated advanced GI cancers.
This year, KLUS Pharm, a subsidiary of Sichuan Kelun Pharmaceutical (Sichuan Chengdu, China)* presented updated data from SKB264, the company’s a third-generation antibody-drug conjugate (ADC) targeting trophoblast cell surface antigen 2 (TROP2) during 2020 virtual ASCO meeting.
SKB264 includes a moderately potent, belotecan-derived, topoisomerase I inhibitor, site-specific conjugation, and highly stable chemical linkers. Preclinical in vivo studies of SKB264 showed similar or better safety and efficacy results when compared to sacituzumab govitecan. These studies confirmed significant anti-tumor activity in animal models of breast cancer, gastric cancer, lung cancer, and colorectal cancer with overexpression of TROP2. Preclinical studies also confirmed SKB264 to be well tolerated with a good safety profile.
SKB264 has received U.S. FDA IND clearance to start Phase I clinical trials in the United States. In and in Apil 2020 the KLUS Pharma’s parent company also received the green light from the National Medical Products Administration (NMPA) to conduct clinical studies for SKB264 in solid tumors in China.
The company’s first-in-human open-label, Phase I-II clinical trial in which SKB264 will be studied as monotherapy in patients who have a locally advanced unresectable or metastatic solid tumor that is refractory to all standard therapies, is currently recruiting patients in both the United States and China, open for patients with locally advanced and/or metastatic solid tumors who are refractory to available standard therapies.
This study, which is divided into 2 parts, is designed to establish the safety profile, define MTD and/or the RP2D, and characterize DLTs of the investigational agent. The dose-escalation and MTD identification will be based on a Bayesian logistic regression model (BLRM) with overdose control. The second part of the study is designed to evaluate the efficacy and obtain clinical activity data of SKB264 as monotherapy at the RP2D.
A166 (KLUS Pharm) is an ADC targeting HER2, developed by conjugating trastuzumab via a stable protease-cleavable valine citrulline (Val-Cit) linker to a novel auristatin-based payload for the treatment HER2-positive solid tumors.
Results from a single-arm, open-label, multicenter, dose-escalating phase I clinical trials conducted in the United States and China showed that the investigational drug was well tolerated at 4.8 mg/kg. The Disease Control Rate (DCR) reached 100% in patients with HER2+ breast cancer.
Dose escalation and MTD identification were directed using a Bayesian logistic regression model with overdose control.
Results from the study, which included 35 patients, confirmed an overall acceptable toxicity profile with no unexpected toxicities related to the study drug. The investigators did not observe adverse events meeting the protocol-specified definition of dose-limiting toxicity at any studied dose level (0.3, 1.2, 3.6, 4.8 mg/kg).
The most frequently occurring treatment-related adverse events (≥10%) included Keratitis, decreased appetite, dry eye, and blurred vision blurred. The incidence of ophthalmic toxicities in the 3.6 mg/kg cohort was 80% and in the 4.8 mg/kg cohort it was 83%.
Finally, among the 27 patients evaluable for efficacy, the best response was a progression of disease in 11 patients (41%), stable disease in 9 patients (33%), and partial response in 7 patients (26%), for the total disease control rate of 59%. Responses were seen only at the dose levels of 3.6 mg/kg and 4.8 mg/kg.
Based on these promising, clinically meaningful results in heavily pretreated patients with relapsed or refractory advanced solid cancers, investigators are expected to initiate a Phase II clinical study by the end of 2020.
MGC018 With or Without MGA012 in Advanced Solid Tumors – NCT03729596
A Study to Investigate the Efficacy and Safety of Two Doses of GSK2857916 in Participants With Multiple Myeloma Who Have Failed Prior Treatment With an Anti-CD38 Antibody – NCT03525678
To Evaluate Safety, Tolerability, and Clinical Activity of the Antibody-drug Conjugate, GSK2857916 Administered in Combination With Lenalidomide Plus Dexamethasone (Arm A), or in Combination With Bortezomib Plus Dexamethasone (Arm B) in Participants With Relapsed/Refractory Multiple Myeloma (RRMM) – NCT03544281
Clinica trials: A Study of AbGn-107 in Patients With Gastric, Colorectal, Pancreatic or Biliary Cancer – NCT02908451
Phase I-II, FIH, TROP2 ADC, Advanced Unresectable/Metastatic Solid Tumors, Refractory to Standard Therapies (A264) – NCT04152499
Study of A166 in Patients With Relapsed/Refractory Cancers Expressing HER2 Antigen or Having Amplified HER2 Gene – NCT03602079
* Sichuan Kelun Pharmaceutical acquired KLUS Pharma in 2016 for U.S. $ 12.82 million.
 Italia J. A site-specific approach to improved antibody-drug conjugates. J Clin Oncol 38: 2020 (suppl; Abstr e13009); 10.1200/JCO.2020.38.15_suppl.e13009
 Powderly JD, Jang S, Lohr J, Spira AI, Bohac GC, Sharma M. Preliminary dose escalation results from a phase I/II, first-in-human study of MGC018 (anti-B7-H3 antibody-drug conjugate) in patients with advanced solid tumors. J Clin Oncol 38: 2020 (suppl; abstract 3071); 10.1200/JCO.2020.38.15_suppl.3071 [Abstract]
 Ko AH, Coveler AL, Schlechter BL, Bekaii-Saab TS, Wolpin BM, Clark JW, Bockorny B, et al. Phase I, first-in-human study of AbGn-107, a novel antibody-drug conjugate (ADC), in patients with gastric, colorectal, pancreatic or biliary cancers. J Clin Oncol 38: 2020 (suppl; Abstract e16771) 10.1200/JCO.2020.38.15_suppl.e16771 [Abstract]
 Yongheng Liu, Wei Lian, Xi Zhao, Yina Diao, Jian Xu, Liang Xiao, Yan Qing, Tongtong Xue, Jingyi Wang. SKB264 ADC: A first-in-human study of SKB264 in patients with locally advanced unresectable/metastatic solid tumors who are refractory to available standard therapies. J Clin Oncol 38: 2020 (suppl; abstr TPS3659). 10.1200/JCO.2020.38.15_suppl.TPS3659 [Abstract]
 Yongheng Liu, Wei Lian, Xi Zhao, Wei Qi, Jian Xu, Liang Xiao, Yan Qing, Tongtong Xue, Jingyi Wang. A first-in-human study of A166 in patients with locally advanced/metastatic solid tumors which are HER2-positive or HER2-amplified who did not respond or stopped responding to approved therapies. J Clin Oncol 38: 2020 (suppl; abstract 1049); 10.1200/JCO.2020.38.15_suppl.1049 [Abstract]