Reversible HER2 antibody-drug conjugate–induced ocular toxicity

Sharma, Asha; Riaz, Kamran M.; Gill, Mohsain; Patnaik, Amita; Ulahannan, Susanna; Wang, Judy S.; Gombos, Dan S.; Ang, Qiuqing; Cicic, Dragan; Bergonio, Gregory; Zhang, Cong; Wirostko, Barbara

doi:10.1016/j.jcjo.2021.02.028

Cited by 12 publications

(5 citation statements)

References 23 publications

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“…Using this strategy, A166-induced corneal epitheliopathy was generally well managed and reversible in our patients (Supplementary Fig. 3), which was further supported by a report in American patients by Sharma et al 21 . As previously reported, ocular surface AEs occurred more often in ADCs with auristatin-F or maytansinoid DM4 as the payload (i.e., belantamab mafodotin) and conventional tubulin-binding chemotherapeutic agents (i.e., docetaxel and paclitaxel) [22][23][24][25][26][27] .…”

Section: Discussionsupporting

confidence: 90%

Phase I study of A166, an antibody‒drug conjugate in advanced HER2-expressing solid tumours

et al. 2023

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In this phase I study, the safety, pharmacokinetics, and antitumour activity of the HER2-targeted antibody–drug conjugate A166 were evaluated in patients with HER2-expressing advanced solid tumours. Patients with advanced solid tumours refractory to standard therapies received A166 at doses of 0.1, 0.3, 0.6, 1.2, 2.4, 3.6, 4.8 or 6.0 mg/kg Q3W in a standard “3 + 3” design. Dose cohorts were expanded at 4.8 and 6.0 mg/kg Q3W. Primary endpoints were assessment of the safety and tolerability of A166 and identification of the maximum tolerated dose or recommended phase II dose. In total, 81 patients were enroled and received A166 (n = 1 for 0.1 mg/kg; n = 3 for each of 0.3, 0.6, 1.2, 2.4 and 3.6 mg/kg doses; n = 27 for 4.8 mg/kg; n = 38 for 6.0 mg/kg). No dose-limiting toxicity or drug-related deaths occurred. The most common treatment-related adverse events at grade 3 or higher were corneal epitheliopathy (30.9%), blurred vision (18.5%), dry eyes (7.4%), and peripheral sensory neuropathy (6.2%). The Cmax and area under the curve of Duo-5, its free payload, were approximately 0.1% and 0.2% of those of the ADC, respectively. For all assessable HER2-positive breast cancer patients enroled in the 4.8 mg/kg and 6.0 mg/kg cohorts, the corresponding ORRs were 73.9% (17/23) and 68.6% (24/35), respectively, and the median PFS was 12.3 and 9.4 months, respectively. A166 has a recommended phase II dose of 4.8 mg/kg Q3W, manageable toxicity, good stability in the circulation and promising antitumour activities in HER2-positive breast cancer patients.

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Section: Discussionsupporting

confidence: 90%

Phase I study of A166, an antibody‒drug conjugate in advanced HER2-expressing solid tumours

et al. 2023

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“…In addition, unplanned visits were encouraged in the protocol in case ocular symptoms appeared or deteriorated. Using this strategy, A166 induced corneal epitheliopathy was generally well managed and reversible in our patients (Figure S2), which was further supported by a report in American patients by Sharma et al 17 As previously reported, ocular surface AEs occurred more often in ADCs with auristatin-F or maytansinoid DM4 as the payload (i.e., Belantamab mafodotin) and conventional tubulin-binding chemotherapeutic agents (i.e., docetaxel and paclitaxel). [18][19][20][21][22][23] In our trial, the percentages of ocular AEs of grade 1, 2, 3, 4 and 5 at the most severity in 4.8 mg/kg cohort were 33.3%, 22.2%, 44.4%, 0% and 0%, respectively, which is in the similar range to the corresponding 8%, 17%, 45%, 1% and 0% reported for FDA-approved 2.5 mg/kg Belantamab mafodotin for 95 patients with multiple myeloma.…”

Section: Discussionsupporting

confidence: 89%

Phase I Study of A166, a Novel Antibody-Drug Conjugate in Advanced HER2-expressing Solid Tumors

Zhang²,

Liu

et al. 2022

Preprint

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Purpose: In this phase I study, the safety, pharmacokinetics, and antitumor activity of a novel HER2 targeted antibody–drug conjugate A166 were evaluated in patients with HER2-expressing advanced solid tumors. Experimental Design: Patients received A166 at doses of 0.1, 0.3, 0.6, 1.2, 2.4, 3.6, 4.8, or 6.0 mg/kg Q3W. Results: In total, 81 patients who had progressed on standard treatment were enrolled. No dose-limiting toxicity was observed. The most common treatment-related adverse events at grade 3 or higher were corneal epitheliopathy (30.9%), blurred vision (18.5%), dry eyes (7.4%), and peripheral sensory neuropathy (6.2%). The Cmax and area under curve of Duo-5, its free payload, were about 0.1% and 0.2% of those of the ADC, respectively. For all assessable HER2-positive breast cancer patients enrolled in 4.8 mg/kg and 6.0 mg/kg cohorts, corresponding ORR was 73.9% (17/23) and 68.6% (24/35), respectively; and median PFS was 12.3 and 9.4 months, respectively. Conclusions: A166 had a recommended phase II dose of 4.8 mg/kg, manageable toxicity, good stability in the circulation and promising antitumor activities in HER2-positive breast cancer patients. Trial registration: CTR20181301 (www.chinadrugtrials.org.cn)

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“…Previous studies of anti-HER2 monoclonal antibodies have reported blurred vision as an adverse event ( Papageorgiou et al, 2021 ; Sterenczak et al, 2021 ). Some studies have attributed this symptomatology to corneal lesion development, mostly reversible ( Kreps et al, 2018 ; Deklerck et al, 2019 ; Sharma et al, 2021 ). Corneal nerves are part of the peripheral nervous system, and peripheral neuropathy was observed as a common adverse reaction (>30%) in the FDA’s approval of Perjeta ® ( Blumenthal et al, 2013 ; Howie et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

A randomized, double-blind, parallel control study to evaluate the biosimilarity of QL1209 with Perjeta® in healthy male subjects

Sun

Yang

et al. 2022

Front. Pharmacol.

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Purpose: This is the first study to compare the pharmacokinetics, safety and, immunogenicity of QL1209, a biosimilar of Perjeta®.Methods: This study was a randomized, double-blind, parallel-controlled clinical trial evaluating the biosimilarity between QL1209 (specification: 420 mg:14 ml, single use via, manufacturer: Qilu Pharmaceutical Co., Ltd., batch number: 201808001KJL) and Perjeta® (specification: 420 mg: 14 ml, single use via, manufacturer: Roche Pharma AG, batch number: H0309H02). The trial period was 99 days (blood samples for PK were collected 99 days after infusion). Serum concentrations were determined using a validated assay. PK parameters were calculated using a non-compartmental model and analyzed statistically. Anti-drug antibody (ADA)-positive samples were further tested for the presence of neutralization antibody detection (NAb).Results: A total of 137 healthy subjects were administrated. The subjects were randomized 1:1 to receive QL1209 or Perjeta® 420 mg intravenously. The geometric mean ratio (GMRs) for QL1209 versus Perjeta® are 104.14%, 104.09%, and 110.59% for Cmax, AUC0-t, and AUC0-∞, respectively, and their 90% confidence interval (CIs) all fell within the predefined bioequivalence margin 80.00–125%. The incidence of drug-related adverse events was 95.6% and 95.5% in the QL1209 and Perjeta® groups, respectively, also comparable between the two groups.Conclusion: The results of this comparative clinical pharmacology study demonstrated the PK similarity of QL1209 (420 mg: 14 ml) and Perjeta® (420 mg: 14 ml) and there was no significant difference in safety and immunogenicity between QL1209 and Perjeta® manufactured by Roche Pharma AG.

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Reversible HER2 antibody-drug conjugate–induced ocular toxicity

Cited by 12 publications

References 23 publications

Phase I study of A166, an antibody‒drug conjugate in advanced HER2-expressing solid tumours

Phase I study of A166, an antibody‒drug conjugate in advanced HER2-expressing solid tumours

Phase I Study of A166, a Novel Antibody-Drug Conjugate in Advanced HER2-expressing Solid Tumors

A randomized, double-blind, parallel control study to evaluate the biosimilarity of QL1209 with Perjeta® in healthy male subjects

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