Safety, Efficacy, and Pharmacokinetics of SHR-A1811, a Human Epidermal Growth Factor Receptor 2-Directed Antibody-Drug Conjugate, in Human Epidermal Growth Factor Receptor 2-Expressing or Mutated Advanced Solid Tumors: A Global Phase I Trial.

Yao H ，Yan M ，Tong Z ，Wu X ，Ryu MH ，Park JJ ，Kim JH ，Zhong Y ，Zhao Y ，Voskoboynik M ，Yin Y ，Liu K ，Kaubisch A ，Liu C ，Zhang J ，Wang S ，Im SA ，Ganju V ，Barve M ，Li H ，Ye C ，Roy AC ，Bai LY ，Yen CJ ，Gu S ，Lin YC ，Wu L ，Bao L ，Zhao K ，Shen Y ，Rong S ，Zhu X ，Song E ... -  《-》

Trastuzumab deruxtecan in patients with metastatic non-small-cell lung cancer (DESTINY-Lung01): primary results of the HER2-overexpressing cohorts from a single-arm, phase 2 trial.

DESTINY-Lung01 is a multicentre, open-label, phase 2 study evaluating the antitumour activity and safety of trastuzumab deruxtecan, a HER2-directed antibody-drug conjugate, in patients with HER2-overexpressing or HER2 (ERBB2)-mutant unresectable or metastatic non-small-cell lung cancer (NSCLC). The results of the HER2-mutant cohort (cohort 2) have been reported elsewhere. Herein, we report the primary analysis of cohorts 1 and 1A, which aimed to evaluate the activity and safety of trastuzumab deruxtecan 5·4 mg/kg and 6·4 mg/kg in patients with HER2-overexpressing NSCLC. Patients aged 18 years or older with unresectable or metastatic (or both unresectable and metastatic) non-squamous NSCLC who had relapsed following or were refractory to standard treatment or for whom no standard treatment was available, with an HER2 immunohistochemistry score of 3+ or 2+ (without known HER2 mutations) and an Eastern Cooperative Oncology Group performance status score of 0 or 1, were enrolled at 20 specialist hospitals in France, Japan, the Netherlands, Spain, and the USA. Patients were assigned to cohorts sequentially, first to cohort 1, to receive trastuzumab deruxtecan 6·4 mg/kg (cohort 1), then to cohort 1A, to receive trastuzumab deruxtecan 5·4 mg/kg, both administered intravenously once every 3 weeks. The primary endpoint was confirmed objective response rate by independent central review and was assessed in the full analysis set, which included all patients who signed an informed consent form and were enrolled in the study. Safety was assessed in all enrolled patients who received at least one dose of trastuzumab deruxtecan. This trial is registered with ClinicalTrials.gov, NCT03505710, and is ongoing (closed to recruitment). Between Aug 27, 2018, and Jan 28, 2020, 49 patients were enrolled in cohort 1 (median age 63·0 years [IQR 58·0-68·0], 30 [61%] male, 19 [39%] female, and 31 [63%] White), and from June 16 to Dec 9, 2020, 41 patients were enrolled in cohort 1A (median age 62·0 years [IQR 56·0-66·0], 22 [54%] male, 19 [46%] female, and 31 [76%] White). As of data cutoff (Dec 3, 2021), the median treatment duration was 4·1 months (IQR 1·4-7·1) in cohort 1 and 5·5 months (1·4-8·7) in cohort 1A, and median follow-up was 12·0 months (5·4-22·4) in cohort 1 and 10·6 months (4·5-13·5) in cohort 1A. Confirmed objective response rate by independent central review was 26·5% (95% CI 15·0-41·1; 13 of 49, all partial responses) in cohort 1 and 34·1% (20·1-50·6; 14 of 41; two complete responses and 12 partial responses) in cohort 1A. The most common treatment-emergent adverse events of grade 3 or worse were neutropenia (12 [24%] of 49 in cohort 1, none in cohort 1A), pneumonia (six [12%] and two [5%], respectively), fatigue (six [12%] and three [7%], respectively), and disease progression (six [12%] and four [10%], respectively). Drug-related treatment-emergent adverse events of grade 3 or worse occurred in 26 (53%) of 41 patients in cohort 1 and nine (22%) of 49 patients in cohort 1A. Drug-related serious adverse events were reported in ten (20%) patients and three (7%) patients, respectively. Deaths due to treatment-emergent adverse events occurred in ten (20%) patients in cohort 1 (disease progression in six (12%) patients and bronchospasm, hydrocephalus, respiratory failure, and pneumonitis in one [2%] patient each), and in seven (17%) patients in cohort 1A (due to disease progression in four (10%) patients and dyspnoea, malignant neoplasm, and sepsis in one (2%) patient each). One death due to a treatment-emergent adverse event was determined to be due to study treatment by the investigator, which was in cohort 1 (pneumonitis). Independent adjudication of interstitial lung disease or pneumonitis found that drug-related interstitial lung disease or pneumonitis occurred in ten (20%) patients in cohort 1 (two [4%] grade 1, five [10%] grade 2, and three [6%] grade 5) and two (5%) patients in cohort 1A (one [2%] grade 2 and one [2%] grade 5). An additional patient in cohort 1A had grade 4 pneumonitis after the data cutoff, which was subsequently adjudicated as drug-related grade 5 interstitial lung disease or pneumonitis. Given the low antitumour activity of existing treatment options in this patient population, trastuzumab deruxtecan might have the potential to fill a large unmet need in HER2-overexpressing NSCLC. Our findings support further investigation of trastuzumab deruxtecan in patients with HER2-overexpressing NSCLC. Daiichi Sankyo and AstraZeneca.

Smit EF ，Felip E ，Uprety D ，Nagasaka M ，Nakagawa K ，Paz-Ares Rodríguez L ，Pacheco JM ，Li BT ，Planchard D ，Baik C ，Goto Y ，Murakami H ，Saltos A ，Pereira K ，Taguchi A ，Cheng Y ，Yan Q ，Feng W ，Tsuchihashi Z ，Jänne PA ... -  《-》

Trastuzumab rezetecan, a HER2-directed antibody-drug conjugate, in patients with advanced HER2-mutant non-small-cell lung cancer (HORIZON-Lung): phase 2 results from a multicentre, single-arm study.

Trastuzumab rezetecan (also known as SHR-A1811) is a novel antibody-drug conjugate consisting of a humanised HER2-directed monoclonal antibody, cleavable tetrapeptide-based linker, and DNA topoisomerase I inhibitor. In the phase 1 portion of this phase 1/2 study, trastuzumab rezetecan showed preliminary anti-tumour activity and a favourable safety profile in patients with HER2-mutant non-small-cell lung cancer (NSCLC). We present phase 2 results from the study, which aimed to further evaluate the activity and safety of trastuzumab rezetecan at the recommended dose. In this multicentre, single-arm, phase 2 trial, conducted in 35 hospitals in China, we recruited patients aged 18-75 years, with locally advanced or metastatic NSCLC with an activating HER2 mutation and an Eastern Cooperative Oncology Group performance status score of 0-1, who had disease progression after or were intolerant to platinum-based chemotherapy and anti-PD-1 treatment or anti-PD-L1 treatment. Trastuzumab rezetecan was administered at 4·8 mg/kg intravenously once every 3 weeks. The primary endpoint was objective response rate assessed by an independent review committee in patients who received at least one cycle of study treatment. All patients who received at least one cycle of study treatment were included in safety analyses. This study is registered with ClinicalTrials.gov, NCT04818333, and is ongoing but not recruiting. Between April 14, 2023, and Dec 14, 2023, 94 patients were enrolled and treated. 42 (45%) patients were male, 52 (55%) female, 92 (98%) were Han Chinese, and two (2%) were other ethnicity Chinese. At data cutoff (June 14, 2024), the median duration of follow-up was 8·7 months (IQR 7·0-10·4). 69 (73%; 95% CI 63·3-82·0) of 94 patients had a confirmed objective response, as assessed by independent review committee. The most common grade 3-4 treatment-related adverse events were decreased neutrophil count (38 [40%] patients), decreased white blood cell count (25 [27%]), anaemia (22 [23%]), decreased platelet count (10 [11%]), and decreased lymphocyte count (seven [7%]). Treatment-related serious adverse events occurred in 22 (23%) patients, which were decreased platelet count (six [6%]), decreased neutrophil count (six [6%]), interstitial lung disease (five [5%]), decreased white blood cell count (four [4%]), anaemia (four [4%]), vomiting (three [3%]), pneumonia (three [3%]), hyponatraemia (two [2%]), and pyrexia (one [1%]), small intestinal obstruction (one [1%]), nausea (one [1%]), and chronic obstructive pulmonary disease (one [1%]). There were no treatment-related deaths. Trastuzumab rezetecan showed clinically meaningful activity and manageable safety in patients with previously treated HER2-mutant NSCLC. Further trials are justified. Jiangsu Hengrui Pharmaceuticals, National Multi-disciplinary Treatment Project for Major Diseases, Collaborative Innovation Center for Clinical and Translational Science by the Ministry of Education & Shanghai. For the Chinese translation of the abstract see Supplementary Materials section.

Li Z ，Wang Y ，Sun Y ，Wang L ，Li X ，Sun L ，He Z ，Yang H ，Wang Y ，Wang Q ，Song Z ，Hong W ，Wang Y ，Xia G ，Yu Y ，Peng M ，Song Y ，Wang D ，Meng R ，Fang J ，Luo Y ，Liang W ，Hu S ，Wang Z ，Song K ，Li Y ，Yang L ，Shi W ，Lu S ... -  《-》

A phase Ia study of a novel anti-HER2 antibody-drug conjugate GQ1001 in patients with previously treated HER2 positive advanced solid tumors.

A novel anti-human epidermal growth factor receptor 2 (HER2) antibody-drug conjugate (ADC) GQ1001 was assessed in patients with previously treated HER2 positive advanced solid tumors in a global multi-center phase Ia dose escalation trial. In this phase Ia trial, a modified 3 + 3 study design was adopted during dose escalation phase. Eligible patients were enrolled, and GQ1001 monotherapy was administered intravenously every 3 weeks. The starting dose was 1.2 mg/kg, followed by 2.4, 3.6, 4.8, 6.0, 7.2 and 8.4 mg/kg. Extra patients were enrolled into 6.0, 7.2, and 8.4 mg/kg cohorts as dose expansion phase. The primary endpoints were safety and to determine the maximum tolerated dose (MTD) based on dose limiting toxicities (DLTs). Pharmacokinetics and anti-tumor efficacy of GQ1001 were assessed. The plasma concentration of free DM1, the payload of GQ1001, was quantitated. A total of 32 patients were enrolled, predominantly in breast (9), gastric or gastro-esophageal junction (9) and salivary gland cancer (4). Median number of prior-line of therapies was 3 (0-11) and 37.5% patients received ≥ 2 lines of anti-HER2 therapies. No DLT was observed during dose escalation. MTD was not reached and dose recommended for dose expansion (DRDE) was determined as 8.4 mg/kg. Grade ≥ 3 treatment-related adverse events rate was 28.1% (9/32) and platelet count decreased (4/32, 12.5%) was the most common one. No drug-related death was observed. Objective response rate and disease control rate of 15 evaluable patients in 7.2 mg/kg and 8.4 mg/kg cohorts were 40.0% (6/15) and 60.0% (9/15). Pharmacokinetics analysis showed low exposure and accumulation of free DM1 in circulation. GQ1001 is well tolerated and shows promising efficacy in previously treated HER2-positive advanced solid tumors. DRDE was determined as 8.4 mg/kg for following trials. Trial registration NCT, NCT04450732, Registered 23 June 2020, https://clinicaltrials.gov/study/NCT04450732.

Zhou C ，Wang B ，Teng C ，Yang H ，Piha-Paul SA ，Richardson G ，Malalasekera A ，Sun Y ，Wang W ，Liu J ，Shi Y ，Zhan X ，Lemech C ... -  《-》

A novel anti-HER2 monoclonal antibody IAH0968 in HER2-positive heavily pretreated solid tumors: results from a phase Ia/Ib first-in-human, open-label, single center study.

IAH0968 is an afucosylated anti-epidermal growth factor receptor 2 (HER2) monoclonal antibody which improved the activity of antibody-dependent cellular cytotoxicity (ADCC) and superior anti-tumor efficacy. To determine the maximum tolerated dose (MTD) with dose-limiting toxicity (DLT), a single institution, phase Ia/Ib study was undertaken, using 3 + 3 design. The primary endpoints were safety, tolerability and preliminary clinical activity. Eighteen patients were evaluable for safety and fifteen patients were suitable for efficacy analysis. Dose escalations were 6 mg/kg (N = 2), 10 mg/kg (N = 7), 15 mg/kg (N = 5), and tolerable up to 20 mg/kg (N = 4). Only one DLT was found at dosage 10 mg/kg, and no MTD was reached. The most common Grade 3 treatment-related adverse events (TRAEs) were hypokalemia (5.6%), supraventricular tachycardia (5.6%), interval extension of QTC (5.6%), and infusion reaction (5.6%). Grade 4 TRAE was arrhythmia (5.6%). No serious TRAE or Grade 5 was reported. 22.2% of patients had a TRAE leading to dose adjustment and 16.7% of patients had a TRAE resulting in discontinuation of IAH0968. After a median follow-up of 9.7 months (range, 3.7 - 22.0), the objective response rate (ORR) was 13.3% (2/15), the disease control rate (DCR) was 53.3% (8/15), and median progression-free survival (mPFS) was 4.2 months (95% CI: 1.4 - 7.7), and the median duration of disease control (DDC) was 6.3 months (95% CI: 2.9-not reached), with 4/15 responses ongoing. In HER2-positive heavily pretreated metastatic patients, IAH0968 demonstrated promising clinical activity with durable responses and tolerable safety profiles. ClinicalTrials.gov, identifier NCT04934514.

Song N ，Teng Y ，Shi J ，Teng Z ，Jin B ，Qu J ，Zhang L ，Yu P ，Zhao L ，Wang J ，Li A ，Tong L ，Jiang S ，Liu Y ，Yin L ，Jiang X ，Xu T ，Cui J ，Qu X ，Liu Y ... -  《-》