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 ... -  《-》

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 ... -  《-》

Brain radiotherapy combined with camrelizumab and platinum-doublet chemotherapy for previously untreated advanced non-small-cell lung cancer with brain metastases (C-Brain): a multicentre, single-arm, phase 2 trial.

Brain metastases are a common complication in patients with non-small-cell lung cancer (NSCLC) lacking actionable driver mutations, with limited treatment options and poor prognosis. We aimed to investigate the efficacy and safety of brain radiotherapy combined with camrelizumab and platinum-doublet chemotherapy in patients with newly diagnosed advanced NSCLC and brain metastases. This multicentre, single-arm, phase 2 trial was done across nine tertiary hospitals in China. Eligible patients were aged 18 years or older, had newly diagnosed brain metastases from NSCLC with no actionable driver mutations (EGFR, ALK, or ROS1), and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Eligible patients were treated with stereotactic radiosurgery or whole-brain radiotherapy combined with camrelizumab (200 mg intravenously once every 3 weeks) and investigator-selected platinum-doublet chemotherapy (pemetrexed 500 mg/m2 plus platinum [carboplatin, area under curve (AUC) of 5, or cis-platinum 75 mg/m2] for non-squamous NSCLC, and nab-paclitaxel 260 mg/m2 plus platinum [carboplatin AUC 5, or cis-platinum 75 mg/m2] for squamous NSCLC) for four to six cycles. Patients with controlled disease then received maintenance treatment with camrelizumab alone (200 mg intravenously once every 3 weeks; for squamous NSCLC) or camrelizumab plus pemetrexed (500 mg/m2 every 3 weeks; for non-squamous NSCLC). The primary endpoint was 6-month progression-free survival rate in the full analysis set, which included all patients who received at least one dose of study treatment regardless of whether they had measurable brain lesions per RECIST 1.1. The trial was registered with ClinicalTrials.gov, NCT04291092, and is ongoing. Between May 6, 2020, and Jan 30, 2023, 67 patients were assessed for eligibility. Two patients were excluded (brain lesions less than 5 mm) and 65 patients were enrolled and treated. Median age was 66 years (IQR 62-70). 60 (92%) of 65 patients were male and five (8%) were female. All 65 patients were Han Chinese. 50 (77%) of 65 patients had non-squamous NSCLC and 46 (71%) were symptomatic. The 6-month progression-free survival rate was 71·7% (95% CI 58·9-81·1) during the median follow-up of 14·1 months (IQR 9·0-20·3; data cutoff Dec 13, 2023). The most common grade 3-4 treatment-related adverse events were decreased neutrophil count (14 [22%] of 65 patients), decreased white blood cell count (ten [15%]), decreased platelet count (ten [15%]), and decreased lymphocyte count (nine [14%]). Neurological toxic effects of grade 3 occurred in three (5%) of 65 patients. Radiation necrosis occurred in three (5%) of 65 patients; all were grade 1 or 2. There were no treatment-related deaths. Brain radiotherapy combined with camrelizumab and platinum-doublet chemotherapy shows promising efficacy and manageable toxicity and could be a potential treatment option for patients with brain metastases from NSCLC. Randomised controlled trials will be required to confirm these findings. Beijing Xisike Clinical Oncology Research Foundation and Jiangsu Hengrui Pharmaceuticals. For the Chinese translation of the abstract see Supplementary Materials section.

Xu Y ，Chen K ，Xu Y ，Li H ，Huang Z ，Lu H ，Huang D ，Yu S ，Han N ，Gong L ，Qin J ，Chen J ，Xie F ，Hong W ，Lin X ，Cheng F ，Luo X ，Fan Y ... -  《-》

Primary lung tumour stereotactic body radiotherapy followed by concurrent mediastinal chemoradiotherapy and adjuvant immunotherapy for locally advanced non-small-cell lung cancer: a multicentre, single-arm, phase 2 trial.

Patients with locally advanced non-small-cell lung cancer (NSCLC) who undergo concurrent chemotherapy and radiotherapy often experience synergistic toxicity, and local regional control rates remain poor. We assessed the activity and safety outcomes of primary tumour stereotactic body radiotherapy (SBRT) followed by conventional chemoradiotherapy to the lymph nodes and consolidation immunotherapy in patients with unresectable locally advanced NSCLC. In this multicentre, single-arm, phase 2 trial, patients aged 18 years and older were enrolled at eight regional cancer centres in North Carolina and South Carolina, USA. Patients were eligible if they had stage II-III, unresectable, locally advanced NSCLC (any histology), with peripheral or central primary tumours that were 7 cm or smaller, excluding central tumours within 2 cm of involved nodal disease, and an Eastern Cooperative Oncology Group performance status of 0-2. Patients who had previously received systemic therapy or radiotherapy were excluded. Participants received SBRT to the primary tumour (50-54 Gy in three to five fractions) followed by standard radiotherapy (planned up to 60 Gy in 30 2 Gy fractions) to the involved lymph nodes with concurrent platinum doublet chemotherapy (either paclitaxel 50 mg/m2 intravenously plus carboplatin area under the curve 2 mg/mL per min every 7 days for a total of six 1-week cycles or etoposide 50 mg/m2 intravenously on days 1-5 and days 29-33 plus cisplatin 50 mg/m2 intravenously on days 1, 8, 29, and 36 for two cycles of 4 weeks). An amendment to the protocol (Dec 11, 2017) permitted the administration of consolidation durvalumab at the discretion of the treating investigator. An additional protocol amendment on Jan 13, 2021, directed patients without disease progression after chemoradiotherapy to receive consolidation durvalumab (10 mg/kg intravenously on day 1 and day 15 of a 4-week cycle for up to 12 cycles or 1500 mg intravenously on day 1 of a 4-week cycle for up to 12 cycles). The primary endpoint was 1-year progression-free survival (per Response Evaluation Criteria in Solid Tumours version 1.1), assessed in all participants who received at least one fraction of SBRT and had radiological follow-up data up to 1 year. A 1-year progression-free survival rate of greater than 60% was required to reject the null hypothesis and show significant improvement in 1-year progression-free survival. One-sided exact binomial tests were used to compare the primary endpoint versus the historical control 1-year progression-free survival rate used to determine the sample size. Safety was assessed in all patients who received at least one fraction of SBRT. This study is registered with ClinicalTrials.gov, NCT03141359, and is closed to accrual. Between May 11, 2017, and June 27, 2022, 61 patients were enrolled and received at least one dose of fractionated SBRT, of whom 59 were evaluable for the primary endpoint. Median age was 67 years (IQR 61-72), 28 (46%) of 61 were female, 33 (54%) were male, 51 (84%) were White, seven (11%) were Black, and three (5%) were of other or unknown race. Of the 61 patients enrolled, 47 received at least one dose of consolidation durvalumab. As of data cutoff (July 12, 2023), median follow-up was 29·5 months (IQR 14·9-47·1). 1-year progression-free survival was 62·7% (90% CI 51·2-73·2; one-sided p=0·39, compared with the historical control rate), with 37 of 59 evaluable participants progression free and alive 1 year after enrolment (n=14 progressed, n=8 died). The most common grade 3-4 treatment-related adverse events were decreased neutrophil count (nine [15%] of 61 patients), decreased white blood cell count (five [8%]), and anaemia (four [7%]). Treatment-related serious adverse events occurred in 11 (18%) of 61 patients, which included lung infection (three [5%]), pneumonitis (two [3%]), decreased neutrophil count (two [3%]), febrile neutropenia (two [3%]), and dyspnoea, hypoxia, respiratory failure, sinus tachycardia, bronchial infection, and acute kidney injury (each in one [2%] patient). Treatment-related deaths occurred in four (7%) of 61 patients (one each of respiratory failure, respiratory failure and dyspnoea, lung infection, and pneumonitis). Although this study did not meet the primary endpoint, activity and safety profiles of primary lung tumour SBRT followed by concurrent mediastinal chemoradiotherapy were favourable compared with other modern trials treating locally advanced NSCLC with chemoradiotherapy. These findings serve as the basis for the ongoing randomised phase 3 study NRG Oncology LU008 (NCT05624996). AstraZeneca and Atrium Health Levine Cancer Institute.

Heinzerling JH ，Mileham KF ，Robinson MM ，Symanowski JT ，Induru RR ，Brouse GM ，Corso CD ，Prabhu RS ，Haggstrom DE ，Moeller BJ ，Bobo WE ，Fasola CE ，Thakkar VV ，Pal SE ，Gregory JM ，Norek SL ，Begic XJ ，Kesarwala AH ，Burri SH ，Simone CB 2nd ... -  《-》

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 ... -  《-》