A Multicenter, Single-Arm, Prospective Phase II Clinical Study of Trastuzumab Rezetecan Combined With Radiotherapy in Patients With HER2-Mutated Oligoprogressive Advanced Non-Small Cell Lung Cancer

1.Presence of EGFR sensitizing mutations (Exon 19 deletion / Exon 21 L858R), 2.ALK rearrangements, positive ROS1/RET fusions, MET exon 14 skipping mutations, or KRAS G12C mutations.

3.Uncontrolled or severe cardiovascular diseases, such as severe/unstable angina, symptomatic congestive heart failure (NYHA Class II-IV), myocardial infarction within 6 months prior to the first study treatment, or unstable angina or unstable arrhythmia occurring within 1 month before initiation of study treatment.

4.Active central nervous system (CNS) tumor metastases. Subjects with a history of leptomeningeal metastasis or current leptomeningeal metastasis are excluded. Exception: Subjects with CNS metastases who have received adequate local therapy (surgery or radiotherapy) at least 2 weeks prior to the first dose, do not require steroid therapy, have neurologically recovered to baseline (excluding residual signs/symptoms related to CNS treatment), and whose brain lesions are not oligoprogressive lesions in this study may be enrolled.

5.Presence of pleural effusion, ascites or pericardial effusion requiring intervention within 7 days before the first dose.

6.Receipt of extensive-field radiotherapy within the past 4 weeks, or anticipated overlap with the radiotherapy field in this study where organ risk constraints cannot be satisfied.

7.Toxicities and/or complications from prior interventions that have not recovered to NCI-CTCAE Grade ≤1. Exception: Subjects may be enrolled if the investigator judges that adverse events are NCI-CTCAE Grade ≤2 and pose no safety risks. Subjects previously treated with immune checkpoint inhibitors with stable Type 1 diabetes or hypothyroidism under hormone replacement therapy are eligible.

8.Receipt of strong/moderate CYP3A4 inhibitors or strong/moderate CYP3A4 inducers within the shorter of either 3 drug half-lives or 14 days prior to the first dose.

9.Subjects with known or suspected interstitial lung disease; moderate to severe pulmonary diseases that may interfere with detection or management of drug-related pulmonary toxicity and severely impair respiratory function within 3 months before the first dose, including but not limited to idiopathic pulmonary fibrosis, organizing pneumonia/bronchiolitis obliterans, pulmonary embolism, severe asthma, severe COPD, severe obstructive/restrictive ventilatory dysfunction; any autoimmune, connective tissue or inflammatory diseases involving the lungs (e.g., rheumatoid arthritis, sicca syndrome, sarcoidosis), or history of prior pneumonectomy. Subjects who developed Grade ≥3 interstitial lung disease during previous immune checkpoint inhibitor treatment are excluded.

10.Other concurrent malignant tumors diagnosed within ≤3 years prior to the first dose, except for adequately treated papillary thyroid carcinoma, cervical carcinoma in situ, basal cell or squamous cell skin cancer, locally confined prostate cancer after radical resection, and ductal carcinoma in situ after radical resection (hormonal therapy for non-metastatic prostate or breast cancer is permitted).

11.Severe infection within 4 weeks prior to the first dose, including but not limited to bacteremia requiring hospitalization, severe pneumonia; active infection of CTCAE Grade ≥2 requiring systemic antibiotic therapy within 2 weeks prior to the first dose.

12.Active hepatitis B or hepatitis C infection. Subjects positive for HBsAg or HBc Ab may participate if HBV DNA is below the upper limit of normal (ULN) of the local study laboratory; if no ULN is available at the site, HBV DNA must be \<1000 copies/mL or 500 IU/mL. Subjects positive for anti-HCV antibody may participate if HCV RNA is below the ULN of the local study laboratory.

13.History of active pulmonary tuberculosis infection within 1 year before enrollment confirmed by medical history or CT scan; or history of active pulmonary tuberculosis infection more than 1 year previously without standardized treatment.

14.History of immunodeficiency, including positive HIV serology or history of organ transplantation.

15.Major surgery within 28 days prior to the first dose (excluding diagnostic surgery), or planned major surgery during the study period (excluding diagnostic surgery).

16.Administration of live attenuated vaccines within 28 days before the first dose, or planned administration of live attenuated vaccines during the study.

17.Known history of severe allergic reaction to any component of trastuzumab rezetecan or radiotherapy.

18.Known psychiatric disorders, alcohol abuse, drug addiction or substance abuse.

19.Female subjects who are pregnant, breastfeeding, or planning to become pregnant during the study period.

20.Any other conditions that, in the investigator's judgment, may increase risks associated with study participation, interfere with study outcomes, or render the subject unsuitable for enrollment.

What this study is about