The investigators investigate whether PET imaging with ⁸⁹Zr-trastuzumab can reliably demonstrate the extent of tracer accumulation in tumors of patients with HER2-mutated or HER2-overexpressing non-small cell lung cancer (NSCLC). The aim is to determine whether differences in tracer uptake can be detected between these groups, as translational studies indicate that HER2-mutated tumors may internalize trastuzumab-based agents more efficiently than tumors that solely overexpressed HER2.

Inclusion Criteria:

• Signed written informed consent
• Age≥ 18 years, willing and able to comply with the protocol as judged by the investigator
• Eastern Cooperative Oncology Group performance status (ECOG PS) 0 or 1 at screening.
• Patients with histologically or cytologically confirmed diagnosis of advanced stage:
• HER2 overexpression, defined as an immunohistochemistry score (IHC) of 2+ or 3+ in at least 10% of tumour cells without an activating HER2 mutation
• HER2 activating (insertion) mutation diagnosed through RNA sequencing (RNAseq)
• Disease progression after at least one line of platinum-based chemotherapy ± immunotherapy and starting (new) systemic treatment.
• Be willing to provide a recent tumor tissue specimen after the last line of therapy. Samples must be of sufficient quantity and of adequate tumor tissue content.
• Able to undergo PET imaging procedures.
• Measurable disease according to RECIST 1.1.
• At least two measurable lesions with a long axis diameter ≥2 cm.
• Adequate organ and bone marrow function within 21 days prior to tracer injection, defines as:

Laboratory Test Laboratory Value Platelet count ≥100 000/mm3 or ≥100 × 109/L (platelet transfusions are not allowed up to 14 days prior to Cycle 1 Day 1 to meet eligibility) Hemoglobin ≥9.0 g/dL or 5.6 mmol/L (transfusion and/or growth factor support is allowed) Absolute neutrophil count (ANC) ≥1500/mm3 or ≥1.5 × 109/L Aspartate aminotransferase /alanine aminotransferase ≤3 × ULN (if liver metastases are present, ≤5 ×ULN) Total bilirubin ≤1.5 × ULN if no liver metastases (<3 x ULN in the presence of documented Gilbert's Syndrome (unconjugated hyperbilirubinemia) or liver metastases Creatinine Creatinine clearance (CrCl) ≥30 mL/min as calculated using the Cockcroft-Gault equation.

International normalised ratio (INR)/Prothrombin time and activated partial thromboplastin time (aPTT) ≤1.5 × (ULN), except for subjects on coumarinderivative anticoagulants or other similar anticoagulant therapy, who must have PT-INR within therapeutic range as deemed appropriate by the Investigator

• Women aged <50 years will be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels in the post-menopausal range for the site.

• Women aged ≥ 50 years will be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses >1 year ago, had chemotherapy-induced menopause with last menses >1 year ago.

• Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the contraception methods outlined for women of childbearing potential if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to randomization/study enrolment. For most forms of HRT, at least 2-4 weeks will elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT. Following confirmation of their post-menopausal status, they can resume use of HRT during the study without use of a contraceptive method.

• Female patients of childbearing potential who are sexually active with a non-sterilized male partner must use at least one highly effective method of contraception, presented in Table 3. from the time of screening and must agree to continue using such precautions for 7 months after the last dose of IMP. Not all methods of contraception are highly effective. Female patients must refrain from breastfeeding while on study and for 7 months after the last dose of IMP. Complete heterosexual abstinence for the duration of the study and drug washout period is an acceptable contraceptive method if it is line with the patient's usual lifestyle (consideration must be made to the duration of the clinical trial); however, periodic or occasional abstinence, the rhythm method, and the withdrawal method are not acceptable.

• Female subjects must not donate, or retrieve for their own use, ova from the time of screening and throughout the study treatment period, and for at least 7 months after the final study drug administration

• Highly Effective Methods of Contraception (<1% failure rate) include:

  • Total heterosexual abstinence (evaluate in relation to the duration of the clinical study and the preferred and usual lifestyle choice of the participant)
  • Vasectomised sexual partner (provided that partner is the sole sexual partner of the trial participant and that the vasectomised partner has received medical assessment of the surgical success)
  • Bilateral tubal occlusion
  • Intrauterine device (provided coils are copper banded)
  • Combined (oestrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation i. Oral ii. Intravaginal iii. transdermal
  • Progestogen-only hormonal contraception associated with inhibition of ovulation (oral/injectable/implantable)
  • Intrauterine hormone-releasing system (IUS)
  • All methods of contraception must be used in combination with the use of a condom by their male sexual partners for intercourse.

Exclusion Criteria:

• Contraindications for systemic treatment (as will be assigned by the treating physician)
• Pregnant or lactating women
• Prior allergic reaction to immunoglobulins or immunoglobulin allergy
• Inability to comply with study procedures
• Has substance abuse or any other medical conditions such as clinically significant cardiac or psychological conditions, that may, in the opinion of the investigator, interfere with the subject's participation in the clinical study or evaluation of the study results
• Prior treatment with HER2-targeted therapies (except pan HER TKIs).