Unfortunately, most patients are already at a very advanced stage when they are diagnosed with lung cancer, i.e. the cancer has already spread outside the lungs forming metastases. The current standard of care therapy at this advanced stage of lung cancer includes systemic anti-cancer therapy such as chemotherapy, immunotherapy to boost the body's immune response, or targeted therapy that directly hinders tumor growth. In this study, the aim is to find out whether it is better if, after a good response to the standard therapy, the remains of main tumor and the metastases are additionally treated by surgery and/or radiation.

In this study, the aim is to find out whether, after a good response to standard therapy, it is better if the main tumor and metastases are additionally removed by surgery and/or radiation. This intervention is referred to as local ablative therapy (LAT). There is evidence to suggest that this additional intervention may prolong the average time to possible cancer recurrence (PFS: Progression-free survival) or lead to longer survival on average. Therefore, the question is to know if these treatments prolong life, and if so, by how much and with what implications. Currently, patients who respond to initial standard therapy are not routinely offered LAT. If the results of this study are positive, it will lead to a fundamental change in the current standard of practice.

The benefit of a therapy is not solely determined by the extension of PFS or overall survival but also heavily influenced by how the therapy impacts patient's quality of life. Medication side effects, pain, fatigue, nausea or extended hospital stays can significantly diminish the perceived positive effects of a treatment from the patient's viewpoint, even if it appears favorable from a medical standpoint. Therefore, the assessment of quality of life through patient-reported outcome measures (PROMs) is a central aspect of this study.

This study will enroll 128 patients from different Swiss hospitals, randomly assigning them to either the intervention group (LAT) or a control group (standard therapy). The study is expected to span approximately two years for each patient.

Inclusion Criteria:

Patients fulfilling all of the following inclusion criteria at screening may be enrolled in the trial.

• The inclusion criteria are irrespective from the tumor burden at the time of primary diagnosis before initiation of first line systemic therapy. Treatment of brain metastases upfront or after an induction phase of standard systemic therapy is done according to the standard practice of the treating center.
• Adults (18 years or older)
• Tissue confirmed, pre-treatment clinical stage IV NSCLC
• ECOG performance status ≤ 1
• Patients responding after 3 cycles (4th bridging cycle up until randomization is allowed) or 3 months of first line SoC systemic therapy with PR or SD in restaging imaging, and presenting with (induced) oligometastatic or oligopersistent NSCLC defined as a maximum of 5 residual extracranial, distant metastases
• Patients may have up to 5 cranial metastases in addition to the oligoresidual extracranial metastases as long as they are amenable for radiotherapy or surgery.
• The primary tumor and all oligopersistent metastases must be amenable for radical LAT (surgery or radiotherapy)
• Patients of reproductive age agree to use double contraception during the study
• Patient is able to understand trial procedures and is able/willing to adhere to trial procedures as confirmed by signature

Exclusion Criteria:

The presence of any one of the following exclusion criteria at screening will lead to exclusion of the participant:

• Serious concomitant disorder that would compromise patient safety during LAT
• Unresolved complications from initial systemic anticancer treatment, higher than CTCAE grade 2
• Metastatic locations such as malignant ascites, malignant pleural or malignant pericardial effusion, diffuse lymphangiosis of skin or lung, diffuse bone marrow metastasis, abdominal masses/abdominal organomegaly, identified by physical exam that is not measurable by reproducible imaging techniques, leptomeningeal carcinomatosis
• Women who are pregnant or breast feeding
• Patient is currently involved in a trial that either does not permit participation in other trials or would result in excessive patient burden if another trial were joined. In such cases, the co-investigators' team and the Patient Advisory Board will decide on participation on an individual basis.