A randomized controlled phase III study comparing drug therapy for cancer with or without additional local treatment (surgery and/or radiation) in patients with advanced stage IV non-small cell lung cancer (the "salVage" study)

Non-small Cell Lung Cancer (NSCLC)Stage IV

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Other: Systemic therapy alone or in combination with LAT (surgery and/or radiotherapy)Other: SurgeryRadiation: Radiotherapy

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Allocation: Randomized. Intervention model: Parallel Assignment. Primary purpose: Treatment. Masking: None (Open Label).

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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.

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Progression-Free Survival (PFS) l in the Local Ablative Therapy (LAT) arm is superior to Standard of Care (SoC);Quality of life (QoL) in the LAT arm is non-inferior to the control arm as measured with the European Quality of Life 5 Dimensions 3 Level (EQ-5D-5L) questionnaire-based score at 6 months after randomization

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Patients undergoing LAT maintain Quality of Life (QoL);To assess safety and tolerability of the LAT strategy as compared to standard of care;To compare quality-adjusted life years;To evaluate the economic impact of the LAT approach;To assess the response of primary tumor and metastases to systemic treatment alone and in combination with LAT (according to (i)RECIST criteria)

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