Outcome for patients diagnosed with advanced lung cancer remains poor; alternative treatment options are urgently needed. Studies in other metastatic cancers indicate radiotherapy to the primary tumour can improve outcomes. The investigators postulate this will also be observed in lung cancer patients. The aim of this pilot study is to assess the safety and feasibility of stereotactic ablative radiotherapy (SABR) to the lung primary prior to standard of care (SoC) systemic therapy in advanced non-small cell lung cancer (NSCLC). Forty patients with advanced (Stage IV) NSCLC will be recruited across the five Peter Mac campuses. Patients will be randomised to receive SoC systemic therapy with or without radiotherapy to the lung primary. Radiotherapy will be delivered before cycle 3 of SoC systemic therapy. Biospecimens will be collected for future translational research. The primary outcome of the study (feasibility of the protocol) will be assessed by the ability to deliver radiotherapy to the lung cancer primary, whilst meeting dose constraints. The study will also 1) evaluate proportion of patients who are willing to be randomised; 2) describe toxicity during the follow up period in each arm; 3) describe progression free survival.

PRIME-Lung is an open-label randomised pilot study designed to assess the safety and feasibility of radiotherapy to the lung primary prior to commencement of standard of care (SOC) systemic therapy in advanced lung cancer. The study is designed to assess the feasibility of the protocol, and will be escalated, without major modification, directly to a randomised phase III design. This will occur if the following objectives are met in ≥ 66% of patients:

1. Receipt of radiotherapy before cycle 3 of systemic therapy.
2. Ability to meet dose constraints in delivering radiotherapy to the lung primary

The secondary objectives are:

• Evaluate proportion of patients who are willing to be randomized.
• To describe toxicity within 90 days of RT delivery
• To describe progression free survival Blood samples for future translational research will also be established.

Newly diagnosed patients with advanced (Stage IV) non-small cell lung cancer (NSCLC) who have received no prior lines of systemic therapy will be invited to participate (refer to protocol for full inclusion/exclusion criteria). Consenting patients will be randomised to either:

• Arm 1: Systemic therapy alone
• Arm 2: Radiotherapy before cycle 3 of systemic therapy

The trial treatment is therefore the addition of radiotherapy before cycle 3 of SOC systemic therapy.

During treatment (standard and experimental arm) participants will be assessed for radiation toxicity and the occurrence of adverse events. The recruitment period is over 18 months, with study visits at Baseline, radiotherapy (patients in Arm 2 only), Cycle 3 of SOC systemic therapy, 12 and 24 weeks after initiation of therapy, and at disease progression. SOC CT Staging scans will occur every 6 weeks from initiation of SOC systemic therapy.

Inclusion Criteria:

• Have provided written informed consent for the trial.
• Be ≥ 18 years of age on day of signing informed consent.
• Newly diagnosed, metastatic (stage IV), non-small cell lung cancer (NSCLC), not amenable to curative surgery or curative radiotherapy
• Histological or cytologically documented NSCLC
• EGFR/ALK/ROS1 Wild-type
• Primary disease suitable for radiotherapy and not requiring immediate palliative irradiation
• ECOG 0-1

Exclusion Criteria:

• Medically unfit for systemic therapy
• EGFR/ALK/ROS1 mutation positive
• Has had previous thoracic radiotherapy of > 36Gy in 12 fractions (or equivalent) within the 6 months prior to randomisation.
• Has diagnosed and/or treated additional malignancy within 3 years prior to randomisation with the exception of: curatively treated basal cell carcinoma of the skin, squamous cell carcinoma of the skin, curatively treated early-stage cervical cancer, breast cancer or prostate cancer with no evidence of active disease. Other exceptions may be considered following consultation with the principal investigator.
• Has a history of (non-infectious) pneumonitis or current pneumonitis that requires active corticosteroids with a dose equivalent of prednisolone>10mg/d.
• Has had any systemic anti-cancer therapy within 4 weeks prior to randomisation
• A known diagnosis of idiopathic pulmonary fibrosis
• Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
• Uncontrolled brain metastases defined as not amenable to surgery or stereotactic radiotherapy