Testing Targeted Radiotherapy while Continuing Ongoing Immunotherapy (with or without Chemotherapy) versus Switching to a Different Chemotherapy for Metastatic Non-small Cell Lung Cancer

Inclusion Criteria

• Metastatic disease (stage IV) detected on imaging and histologically confirmed NSCLC as per the World Health Organization (WHO) Classification of Tumors and American Joint Committee on Cancer (AJCC) 8th Edition TNM Classification, without an actionable driver mutation, for whom either ICI alone or combination ICI + chemotherapy is indicated
• Oligoprogression on first-line ICI +/- chemotherapy systemic therapy after at least 3 cycles. Oligoprogression is evaluated independently for each lesion, and will be defined as follows: * Modified Response Evaluation Criteria in Solid Tumours (RECIST 1.1 [Eisenhauer 2009]): ** At least a 20% increase in the longest diameter (LD) of a lesion except for lymph nodes where only the short axis is measured, taking as reference the smallest LD/short axis recorded since nadir, and ≥ 5 mm increase in the LD/short axis, OR; ** The appearance of one or more new lesions, each ≥ 5 mm in size OR * Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST [Wahl 2009]): ** > 30% increase in fludeoxyglucose F-18 (18F FDG) standard uptake value (SUV) peak, with > 0.8 SUV units increase in tumor SUV from previous baseline scan in pattern typical of tumor and not of infection/treatment effect, OR; ** Visible increase in the extent of 18F-FDG tumor uptake, OR; ** New 18F-FDG avid lesions typical of cancer (including new bone lesion) and not related to treatment effect and/or infection * There is no upper limit to the number of total metastatic sites, but a maximum of 5 progressive metastatic sites, inclusive of primary disease and metastatic lesions, all of which must be extracranial
• All sites of oligoprogression can be safely treated with SBRT or ablative radiotherapy as determined by the treating radiation oncologist, including availability and tolerability of necessary technologies (e.g. active breathing control, magnetic guided linear accelerator [MR-Linac], fiducial insertion, etc.) and accounting for previous radiotherapy overlap. Safety must be assessed and determined by a radiation oncologist prior to enrollment
• Participants with treated central nervous system (CNS) disease who have radiologic and clinical evidence of stable brain metastases, , with no evidence of cavitation or hemorrhage in the brain lesion, are eligible providing that they are asymptomatic and do not require corticosteroids (must have discontinued steroids at least 1 week prior to randomization). Anticonvulsants are allowed. Participants with new or progressive brain metastases (at screening) are eligible if they are asymptomatic and do not require CNS-specific treatment.
• Candidate for regulatory approved SOC second-line systemic therapy options if randomized to Arm 1
• Participants must have adequate organ and marrow function according to the relevant systemic therapies’ current product monographs and local/provincial/institutional formulary guidelines
• Participants must be ≥ 18 years of age
• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2
• Participants that received prior adjuvant/neoadjuvant/consolidation systemic therapy (including chemotherapy and ICI) are eligible if at least 6 months have elapsed between the completion of prior therapy and start of first line treatment for metastatic disease
• Patients must meet the criteria for oligoprogression on first-line ICI +/- chemotherapy for metastatic disease
• Participants must have recovered to ≤ grade 1 from all reversible toxicity related to prior systemic therapy. Participants that experienced prior immune-mediated toxicity during the initial cycles of first-line metastatic SOC of ICI +/- chemotherapy must have successfully re-initiated ICI therapy. Please contact CCTG if participants have ongoing toxicity ≥ grade 1 felt to be clinically insignificant
• Previous surgery related to NSCLC in the curative or metastatic disease setting is permitted. Previous major surgery is permitted provided that the participant has recovered from related clinically significant adverse events upon enrollment
• Prior external beam radiation related to NSCLC in the metastatic disease setting is permitted provided the participant has recovered from related clinically significant adverse events upon enrollment. Participants that received prior external beam radiation therapy in the NSCLC curative disease setting (including the primary lesion) are eligible. Oligoprogressive lesions previously treated with external beam radiation are eligible as long as they are clinically asymptomatic, and re-treatment is possible according to the investigator
• Prior conventional, non-stereotactic radiotherapy for palliative purposes is allowed, and if the palliated lesion subsequently progressed but remains asymptomatic and does not require immediate radiotherapy, the lesion can still be counted toward one of the five oligoprogressive lesions
• Participant is able (i.e. sufficiently fluent) and willing to complete the quality of life and/or health utility questionnaires in either English, French, or Spanish. The baseline assessment must be completed within required timelines, prior to enrollment. Inability (lack of comprehension in English, French, Spanish, or other equivalent reason such as cognitive issues or lack of competency) to complete the questionnaires will not make the participant ineligible for the study. However, ability but unwillingness to complete the questionnaires will make the participant ineligible
• Reimbursement of continued SOC ICI and chemotherapy systemic therapies may not be uniform across all sites. In the event that a site/investigator is unable to provide access to the drug, the participant will not be eligible for this trial
• Participant consent must be appropriately obtained in accordance with applicable local and regulatory requirements. Each participant must sign a consent form prior to enrollment in the trial to document their willingness to participate * A similar process must be followed for sites outside of Canada as per their respective cooperative group’s procedures
• Participants must be accessible for treatment and follow-up. Investigators must assure themselves the participants enrolled on this trial will be available for complete documentation of the treatment, adverse events, and follow-up
• Participants of reproductive potential must have agreed to use a highly effective contraceptive method. A woman is considered to be of "childbearing potential" if she has had menses at any time in the preceding 12 consecutive months. In addition to routine contraceptive methods, "effective contraception" also includes celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation, or vasectomy/vasectomized partner. However, if at any point a previously celibate participant chooses to become sexually active during the time period for use of contraceptive measures outlined in the protocol, they are responsible for beginning contraceptive measures
• Women of childbearing potential will have a pregnancy test to determine eligibility as part of the pre-study evaluation; this may include an ultrasound to rule-out pregnancy if a false-positive is suspected. For example, when beta-human chorionic gonadotropin is high and partner is vasectomized, it may be associated with tumor production of human chorionic gonadotropin (hCG), as seen with some cancers. Participant will be considered eligible if an ultrasound is negative for pregnancy

Exclusion Criteria

• Large-cell neuroendocrine carcinoma (LCNEC), pulmonary carcinoid tumour or mixed small cell and non-small cell lung cancer are not eligible
• Presence of leptomeningeal disease
• Pregnancy
• Serious medical conditions in which radiotherapy of target lesions is contraindicated (e.g. scleroderma, ataxia telangiectasia [ATM], interstitial lung disease [ILD], Child-Pugh C liver function)
• Any other condition in which in the judgement of the investigator would make the participant inappropriate for study entry
• Participants who are not actively on ICI alone or ICI + chemotherapy
• Participants with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
• Concomitant medications should only exclude participants from trial participation when clinically relevant known or predicted drug–drug interactions or potential overlapping toxicities will impact safety or efficacy; please consult the relevant product monographs
• Concurrent treatment with other anti-cancer therapy, including investigational agents
• Live attenuated vaccination administered within 30 days prior to enrollment/randomization * Note: Seasonal vaccines for influenza are generally inactivated vaccines and are allowed. Intranasal vaccines are live vaccines and not allowed
• Human immunodeficiency virus (HIV)-infected participants on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
• For participants with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
• Participants with a history of hepatitis C virus (HCV) infection must have been treated and cured. For participants with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
• Participants with a history of HIV, HBV or HCV should be managed according to the current anti-cancer systemic therapy product monographs and local/provincial formulary guidelines