A Biomarker-Directed, Multi-Centre Phase II/III Study of ctDNA Response Adaptive Immuno-Chemotherapy in Lung Cancer - BR.36

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• Patients with a prior malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the protocol treatment regimens are eligible for this trial. 2. Patients with symptomatic central nervous system (CNS) metastases and/or CNS metastases requiring immunosuppressive doses of systemic corticosteroids (>10 mg/day prednisone equivalents). Patients with known central nervous system metastases who are asymptomatic and on a stable dose of corticosteroids ≤ 10 mg/day prednisone equivalents are eligible. 3. Patients who are not suitable candidates for treatment with pembrolizumab as a single agent or in combination with standard platinum combination chemotherapy according to the current guidance/indications described in the Product Monograph (Canada) or Drug Label (U.S.) and practice guidelines including but not limited to patients with active infection, autoimmune disease, conditions that require systemic immunosuppressive therapy (such as transplant patients) and patients with a history of severe immune-mediated adverse reactions, or known hypersensitivity to pembrolizumab or its components. Patients with pre-existing conditions such as colitis, hepatic impairment, respiratory or endocrine disorders (such as hypo or hyperthyroidism or diabetes mellitus), can be considered for enrollment to this study provided pembrolizumab is administered with caution and patients are closely monitored. Patients should not have contraindications to platinum combination chemotherapy. 4. History of significant neurologic or psychiatric disorder which would impair the ability to obtain consent or limit compliance with study requirements. 5. Concurrent treatment with other anti-cancer therapy or other investigational anti-cancer agents. 6. Pregnant or lactating women.

• Histologically or cytologically confirmed metastatic NSCLC. Patients with stage III disease are eligible if they are not candidates for surgical resection or definitive chemoradiation. Patients with Large Cell Neuroendocrine Carcinoma (LCNEC) are not eligible. 2. Confirmed EGFR and ALK mutation negative disease based on testing consistent with local guidelines. 3. Patients must have a PD-L1 test result from a certified laboratory indicating PD-L1 expression Tumour Proportion Score (TPS) ≥ 50%. Patients with lower PD-L1 TPS scores treated with single agent pembrolizumab consistent with local guidelines and regulatory approvals may be eligible following discussion with CCTG. 4. Patients are to be registered prior to starting immunotherapy. Screening ctDNA is to be drawn following registration prior to starting immunotherapy and after not more than 2 cycles of the 200 mg or 2 mg/kg IV Q3W dose/schedule of pembrolizumab, or at least and not more than 1 cycle of 400 mg or 4 mg/kg IV Q6W dose/schedule of pembrolizumab as first line systemic immunotherapy for advanced metastatic NSCLC at the time Eligible patients with detectable ctDNA at 6 weeks may proceed to enrollment and randomization. 5. Prior chemotherapy or immunotherapy for non-metastatic disease (e.g. adjuvant and/or neoadjuvant therapy) is allowed if at least 6 months have elapsed between the completion of prior therapy and start of pembrolizumab as first line treatment for metastatic disease. Local therapy, e.g. palliative extra-cranial radiation, is allowed as long as a period of 2 weeks has passed since completion and screening as ctDNA level may be altered by radiotherapy. Please contact CCTG if a patient has received palliative extra-cranial radiation and a 2 weeks delay is not possible. Eligibility will be considered on a case by case basis. There is no requirement for delay for patients who have received brain radiation. Patients must have recovered to ≤ grade 1 from all reversible toxicity related to prior systemic or radiation therapy. Previous major surgery is permitted provided that surgery occurred at least 14 days prior to screening of ctDNA and 28 days prior to patient enrollment and that wound healing has occurred. 6. Eligible and suitable to receive continued treatment with pembrolizumab OR the addition of chemotherapy to pembrolizumab. Patients should be clinically stable without evidence of clinical progression or symptomatic deterioration that requires change in cancer treatment. 7. Must be ≥ 18 years of age. 8. ECOG performance status 0-2. 9. Clinically and/or radiologically documented and evaluable disease. Measurable disease as defined by RECIST is not required. 10. Imaging investigations including CT of the chest, abdomen and pelvis and MRI/CT of the brain (if known brain metastases) or other scans as necessary to document all sites of disease must be done within 14 days prior to randomization to ensure patients do not have clinical progression requiring change in systemic treatment.at the time of registration and again at the time enrollment and randomization following discussion with CCTG.11. Patients must have RECIST non-PD or clinically stable PD documented prior to enrollment that can continue on IO therapy if randomized to that arm. 12. Detectable ctDNA on screening at 6 weeks is required for subsequent enrollment and randomization. For other criteria see the protocol