This is a randomized, non-comparative, phase II study investigating whether: 1) the addition of durvalumab to investigator's choice second line chemotherapy prolongs survival versus investigator's choice second line chemotherapy in NSCLC patients with locally advanced disease progressing on durvalumab given after concomitant chemoradiotherapy; 2) whether the addition of olaparib to durvalumab improves survival over durvalumab alone after induction chemoimmunotherapy in patients relapsing after completing durvalumab maintenance therapy for stage III disease.
After evaluation of inclusion and exclusion criteria and after consent form signature, all eligible patients progressing during durvalumab therapy will be in the Part A of the trial randomized to in a 1:1 ratio to investigator's choice single-agent chemotherapy plus durvalumab (Arm A: experimental arm) or to investigator's choice single-agent chemotherapy (Arm B: standard arm). In the clinical trial's Part B, patients progressing after completion of durvalumab therapy will be further randomized in a 1:1.7 ratio to investigator's choice platinum doublet chemotherapy plus durvalumab for 4 cycles followed by maintenance durvalumab plus olaparib (Arm C: experimental arm) or to investigator's choice platinum doublet chemotherapy plus durvalumab for 4 cycles followed by durvalumab (Arm D: experimental arm). Therapy will be continued up to disease progression, toxicity or patient refusal.
Body weight >30kg
Recurrent or metastatic NSCLC relapsed during or after completion of chemoradiotherapy with curative intent and maintenance durvalumab for stage III disease. Patients are eligible if they receive at least two cycles of platinum based chemotherapy or radical radiotherapy
Tumor tissue available for biomarker testing.
Evidence of disease progression during durvalumab maintenance or at the end of planned treatment. Patients who have interrupted planned durvalumab treatment after at least 6 months for reasons other than toxicity or progression (e.g. patient's choice, logistic reasons, intercurrent acute illnesses) are eligible. Patients progressing during the first three months of Durvalumab are not eligible
No evidence of disease progression
Patients receiving any systemic chemotherapy or radiotherapy (except for palliative reasons) within 3 weeks prior to study treatment
Patients not pretreated with durvalumab with curative intent
Patients treated with non-radical radiotherapy or with non conventional radiotherapy
Parallel
Durvalumab
DrugDurvalumab concentrate for solution for infusion will be supplied in glass vials containing 500 mg durvalumab at a concentration of 50 mg/mL
Olaparib tablet
DrugOlaparib tablets (100 mg and 150 mg strengths) supplied in high-density polyethylene (HDPE) bottles.
Single-agent chemotherapy
DrugInvestigator's choice single-agent chemotherapy regimen
Platinum doublet chemotherapy
DrugInvestigator's choice platinum doublet chemotherapy
Overall survival (OS)
Overall Survival (OS) rate at 12 months in patients treated in arm A versus B and in patients treated in arm C versus arm D.
Progression-free survival (PFS)
Progression free survival (PFS) will be calculated from the date of randomization to the first documented evidence of progressive disease or death due to any cause (whichever occurs first) in patients treated in arm A versus B and in patients treated in arm C versus arm D.
Objective response rate (ORR)
Objective response rate (ORR) is defined as the number of subjects with a best overall response (BOR) of CR or PR divided by the number of randomized subjects for each treatment in each coort.
Safety and Incidence of AEs
All adverse events will be reported until 30 days after the final dose of study treatment or until initiation of new systemic anti-cancer therapy, whichever occurs first, and serious adverse events and adverse events of special interest will continue to be reported until 90 days after the final dose of study treatment or until initiation of new systemic anti-cancer therapy, whichever occurs first.
Progression-free survival (PFS) and Overall survival (OS)
Progression-free survival (PFS) and Overall survival (OS) will be evaluated according to biomarkers ((i.e., PD-L1, ERCC1, SLFN11, STK11, KEAP1, p53 expression, DNA repair genes \[including BRCA 1-2 mutations\] and tumor mutational burden).
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