This is a phase II, single-arm, multicenter study to evaluate the activity and safety of durvalumab in combination with carboplatin or cisplatin plus etoposide in patients with treated ES-EPSCC.
1. Age ≥ 18 years on day of signing informed consent. 2. Written informed consent and any locally required authorization obtained from the patient/legal representative prior to performing any protocol-related procedures, including screening evaluations.
Haemoglobin ≥9.0 g/dL
Absolute neutrophil count (ANC) ≥1.0 × 109 /L
Platelet count ≥75 × 109/L
Subjects with active, known or suspected autoimmune disease requiring systemic treatment (systemic steroids or immunosuppressive agents) prior 14 days before the first dose of durvalumab.
Intranasal, inhaled, topical steroids or local steroid injections (eg, intra articular injection).
Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent.
Steroids as premedication for hypersensitivity reactions (eg, CT scan premedication).
Single group
Durvalumab
DrugAll drugs will be administered intravenously. Induction treatment will be administered on a 21-day cycle for four cycles and will consist of: * etoposide 80-100 mg/m² (administered on days 1-3 of each 21-day cycle); * investigator's choice of either carboplatin area under the curve 5-6 mg/mL per min or cisplatin 75-80 mg/m² (administered on day 1 of each cycle); * durvalumab 1500 mg every 3 weeks in combination with chemotherapy (induction phase) followed by maintenance phase with durvalumab 1500 mg every 4 weeks. Patients will continue treatment until disease progression per investigator assessment, unacceptable toxicity, or other discontinuation criteria were met for a maximum of 24 months. Continuation of study treatment after disease progression will be permitted if there is evidence of clinical benefit for a maximum 24 months.
progression free survival (PFS)
To evaluate the preliminary efficacy in terms of 12 months progression free survival (PFS) of durvalumab in association with carboplatin or cisplatin and etoposide in first line patients affected by extensive stage EPSCC. PFS isdefined as the time from initiation of study treatment to the first occurrence of disease progression or death from any cause, whichever occurs first. According to the results of the CASPIAN trial \[18\] in which was observed a 12-month progression-free survival rates of 5% (2.4-8.0) for patients that had received Platinum-etoposide, it is expected to detect an increasing of at least 10 percentage points (to 15%).
Objective Response Rate (ORR)
Activity of durvalumab in combination with carboplatin or cisplatin plus etoposide in patients with untreated extensive- stage extrapulmonary small cell lung cancer (EPSCC). Activity will be measured as Objective Response Rate (ORR), defined as the percentage of patients who attain complete response (CR) or partial response (PR) according to RECIST v1.1.
Disease control rate (DCR)
Disease control rate (DCR) measured as the percentage of patientswho have archived CR, PR, and stable disease (SD).
Overall survival (OS)
Overall survival (OS), defined as the time from initiation of study treatment to death from any cause.
Duration of response (DOR)
Duration of response (DOR), is defined as the time from initial response to disease progression or death among patients who have experienced a CR or PR (unconfirmed) during the study. Duration of response will be calculated based on disease status evaluated by the investigator according to RECIST v1.1.
biomarkers associated with sensitivity/resistance to immune checkpoint inhibitors
To identify possible biomarkers associated with sensitivity/resistance to immune checkpoint inhibitors, tumor samples from enrolled patients will undergo whole exome sequencing (WES) and gene expression profiling by using a 3' RNA Seq approach. For all the patients enrolled to investigate the occurrence of genetic alterations that might be associated with acquired resistance to immune checkpoint inhibitors, blood samples will be collected by analyzing the circulating free DNA (cfDNA). To this end, plasma will be collected at baseline, prior to cycle 5, and at the end of treatment (progression of disease). The cfDNA will be analyzed by targeted sequencing panels.
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