International, randomized phase III trial. Patients will be randomized 1:1 stratified for established prognostic factors (presence of brain metastases, and presence of liver metastases) to receive chemoimmunotherapy plus TRT or chemoimmunotherapy alone.

• Reference therapy: Durvalumab plus carboplatin/etoposide
• Investigational therapy: Durvalumab plus carboplatin/etoposide and TRT

Primary Objective:

• To investigate whether adding TRT to durvalumab plus chemotherapy improves 1-year survival.
  Secondary Objectives:
• To investigate whether adding TRT improves 2-, 3-, 4- and 5-year overall survival.
• To investigate whether adding TRT improves overall response rates, response rates in non-irradiated lesions and PFS.
• To investigate whether TRT improves local control.
• To compare the frequency and severity of adverse events between the treatment arms.
• To compare health related quality of life between treatment arms.
  Exploratory Objectives:
• To compare the duration of severe adverse events between the treatment arms.
• To compare the frequency and timing of brain metastases between treatment arms.
• To assess cognitive function in the whole study cohort and compare cognitive function between those who receive PCI and those who do not.
• To investigate associations between outcomes of study treatment and biomarkers in tissue, blood and stool (e.g. ctDNA in blood, miRNA, gut microbiome).

• Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. Written informed consent and any locally required authorization (e.g. Health Insurance Portability and Accountability Act in the US, European Union [EU] Data Privacy Directive in the EU) obtained from the patient/legal representative prior to performing any protocol-related procedures, including screening evaluations.
• Age > 18 years at time of study entry.
• ECOG performance status of 0 or 1.
• Body weight >30 kg.
• Adequate normal organ and marrow function as defined below:
  • Haemoglobin ≥10.0 g/dL, absolute neutrophil count (ANC) ≥1.5 × 109 /L and platelet count ≥100 × 109/L (lower values might be acceptable if considered due to bone-marrow infiltration of SCLC).
  • Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN). This does not apply to patients with confirmed Gilbert’s syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology).
  • ALT (SGPT) ≤2.5 x institutional upper limit of normal unless liver metastases are present, in which case it must be ≤5 x ULN.
  • Measured creatinine clearance (CL) >40 mL/min or Calculated creatinine CL>40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance.
• Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow-up.
• Life expectancy of at least 3 months.
• At least 1 lesion in the thorax, not previously irradiated, that qualifies as a RECIST 1.1 target lesion (TL) at baseline and is possible to irradiate to 30 Gy in 10 fractions. Tumor assessment by computed tomography (CT) scan or magnetic resonance imaging (MRI) must be performed within 28 days prior to randomization.
• Histologically or cytologically confirmed SCLC. Mixed histology may be acceptable as long as the SCLC component accounts for more than 90%.
• Stage IV disease according to the TNM v8. Patients with stage III disease are eligible if the disease is too widespread to be treated as limited stage SCLC.
• Pulmonary function: FEV1 >1 L or >30 % of predicted value and DLCO >30 % of predicted value (not applicable if there is tumor compression of central airways).
• Female patients of childbearing potential (postmenarcheal, not postmenopausal [>12 continuous months of amenorrhea with no identified cause other than menopause], and no surgical sterilization) should use highly effective contraception and take active measures to avoid pregnancy while undergoing systemic study therapy and monthly pregnancy testing and the use of highly effective contraceptive measures should be maintained during at least six months after the end of treatment with etoposide and at least three months after then end of treatment with durvalumab.
• Patients with brain metastases are eligible provided they are asymptomatic or treated and stable on steroids and/or anticonvulsants prior to the start of treatment.

• Participation in another clinical study with an investigational product during the last 30 days.
• Concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study.
• Previous chemo- or radiotherapy for SCLC. Patients who have undergone surgery, but no adjuvant therapy are eligible.
• Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria.
• Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with the Chief Investigator.
• Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab may be included only after consultation with the Chief Investigator.
• Any concurrent chemotherapy, investigational product or biologic cancer therapy.
• Any prior checkpoint inhibitor therapy for SCLC, including durvalumab. Previous adjuvant checkpoint inhibitor therapy >6 months earlier is allowed.
• Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks of the first dose of study drugs.
• Immediate need for thoracic radiotherapy or bulky disease outside the thorax, or need for such radiotherapy before completion of chemo-immunotherapy.
• Major surgical procedure within 28 days prior to the first dose of study drugs. Note: Local surgery of isolated lesions for palliative intent is acceptable.
• History of allogenic organ transplantation.
• Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc]). The following are exceptions to this criterion:
  a. Patients with vitiligo or alopecia.
  b. Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement.
  c. Any chronic skin condition that does not require systemic therapy.
  d. Patients without active disease in the last 5 years may be included but only after consultation with the Chief Investigator.
  e. Patients with celiac disease controlled by diet alone.
• Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia or QTcF value >470 ms on ECG, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent.
• Other active primary malignancy except for:
  a. Malignancy treated with curative intent and with no known active disease ≥5 years before the first dose of IP and of low potential risk for recurrence.
  b. Localized breast or prostate cancer treated with hormonal therapy alone.
  c. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease.
  d. Adequately treated superficial cancer or carcinoma in situ without evidence of disease.
  e. Other malignancy with low risk of metastases which is unlikely to require systemic cancer therapy or reduce the patient’s survival time.
• Leptomeningeal carcinomatosis.
• Untreated, symptomatic central nervous system (CNS) metastases. Any neurologic symptoms that developed either as a result of the brain metastases or their treatment must have resolved or be stable either, without the use of steroids, or are stable on steroids and/or anticonvulsants prior to the start of treatment.
• History of active primary immunodeficiency.
• Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice), HIV, hepatitis B (known positive HBV surface antigen (HBsAg) result), hepatitis C. Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
• Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab. The following are exceptions to this criterion:
  a. Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection).
  b. Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent.
  c. Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication).
• Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note: Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to 30 days after the last dose of IP.
• Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 90 days after the last dose of durvalumab monotherapy.
• Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients.