Durvalumab and Chemotherapy Induction Followed by Durvalumab and Radiotherapy in Large Volume Stage III NSCLC

Exclusion Criteria

• •* Total mean lung dose (Right Lung+Left Lung-GTV) \< 20 Gy and/or
• •* Lung V20 defined as percentage of normal parenchyma receiving 20 Gy or more (Right Lung+Left Lung-PTV) \< 35%
• •* Heart V45 \<30% and/or Mean Heart Dose \<20 Gy
• •If the dosimetry criteria are met, other clinical conditions for avoiding concurrent chemoradiation are:
• •* Bilateral supraclavicular involvement
• •* Contralateral mediastinal and/or hilar involvement
• •* Primary tumor \> 7 cm or several nodules in different lobes of the same lung or bulky mediastinal lymphonodes.
• •6. Tumor sample requirements: availability of an archived tumour tissue block (or unstained slides to perform local PDL1 assessment following protocol procedure)
• •7. Patient's willingness to undergo blood draws to provide plasma and blood samples for analysis according to study objectives
• •8. Patients without history of previous radiotherapy. Patients with previous radiotherapy performed to the thorax, including radiotherapy for breast cancer, especially in the last 10 years, have to be discussed case by case in the Multidisciplinary Team Meeting
• •9. Life expectancy ≥12 weeks at the start of treatment
• •10. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• •11. Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply:
• •1. Women \<50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle- stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy).
• •2. Women ≥50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses \>1 year ago, had chemotherapy-induced menopause with last menses \>1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy).
• •12. Patient 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.
• •13. Adequate normal organ and marrow function as defined below:
• •* Haemoglobin ≥9.0 g/dL (5.59 mmol/L)
• •* Absolute neutrophil count (ANC) \> 1.5 x 109/L (\> 1500/mm3)
• •* Platelet count ≥100 x 109/L (100000/mm3)
• •* Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN). This will 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), who will be allowed only in consultation with their physician.
• •* AST (SGOT)/ALT (SGPT) ≤2.5 x institutional upper limit of normal
• •* Adequate renal function defined as normal serum creatinine levels or calculated creatinine clearance (according to Cockroft-Gault or by 24 hour-urine collection): ≥60 ml/min for patient receiving cisplatin ≥45 ml/min for patient receiving carboplatin.
• •14. Body weight \> 30 Kg
• •15. Absence of a known severe hypersensitivity (≥ Grade 3) to any of the study chemotherapy agents and/or to durvalumab and/or to any of their excipients.
• •FOR PART 2 (RADIOTHERAPY CONCURRENTLY WITH DURVALUMAB):
• •1. Absence of progressive disease by RECIST 1.1 together with evidence of tumor shrinkage at the evaluation conducted at the end of part 1. Whether the degree of tumor shrinkage will be sufficient to consider the patient eligible for part 2 will be discussed in a web multidisciplinary team among involved CCE centers.
• •2. ECOG Performance Status of 0 - 1
• •3. Absence of dyspnea of minimal exertion or oxygen requirement after CT+D
• •4. Sufficient PFTs performed after the last cycle of CT+D:
• •* FEV1 \> 1L or ≥ 30%
• •* DLCO \> 30%
• •5. The patient's dosimetry must meet the following constraints to organs at risk (Kong 2011, Marks 2010, De Ruysscher 2017, Marks 2010, Gagliardi 2010, Wang 2017, Antonia 2017, Kirkpatrick 2010):
• •* Spinal cord maximum dose \< 50 Gy
• •* Total mean lung dose (Right Lung+Left Lung-GTV) \< 20 Gyand/or
• •* Lung V20 defined as percentage of normal parenchyma receiving 20 Gy or more (Right Lung+Left Lung-PTV) \< 35%
• •* Heart V45 \<30% and/or Mean Heart Dose \<20 Gy
• •6. In case of dosimetry criteria met before part 1, confirmed resolution of clinical condition(s) that led to initial inegibility. The resolution of the clinical condition is discussed in the multidisciplinary team, at least 2 out of 3 CCE must agree.
• •FOR PART 3 (MAINTENANCE WITH DURVALUMAB):
• •1. Evidence of partial response or stable disease at the evaluation conducted at the end of Part 2
• •2. Absence of grade 2-3 pneumonitis
• •1. Stage IV NSCLC
• •2. Patient amenable to curative intent surgery or concurrent chemoradiation
• •3. Mixed small cell and non-small cell lung cancer histology
• •4. Patients who already received therapy for locally advanced NSCLC
• •5. Dyspnea of minimal exertion or oxygen requirement
• •6. Recent medical history of cardiac events during the last 6 months (ischemic or congestive heart failure)
• •7. Pancoast tumors
• •8. Prior exposure to any anti-PD-1 or anti-PD-L1 antibody, including durvalumab
• •9. Participation in another clinical study with an investigational product during the last 4 weeks, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study
• •10. Any concurrent chemotherapy, immunotherapy, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone replacement therapy) is acceptable.
• •11. Active or prior documented autoimmune disease within the past 2 years 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:
• •1. Patients with vitiligo or alopecia
• •2. Patients with Grave's disease not requiring systemic treatment within the past 2 years
• •3. Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement
• •4. Any chronic skin condition that does not require systemic therapy (e.g. patients with psoriasis not requiring systemic treatment within the past 2 years)
• •5. Patients without active disease in the last 2 years may be included but only after consultation with the study physician
• •6. Patients with celiac disease controlled by diet alone
• •12. Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, active bleeding diatheses, ongoing or active infection, including any patient known to have evidence of acute or chronic hepatitis B (positive HBV surface antigen (HBsAg) result), hepatitis C, human immunodeficiency virus (HIV) (positive HIV 1/2 antibodies) or tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice), psychiatric illness/social situations that would limit compliance with study requirements or compromise the ability of the patient to give written informed consent. \[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.\]
• •13. History of another primary malignancy except for
• •1. Malignancy treated with curative intent and with no known active disease ≥3 years before the first dose of study drug and of low potential risk for recurrence
• •2. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
• •3. Adequately treated carcinoma in situ without evidence of disease, e.g. cervical cancer in situ
• •4. Superficial bladder cancer without evidence of disease
• •14. 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