Intensified Chemo-immuno-radiotherapy With Durvalumab for Stage III Non-Small Cell Lung Cancers

Prospective, non-randomized, open label, single arm, multi-institutional, phase 2 study, including patients with stage III non-small cell lung cancer able to receive concurrent chemoradiation. Eligible patients will then receive treatment as follows:

Induction chemo-immunotherapy Two 21-day cycles of carboplatin, paclitaxel and durvalumab will be given BEFORE concurrent chemo-immuno-radiotherapy.

Thereafter, patients without progressive disease (or patients with disease progression that is still locally advanced and can be safely encompassed within tolerable radiation fields) will receive concurrent chemo-immuno-radiotherapy, as follows:

Concurrent chemo-immuno-radiotherapy Concurrent carboplatin, paclitaxel, and durvalumab with radiation therapy, initiated preferably 3-5 weeks after the last dose of induction chemo-immunotherapy.

Thereafter, patients without progressive disease will receive consolidation immunotherapy, as follows:

Consolidation immunotherapy Twelve 28-day cycles of durvalumab will be given, initiated preferably within one week following concurrent chemo-immuno-radiotherapy.

Inclusion criteria

• Histologically or cytologically confirmed non-small cell lung cancer.
• Stage III according to the American Joint Committee on Cancer (AJCC) Staging Manual, 8th edition.
• No prior systemic therapy, radiation therapy, or surgery for the current cancer.
• Age ≥ 18 years at time of study entry
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Body weight >30kg
• Pre- or post-bronchodilator forced expiratory volume 1 ≥ 1.2 litres/second or ≥ 50% of predicted value
• Adequate normal organ and marrow function

Exclusion criteria

• Patients whose radiation treatment is likely to encompass a volume of whole lung receiving ≥ 20 Gy in total of more than 35% of lung volume.
• Patients whose radiation treatment is likely to deliver a cardiac dose V50 > 25%
• Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients
• Participation in another clinical study with an investigational product with anti-neoplastic activity during the last 3 weeks prior to treatment initiation
• 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
• History of allogenic organ transplantation.
• 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
• Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab.
• Prior randomisation or treatment in a previous durvalumab clinical study regardless of treatment arm assignment.
• Patients who have received prior anti-PD-1, anti PD-L1 or anti CTLA-4 antibodies
• Receipt of live attenuated vaccine within 30 days prior to the first dose of investigational product.
• Prior radiation therapy to the region of the study cancer that would result in overlap of radiation therapy fields.
• Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of the investigational product.
• Active or prior documented autoimmune or inflammatory disorders
• Uncontrolled intercurrent illness
• History of another primary malignancy
• Known active infection including tuberculosis , hepatitis B, hepatitis C, or human immunodeficiency virus.