Rationale and Design of the AUSTRAL trial: An Open-Label, Multicenter, Phase II Study Evaluating Radiotherapy Followed by Durvalumab (MEDI4736) and Ceralasertib (AZD6738) in Stage III NSCLC Patients With Thoracic Relapses and/or Oligometastases After the PACIFIC Regimen.

Non-small-cell lung cancer (NSCLC) is a leading cause of death for cancer worldwide. Standard treatment for patients for whom surgical resection is not feasible is concurrent (PACIFIC regimen) or sequential (PACIFIC-like regimen) chemoradiotherapy with platinum-based doublet chemotherapy followed by durvalumab maintenance. The progression-free survival (PFS) rate after the PACIFIC regimen was 55.3% at 12 months, with the primary site of recurrence being intrathoracic. In retrospective studies, a relevant proportion of patients presented a combination of intrathoracic failure and limited extra-thoracic metastatic disease. For patients with local progression only, or with loco-regional progression and limited metastatic burden, the use of chemotherapy or other agents without the addition of a local therapy may represent a missed opportunity for a second curative intent treatment approach. The AUSTRAL trial, a phase II, interventional, multicenter, single-arm, study (ClinicalTrials.gov identifier, NCT06680050) aims to investigate the combination of thoracic irradiation ± Stereotactic Body Radiation Therapy (SBRT) to oligometastatic sites followed, after 2 to 4 weeks, by durvalumab and ceralasertib, administered until progression or severe toxicity. The study population will include 21 stage III NSCLC patients with loco-regional relapse after >12 months from the end of CRT ± ≤3 metastatic lesions following PACIFIC/PACIFIC-like regimens. The study will last approximately 40 months and involve 7 Italian and 2 Swiss sites. Primary hierarchical endpoints are safety, assessed by the continuous toxicity monitoring approach, and efficacy, assessed by PFS. Secondary endpoints are objective response rate (ORR), 6- and 12-month PFS and OS rate.