1477TiP - A phase Ib trial of neoadjuvant chemoradiotherapy and durvalumab (MEDI4736) for potentially resectable stage III non-small cell lung cancer (NSCLC)

Abstract

BackgroundAlthough definitive concurrent chemoradiotherapy (CRT) is considered standard of care for most of stage III NSCLC patients, neoadjuvant treatment followed by surgery can be considered for some potentially resectable patients. Rationales for neoadjuvant treatment are tumor regression effect before surgery, early eradication of micrometastasis and better tolerability of chemotherapy than in the post-surgical setting. Regarding potential benefits of combining PD-1 blockade with CRT, here we have an ongoing phase Ib trial which assesses the safety and feasibility of the combination of neoadjuvant CRT with durvalumab in potentially resectable stage III NSCLC (NCT03694236). Trial designEligible patients with histologically confirmed NSCLC (potentially resectable clinical stage III according to the American Joint Committee on Cancer 8th staging system) are enrolled. Patients receive CRT (weekly paclitaxel 45mg/m2 and carboplatin AUC 2 with radiotherapy of 45Gy in 25 fractions) and durvalumab (Day 1 and 29, 1500mg) during 5 weeks followed by surgery. After surgery, patients are treated with durvalumab for one year (every 4weeks, 1500mg). The primary endpoints are safety and tolerability. The secondary endpoints are objective response rate (ORR), R0 resection rate, disease-free survival (DFS), overall survival (OS), clinical or pathological downstaging rate and, pathologic complete response (pCR) rate in the primary tumor. Immune marker analysis by FACS, exome sequencing and RNA sequencing using cancer tissue of pre-treatment, after surgery, and after recurrence will be performed.Table1477TiPTableSteps of trialNo. of patientsConsiderationsNeoadjuvant (weekly paclitaxel 45mg/m2 and carboplatin AUC 2, radiotherapy 45Gy in 25 fractions, durvalumab day 1 and 29, 1500mg)Stage 1191) If patients of≥5 has grade≥3 TRAE the trial holds 2) If patients of≤4 has grade≥3 TRAE the trial proceeds to the 2nd stage.Stage 221If patients of≤13(43%) has grade≥3 TRAE during the neoadjuvant treatment it will be considered tolerable and further analysis will be performed.2SurgeryThe time and modality of surgery will depend on the surgeon’s discretion. The maximum allowed interval between the end of neoadjuvant therapy and surgery is 9 weeks. If disease progresses during or after the neoadjuvant therapy, or if the surgeon thinks that the surgery is not feasible, concurrent chemoradiation or chemotherapy alone can be continued.Adjuvant (durvalumab 1500mg for one year every 4 weeks, total of 13 times.)The maximum allowed interval between the surgery and adjuvant therapy is 12 weeks.Follow upResponse evaluation will be done until 5 years after the surgery.3 (Chest CT every 3 months, Abdominal pelvic CT at 1, 2, 5 years after the surgery)1Additional enrollment will be hold until the first 9 patients proceeds surgery.2Grade≥3 TRAE during neoadjuvant chemoradiotherapy is expected to be 30∼50% according to the previous data.3Assessed according to the Response Evaluation Criteria in Solid Tumors(RECIST), version 1.1. TRAE; treatment-related adverse event, CT; Computed tomography. Clinical trial identificationNCT03694236. Legal entity responsible for the studyThe authors. FundingAstraZeneca. DisclosureAll authors have declared no conflicts of interest.