Phase Ib study of neoadjuvant concurrent chemoradiation plus durvalumab followed by surgery and adjuvant durvalumab for resectable stage III NSCLC.
Authors: Lee Jiyun , Cho Jaeho , Lee Chang , Lee Chang Young , Lee Jin Gu , Kim Dae Joon , Shim Hyo Sup , Lim Sun Min , Kim Hye Ryun , Cho Byoung Chul , Hong Min Hee 
Published: June 2023

8556 Background: The use of neoadjuvant and adjuvant immunotherapy in resectable non-small cell lung cancer (NSCLC) has become a standard of care. However, the integration of immunotherapy into a trimodality treatment regimen has not been widely explored. We hypothesized that adding durvalumab to neoadjuvant concurrent chemoradiation and surgery would not increase treatment-related adverse events (TRAE) during neoadjuvant period. Methods: This was a prospective, single center, single-arm, open-label phase Ib study. Patients with resectable, stage III N2 NSCLC received concurrent chemoradiation [weekly paclitaxel (45mg/m2)/carboplatin (AUC 2.0) for 5 weeks with radiotherapy 45Gy] and durvalumab 1,500mg Q4W for 2 cycles followed by surgical resection and adjuvant durvalumab for 1 year. The primary endpoint was the frequency of patients who experience grade 3 or more TRAE during neoadjuvant therapy based on CTCAE 4.03. Results: Of 30 patients (median age 65.5 years; 67% male), 56.7% had squamous histology and 60.0% had stage IIIA. Any grade AEs and TRAEs (neoadjuvant/adjuvant) were reported in 83.3%/76.7% and 70.0%/63.3% of patients, respectively. Grade 3 or more AEs and TRAEs (neoadjuvant/adjuvant) were reported in 10.0/3.3% and 10.0%/0.0%, respectively. Grade 3 or more TRAE reported during neoadjuvant treatment were neutropenia, anemia, and nausea, one each; no Grade 5 AEs occurred. Surgical resection was not performed in three patients: two due to treatment-related adverse events (AEs) and one due to patient refusal. Among 27 patients who received complete resection, the pathologic complete response (pCR) rate and major pathologic response (MPR) rate were 40.7% (95% CI, 22.4 – 61.2) and 74.1% (95% CI, 53.7 – 88.9), respectively. Excluding four patients with EGFR, ALK, KRAS G12C, or MET ex14skipping mutations, the pCR rate was 47.8% (95% CI, 26.8 – 69.4) and MPR rate was 87.0% (95% CI, 66.4 – 97.2). Overall, pathologic downstaging was achieved in 70.4% (95% CI, 49.8 – 86.2). Objective response rate according to RECIST v1.1 was 50.0% (95% CI, 31.3 – 68.7). One patient delayed the schedule for surgical resection due to radiation pneumonitis (G2), unrelated to the drug administered. Otherwise, there were no peri-operative mortality or morbidity. All patients who underwent surgery, except one whose disease progressed immediately after resection, received at least one dose of adjuvant durvalumab; 61.5% completed 1-year treatment, 11.5% were continuing treatment, 11.5% discontinued due to AE, and 11.5% discontinued due to disease progression at the time of data cutoff. Grade 3 or more TRAE reported during adjuvant treatment were radiation pneumonitis and proteinuria, one each. Conclusions: This study confirms the manageable safety profile of adding durvalumab to neoadjuvant concurrent chemoradiation for treatment of resectable stage III NSCLC. Clinical trial information: NCT03694236 .