Association of early immune-related adverse events with treatment efficacy of neoadjuvant Toripalimab in resectable advanced non-small cell lung cancer

Abstract

BackgroundNeoadjuvant immunotherapy with anti-PD-1 was proved promising in resectable non-small cell lung cancer (NSCLC). Immune-related adverse events (irAEs) have been preliminarily implicated their association with treatment efficacy. Here we elucidated the early onset of irAEs associated with better clinical outcomes in a prospective study (Renaissance study).MethodsWe conducted the prospective study of NSCLC patients treated by neoadjuvant Toripalimab (240mg, every 3 weeks) plus double platinum-based chemotherapy from December 2020 to March 2022 at Peking University Cancer Hospital. Patients were enrolled if they have resectable IIB-IIIB NSCLC without EGFR/ALK mutation. Data were analyzed to explore the relationship between clinical outcome and irAEs after neoadjuvant treatment. A multidisciplinary team including physicians, surgeons, and radiologists, confirmed the irAEs according to the clinical manifestation. The relationship between irAEs and pathological outcomes was analyzed. The Renaissance study was approved by the Peking University Ethic board (2020YJZ58) and registered at https://clinicaltrials.gov/ as NCT04606303.ResultsFifty-five consecutive patients were enrolled with a male-to-female ratio of 10:1, the median age was 62 years old (IQR: 45-76), of which 44 patients (80%) were diagnosed with squamous cell carcinoma. Forty-eight of 55 patients finally received thoracic surgery with a median preoperative waiting time of 67 days (IQR 39-113 days). Pathological results demonstrated that 31 (64.6%) patients achieved major pathological response (MPR) and 24 (50.0%) achieved complete pathological response (pCR). Among 48 patients who received R0 resection, immunotherapy-related thyroid dysfunction, rash/pruritus and enteritis occurred in 11 patients (22.9%), 7 patients (14.6%), and 1 patient (2.1%), respectively. Six patients (54.5%) with thyroid dysfunction achieved MPR with 5 (45.5%) achieved pCR, and a median time to onset was 45 days (IQR 21-91 days). Six patients (85.7%) with rash or pruritus achieved MPR and 5 patients (71.4%) achieved pCR, with median time to onset being 8 days (IQR 6-29 days). Furthermore, irAEs had no significant influence on operation time (170.6 min vs 165.7 min, P=0.775), intraoperative blood loss (67.4 mL vs 64.3 mL, P=0.831) and preoperative waiting time (93 days vs 97 days, P=0.630) when comparing with patients without irAEs (Figure 1).ConclusionThe immunotherapy-related rash is potentially associated with pathological outcomes in NSCLC patients after neoadjuvant chemo-immunotherapy, suggesting easy-to-find irAEs, such as rash, can be used as indicators to predict response to neoadjuvant chemo-immunotherapy.Clinical trial registrationclinicaltrials.gov/, identifier NCT04606303.

Neoadjuvant Chemoimmunotherapy for NSCLC

“…Overall, there was a low risk of bias among RCTs, with bias arising due to unbalanced treatment arms in 1 study and potentially multiple analyses of the same data in another study (eFigure 2 in Supplement 1). For nonrandomized studies, bias concerns were mostly associated with inadequate length of follow-up (eTable 4 in Supplement 1).…”

“…After title and abstract screening, 519 studies were excluded, and an additional 41 studies were removed after full-text screening. A total of 42 publications and 6 abstracts met inclusion criteria, including 43 trials and 5 follow-up studies, from which we extracted 54 study arms; 5431 patients were included overall in the 43 trials (4020 males [74.0%]; median age range, 55-70 years) (Table; eTable 3 and eFigure 1 in Supplement 1). There were 8 RCTs comparing neoadjuvant chemoimmunotherapy with chemotherapy, namely CheckMate 816, KEYNOTE-671, NADIM II, AEGEAN, Neotorch, Checkmate 77T, TD-FOREKNOW, and RATIONALE 315 (Table).…”

“…Across 3387 patients (2582 males [76.2%]; median age range, 61-66 years) included in 8 RCTs, there were 1688 patients (49.8%) treated with chemotherapy, 1699 patients (50.2%) treated with chemoimmunotherapy, 1882 patients (55.6%) who had squamous histology, and 2443 patients (72.1%) who had stage III disease. Across all studies, there were 27 neoadjuvant chemotherapy and 27 neoadjuvant chemoimmunotherapy arms; 21 arms included only patients with stage III disease. Studies ranged from 10 patients to 400 patients per arm, and there were 2347 patients assigned to neoadjuvant chemoimmunotherapy and 3084 patients assigned to neoadjuvant chemotherapy.…”

“…With regard to histology, 2767 patients had squamous cell carcinoma, with the remaining patients having nonsquamous histologies. For neoadjuvant chemoimmunotherapy studies, there were 533 patients treated with nivolumab, 434 patients treated with pembrolizumab, 433 patients treated with durvalumab, 381 patients treated with toripalimab, 226 patients treated with tislelizumab, 169 patients treated with sintilimab, 46 patients treated with ipilimumab, 43 patients treated with camrelizumab, 37 patients treated with adebrelimab, 30 patients treated with atezolizumab, and 15 patients treated with avelumab. For 11 studies, more than a single arm was extracted per study.…”

“…We also compared these clinical variables across all trials, including RCTs and nonrandomized single-arm trials . For single-arm studies, there was also a significantly higher MPR and pCR for chemoimmunotherapy than chemotherapy (eFigures 27-28 in Supplement 1).…”