Perioperative nivolumab combined with neoadjuvant chemotherapy significantly improves the event-free survival of patients with resectable non-small cell lung cancer
Results of a prespecified interim analysis of the phase III CheckMate-77T trial demonstrate that a perioperative regimen consisting of neoadjuvant nivolumab plus chemotherapy followed by surgery and adjuvant nivolumab results in a statistically significant and clinically meaningful improvement in event free survival (EFS) compared with neoadjuvant chemotherapy plus placebo followed by surgery and adjuvant placebo in patients with resectable stage IIA to IIIB non–small cell lung cancer (NSCLC).
Background
The combination of nivolumab and chemotherapy is already an established neoadjuvant treatment for eligible patients with resectable NSCLC. However, a perioperative treatment approach in which this regimen is followed up by surgery and adjuvant nivolumab could potentially further reduce the risk of relapse and improve the outcome for patients with resectable NSCLC. To this end, the randomized, double-blind, phase III CheckMate 77T study compares a regimen consisting of neoadjuvant nivolumab + chemotherapy followed by adjuvant nivolumab (NIVO/chemo + NIVO) to neoadjuvant chemotherapy in combination with placebo followed by adjuvant placebo (chemo/PBO + PBO) as a treatment for patients with resectable stage II–IIIB NSCLC. During ESMO 2023, results of a preplanned, interim analysis for EFS were presented.
Study design
CheckMate 77T randomized a total of 461 patients with resectable stage IIA (> 4cm) to IIIB (N2) NSCLC (AJCC 8th edition) who did not receive no prior systemic therapy to receive 4 cycles of neoadjuvant nivolumab (360 mg q3w) or placebo in combination with chemotherapy. In patients with a non-squamous histology, the neoadjuvant chemotherapy consisted of cisplatin/carboplatin + pemetrexed, or carboplatin + paclitaxel, whereas patients with a squamous histology received either cisplatin + docetaxel or carboplatin + paclitaxel. Within 6 weeks following the end of the neo-adjuvant therapy, patients underwent surgery after which patients in the experimental and control respectively received 1 year of adjuvant therapy with nivolumab (480mg q4w for 1 year), or placebo. The primary endpoint of the study was EFS, with pathological complete response (pCR) rate, major pathological response (MPR), overall survival (OS) and safety as secondary objectives.
Results
Patient characteristics were well-balanced between the two treatment arms. The median age of patients in the study was 66 years, about 70% were male and 64% had stage IIIA-B disease at diagnosis. Furthermore, ~90% were current or former smokers and 40% had a PD-L1 tumor expression of less than 1%. In the NIVO/chemo + NIVO and chemo/PBO + PBO arms, respectively 85% and 89% of patients completed the neoadjuvant therapy after which 78% and 77% underwent surgery. Adjuvant therapy was initiated in 62% of patients in the NIVO/chemo + NIVO arm and in 66% in the chemo/PBO + PBO arm. The rate of R0 resection was comparable in both arms at 89% and 90%, respectively.
After a median follow-up of 25.4 months, the median EFS with chemotherapy alone was reported at 18.4 months, while the median was not yet been reached for patients receiving perioperative nivolumab. This corresponded to a 42% reduction in risk of disease progression, recurrence, or death for patients receiving the perioperative nivolumab regimen (HR[95%CI]: 0.52[0.42-0.81]; p= 0.00025). At 18 months, this translated into a 70% EFS rate for patients in the NIVO/chemo + NIVO arm as compared to 50% in the control arm. Furthermore, patients who received the perioperative nivolumab-based regimen also had a significantly higher rate of pCR (25.3% vs. 4.7%; OR[95%CI]: 6.64[3.40-12.97]) and MPR (35.4% vs. 12.1%; OR[95%CI]: 4.01[2.48-6.49]) compared to patients who did not receive perioperative nivolumab.
In an exploratory analysis, perioperative nivolumab favored EFS in patients with a pCR following neoadjuvant therapy, with a trend for an improved EFS in patients without a pCR. Among patients who were eligible for adjuvant therapy, perioperative nivolumab improved the EFS compared to chemo/PBO, regardless of the pCR status. Of note, neoadjuvant nivolumab + chemotherapy continued to provide a benefit over chemotherapy alone in patients who were unable to receive adjuvant therapy.
The data did not show any new safety signals with the perioperative nivolumab regimen, with a safety profile that was consistent with the known safety profiles of the individual agents. Grade ≥3 treatment-related side effects were observed in 32% and 25% of patients receiving the perioperative nivolumab regimen or control therapy, respectively. Surgery-related adverse events occurred in 12% of patients in both treatment arms.
Conclusions
Neoadjuvant nivolumab + chemotherapy followed by surgery and adjuvant nivolumab demonstrated statistically significant and clinically meaningful EFS improvement compared to chemo/PBO + PBO in patients with resectable NSCLC. As such, these data support perioperative nivolumab as a potential new treatment strategy for patients with resectable NSCLC.
Reference
Cascone T, et al. CheckMate 77T: Phase 3 study comparing neoadjuvant nivolumab plus chemotherapy with neoadjuvant placebo plus chemotherapy followed by surgery and adjuvant nivolumab or placebo for previously untreated, resectable stage II–IIIB NSCLC. Presented at ESMO 2023; Abstract LBA1.
