Discussion
NSCLC, tumor, trauma
RECURRENCES, DISEASE PROGRESSION, TUMOR, ADVERSE EVENTS, DISEASE, IMMUNE-MEDIATED PNEUMONITIS, NSCLC, RESIDUAL DISEASE
Our study is the first prospective investigator-initiated study examining the roles of PD-L1 expression in neoadjuvant N and N/C efficacy. Both the prespecified subgroups, with an overall 50% MPR rate, met the primary endpoint. Our results further demonstrated that, even in resectable NSCLC with PD-L1 expression ≥ 50%, neoadjuvant N resulted in a significantly lower MPR rate than N/C (16.7% vs. 66.7%). Other key outcomes, including radiographic objective responses and pathological complete responses, also favored N/C, regardless of PD-L1 expression at the tumor baseline. In further exploratory analysis, ctDNA clearance prior to surgery was also more common among the patients receiving N/C and was significantly associated with pCR. Moreover, the continued reduction in postoperative ctDNA detection indicated the necessity of surgery as well.As the goal of early-stage NSCLC treatments is curing the disease, one of the main objectives of neoadjuvant treatments is to increase resectability. Therefore, radiographic responses are crucial for evaluating efficacy owing to their critical correlation with surgical feasibility. The other main goal should be to elevate MPR and/or pCR, which has been considered a promising predictor of survival benefits.Surgical outcomes were also acceptable with immunochemotherapy, with greater use of minimally invasive surgery, fewer surgery cancellation (including disease progression), and less pneumonectomy cases, which is a type of surgery typically characterized by trauma and a poorer prognosis. In the CheckMate-816 trial, only 30% of enrolled patients underwent minimally invasive surgery, whereas 95.7% underwent this procedure in this study. This is similar to our previous neoadjuvant immunotherapy trial, which showed that minimally invasive surgery is feasible after neoadjuvant immunochemotherapy.The safety profile was in accordance with that of previous reports. The onset of only one case of grade 5 immune-mediated pneumonitis occurred one cycle after neoadjuvant immunochemotherapy, despite optimal medical management. Moreover, nivolumab did not hinder the surgery feasibility or increase surgery-related adverse events when added to neoadjuvant chemotherapy. Overall, considering its safety, surgical feasibility, and efficacy, nivolumab combined with chemotherapy is a rational choice for the neoadjuvant setting.However, no associations between the pathologic response and the baseline PD-L1 expression in patients receiving immunochemotherapy were observed, being consistent with those found in the NADIM study.Perioperative ctDNA detection is minimally invasive to detect MRD and relapse risk stratification of early-stage NSCLC.In this study, post-treatment ctDNA status was significantly correlated with pathological responses. ctDNA clearance prior to surgery was also more common among the patients receiving immunochemotherapy, and was significantly associated with pCR. As pCR is a promising early indicator of survival efficacy in the patients with resectable NSCLC, ctDNA clearance during neoadjuvant therapy might serve as an early candidate predictor for favorable outcomes. Additionally, patients with ctDNA negativity at both post-neoadjuvant and post-surgery time points achieved a significantly higher 18-month EFS rate than patients who remained ctDNA-positive at either time point. Thus, the combined detection of MRD after the completion of neoadjuvant treatment and surgical practices might assist in identifying the patients who potentially have already been cured and do not require a 12-month-course adjuvant therapy.We acknowledge that the current study is associated with limitations including its relatively short follow-up duration and relatively small sample size. Regarding neither the median EFS nor OS was reached, the interpretation of the survival outcomes might be limited. Additionally, a longer follow-up period is essential for capturing the clinical benefits of post-neoadjuvant ctDNA clearance and post-surgery MRD status in patients with a more favorable prognosis. We have since expanded this study to include perioperative monitoring of ctDNA focusing on prediction of recurrences and detection of residual diseases. Longitudinal plasma samples were also prospectively collected to assess post-surgical MRD status. Data on longitudinal MRD detection was exploratory and will be presented elsewhere. It should be noted that, owing to the limited MPR rate of 18.2% induced by neoadjuvant nivolumab alone, we merely recommend neoadjuvant nivolumab combined with chemotherapy in the expanded cohort (NCT04015778). If validated, dynamic evaluations of ctDNA by liquid biopsy might facilitate individualize perioperative treatment to maximize the curing possibility and avoid the risk of overtreatment.In conclusion, neoadjuvant immunochemotherapy is a standard therapeutic approach for patients with resectable NSCLC. Moreover, ctDNA analysis at both post-surgery and post-neoadjuvant treatment time points could help identify superior pathological responses and survival benefits, which requires a prospective clinical trial (NCT04015778) for further confirmation.