PERIOPERATIVE IMMUNOTHERAPY in resectable NSCLC

The AEGEAN and Checkmate 77T trials investigated perioperative chemotherapy combined with immunotherapy in patients with resectable non-small cell lung cancer (NSCLC). Previous data showed an improvement in event-free survival (EFS) with the addition of either durvalumab or nivolumab to neoadjuvant chemotherapy. Following surgery, patients received one year of adjuvant durvalumab or nivolumab.

A significant discussion in the medical community over the past two years has centered around the definition of resectable NSCLC, particularly in stage III and N2 disease. Historically, N2 disease was considered unresectable, but recent perioperative trials with immunotherapy have challenged this notion. The key issue is whether surgery can improve survival in patients with N2 disease. Previous trials comparing surgery to chemoradiotherapy in this group did not show a survival advantage with surgery. In response, the EORTC Lung Cancer Group launched an initiative to define resectability in stage III NSCLC. They proposed that patients with single-station N2 disease are eligible for surgery within the context of a trial, while those with multiple-station N2 disease remain an area of ongoing research and debate.

We now have data from the AEGEAN and Checkmate 77T trials, in addition to previous data from the NADIM2 and Keynote 671 trials, demonstrating that patients with N2 disease benefit from the combination of chemotherapy and immunotherapy. In the AEGEAN trial, half of the patients had N2 disease, with 80% having single-station N2 and 20% having multiple-station N2. In the Checkmate 77T trial, two-thirds of the patients had N2 disease. Both trials showed similar pCR rates between N2 and non-N2 populations. In AEGEAN, the pCR rate was 17% for both groups, while in Checkmate 77T, it was 22% for N2 and 26% for non-N2. Interestingly, within the N2 group, single-station N2 had a 19% pCR, and multiple-station N2 had a 29% pCR, though these small numbers do not allow for direct comparisons.

Regarding surgery, the AEGEAN trial data indicated a slightly lower proportion of N2 patients undergoing surgery (74% in N2 vs. 78% overall), but these differences were minimal. 

The crucial point is survival data. The AEGEAN trial showed a hazard ratio of 0.68 for EFS in the overall population, 0.61 for single-station N2, and 0.69 for multiple-station N2, indicating no significant difference in benefit. Similarly, in the Checkmate 77T trial, the hazard ratio for EFS was 0.46 for N2 and 0.60 for non-N2, with overlapping confidence intervals suggesting no statistically significant difference. These results reinforce the oncological resectability of N2 disease, indicating that surgery may benefit these patients when combined with immunotherapy. 

However, several questions remain. Pathological assessment of N2 was recommended but not mandatory in both trials, meaning some patients classified as N2 might not have had lymph node disease. Additionally, specific details about the N2-multiple disease, such as the number of stations affected and their locations, were not provided. Information on whether patients with small or bulky N2 disease were included is also lacking. These details are crucial for informing future trials and clinical practice.

Although the AEGEAN and Checkmate 77T regimens are not yet approved in Belgium, other approved regimens, such as the perioperative pembrolizumab from the Keynote 671 trial, also show promising results for N2 disease. A soon-to-be-published pooled analysis of EFS benefit in N2 disease shows a hazard ratio of 0.59, indicating a long-term benefit of adding immunotherapy for these patients.

In conclusion, the evidence suggests that patients with resectable N2 disease should receive upfront chemotherapy plus immunotherapy as an induction regimen, potentially improving their long-term outcomes.