Neoadjuvant Immunochemotherapy for Resectable Lung Cancer

Immune checkpoint inhibitors have improved the outlook of metastatic non-small cell lung cancer (NSCLC) for many patients, with average survival times measured in years and over 25% of patients alive after 5 years.1 Given this success in advanced incurable disease, there has been a natural focus on its potential benefits in early stage lung cancer to improve the chances of cure. Several years ago, studies of neoadjuvant (preoperative) chemotherapy in resectable NSCLC showed only modest benefit.2 Apart from concerns regarding is efficacy, there was worry among thoracic oncologists and surgeons alike, that immunotherapy given prior to surgery would impact on surgical outcomes. This was disproven by retrospective data from the American National Cancer Registry suggesting similar surgical outcomes in patients treated with chemotherapy or immunotherapy in the neoadjuvant setting.3 Recently prospective trials have confirmed a benefit to this approach without a negative impact on surgery in what will become a new standard of care for selected patient groups.

The first prospective trial in 2018 studied the feasibility of giving two doses of neo-adjuvant Nivolumab in a small sample of 22 patients with resectable NSCLC, in which 45% of patients achieved major pathological responses.4 Other studies for example the LCMC-3 study, have evaluated atezolizumab in the neoadjuvant setting, giving two cycles prior to surgery with 20% rate of major pathological response.5 These studies and others looking at neoadjuvant immunotherapy showed improved outcomes including endpoints of overall response rate (ORR), disease free survival (DFS) and major pathological response (MPR), defined as <10% residual viable tumour after neo-adjuvant treatment.6 The NEOSTAR study compared neoadjuvant nivolumab with or without ipilimumab.7 This study met its primary endpoint, with improvement in MPR (38.1% vs 21.7%), as well as secondary endpoints of pathologic complete response (pCR; 28.6% vs 8.7%) and ORR (21.7% vs 19%) for the dual checkpoint inhibitor arm. Overall, studieslooking at combinationimmunochemotherapy appear more favourable compared with neoadjuvant immunotherapy alone. Three single arm phase 2 studies have been completed, in Spain, Switzerland and China, all studying the use of immune checkpoint inhibitors in combination with chemotherapy in the neoadjuvant setting. The NADIM II Trial enrolled 46 patients, 41 of whom underwent surgical resection and of these, 63% had pCR with no residual viable tumour in the resection specimen, and 83% had MPR.8 A Chinese trial of 30 patients with stage IIIa NSCLC who received toripalimab with chemotherapy reported pCR in 45.5% of patients and MPR in 60.6%.9 The Swiss cooperative group for Cancer Research (SAKK) trial of 67 patients reported MPR in 62% and pCR in 19%.10 In all of these trials, there was no impact on surgical complication rates. It is clear based on these results that a neoadjuvant approach results in major pathologic responses without jeopardising the safety or feasibility of surgery.