Written by Dr Rachel Clarke, Oncology SPR, Dr Mark Doherty, Consultant Oncologist, St Vincent’s University Hospital
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.
Recently the U.S Food and Drug Administration (FDA) approved neoadjuvant nivolumab in combination with chemotherapy in operable NSCLC based on evidence from the phase 3 study Checkmate 813 study. This trial enrolled 505 patients in a 1:1 ratio to receive nivolumab with platinum chemotherapy vs chemotherapy alone for 3 cycles in stage IB to IIIA disease.11 The median event-free survival was 31.6 months with nivolumab plus chemotherapy and 20.8 months with chemotherapy alone regardless of PDL-1 score. It cited percentage of patients with a pCR was 24% versus 2.2% in the chemotherapy alone arm. The addition of immunotherapy did not negatively delay or impede surgery with a slightly higher proportion of the patients in the experimental arm successfully getting to resection (83% vs 75% in control arm).
Following this, results from the AEGEAN study were presented earlier this year. This was a randomized trial where 802 patients with resectable NSCLC, irrespective of PD-L1 expression were assigned to receive neoadjuvant platinum based chemotherapy with either durvalumab or placebo for 4 cycles. Following surgery patients continued on either durvalumab or placebo for a year. In total 77.6% of the treatment arm vs 76.7% of patients in placebo arm underwent surgery. The experimental group had a pCR rate of 17.2% vs 4.3% of the placebo group. After a median follow-up of 11.7 months, median event free survival (EFS) was not reached in the durvalumab arm vs 25.9 months in the placebo arm. Neither trial has yet been able to report mature survival outcomes and the gold standard of an overall survival analysis is awaited.
Despite the evidence above there are still multiple uncertainties surrounding neoadjuvant treatment in resectable NSCLC. Many of the trials discussed have had different end points (eg. MPR, pCR, median EFS and PFS) as well as different inclusion criteria in terms of staging. Another concern is the potential risk of nodal immune flare which may lead to patients being deemed unresectable due to nodal progression which may only be an immunotherapy treatment response. This phenomenon was observed in the NEOSTAR trial where some patients had observed stable disease or progressive nodal disease on imaging but pathologically were non caseating granulomas. Another unresolved issue is the optimal sequencing of treatment between neo-adjuvant, peri-operative or adjuvant. Both preclinical models and research in other tumour types have shown increased antitumour activity of immunotherapy in the neoadjuvant setting, but there is no current evidence that this translates into clinical benefit. Another question left unresolved is whether patients should have postoperative treatment after neoadjuvant immunochemotherapy, and whether we can move towards de-escalation of therapy. In these circumstances we could consider the utility of circulating tumour DNA testing although this is relatively unsupported at present. We are finally seeing the promise of immunotherapy translating into better curative treatment strategies for patients with lung cancer. Of course, there are still challenges to address due to the heterogeneity of patient factors (eg clinical stage, pathological alterations) as well as the optimal use and sequencing of diverse treatment strategies, but we expect that the importance of using immune checkpoint inhibitors in early stage lung cancer will continue to rise.
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2. NSCLC Meta-analysis Collaborative Group. Preoperative chemotherapy for non-smallcell lung cancer: a systematic review and meta-analysis of individual participant data. Lancet. 2014;383(9928):1561-1571
3. Mathey-Andrews C, McCarthy M, Potter AL, et al. Safety and feasibility of minimally invasive lobectomy after neoadjuvant immunotherapy for non-small cell lung cancer. J Thorac Cardiovasc Surg. 2023;166(2):347-355.e2. doi:10.1016/j.jtcvs.2022.12.006
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5. Carbone D, Lee J, Kris M, et al. OA06.06 Clinical/biomarker data for neoadjuvant atezolizumab in resectable stage IB-IIIB NSCLC: primary analysis in the LCMC3 study. J Thorac Oncol. 2021;16(suppl 3):S115-S116.
6. Wislez M, Mazieres J, Lavole A, et al. Neoadjuvant durvalumab for resectable non-small-cell lung cancer (NSCLC): results from a multicenter study (IFCT-1601IONESCO). J Immunother Cancer. 2022;10(10):e005636. doi:10.1136/ jitc-2022-005636
7. Cascone, T., William, W.N., Weissferdt, A. et al. Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial. Nat Med 27, 504–514 (2021). https://doi.org/10.1038/s41591020-01224-2
8. Provencio M, Nadal E, Insa A, et al. Neoadjuvant chemotherapy and nivolumab in resectable nonsmall-cell lung cancer (NADIM): an open-label, multicentre, single-arm, phase 2 trial. Lancet Oncol. 2020;21(11):14131422. doi:10.1016/S14702045(20)30453-8
9. Zhao ZR, Yang CP, Chen S, et al. Phase 2 trial of neoadjuvant toripalimab with chemotherapy for resectable stage III non-small-cell lung cancer. Oncoimmunology. 2021;10(1):1996000. Published 2021 Oct 25. doi:10.1080/216240 2X.2021.1996000
10. Rothschild SI, Zippelius A, Eboulet EI, et al. SAKK 16/14: Durvalumab in Addition to Neoadjuvant Chemotherapy in Patients With Stage IIIA(N2) Non-Small-Cell Lung Cancer-A Multicenter Single-Arm Phase II Trial. J Clin Oncol. 2021;39(26):2872-2880. doi:10.1200/JCO.21.00276
11. Forde PM, Spicer J, Lu S, et al. Neoadjuvant Nivolumab plus Chemotherapy in Resectable Lung Cancer. N Engl J Med. 2022;386(21):1973-1985. doi:10.1056/NEJMoa2202170
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