The opening gambit: CheckMate 159 and the immunotherapy neoadjuvant era in non-small cell lung cancer

Introduction

Non-small cell lung cancer (NSCLC) accounts for up to 85% of all lung cancer diagnoses and is a leading cause of morbidity and mortality worldwide (1). The majority of cases are diagnosed at an advanced stage, but up to 25% present with resectable disease, which holds potential for a cure (2). In the following years, this percentage could increase due to the adoption of screening programs (3). Unfortunately, the prognosis after surgery alone is not encouraging, with 5-year survival rates as low as 36% for stage IIIA disease (4).

Multimodality treatment has been the standard of care for patients diagnosed with resectable disease whose tumour size is higher than 4 cm or with node positive disease. Cisplatin-base adjuvant chemotherapy consistently shows an increase in overall survival (OS), though the absolute survival benefit is 5.4% at 5 years, accompanied by a significant incidence of adverse events (AEs) (5). This highlights the need for more effective treatment strategies which could improve patient outcomes in this setting.

Immune checkpoint inhibitors (ICIs) against the programmed cell death protein 1 (PD-1) and programmed death ligand 1 (PD-L1) have revolutionised the treatment landscape of metastatic or advanced NSCLC without targetable mutations, either alone or in combination with chemotherapy (6). It has also been demonstrated to improve the outcomes of patients diagnosed with locally advanced disease when an anti-PD-L1 was administered after chemoradiotherapy (7). Therefore, its inclusion in the perioperative setting deserved exploration.

Trial design

CheckMate 159 was a phase Ib/II, single arm, pilot study that for the first time tested the addition of immunotherapy in the neoadjuvant setting for resectable NSCLC (8). It evaluated two cycles of nivolumab (an anti-PD-1 ICI) at a dose of 3 mg per kilogram of body weight every two weeks, with surgical intervention occurring 4 weeks after the first dose. The primary objectives of the trial were to assess the safety and tolerability of the regimen.

Initial results

The initial results were published in 2018 (8). In total, 21 patients were included in the study, with stages between I and IIIA [American Joint Committee on Cancer (AJCC) 7th edition], and of whom the majority (68%) were diagnosed with adenocarcinoma. The main findings showed that preoperative nivolumab did not significantly delay surgery and that almost half of the tumours had experienced a major pathological response (MPR), defined as less than ten percent residual viable tumour in the surgical sample.

Update

Rosner et al. have recently published the five-year outcomes of the trial (9). This represents the longest follow-up data ever released from a neoadjuvant immunotherapy trial. Disseminating these findings is crucial, as long-term assessment is key for accurately evaluating clinical outcomes in the perioperative setting and for identifying delayed immune-related toxicities. The study also presents some interesting subgroup data besides providing long-term clinical outcomes.

Although the number of patients included in the trial was small, it is worth noting that 5-year recurrence-free survival (RFS) and OS were 60% and 80%, respectively. Interestingly, the study presents the survival data of patients with and without an MPR. As previously reported, almost half of the patients in the trial obtained an MPR (45%) (8). Notably, 89% of those MPR patients had not experienced recurrence or death at 5-year follow-up. While neoadjuvant chemotherapy has demonstrated a correlation between MPR and OS (10), this relationship with immunotherapy remains less clear and has not yet been validated (11). These results could point towards a similar association, but we will have to wait until have the long-term outcomes of the phase III randomized trials to obtain a definite conclusion.

There are some significant limitations regarding the different outcomes between patients with and without MPR. Some of them are inherent to an early phase trial with few patients, but others deserve further comment. Although the sociodemographic characteristics of the groups were similar, some clinical features were imbalanced. First, more patients with a stage IIIA tumour were included in the group that did not obtain an MPR, which bestows per se a worse prognosis. Furthermore, the number of never smokers and patients with squamous cell carcinoma were also higher in the group without MPR, which could act as confounding variables.

The authors also present an analysis of RFS stratifying patients by their pre-treatment tumour PD-L1 status (<1% vs. ≥1%). It showed a trend towards improved outcomes in patients with PD-L1 positive tumours, which did not reach statistical significance. Those results align with the knowledge generated by the trials in the metastatic setting, showing that PD-L1 is a predictive factor of efficacy for ICI. Notably, 6 patients had unknown PD-L1 status, and those were mostly present in the group that achieved MPR, which could confound the analysis.

Seven patients experienced recurrence and 4 of those events occurred later than one-year post-surgery, demonstrating the importance of obtaining long-term follow-up data for perioperative trials. The authors also presented the molecular analysis of those patients, with some interesting findings like STK11 mutation in one case or driver mutations like ROS1, NRG1 fusion, and KRAS G12C in three patients.

Long term follow up did not change the AE profile (9). The initial publication identified treatment-related AEs in 5 of 21 (23.8%) patients, and only 1 grade 3 event (8). Importantly, there were no AEs that led to delayed surgery (9). The update has only shown one late-onset AE, which appeared 16 months after the last nivolumab dose and consisted of a grade 3 dermatological immune-related AE (9).

Comparative analysis

This trial was the first of a number of studies looking at perioperative immunotherapy. In the following years, several phase II trials were conducted with different combinations of immunotherapies. Overall, the MPR rates and the pathological complete response (pCR) rates ranged between 11–45%, and 4–29% (12), respectively, confirming the activity of ICIs in this setting.

The subsequent logical step involved incorporating immunotherapy into the perioperative setting alongside chemotherapy, which, as previously mentioned, has been the standard of care for decades.

The first phase III trial showing better outcomes with this strategy was the study Checkmate 816, which demonstrated longer event-free survival (EFS) [hazard ratio (HR) 0.63; 97.38% confidence interval (CI): 0.43 to 0.91; P=0.005] and higher pCR rates [24% vs. 2.2%; odds ratio (OR) 13.94; 99% CI: 3.49 to 55.75; P<0.001] of the combination of chemotherapy and nivolumab vs chemotherapy alone (13). Afterward, several phase III trials confirmed longer EFS for the combination ICI plus chemotherapy vs chemotherapy alone: pembrolizumab (14), durvalumab (15) and toripalimab (16). As shown in Table 1, the MPR rates of the trials were between 24% and 48%, while the MPR rate of Checkmate 159 was 45%.

Many questions remain unanswered regarding perioperative immunotherapy strategies. Firstly, similar results of the phase III trials preclude drawing definitive conclusions about the advantages of the neoadjuvant regimen in Checkmate 816 versus the perioperative approaches in Keynote 671 (14), Aegean (15), and Neotorch (16).

Secondly, it remains unclear if ICI alone could be a feasible strategy for some patients. As Rosner et al. highlight in the paper, it may be reasonable to test this regimen vs chemoimmunotherapy in patients with high expression of PD-L1 and/or low risk disease (stage I–II), but this question should be addressed in well-designed prospective trials.

Conclusions

CheckMate 159 remains a landmark study evaluating neoadjuvant immunotherapy for NSCLC. Its findings have set the stage for subsequent trials exploring both immunotherapy and chemoimmunotherapy. The long-term outcomes presented by Rosner et al. are a valuable contribution to our growing body of knowledge in this evolving landscape.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-23-37/prf

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-23-37/coif). R.C. reports grants paid to institution from Roche, AstraZeneca, Pfizer, Clovis, Lilly Oncology, MSD, BMS, Abbvie, Takeda, Janssen, Novartis, and has received consulting fees from AstraZeneca, Boeringher Ingelheim, Lilly Oncology, Roche, Pfizer, MSD, BMS, Takeda, Janssen, Bayer, Novartis, and holds stock or stock options of The Christie Private Care. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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