Adjuvant immune checkpoint inhibitor therapy for resected non-small-cell lung cancer: dessert, starters, or a sandwich?

Immune checkpoint inhibitor (CPI) therapy has transformed advanced and inoperable stage 3 non-small-cell lung cancer (NSCLC) outcomes. For operable early-stage NSCLC, despite a high relapse rate of 60% by 5 years,1Pignon J.P. Tribodet H. Scagliotti G.V. et al.LACE Collaborative GroupLung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group.J Clin Oncol. 2008; 26: 3552-3559Crossref PubMed Scopus (1930) Google Scholar adjuvant chemotherapy only modestly improves the 5-year overall survival (OS) rate by 5.4%,1Pignon J.P. Tribodet H. Scagliotti G.V. et al.LACE Collaborative GroupLung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group.J Clin Oncol. 2008; 26: 3552-3559Crossref PubMed Scopus (1930) Google Scholar and since its widespread implementation after 2002, little has changed to improve the cure rate for these patients. Large registrational phase III trials of adjuvant CPI therapy were launched to evaluate its potential benefit after surgery: IMpower010 (atezolizumab), KEYNOTE091/PEARLS (pembrolizumab), BR.31 (durvalumab), and ANVIL (nivolumab). While these were accruing and events maturing, additional registrational phase III trials of neoadjuvant chemo-CPI were launched, mostly also featuring post-operative adjuvant CPI, following on from window-of-opportunity and single-arm neoadjuvant trials of CPI and combination chemo-CPI, which reported the faster readout of pathological response and identified rates much higher than the historical chemotherapy experience. IMpower010 was the first adjuvant randomized phase III CPI trial to report, accruing patients that underwent mandatory adjuvant cisplatin-based chemotherapy, and with hierarchical analysis, reporting the primary endpoint of disease-free survival (DFS) in stage II-IIIA NSCLC with programmed death-ligand 1 (PD-L1) ≥1% having an important and meaningful benefit [hazards ratio (HR) = 0.66, 95% confidence interval (CI) 0.50-0.88]. This trial identified several important unknowns for CPI therapy in the adjuvant setting for NSCLC, including consistent benefits across histology, stage, and nodal involvement, and a differential magnitude of benefit across PD-L1 strata, reflecting the metastatic setting experience. Indeed, in the stage II-IIIA population, the magnitude of benefit in the PD-L1 strata was strongest when PD-L1 ≥50% (HR = 0.43, 95% CI 0.27-0.68) followed by the 1%-49% group (HR = 0.87, 95% CI 0.60-1.26), followed by the negative group (HR = 0.97, 95% CI 0.72-1.31), fuelling debate as to whether DFS, a surrogate for OS, was a meaningful endpoint in itself for clinical decision making, and if so, in which PD-L1 strata for clinical implementation. The role of DFS as a surrogate for OS in resected NSCLC has been controversial. Drugs used in the adjuvant setting expose patients to toxicities and a potential deterioration in quality of life at a time where no cancer is identifiable, potentially including a population not likely to benefit. Hence in the absence of mature OS data a large DFS benefit alone may be adequate for clinical implementation, as seen in the case of adjuvant osimertinib.2Wu Y.L. Tsuboi M. He J. et al.ADAURA Investigators. Osimertinib in resected EGFR-mutated non-small-cell lung cancer.N Engl J Med. 2020; 383: 1711-1723Crossref PubMed Scopus (884) Google Scholar It against this backdrop that in this month’s edition of the Annals of Oncology, Dr Felip and colleagues present the highly anticipated results from an updated analysis of IMpower010.3Felip E. Altorki N. Zhou C. et al.IMpower010 InvestigatorsOverall survival with adjuvant atezolizumab after chemotherapy in resected stage II-IIIA non-small cell lung cancer (IMpower010): a randomised, multicentre, open-label, phase 3 trial.Ann Oncol. 2022; 34: 907-919Abstract Full Text Full Text PDF Scopus (2) Google Scholar Here, outcomes with an additional 13 months of follow-up from the initial data cut were published, and while DFS was not updated per the statistical analysis plan, importantly, the first protocol-specified interim analysis of OS is presented, performed at 25% of intention-to-treat (ITT) population events, alongside updated safety analysis. For OS, prespecified analysis was performed in the all-stage II-IIIA and PD-L1 ≥1% stage II-IIIA populations. In the all stage II-IIA population, OS was not improved (HR = 0.95, 95% CI 0.74-1.24) and in the PD-L1 ≥1% stage II-IIIA population, an improved OS for atezolizumab was observed (HR = 0.71, 95% CI 0.49-1.03). Post hoc exploratory analyses of OS in the stage II-IIIA population by PD-L1 strata (≥50%, 1%-49%, and <1% populations) were also conducted. Here, in the all stage II-IIIA population, OS remained immature (medians nonestimable; HR = 0.95, 95% CI 0.74-1.24). When evaluating OS by PD-L1 strata in stage II-IIIA, a clear improvement in the PD-L1 ≥50% subgroup was observed (HR = 0.43, 95% CI 0.24-0.78) and less so in both the PD-L1 1%-49% subgroup (HR = 0.95, 95% CI 0.59-1.54) and the PD-L1 <1% subgroup (unstratified HR = 1.36, 95% CI 0.93-1.99). Removing the 20 patients with epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) alterations from OS analyses made little difference to outcomes reported. From a safety viewpoint, with additional follow-up, reassuringly there were no new major safety concerns: immune-mediated adverse events occurred in 52.1% patients receiving atezolizumab, but only 7.9% at grade 3/4, with two grade 5 pulmonary events. So, how should these updated results be interpreted? Focussing on stage II-IIIa tumours, the strong OS benefit identified for PD-L1 ≥50%, while carrying out a post hoc analysis, seems to be driving the OS benefit identified in the prespecified PD-L1 >1% subgroup, reinforcing a strong role for atezolizumab in PD-L1 ≥50% tumours. Whether the benefit observed for the PD-L1 1%-49% population is meaningful (DFS HR = 0.79, 95% CI 0.67-0.99;4Felip E. Altorki N. Zhou C. et al.IMpower010 Investigators. Adjuvant atezolizumab after adjuvant chemotherapy in resected stage IB-IIIA non-small-cell lung cancer (IMpower010): a randomised, multicentre, open-label, phase 3 trial.Lancet. 2021; 398: 1344-1357Abstract Full Text Full Text PDF PubMed Scopus (500) Google Scholar OS HR = 0.95, 95% CI 0.59-1.543Felip E. Altorki N. Zhou C. et al.IMpower010 InvestigatorsOverall survival with adjuvant atezolizumab after chemotherapy in resected stage II-IIIA non-small cell lung cancer (IMpower010): a randomised, multicentre, open-label, phase 3 trial.Ann Oncol. 2022; 34: 907-919Abstract Full Text Full Text PDF Scopus (2) Google Scholar) remains debated with regulatory approval of this subset in the United States, China, and Japan but not in the United Kingdom, Canada, Switzerland, Australia, or Singapore; additional maturity will certainly help interpret this subgroup. Results of IMpower010 should also be considered in the context of the second adjuvant CPI randomized phase III trial to report, KEYNOTE-091/PEARLS.5O’Brien M. Paz-Ares L. Marreaud S. et al.EORTC-1416-LCG/ETOP 8-15 – PEARLS/KEYNOTE-091 Investigators. Pembrolizumab versus placebo as adjuvant therapy for completely resected stage IB-IIIA non-small-cell lung cancer (PEARLS/KEYNOTE-091): an interim analysis of a randomised, triple-blind, phase 3 trial.Lancet Oncol. 2022; 23: 1274-1286Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar Whilst adjuvant pembrolizumab demonstrated a similar DFS relative improvement in the ITT population in this differently designed study (in which adjuvant chemotherapy was not mandatory, stratification and efficacy analyses both utilised the same PD-L1 clone, and the control arm was blinded), this was significant for PEARLS/KEYNOTE-091 but not yet for IMpower010. However, unlike IMpower010, the DFS effect for the PD-L1 ≥50% subgroup was not significant, although the populations examined are different, and ongoing maturity may clarify this current discrepancy. Meanwhile, the FDA has approved pembrolizumab PEARLS/KEYNOTE-091 for the ITT population regardless of PD-L1 strata, and we await review outcomes by other regulatory agencies alongside results of BR.31 and ANVIL to better understand adjuvant CPI efficacy, its role in node-negative disease, and the predictive utility of PD-L1 expression. However, the bigger question is the relevance of much of these data given the rapidly evolving perioperative NSCLC space. One registrational trial (CHECKMATE-816) of neoadjuvant chemo-CPI only, and three perioperative trials (AEGEAN, Neotorch, and KEYNOTE-761) of neoadjuvant chemo-CPI followed by adjuvant CPI have been presented, each demonstrating marked DFS benefits in their primary endpoint populations, questioning if patients should undergo surgery followed by adjuvant CPI or have neoadjuvant chemo-CPI prior to surgery, or a combination of both approaches: dessert, starters, or a sandwich. Referral/presentation flows and individual decision making will inevitably drive treatment planning for the time being as all strategies bed down. Nevertheless, we do definitively know that for resected stage II-IIIa NSCLC with PD-L1 ≥50% adjuvant atezolizumab’s OS benefit is marked and important. AJ and SP acknowledge NHS funding to the NIHR Biomedical Research Centre at the Royal Marden Hospital/Institute of Cancer Research. None declared.