What is the role of consolidation immunotherapy after chemoradiotherapy in stage III EGFR-mutant non-small cell lung cancer?

Prior to the clinical application of immune checkpoint inhibitor treatment, concurrent chemoradiotherapy had been the standard treatment for patients with unresectable locally advanced non-small cell lung cancer (NSCLC), with a 5-year overall survival (OS) of approximately 20% (1). In a randomized phase III trial (i.e., PACIFIC trial), consolidative durvalumab, a programmed death-ligand 1 (PD-L1) inhibitor, led to an impressive increase in median progression-free survival (PFS) and OS compared with the outcomes of observation after concurrent chemoradiotherapy (2,3). Moreover, recently updated analyses demonstrated robust and consistent OS and PFS benefits with durvalumab after chemoradiotherapy. Among the patients who were randomly assigned to durvalumab, approximately 42.9% continued to live after 5 years and 33.1% remained free of disease progression, thereby establishing a new benchmark for standard of care in this setting (4). The PACIFIC study was planned to investigate the clinical results with durvalumab in an all-comers population; therefore, the subgroup analyses were limited by small sample sizes and the resulting lack of statistical power, which precluded definitive conclusions for the subgroups.

A post hoc exploratory efficacy and safety analysis of a subgroup of patients with EGFR mutation from the PACIFIC study was reported recently, as the benefit of immunotherapy in patients with stage III EGFR-mutant NSCLC is not well characterized (5). Of the 713 patients randomized, 35 were locally confirmed to have the EGFR-mutant NSCLC (24 patients with durvalumab and 11 with placebo). At the time of data cutoff, the median duration of the follow-up for survival was 42.7 months for all the randomized patients in the subgroup. The median PFS was 11.2 months with durvalumab and 10.9 months with placebo [hazard ratio (HR), 0.91; 95% confidence interval (CI): 0.39–2.13]. The median OS was 46.8 months with durvalumab and 43.0 months with placebo (HR, 1.02; 95% CI: 0.39–2.63). The adverse events of durvalumab in the subgroup generally coincided with those in the parent group and with the known profile for durvalumab. It was observed that PFS and OS were similar between durvalumab and placebo, with wide CIs, in patients with EGFR mutation, suggesting that epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) may provide an effective treatment option for patients after chemoradiotherapy. However, owing to the small number of patients and lack of a prospective analysis that could evaluate clinical results based on tumor biomarker status, the data must be interpreted carefully. In their data set, 31% of patients had genetic abnormalities other than exon 19 del or L858R. Additionally, it is also important to note that the overall EGFR-mutant subgroup included 11% patients with squamous tumors, 51% smokers, and 60% men; all of these were not typical characteristics of a cohort of patients with EGFR mutation.

Currently, several published data collected mainly from subgroup analyses of prospective and retrospective studies do not support the use of durvalumab for unresectable stage III NSCLC with EGFR mutation (6-9). Moreover, in a current European Society for Medical Oncology (ESMO) consensus, over 90% of specialists did not advise the use of consolidation durvalumab therapy following curative-intent concurrent chemoradiotherapy for EGFR-mutant NSCLC (10).

Recently, a real-world report on consolidation durvalumab following concurrent chemoradiotherapy for stage III NSCLC, regardless of EGFR mutation status, depicted longer PFS and OS with consolidation durvalumab than with concurrent chemoradiotherapy alone, although the magnitude of benefit appeared to be greater in those who were EGFR-negative than in those who were EGFR-positive (11). In a multi-institutional prospective biomarker study (WJOG11518L/SUBMARINE), Haratani et al. explored the mechanisms of resistance to the PACIFIC regimen in stage III NSCLC including EGFR mutation positive (n=13), negative (n=72), and unknown (n=50) patients (12). Their results were based on the investigation of clinical samples, including tumor tissue and peripheral blood collected before and after PACIFIC therapy, and shed light on the tumor microenvironment of stage III NSCLC and its association with treatment efficacy. They suggested that the preexistence of immune activation in the tumor as evidenced by PD-L1 expression on cancer cells, a high tumor mutation burden, and a high density of CD8⁺ tumor-infiltrating lymphocytes (TILs) were the key determinants of durvalumab efficacy and that CD73-expressing cancer cells might relate to durvalumab resistance. After coordination for these key factors, EGFR mutation was not clearly related to a poor PFS in their cohort. In cases of stage IV NSCLC, less immunogenic tumor microenvironment profiles of low PD-L1 expression and low CD8⁺ TIL density in tumors with EGFR mutations had been thought to be responsible for the low sensitivity to immunotherapy (13-15). Interestingly, in their dataset of stage III NSCLC, the similar CD8⁺ TIL density between tumors with and without EGFR mutations possibly accounted for the equivalent treatment outcomes. Notably, in a recent randomized phase II trial (i.e., COAST), patients with stage III NSCLC had better PFS when treated with the CD73 inhibitor oleclumab in addition to the PACIFIC regimen (16). In COAST study, patients with stage III NSCLC who had completed concurrent chemoradiotherapy were randomly assigned to either consolidation durvalumab alone or in combination with one of the two experimental agents, oleclumab or monalizumab. A large phase III trial (i.e., NCT05221840; PACIFIC-9 study) is currently in progress to investigate the additional benefit of oleclumab. This study could provide new insights to suggest patient stratification and future research directions.

The role of targeted therapy is currently anticipated. Based on the ADAURA trial results of significantly improved OS with adjuvant osimertinib after resection (17), the combination of local and targeted therapies could be efficacious for stage III NSCLC harboring EGFR mutations. The ongoing LAURA trial on osimertinib following concurrent chemoradiotherapy (18) may clarify the optimal treatment strategy for this population. Additionally, the Haratani data may spotlight the clinical challenge of determining the optimal therapy between osimertinib and durvalumab for this subset of patients with tumors that have a high number of CD8⁺ TILs and low CD73 expression. However, there are several points to be considered including the importance of sequence and timing of durvalumab and osimertinib, because durvalumab followed by osimertinib is associated with severe adverse events and is most frequent among patients who recently received durvalumab. Thus, these recent research findings may provide a basis for the development of novel therapeutic strategies. The results of the several potential strategies being tested in patients with stage III NSCLC are awaited with anticipation.

Acknowledgments

Funding: None.

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