The benefit of the doubt: PD-L1 status in unresectable stage III NSCLC management

Programmed death ligand-1 (PD-L1) tumor proportion score (TPS), although imperfect, is the best biomarker identified so far to guide the treatment of metastatic non-small cell lung cancer (NSCLC) with immune checkpoint inhibitors (ICI).Landmark trials in the firstline metastatic setting support its predictive value for response to immunotherapy in this population (1,2).As such, international guidelines recommend single agent anti-PD-1/ PD-L1 treatment in the PD-L1 ≥50% population, while those agents should be combined with either chemotherapy, anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) or both in PD-L1 1-49% and <1% patients (3,4).The role of PD-L1 as a biomarker for consolidation durvalumab after chemoradiotherapy (CRT) in unresectable stage III NSCLC, however, remains controversial.The European Medicines Agency approved adjuvant durvalumab for PD-L1 ≥1% NSCLC (5), while North American health authorities did not make this distinction (6,7).In this study, Bryant et al. conducted a retrospective analysis of 312 patients treated with adjuvant durvalumab after CRT in 2017-2021 (8).Every absolute increase of 25% in PD-L1 TPS was associated with significant improvement of both progression-free survival (PFS) and overall survival (OS).There were also significant benefit in PFS for the PD-L1 ≥50% and 1-49% subgroups compared to the <1% subgroup.OS followed the same trend, although the difference between the 1-49% and <1% was not statistically significant.The cohort of durvalumab patients was compared to a historical cohort from 2015-2016 which did not receive durvalumab.PD-L1 expression was unknown in this second cohort.Subgroups of durvalumab patients with PD-L1 ≥50% and 1-49% both had improved PFS and OS compared to the no-durvalumab patients, but not the <1% subgroup.Bryant et al. results suggest a predictive role of PD-L1 TPS in patient receiving durvalumab.Findings from PACIFIC-R, a retrospective study including 1,399 patients started on durvalumab through an extended access program in 2017-2018, point in the same direction (9).Real-world PFS was longer in PD-L1 ≥1% (22.4 months) versus <1% (15.6 months) patients.Published OS data remain preliminary and do not address PD-L1 expression.Two prior, smaller retrospective analyses of patients who received durvalumab between 2017 and 2020 demonstrated improved outcomes in PD-L1 ≥50% compared to PD-L1 <1% patients, but there was no significant difference between the 1-49% and <1% groups (10,11).Do PD-L1 negative CRT patients actually benefit from adjuvant durvalumab?No conclusions can be drawn from Bryant et al. comparative analysis, since PD-L1 expression was unknown in the no-durvalumab cohort.A posthoc, unplanned analysis of 451 PD-L1 assessable patients from

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