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 first-line 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 PACIFIC provides some insight (12). Compared to placebo, durvalumab seemed to improve PFS in both PD-L1 ≥1% [hazard ratio (HR) 0.46; 95% confidence interval (CI): 0.33–0.64, n=303] and PD-L1 <1% patients (HR 0.73; 95% CI: 0.48–1.11, n=148), although the confidence interval crossed unity in the latter. For OS, benefits were seen in the PD-L1 ≥1% subgroup (HR 0.59; 95% CI: 0.41–0.83, n=303) but not in the PD-L1 <1% subgroup (HR 1.14; 95% CI: 0.71–1.84, n=148). However, the trial was not powered for this analysis and randomization was not stratified for PD-L1, which put the PD-L1 <1% subgroup of the durvalumab arm at a disadvantage for demographics and stage. The sample size was also fairly small, with few events (n=60) in the PD-L1 <1% subgroup.

Bryant et al. referred to the prognostic role of PD-L1, but did not investigate this question specifically as PD-L1 expression was unknown in the cohort of patients who did not receive durvalumab. Previous studies had conflicting results, with the most data concerning resectable NSCLC. A recent meta-analysis of 15 studies comprising 3,790 patients with early-stage, resected NSCLC suggested PD-L1 positivity was associated with shorter disease-free survival (DFS) and OS (13). However, the included studies used widely different PD-L1 assays and positivity cutoffs, ranging from 1–100% of tumor cells. Moreover, PD-L1 expression was associated with other disadvantageous characteristics such as male sex, squamous histology, nodal metastases and higher stage, all of which could have been confounders. In patients with unresectable, locally advanced NSCLC treated with CRT alone, without durvalumab, no significant relationship has been demonstrated between PD-L1 expression and PFS or OS (14-16).

Of course, in order to evaluate the predictive and/or prognostic value of PD-L1 TPS, reliable testing is key. When it comes to immunohistochemistry (IHC), considering the type of assay is of the essence, since SP142 has poorer sensitivity compared to SP263, 28-8 or 22C3 (1,17,18). Perhaps another important aspect is the timing of testing, as discussed by the authors. It may be that the PD-L1 status of tumor prior to CRT treatment initiation does not matter as much as the influence of the preceding concurrent chemotherapy and radiotherapy. The interplay between radiotherapy and the immune microenvironment have long been acknowledged, with increased cancer antigen release and visibility, upregulation of MHC-1 expression and priming tumor specific T cells (19). This activation accounts for the abscopal effect and is the impetus for trials utilizing ICI as a radiosensitizer. Chemotherapy promotes immune responses by similar mechanisms in addition to altering whole body physiology to augment immune competence (20). Biomarkers are important and useful but the treatment context is also highly relevant when trying to understand treatment effects. CRT can upregulate PD-L1 expression, questioning the reliability of pre-CRT PD-L1 TPS to guide consolidation immunotherapy treatment (21,22).

Identifying the most effective way to utilize the respective tools for managing unresectable stage III NSCLC is the focus of current clinical trials. A number of different strategies are being explored including induction immunotherapy, concurrent immunotherapy with CRT and the use of doublet checkpoint inhibition (23). What will be critical to advance the field is the collection of biomarker status, with respect to PD-L1 TPS and driver mutations, as treatment of curative intent NSCLC becomes more sophisticated with our understanding of biology.

Bryant et al. demonstrate a correlation between increasing PD-L1 TPS and improved patient outcome paralleling the association of high PD-L1 TPS and benefit in metastatic NSCLC. The effects of radiotherapy and chemotherapy on the immune milieu may serve to augment the beneficial effects of ICI in the PD-L1 TPS <1% population and requires further investigation. With the potential for achieving a cure, it behooves the oncology community to seek better ways to use our treatment tools to improve outcomes for our patients.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Cancer Research. The article did not undergo external peer review.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-22-2843/coif). MHD has received grants from AstraZeneca. CH has received honoraria paid to self from Abbvie, Amgen, AstraZeneca, Bayer, BMS, Eisai, EMD Serono, Janssen, Jazz, Merck, Novartis, Roche, Takeda and has research grants paid to institution from AstraZeneca, EMD Serono and Roche. The authors have no other 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/.

References

1. Herbst RS, Giaccone G, de Marinis F, et al. Atezolizumab for First-Line Treatment of PD-L1-Selected Patients with NSCLC. N Engl J Med 2020;383:1328-39. [Crossref] [PubMed]
2. Mok TSK, Wu YL, Kudaba I, et al. Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. Lancet 2019;393:1819-30. [Crossref] [PubMed]
3. Singh N, Temin S, Baker S Jr, et al. Therapy for Stage IV Non-Small-Cell Lung Cancer Without Driver Alterations: ASCO Living Guideline. J Clin Oncol 2022;40:3323-43. [Crossref] [PubMed]
4. NCCN. Non-small cell lung cancer: version 6.2022. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) 2022. Available online: https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf
5. EMA. IMFINZI, INN-durvalumab. Annex 1: summary of product characteristics. 2021. Available online: https://www.ema.europa.eu/en/documents/product-information/imfinzi-epar-product-information_en.pdf. Accessed 2022-12-15.
6. FDA. IMFINZI (durvalumab) injection, for intravenous use. 2021. Available online: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761069s029lbl.pdf. Accessed 2022-12-14.
7. HealthCanada. Product monograph including patient medication information: IMFINZI. 2022. Available online: https://pdf.hres.ca/dpd_pm/00065291.PDF. Accessed 2022-12-14.
8. Bryant AK, Sankar K, Strohbehn GW, et al. Prognostic and Predictive Role of PD-L1 Expression in Stage III Non-small Cell Lung Cancer Treated With Definitive Chemoradiation and Adjuvant Durvalumab. Int J Radiat Oncol Biol Phys 2022;113:752-8. [Crossref] [PubMed]
9. Girard N, Bar J, Garrido P, et al. Treatment Characteristics and Real-World Progression-Free Survival in Patients With Unresectable Stage III NSCLC Who Received Durvalumab After Chemoradiotherapy: Findings From the PACIFIC-R Study. J Thorac Oncol 2023;18:181-93. [Crossref] [PubMed]
10. Jazieh K, Gad M, Saad A, et al. Tumor PD-L1 expression is associated with outcomes in stage III non-small cell lung cancer (NSCLC) patients treated with consolidation durvalumab. Transl Lung Cancer Res 2021;10:3071-8. [Crossref] [PubMed]
11. A K, H S, W H, et al. Consolidative durvalumab outcomes in stage III non-small cell lung cancer in a multi-centre study. Cancer Treat Res Commun 2021;29:100496.
12. Paz-Ares L, Spira A, Raben D, et al. Outcomes with durvalumab by tumour PD-L1 expression in unresectable, stage III non-small-cell lung cancer in the PACIFIC trial. Ann Oncol 2020;31:798-806. [Crossref] [PubMed]
13. Shi T, Zhu S, Guo H, et al. The Impact of Programmed Death-Ligand 1 Expression on the Prognosis of Early Stage Resected Non-Small Cell Lung Cancer: A Meta-Analysis of Literatures. Front Oncol 2021;11:567978. [Crossref] [PubMed]
14. Vrankar M, Kern I, Stanic K. Prognostic value of PD-L1 expression in patients with unresectable stage III non-small cell lung cancer treated with chemoradiotherapy. Radiat Oncol 2020;15:247. [Crossref] [PubMed]
15. Guberina M, Guberina N, Pöttgen C, et al. Effectiveness of durvalumab consolidation in stage III non-small-cell lung cancer: focus on treatment selection and prognostic factors. Immunotherapy 2022;14:927-44. [Crossref] [PubMed]
16. Tufman A, Neumann J, Manapov F, et al. Prognostic and predictive value of PD-L1 expression and tumour infiltrating lymphocytes (TiLs) in locally advanced NSCLC treated with simultaneous radiochemotherapy in the randomized, multicenter, phase III German Intergroup lung Trial (GILT). Lung Cancer 2021;160:17-27. [Crossref] [PubMed]
17. Hirsch FR, McElhinny A, Stanforth D, et al. PD-L1 Immunohistochemistry Assays for Lung Cancer: Results from Phase 1 of the Blueprint PD-L1 IHC Assay Comparison Project. J Thorac Oncol 2017;12:208-22. [Crossref] [PubMed]
18. Rimm DL, Han G, Taube JM, et al. A Prospective, Multi-institutional, Pathologist-Based Assessment of 4 Immunohistochemistry Assays for PD-L1 Expression in Non-Small Cell Lung Cancer. JAMA Oncol 2017;3:1051-8. [Crossref] [PubMed]
19. Wang Y, Liu ZG, Yuan H, et al. The Reciprocity between Radiotherapy and Cancer Immunotherapy. Clin Cancer Res 2019;25:1709-17. [Crossref] [PubMed]
20. Galluzzi L, Humeau J, Buqué A, et al. Immunostimulation with chemotherapy in the era of immune checkpoint inhibitors. Nat Rev Clin Oncol 2020;17:725-41. [Crossref] [PubMed]
21. Wang Y, Kim TH, Fouladdel S, et al. PD-L1 Expression in Circulating Tumor Cells Increases during Radio(chemo)therapy and Indicates Poor Prognosis in Non-small Cell Lung Cancer. Sci Rep 2019;9:566. [Crossref] [PubMed]
22. Kordbacheh T, Honeychurch J, Blackhall F, et al. Radiotherapy and anti-PD-1/PD-L1 combinations in lung cancer: building better translational research platforms. Ann Oncol 2018;29:301-10. [Crossref] [PubMed]
23. Cortiula F, Reymen B, Peters S, et al. Immunotherapy in unresectable stage III non-small-cell lung cancer: state of the art and novel therapeutic approaches. Ann Oncol 2022;33:893-908. [Crossref] [PubMed]