The evolution of non-surgical management in stage III non-small cell lung cancer

www.nature.com/bjcreports DEBATE OPEN The evolution of non-surgical management in stage III nonsmall cell lung cancer Milit S. Patel1,2, Alessandro Hammond3, Edward Christopher Dee2 and Puneeth Iyengar2 ✉ © The Author(s) 2026 The management of unresectable stage III non-small cell lung cancer (NSCLC) continues to evolve with the integration of immunotherapy and targeted agents into treatment paradigms. The PACIFIC trial established consolidation durvalumab following concurrent chemoradiotherapy (CRT) as the standard of care in many settings. However, emerging evidence challenges the onesize-fits-all approach, particularly for molecularly defined subsets and specific patient populations. This debate article examines the evolving landscape of non-surgical stage III NSCLC management, presenting evidence-based arguments for refining treatment strategies based on molecular biomarkers, novel immunotherapy combinations, and alternative sequencing approaches. 1234567890();,: BJC Reports; https://doi.org/10.1038/s44276-026-00212-2 INTRODUCTION Stage III NSCLC represents approximately 20-30% of newly diagnosed lung cancer cases, encompassing a heterogeneous population with varying tumor burden, nodal involvement, and molecular characteristics [1]. For decades, the standard treatment paradigm consisted of platinum-based concurrent chemoradiotherapy (CRT), yielding 5-year survival rates of only 15-32% [2, 3]. The therapeutic landscape transformed dramatically following the PACIFIC trial, which demonstrated that consolidation durvalumab —a programmed death-ligand 1 (PD-L1) inhibitor—significantly improved progression-free survival (PFS) and overall survival (OS) compared to placebo [4, 5]. The PACIFIC regimen established a new benchmark: median PFS of 16.9 months versus 5.6 months with placebo (HR 0.55, 95% CI 0.45-0.68, p < 0.001), and 5-year OS rates of 42.9% versus 33.4% [5, 6]. These results fundamentally altered clinical practice guidelines worldwide. However, as our understanding of tumor biology deepens and novel therapeutic agents emerge, critical questions arise regarding optimal patient selection, treatment sequencing, and the role of molecular biomarkers in guiding therapy. This debate article examines seven key controversies in the non-surgical management of stage III NSCLC: (1) the essential role of multimodality therapy integration, (2) consolidation immunotherapy strategies, (3) molecular-targeted approaches for oncogene-driven disease, (4) novel immunotherapy combinations, (5) chemotherapy-sparing regimens, (6) neoadjuvant strategies for converting unresectable disease, and (7) biomarker-directed patient selection. Key trials are summarized in Table 1. THE INDISPENSABLE ROLE OF RADIATION THERAPY: TIMING AND SEQUENCING MATTER Position Radiation therapy remains a cornerstone of curative-intent treatment for stage III NSCLC, but the sequence and timing of RT delivery influence outcomes when combined with systemic therapies. The integration of radiation therapy with systemic agents presents both opportunities and challenges. Preclinical evidence demonstrates that radiotherapy induces immunomodulatory changes, including upregulation of PD-L1 expression and enhancement of tumor antigen presentation [7, 8]. However, radiation also exhibits immunosuppressive effects through lymphocyte depletion and upregulation of regulatory T cells and transforming growth factor-beta (TGF-β) [9]. The PACIFIC trial mandated completion of concurrent CRT 1-42 days before randomization [4], with durvalumab benefit observed across all timing subgroups when durvalumab was initiated after completing radiotherapy [10]. Post-hoc analyses suggested that median PFS was numerically longest among patients who started durvalumab ≤14 days after RT completion, though durvalumab improved outcomes regardless of time from CRT completion [10]. This observation aligns with preclinical data suggesting that the immunostimulatory effects of radiation are transient and may be optimally captured by immediate immunotherapy administration [8]. Real-world evidence from the PACIFIC-R study, encompassing 1,399 patients across 11 countries, corroborates these findings [11]. The median time from CRT completion to durvalumab initiation dropped to 31 days overall, and to just 21 days for patients treated since 2020, reflecting updated clinical practice [12]. Despite these improvements, 18% of eligible patients failed to initiate durvalumab, most commonly due to toxicity, poor performance status, and disease progression [12]. Patients unable to start durvalumab were distinguished by significantly higher baseline lactate dehydrogenase, greater cumulative toxicity, worse post-CRT ECOG performance status, and elevated C-reactive protein, as well as lung diffusion capacity, underlining the need for tailored supportive care and prehabilitation strategies to improve treatment completion [12]. Median real-world PFS was 21.7 months (95% CI 19.1-24.5), with 48.2% of patients remaining progression-free at 24 months [11]. Notably, rwPFS (real-world 1 Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX, USA. 2Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. 3Department of Biology, Harvard University, Cambridge, MA, USA. ✉email: Received: 9 December 2025 Revised: 8 February 2026 Accepted: 9 February 2026 M.S. Patel et al. cCRT concurrent chemoradiotherapy, EGFRm epidermal growth factor receptor-mutated, HR hazard ratio, NSCLC non-small-cell lung cancer, ORR objective response rate, OS overall survival, PD-L1 + programmed death ligand-1 positive, PFS progression-free survival. 12-month PFS rate: 72.1%; Median PFS: 25.6 months 12-month PFS Rate Concurrent Durvalumab + Radiotherapy 09/2019 DOLPHIN [31]. Japan 35 (efficacy); 74 enrolled Unresectable Stage III PDL1 + NSCLC PFS HRs vs. Durvalumab alone: 0.59 (Oleclumab), 0.63 (Monalizumab) ORR, PFS Durvalumab vs. Durvalumab + Oleclumab vs. Durvalumab + Monalizumab 01/2019 COAST [24]. United States of America 189 Unresectable Stage III NSCLC, post-cCRT Median PFS: 39.1 vs. 5.6 months; HR 0.16 PFS Osimertinib vs. Placebo Unresectable Stage III EGFRm NSCLC, post-CRT 216 07/2018 LAURA [20]. United States of America Median PFS: 16.9 vs. 5.6 months; HR 0.55 PFS, OS 05/2014 PACIFIC [6]. United States of America 713 Unresectable Stage III NSCLC, post-cCRT Durvalumab vs. Placebo Key Result (Median PFS and Hazard Ratio) Patient Population Patient Count Country of Origin Study Start Trial Acronym Table 1. Summary of Key Clinical Trials Guiding the Treatment of Unresectable Stage III NSCLC Intervention Arms Primary Endpoint 2 progression-free survival) was numerically longer among patients who received concurrent versus sequential CRT (23.7 vs 19.3 months), reinforcing the importance of treatment intensity [11]. These findings highlight that, beyond timing, patient fitness and inflammation are pivotal barrier (...truncated)