Lessons from PACIFIC-2 and the evolving landscape of unresectable stage III non-small cell lung cancer—when synergy blunts the benefit

Lung cancer remains the leading cause of cancer-related mortality worldwide, with non-small cell lung cancer (NSCLC) comprising approximately 85% of cases (1). Stage III NSCLC, which accounts for 25–30% of cases, poses significant clinical challenges. Systemic therapy, surgery, radiotherapy (RT), and their combinations are established treatment modalities (Figure 1). Multidisciplinary tumor boards (MDT) facilitate the selection of optimal therapeutic sequences for individual patients (2). In recent years, global initiatives have sought to standardize criteria for resectable disease (3-5). However, the practical definition of resectability continues to depend on surgical expertise, the availability of specialized surgical teams, and access to postoperative care units (6).

Figure 1 Selected clinical trials incorporating immune-checkpoint inhibitors at different time points in patients with stage Ill non-small cell lung cancer. MDT, multidisciplinary tumor board; SoC, standard of care.

Since 2017, the standard of care for patients with good performance status and unresectable stage III NSCLC has consisted of platinum-based chemotherapy (PBCT) combined with concurrent radiotherapy (cCRT), followed by 12 months of durvalumab as consolidative therapy (7,8). This approach is supported by the phase III PACIFIC trial, which demonstrated significant improvements in progression-free survival (PFS) [hazard ratio (HR) 0.55] and overall survival (OS) (HR 0.72), with 5-year OS rates of 42.9% compared to 33.4% for placebo (9,10).

The survival benefit of consolidative immunotherapy for patients with stage III NSCLC is well established. Multiple clinical trials and real-world studies have consistently demonstrated improved survival outcomes with the addition of durvalumab following concurrent or sequential chemoradiotherapy (11-14). However, despite the efficacy of the PACIFIC regimen, approximately two-thirds of patients experience relapses, and nearly 58% die within 5 years (10). Consequently, alternative strategies are being investigated to decrease progression rates following cCRT, enhance response rates, and improve long-term survival. Enrolling patients in clinical trials of induction or neoadjuvant therapy presents additional challenges (15). Trials such as PACIFIC, LAURA, IMPOWER 010, PEARLS, and NADIM adjuvant included only patients who did not experience disease progression during initial therapy and who did not develop grade 2 or higher adverse events (AEs) (10,16-19). The literature indicates that 15–30% of patients are ineligible for post-cCRT or post-surgical trials due to factors such as disease progression and toxicity (20,21). Therefore, indirect comparisons between induction/neoadjuvant and adjuvant/consolidation trials must account for the highly selected nature of patients in the latter group.

Bradley et al. present the final results of PACIFIC-2, the first phase III randomized study in this context, marking a significant development in the management of unresectable stage III NSCLC. The trial evaluates the impact of initiating durvalumab concurrently with cCRT followed by durvalumab every 4 weeks until disease progression or unacceptable toxicity, in patients with unresectable stage III NSCLC [American Joint Committee on Cancer (AJCC) 8th edition]. Following screening, 328 patients were randomized in a 2:1 ratio to receive either concurrent and consolidative durvalumab or placebo. PFS, the primary endpoint assessed by independent central review, did not demonstrate a statistically significant improvement with durvalumab [HR 0.85, 95% confidence interval (CI): 0.65–1.12; P=0.247]. Median PFS was 13.8 months in the durvalumab arm compared to 9.4 months in the placebo arm. Similarly, OS did not significantly improve with durvalumab (HR 1.03, 95% CI: 0.78–1.39; P=0.823), with median OS of 36.4 vs. 29.5 months. The overall response rate and 24-month OS, both key secondary endpoints, were approximately 60% in each group (22). In contrast, the positive findings from the ADRIATIC study (clinicaltrials.gov identifier: NCT03703297) in patients with limited-stage small cell lung cancer (LS-SCLC) do not support the use of extended consolidative immunotherapy for 24 months or until disease progression in patients with unresectable NSCLC, as indicated by PACIFIC-5 and PACIFIC-6 (12,23).

PACIFIC-2 study design and implications

Several aspects of the PACIFIC-2 trial design are important when interpreting the lack of a statistically significant improvement in the primary endpoint. In contrast to the original PACIFIC trial, which randomized patients after completion of cCRT and in the absence of disease progression, PACIFIC-2 randomized patients 2:1 prior to the start of cCRT. This pre-cCRT randomization resulted in a broader, less-selected study population that more closely reflected real-world “all-comers” patients with unresectable stage III NSCLC [AJCC 8th edition, Eastern Cooperative Oncology Group performance status (ECOG PS) 0–1], as resectability was determined by the treating investigator. Consequently, the study may have included individuals with more heterogeneous disease biology or lower tolerance to intensive combined therapy.

Furthermore, as an international multicenter study conducted across 88 sites in over 20 countries, potential variability in RT planning, dose delivery, and quality control cannot be excluded, even though protocol-defined RT guidelines were followed. Such heterogeneity may influence both the efficacy and toxicity profiles (22).

The concurrent administration strategy aimed to reduce patient attrition, as 27% to 50% of patients progress or become ineligible for consolidation during or shortly after cCRT. Despite this rationale, safety outcomes diminished the theoretical benefits. Although the incidence of grade 3 or higher AEs was similar between groups (53.4% vs. 59.3%), treatment discontinuation rates were twice as high with durvalumab (25.6% vs. 12.0%) in the PACIFIC-2 study. The duration and depth of AEs monitoring were also greater in the durvalumab arm (14.2% vs. 5.6% within the first four months and 5.9% vs. 0.9% beyond 16 months from treatment initiation). The incidence of fatal events was higher with durvalumab (13.7% vs. 10.2%). Rates of pneumonitis or radiation pneumonitis were comparable at approximately 29%, as were rates of radiation esophagitis (2.7% vs. 3.7%). However, early cumulative toxicities, including infections and lymphopenia, likely reduced tolerability and completion rates. Completion of cCRT was achieved by nearly 88% and 91% of patients in the respective arms (22). These design features and tolerability challenges provide important context for the trial’s negative results and highlight the complexities of combining immunotherapy with concurrent chemoradiotherapy.

Positioning PACIFIC-2 in the broader evidence space

Clinically, the benefits of cCRT-immunotherapy combinations have been modest or absent. The negative results of PACIFIC-2 stand in contrast to the substantial benefit observed with consolidative durvalumab in the original PACIFIC trial (PFS HR 0.55; OS HR 0.72), in which immunotherapy was initiated only after completion of chemoradiotherapy and in the absence of disease progression. Similarly, the phase II PACIFIC-6 trial demonstrated clinically meaningful PFS and OS benefit when durvalumab was administered following sequential (rather than concurrent) chemoradiotherapy in patients unsuitable for concurrent treatment (12). In contrast, other contemporary trials evaluating concurrent immunotherapy with chemoradiotherapy have also been negative, including CheckMate 73L (nivolumab) and ECOG-ACRIN EA5181 (durvalumab) in stage III NSCLC, as well as NRG LU005 in LS-SCLC. Collectively, these findings underscore that the timing of programmed death-ligand 1 (PD-L1) inhibition relative to chemoradiotherapy is a critical determinant of therapeutic efficacy in locally advanced NSCLC, with the consolidative approach remaining the only strategy with level 1 evidence of survival benefit (24).

Immunological mechanisms and the importance of timing

Preclinical models have elucidated the mechanisms underlying the synergy between RT and the immune system. Ionizing radiation facilitates the cross-presentation of tumor-associated antigens (TAAs) from apoptotic and necrotic tumor cells (25), thereby inducing in situ vaccination. However, effective tumor burden reduction is largely dependent on T-cell responses and dendritic cell recruitment; immunodeficiency negates the antitumor effects of RT (26). Irradiated tumor cells upregulate chemokine expression, leading to STING- and interferon-β-dependent activation and infiltration of antigen-specific cytotoxic CD8+ T cells (27,28). Natural killer (NK) cells are also critical, mediating antibody-dependent cellular cytotoxicity without requiring antigen presentation via major histocompatibility complex (MHC) class I molecules and preferentially targeting MHC-I-negative cells that evade T-cell recognition. RT induces NKH2D ligands and modulates the expression of chemokines such as CXCL16 and CCL19 in a dose-dependent manner, both of which recruit NK cells (29-31). In addition to these immunostimulatory effects, RT also triggers immunosuppressive molecular signals that diminish the efficacy of the anticancer immune response. RT increases tumor cell PD-L1 expression, promotes the recruitment of regulatory T cells (Treg), and enhances the accumulation of myeloid-derived suppressor cells (MDSC) within the tumor microenvironment (24,32,33). These findings underscore a key biological principle: the timing of therapy is fundamental to efficacy. Concomitant irradiation of tumor-draining lymph nodes (DLN-IR) may contribute to these outcomes. Recent work by Telarovic et al. demonstrated that simultaneous DLN-IR in murine models eliminates the beneficial effects of radioimmunotherapy, whereas delaying DLN irradiation preserves efficacy (34).

Emerging therapeutic strategies

Several promising strategies are currently being investigated to improve outcomes in unresectable stage III NSCLC beyond the current standard of care. Induction or perioperative chemoimmunotherapy approaches are gaining momentum for resectable diseases and are being actively explored in unresectable settings. These regimens have demonstrated high pathological complete response (pCR) rates and improved event-free and OS in resectable NSCLC (35-39). Their potential advantage lies in priming a broader T-cell repertoire while the lymphatic system remains intact and the full spectrum of tumor antigens is present (40). Ongoing trials, such as AFT-16 (NCT03102242), APOLO (NCT04776447), PACIFIC-BRAZIL (NCT04230408), and DEDALUS (NCT05128630), are evaluating the role of induction chemoimmunotherapy prior to chemoradiotherapy (41-43). Nevertheless, the negative results of PACIFIC-2 and the toxicity concerns observed with concurrent immunotherapy plus chemoradiation suggest that concurrent rather than sequential integration of checkpoint inhibitors during chemoradiation may not be the optimal strategy for treatment.

The definition of resectability is continuously evolving. Studies such as MDT-BRIDGE (NCT05925530) and PANDA-1 have shown that induction chemoimmunotherapy followed by a multidisciplinary reassessment of resectability is feasible and safe, with encouraging pathological response rates and clinical downstaging (44,45). Long-term data from these trials, as well as results from randomized studies comparing neoadjuvant and adjuvant systemic therapy (e.g., NCT06632327), are eagerly awaited.

Efforts to improve treatment tolerability are critical. Zhang et al. demonstrated that the addition of inhaled corticosteroids during RT significantly reduced the incidence of radiation-induced pneumonitis in patients with NSCLC without compromising OS (46).

Looking forward, a strong emphasis is being placed on personalized, biomarker-driven approaches. Dynamic changes in PD-L1 expression, tumor mutational burden (TMB), and post-chemoradiation circulating tumor DNA (ctDNA) signatures are promising tools for identifying patients who may benefit from treatment escalation or de-escalation (Figure 2). Combination immunotherapy strategies have also shown encouraging results. The COAST trial demonstrated improved objective response rates with durvalumab plus oleclumab or monalizumab compared with durvalumab alone (35–40% vs. 24%) (47). These findings led to a phase III evaluation in PACIFIC-9 (NCT05221840). Other combinations under active investigation include durvalumab plus domvanalimab (PACIFIC-8; NCT05211895) and durvalumab plus olaparib (KEYLYNK-012; NCT04380636) following chemoradiotherapy. In contrast, dual PD-L1 and TIGIT blockade failed to improve outcomes in the SKYSCRAPER-03 trial. The results of these ongoing trials will help define the next generation of treatment standards for unresectable stage III NSCLC.

Figure 2 Selected phase II and III trials incorporating targeted therapy in patients with stage III NSCLC. NSCLC, non-small cell lung cancer.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

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Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-26-0020/coif). J.Z. has received consulting fees from Roche, Pfizer, Novartis, AstraZeneca, Amgen, MSD, Janssen, and FICMAC; payment or honoraria from Johnson & Johnson, Roche, Pfizer, Novartis, AstraZeneca, BMS, MSD, and Merck Serono; payment for expert testimony from Roche, BMS, Thermo Fisher, Amgen, Bayer, Pfizer, and AstraZeneca; support for attending meetings and/or travel from Roche, Novartis, BMS, Bayer, Eli Lilly, Pfizer, and Astra Zeneca; participation on a Data Safety Monitoring Board or Advisory Board for Roche, Johnson & Johnson, and AstraZeneca; leadership or fiduciary roles in IASLC; and received equipment, materials, drugs, medical writing, gifts or other services from AstraZeneca, and Roche. L.R. has received grants or contracts from Prostate Cancer Foundation and Conquer Cancer Foundation; payment or honoraria from MSD, AstraZeneca, BMS, Johnson & Johnson, Amgen, Merck Serono, and Roche; payment for expert testimony from MSD, AstraZeneca, BMS, Johnson & Johnson, Amgen, Merck Serono, and Roche; support for attending meetings and/or travel from MSD, AstraZeneca, BMS, Johnson & Johnson, Amgen, Merck Serono, and Roche; participation on a Data Safety Monitoring Board or Advisory Board for MSD; and leadership or fiduciary roles in IASLC and ASCO. O.A. has received grants or contracts from AstraZeneca, Boehringer Ingelheim, and Roche; and consulting fees from Pfizer, Lilly, Merck, and Bristol Myers Squibb, AstraZeneca, Boehringer Ingelheim, and Roche. A.F.C. has received grants or contracts from Roche, BI, Novartis, Foundation Medicine, Astra, QQF, Roche Diagnostics, Amgen, Bayer, CCF, and Idylla; consulting fees from Roche, BI, Pfizer, Novartis, Celldex, Astra, Astellas, Amgen, MSD, Merck Serono, EISAI, Janssen, BioNTech, Flatiron Health, Teva Pharma, Takeda, FICMAC, and Servier; payment or honoraria from Johnson & Johnson, Roche, BI, Pfizer, Novartis, Astra, Amgen, BMS, MSD, EISAI, TEVA, Merck Serono, Takeda, Mirati, and Servier; payment for expert testimony from Roche, BI, Novartis, BMS, AbbVie, Celldex, Idylla, Thermo Fisher, Illumina, Amgen, Eli Lilly, Guardant Health, Regeneron, Bayer, Biocartis, Pharma Mar, and Pfizer; support for attending meetings and/or travel from Roche, BI, Novartis, BMS, AbbVie, Celldex, Idylla, Thermo Fisher, Illumina, Amgen, Eli Lilly, Guardant Health, Regeneron, Bayer, Biocartis, and Pfizer; participation on a Data Safety Monitoring Board or Advisory Board for Roche, Johnson & Johnson, and AstraZeneca; leadership or fiduciary roles in IASLC and ASCO; received equipment, materials, drugs, medical writing, gifts or other services from Roche, Rochem Biocare, Thermo Fisher, and Illumina. The other author has no conflicts of interest to declare.

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