Early checkpoint inhibition before chemoradiation: is the strategy ready for stage III non-small cell lung cancer?

Background

The therapeutic landscape of non-small cell lung cancer (NSCLC) has experienced a paradigm change due to the emergence of immune checkpoint inhibitors (ICIs), significantly transforming outcomes in advanced and metastatic cases. The idea behind induction immunotherapy (IIT) is to start immune priming earlier in the treatment process. This is done by using intact tumor antigens to start anti-tumor immune reactions before chemoradiation might change the environment around the tumor. However, for locally advanced, unresectable NSCLC, where concurrent chemoradiotherapy (cCRT) followed by immunotherapy has traditionally been the standard, the incorporation of IIT remains ambiguous.

The phase I Induction Trial conducted by Smeenk et al. highlights the potential of IIT, investigating the viability of tremelimumab and durvalumab prior to cCRT. As the science advances towards earlier immune modulation, a critical question arises: Can immune checkpoint inhibition transform the therapeutic paradigm for unresectable NSCLC, or will concerns regarding toxicity restrict its practical applicability?

Evaluating the induction trial findings

The Induction Trial evaluated tremelimumab and durvalumab across three dosage groups prior to cCRT, emphasizing a nuanced balance between effectiveness and tolerability. Administration of high-dose tremelimumab (300 mg) came with a cost, as six of the seven patients experienced grade ≥3 immune-related adverse events (irAEs), such as aspartate aminotransferase (AST) and alanine aminotransferase (ALT) increase, colitis and gastritis (1). The safety concerns reflect those identified in CheckMate 227, when combination immunotherapy resulted in elevated treatment discontinuation rates despite significant efficacy for the advanced metastatic population (2).

Conversely, a lower-dose regimen (75 mg tremelimumab + durvalumab) demonstrated significantly greater tolerability, satisfying safety standards (1). This highlights a fundamental principle in IIT-cCRT: dosage optimization is essential. Achieving an optimal balance between immune stimulation and toxicity will be essential as IIT techniques advance.

In addition to safety, the most notable outcome of the induction study was significant nodal downstaging; 8 of 11 (73%) patients with baseline multilayer N2/N3 disease exhibited considerable regression with IIT (1). Moreover, multiparametric magnetic resonance imaging (MRI) showed remarkable accuracy in identifying nodal response (7/7 patients), hence stressing the significance of advanced imaging in guiding treatment decisions (1). The results show that by increasing immune priming, IIT might increase the efficacy of cCRT, but more research is required to optimize safe dosing and to see if these results in long-term survival benefits.

How does IIT-cCRT compare to standard chemoradiotherapy?

As IIT-cCRT develops as a viable therapy, it must be evaluated against the benchmark: the PACIFIC trial regimen, which established cCRT followed by durvalumab maintenance as the prevailing standard of care (3,4). The caveat is that the Induction Trial lacked sufficient power to evaluate overall survival (OS) or progression-free survival (PFS) in the locally advanced setting, complicating cross-trial comparisons.

The PACIFIC trial demonstrated that the addition of durvalumab post-chemoradiation therapy significantly enhanced overall survival when compared to placebo (median PFS 16.9 months and 2-year PFS 45%) (4), with OS improvement seen through 5 years [OS 42.9% vs. 33.4%, hazard ratio (HR) 0.72, 95% confidence interval (CI): 0.59–0.89] (5). In contrast, the Induction Trial reports a median PFS of 26.1 months and a 2-year PFS of 52%. Of note, PACIFIC metrics are from the time of completion of chemoradiation, which may inflate rates compared to other studies, such as the Induction Trial.

Although the early results of IIT-cCRT are promising, it is premature to have a significant impact on practice. At this time, the PACIFIC regimen continues to be the standard, and the adoption of IIT-cCRT must be approached with caution until larger trials confirm a survival advantage. The potential for improved immune priming is alluring; however, there are still significant unanswered concerns regarding toxicity, patient selection, and long-term outcomes.

Safety and toxicity

The potential of IIT-cCRT must be evaluated in relation to its safety profile, which continues to be a significant challenge. Although ICIs have revolutionized treatment modalities, they also add a new dimension of complication, as irAEs sometimes manifest unpredictably and can be severe. The Induction Trial’s results on toxicity expose the range of side effects already known to be linked to tremelimumab and durvalumab. Severe adverse effects with grade 3 or higher immune-related side effects occurred in 7 out of 15 patients (47%), most being in the high-dose tremelimumab cohorts (1). The increased toxicity associated with high-dose tremelimumab (cohorts II and III) is particularly concerning, casting doubt on the viability of widespread clinical implementation (1).

The PACIFIC trial is the most suitable benchmark for assessing toxicities of emergent strategies such as IIT-cCRT, as it is the current standard of care for unresectable, locally advanced NSCLC. Durvalumab consolidation after cCRT was associated with a manageable safety profile, as evidenced by a post-hoc analysis of PACIFIC. Grade 3/4 immune-mediated pneumonitis occurred in only 1.9% of patients, and non-pneumonitis grade 3/4 immune-mediated adverse effects occurred in only 1.7% of patients (6). The incidence of fatal events was exceedingly low (0.8%, exclusively pneumonitis). Most events occurred within the first three months of durvalumab initiation and resolved with appropriate management, with thyroid disorders (11.4%) and pneumonitis (10.7%) being the most common (6).

These results support a persistent challenge in immuno-oncology: how to strike a balance between safety and efficacy. The toxicity profile of IIT-cCRT is more complex than that of conventional cCRT. Unlike the relatively well-documented toxicities of cCRT, such as radiation pneumonitis and esophagitis, irAEs can affect nearly every organ system and present with a wide range of severity and onset times. American Society of Clinical Oncology (ASCO) guidelines stress that irAEs can be life-threatening and need to be identified early and managed carefully (7).

Patient selection and predictive biomarkers

The Induction Trial underscores a fundamental principle of IIT-cCRT: not all patients derive equal benefit. Meticulous patient selection is crucial to optimize efficacy and reduce toxicity concerns. Optimal candidates—Eastern Cooperative Oncology Group (ECOG) 0–1 with few comorbidities— are most likely to succeed, but individuals experiencing considerable weight loss (>10%), ECOG >1, or a history of grade ≥2 pneumonitis are at increased risk of toxicity and may necessitate alternate approaches (8).

In addition to clinical factors, biomarkers are transforming patient selection. PD-L1 ≥1% continues to be fundamental for stratification (9); however, emerging biomarkers provide further understanding of both initial eligibility and real-time response assessment. While circulating tumour DNA (ctDNA) clearance was not examined in the Induction Trial, growing evidence suggests that early clearance is associated with improved OS and PFS, implying that it could be a valuable biomarker in future IIT-cCRT trials to monitor response and modify treatment (10). Elevated tumor mutation burden (TMB) has also been correlated with enhanced responses to ICIs, including durvalumab and tremelimumab, underscoring its significance in treatment guidance. Although in the metastatic setting, the MYSTIC study has revealed that patients exhibiting a blood-based tumor mutational burden (bTMB) of ≥20 mutations per megabase (mut/Mb) experienced substantial therapeutic advantages when administered durvalumab in conjunction with tremelimumab, as opposed to chemotherapy (11). In addition, a high number of tumor-infiltrating lymphocytes (TIL) suggests a good immune environment that makes the anti-tumor immune reaction last longer (12). As IIT-cCRT advances, precision oncology should take the place of broad qualifying requirements. Using clinical and genomic predictors together will ensure that the right patient gets the right therapy, which will maximize benefits while minimizing risks.

Emerging directions

Some retrospective studies have demonstrated that induction chemoimmunotherapy is more effective than standard CRT in terms of survival. Guan et al. found that a median PFS of 24.8 months was achieved with induction chemoimmunotherapy followed by cCRT, compared to 13.3 months with cCRT alone (P=0.04). The induction group did not achieve a median OS, while the cCRT group did, with a median OS of 36.6 months (13). This suggests that induction therapy may have a survival advantage, although the current standard of care would be cCRT followed by immunotherapy and not cCRT alone, questioning the study’s relevance. In a similar vein, Zhao et al. discovered that chemoimmunotherapy induction resulted in higher response rates and a longer PFS when compared to chemotherapy induction alone (median PFS 13.5 vs. 11.2 months, HR 0.56, 95% CI: 0.32–0.97; P=0.04) (14). Nevertheless, the necessity of proactive monitoring and toxicity management strategies is underscored by the elevated hematologic toxicity rates observed in certain real-world cohorts (13,14).

The Induction Trial offers compelling preliminary evidence, demonstrating the feasibility, nodal downstaging, and improved efficacy of low-dose tremelimumab. Nevertheless, the toxicity of tremelimumab was exacerbated by higher concentrations, underscoring the need for biomarker-driven adjustments and dose optimization. These findings further raise the question of whether dual checkpoint inhibitor (CPI) induction is required, or if induction with a single CPI alone would suffice, or if induction with a single CPI alone or chemoimmunotherapy would suffice. Early-phase findings from the Induction Trial and meta-analyses indicate that, while CTLA-4 inhibition may improve immune priming, its increased advantage over PD-1/PD-L1 blocking is unknown and is typically linked with higher toxicity (15). As a result, ongoing research is looking into single-agent checkpoint blockade or chemoimmunotherapy as safer and maybe similarly successful induction techniques before cCRT (16). The application of dual CPI in the curative-intent setting is somewhat premature, as it remains less commonly used even in the advanced/metastatic setting, where the therapeutic risk tolerance is typically higher. More research is needed to determine whether single-agent CPI or chemoimmunotherapy induction is as effective as dual CPI approaches in this case.

The CheckMate 816 trial strengthens the case for delivering immunotherapy in the neoadjuvant setting, when the tumor antigen burden is high and immune priming may be most effective. In this phase III study, patients with resectable stage IB–IIIA NSCLC were enrolled. The results showed that neoadjuvant nivolumab plus chemotherapy significantly improved event-free survival (31.6 vs. 20.8 months; HR 0.63, P=0.005) and pathological complete response (24.0% vs. 2.2%) compared to chemotherapy alone, without compromising surgical feasibility or increasing adverse events (17). Grade 3/4 treatment-related adverse events occurred in 33.5% of the nivolumab-chemotherapy group, which was similar to the chemotherapy-alone group (36.9%), indicating the safety and feasibility of this method in the perioperative context (17).

While the disease setting differs, both CheckMate 816 and the Induction Trial explore the immunologic advantages of initiating checkpoint blockade in the presence of an intact primary tumor. Of note, although the primary analysis of CheckMate 816 focused on chemoimmunotherapy, the ipilimumab-nivolumab arm may offer more conceptual relevance to the dual CPI strategy tested in the Induction Trial. A few patients in the Induction Trial who were initially considered unresectable experienced such significant nodal downstaging that they ultimately underwent surgical resection, thereby altering the traditional boundary between resectable and unresectable disease. The SQUAT (WJOG 12119L) study, which was recently published, also corresponds with this framework by incorporating concurrent chemo-immuno-radiotherapy, surgery, and adjuvant durvalumab. The trial demonstrated excellent local efficacy, with a major pathological response rate of 63% and a pathological complete response rate of 23% (18). However, one significant limitation of the Induction Trial is that PD-L1 testing was not required, and no information about driver mutation status was provided. This raises concerns regarding generalizability, as biomarker-based treatment is becoming increasingly used in NSCLC. Without accounting for PD-L1 expression, it is difficult to say if the observed responses are consistent among molecular subtypes.

It is important to keep in mind, however, that PD-L1 testing was not mandated, some patients were PD-L1 negative, and no testing for driver mutations was reported—all of which are important limitations in an era of increasingly personalized, biomarker-driven treatment. It is also unclear whether nodal downstaging—even under the most optimal setting with positron emission tomography (PET), MRI, and repeat bronchoscopy represents actionable data. The Induction Trial advantage is that single station N2 or less is potentially surgically resectable, an approach utilized by many groups. Notably, there are no standard definitions of surgically resectable, and depending on the country, practice, and surgeon, multi-station N2 disease would not be de facto considered unresectable (19). In addition, it is presumed that those with single-station N2, N1, or N0 disease had medical comorbidities making them best-suited for chemoradiation, and reflecting common situations faced by patients with lengthy smoking histories. For these patients, chemoradiation will be the best approach regardless of nodal downstaging. More broadly, there are no data supporting the safety and efficacy of changing the local therapy treatment approach based on downstaging. All of the phase III IIT/chemoimmunotherapy trials included patients who were deemed surgically resectable prior to initiation of systemic therapy. For downstaging to be a clinically useful endpoint and practically actionable, we need randomized data showing that whatever we do for patients with the “downstaged data”, whether to take them to surgery now that they are “resectable”, or to continue the original plan of cCRT followed by consolidation immunotherapy, does not negatively affect recurrence rates at the very least, and to be truly practice changing, the intervention must have a survival advantage.

The ongoing InTRist trial investigates the efficacy of the programmed death-1 (PD-1) inhibitor toripalimab plus chemotherapy followed by cCRT and consolidation toripalimab in patients with bulky locally advanced NSCLC. This study includes exploratory programmed death-ligand 1 (PD-L1) expression analysis, liquid biopsy-based biomarker testing, and single-cell tumor microenvironment profiling (20). Similarly, the AFT-57 trial focuses on the integration of PD-L1 expression and other immune-related biomarkers to personalize treatment strategies. This effort aims to maximize the use of ICIs by means of biomarkers predicting response and assessment of therapy efficacy using liquid biopsy indicators including ctDNA and circulating tumor cells (CTCs) (21). Future phase II/III trials will be critical for determining if IIT-cCRT consistently improves OS and PFS over usual cCRT. As IIT-cCRT becomes more widely used in clinical practice, a precision-oncology framework will be required to optimize patient selection, minimize toxicity, and ensure maximum therapeutic effect for patients with unresectable, locally advanced NSCLC.

Conclusions

The Induction Trial highlights an emerging area of thoracic oncology—can IIT-cCRT offer an effective and feasible strategy for unresectable, locally advanced NSCLC? Although lower-dose tremelimumab shows promise, especially in nodal downstaging and immunological priming, toxicity remains a major obstacle, particularly at higher dosages. Before IIT-cCRT can be applied to patients, some issues have to be resolved. Finding the proper balance of safety and efficacy depends on dose optimization. Treatment approaches must also include comprehensive toxicity management if we are to reduce immune-related side effects without sacrificing efficacy, as maximizing benefit while keeping toxicities under control is critically important in a potentially curable setting. Finding who will benefit most will depend much on biomarker-driven patient selection since immune responses to different forms of NSCLC can vary. Rather than replacing the PACIFIC regimen, IIT-cCRT may eventually complement current standards in selected patients, pending results from ongoing trials like InTRist and AFT-57 that further clarify its role. The response will determine the role of immunotherapy in locally advanced NSCLC and present both new opportunities and ongoing challenges.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the Editorial Office, Translational Lung Cancer Research. The article has undergone external peer review.

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-593/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-593/coif). J.P.H. is on the data safety and monitoring board at the University of California Irvine; and is consultant for Novocure. M.N. is on the advisory board for AstraZeneca, Daiichi Sankyo, Takeda, Johnson and Johnson, Pfizer, Eli Lilly and Company, Bayer, Regeneron, BMS, Boehringer Ingelheim and Genentech; consultant for Caris Life Sciences (virtual tumor board); and speaker for Johnson and Johnson, Mirati and Takeda; and reports travel support from AnHeart/Nuvation Bio Therapeutics; and stock/stock options from MBrace Therapeutics. The other author has no 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/.

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