Canakinumab with chemoradiation and durvalumab consolidation in unresectable stage III non-small cell lung cancer: the phase I/II CHORUS trial

Abstract

CHORUS (NCT04905316) was an open-label, non-randomized, single-arm phase I/II trial of the anti-IL-1beta monoclonal antibody canakinumab given with concurrent chemoradiotherapy and continued with anti-PD-L1 durvalumab consolidation in unresectable stage III non-small cell lung cancer. The primary endpoint was 24-month progression-free survival (PFS) from radiotherapy initiation; secondary endpoints included overall survival, objective response rate, and safety. Forty-one patients were enrolled, 37 received canakinumab, and 32 comprised the prespecified efficacy population. At a median follow-up of 25 months, 24-month PFS was 67% (95% confidence interval, 52–88); the lower bound of the prespecified one-sided 90% confidence interval was 56.5%, exceeding the 46% historical benchmark, and the primary endpoint was met. Twelve- and 24-month overall survival were 93% and 73%, respectively, and the confirmed objective response rate was 81%. Canakinumab-related grade 3–4 events included neutropenia (n = 5), febrile neutropenia (n = 1), lymphopenia (n = 1), lung infection (n = 1), fatigue (n = 1), and hypertension (n = 1); no canakinumab-related deaths occurred. Pneumonitis of any attribution occurred in 9 of 37 patients (24%; grade 2, n = 7; grade 3, n = 2). Peripheral immune cell profiling showed attenuated expansion of myeloid-derived suppressor cells and CTLA-4-expressing CD8 + T-cell subsets among responders. Circulating tumor DNA cleared by week 6 in 20 of 30 evaluable patients (66%). These findings support randomized evaluation of interleukin-1β blockade in this setting.

IL-1β targeting may attenuate myeloid-suppressive pathways and support antitumor immunity. Here, the authors report a phase I/II trial of concurrent canakinumab, an anti-IL-1β antibody, with chemoradiotherapy, followed by consolidation canakinumab plus the anti-PD-L1 antibody durvalumab, in patients with unresectable stage III non-small cell lung cancer.

Introduction

Consolidation durvalumab after concurrent chemoradiotherapy (cCRT) improved survival and established a new standard for unresectable stage III non–small cell lung cancer (NSCLC)^1,2. However, outcomes remain unsatisfactory: many patients never initiate durvalumab because of progression or toxicity, and among those who do, most experience disease recurrence within two years^3,4. Moreover, recent attempts to intensify therapy by adding immunotherapy concurrently with cCRT or incorporating dual PD-1/CTLA-4 blockade as consolidation have failed to improve outcomes^5–7. These limitations highlight the need for novel strategies that enhance disease control without increasing toxicity.

Radiotherapy can promote immunogenic tumor cell death and adaptive immune responses^8,9, but it can also activate counter-regulatory inflammatory pathways that may limit treatment efficacy^10,11. Radiotherapy can trigger inflammasome activation and the release of interleukin-1β (IL-1β)^12–14. IL-1β signaling promotes recruitment of myeloid-derived suppressor cells (MDSCs), expansion of regulatory T cells, and dysfunction of cytotoxic T cells^15–18, and has been associated with tumor progression, resistance to immune checkpoint blockade, and inferior survival outcomes^19,20.

Preclinical studies demonstrate that radiotherapy activates inflammatory pathways that mobilize MDSCs that suppress CD8⁺ T cell effector function and compromise tumor control²¹. In contrast, in preclinical models, IL-1β inhibition blunts MDSC recruitment and restores antitumor immunity²². Collectively, these observations provide a rationale for targeting IL-1β as a strategy to counteract radiation-induced inflammatory and myeloid-suppressive pathways, thereby enhancing treatment sensitivity and augmenting antitumor immune responses.

Canakinumab is a high-affinity, fully human monoclonal antibody that selectively neutralizes IL-1β. Although the phase III CANOPY trials in advanced NSCLC did not demonstrate a survival benefit in unselected populations, exploratory analyses identified a potential benefit for canakinumab combined with chemotherapy and pembrolizumab in tumors with low T cell infiltration¹⁵. This finding suggests that the therapeutic activity of IL-1β blockade may be greatest in biologically defined, immunosuppressive contexts. We hypothesized that IL-1β blockade could improve outcomes in unresectable stage III NSCLC when initiated concurrently with cCRT and continued with consolidative PD-L1 blockade by mitigating radiation-induced inflammatory immunosuppression.

In this work, we report results from the phase I/II CHORUS trial, evaluating canakinumab combined with concurrent chemoradiation followed by durvalumab consolidation in patients with unresectable stage III NSCLC. The regimen met the prespecified 24-month progression-free survival endpoint and was associated with early radiographic responses and circulating tumor DNA clearance, manageable toxicity, and attenuation of myeloid-derived suppressor cell and inhibitory CD8 + T-cell trajectories. These findings support randomized evaluation of interleukin-1β blockade in this setting.

Results

Patient characteristics

Between June 2021 and May 2023, 41 patients were enrolled across MSK sites, including at the main Manhattan campus (n = 10), New Jersey sites (n = 15), Long Island sites (n = 9), and the Westchester site (n = 7). Of these, 37 patients received at least one dose of canakinumab and comprised the modified intention-to-treat (mITT) population. In total, 32 patients met protocol-defined criteria for inclusion in the primary efficacy analysis (Fig. 1). Five patients were excluded from efficacy analysis due to withdrawal of consent (n = 1), receipt of consolidative TKI therapy (n = 1), treatment-related toxicity (n = 1), death unrelated to study treatment (n = 1), and surgical resection (n = 1). Accordingly, safety analyses were performed in the mITT population, and efficacy analyses were conducted in the 32 evaluable patients. At the time of data cutoff, all patients had completed study treatment, with a median follow-up of 25 months (95% CI^21–27).

Fig. 1.

Consort diagram. TKI, tyrosine kinase inhibitor.

Baseline patient characteristics are summarized in Table 1. In the efficacy population (n = 32), the median age was 70 years (range, 46–83) and there were 18 women and 14 men. Most patients had stage IIIB/IIIC disease (22, 69%), adenocarcinoma histology (19, 59%) and had a performance status score of 0 (21, 66%). Most patients had a smoking history (28, 88%). PD-L1 TPS was known for 29 patients (91%), of which 14 (48%) were PD-L1 negative, 7 (24%) had PD-L1 TPS between 1–49% and 8 (28%) had PD-L1 TPS ≥ 50%.

Table 1.

Patient Characteristics

Characteristic	mITT population (n = 37)	Efficacy population (n = 32)
Age, Median (range)	69 (46–83)	70 (46 - 83)
Sex, n (%)
Male	15 (41)	14 (44)
Female	22 (59)	18 (56)
ECOG performance status, n (%)
0	21 (57)	21 (66)
1	16 (43)	11 (34)
Histology, n (%)
Adenocarcinoma	20 (54)	19 (59)
Squamous	14 (38)	11 (34)
NOS	3 (8)	2 (7)
Stage, n (%)
IIIA	10 (27)	10 (31)
IIIB	18 (49)	14 (44)
IIIC	9 (24)	8 (25)
PD-L1 TPS, n (%)
Negative	15 (47)	14 (48)
1-49%	9 (28)	7 (24)
≥50%	8 (25)	8 (28)
Unknown	5	3
Smoking history, n (%)
Ever Smoker	32 (86)	28 (88)

ECOG Eastern Cooperative Oncology Group, NOS not otherwise specified, PD-L1 TPS Programmed death-ligand 1 tumor proportion score.

All patients in the efficacy population received cCRT to a planned dose of 60 Gy, except one who received 56 Gy. Concurrent chemotherapy regimens were carboplatin and paclitaxel (n = 16), carboplatin and pemetrexed (n = 10), cisplatin with pemetrexed (n = 3), and cisplatin with etoposide (n = 3).

Canakinumab treatment exposure

Among the 32 patients evaluable for efficacy, during the cCRT phase, most (29, 91%) received at least 2 doses of subcutaneous canakinumab, and 18 patients (56%) received all three planned doses of subcutaneous canakinumab. During the durvalumab consolidation phase, patients received a median of 7 (range: 1-12) cycles of intravenous canakinumab. Twelve patients (38%) received at least 90% (>10 cycles) of all planned cycles of intravenous canakinumab with durvalumab. Coronavirus disease 2019 (COVID-19) infections notably impacted 2 patients in the consolidation phase of treatment, leading to study withdrawal and discontinuation of protocol therapy (n = 1) and to death (n = 1).

Efficacy

The primary endpoint of the 24-month PFS rate was 67% (95% CI, 52–88) (Fig. 2A). The lower bound of the one-sided 90% confidence interval for the 24-month PFS estimate was 56.5%, exceeding the predefined 46% historical benchmark. The 12-month PFS rate was 75% (95% CI, 61–93). The 12- and 24-month OS rates were 93% (95% CI, 84–100) and 73% (95% CI, 57–92), respectively (Fig. 2B). The median PFS and OS were not reached. The 24-month cumulative incidence of locoregional failure was 14% (95% CI, 4–30).

Fig. 2. Disease and survival outcomes.

Progression free survival (A) Overall survival analysis (B). Blue shading defines 95% confidence interval. Source data are provided as a Source Data file.

In a post hoc sensitivity analysis of the mITT population, the 2-year PFS rate was 66% (95% CI, 51–86%), and the 2-year OS rate was 71% (95% CI, 56–91%) (Supplementary Fig. 2).

On first response assessment after the completion of cCRT + canakinumab and prior to consolidation therapy, 74% (95% CI, 55-88) of patients had an objective response to treatment with canakinumab + cCRT, with a 48% (n = 11) having a ≥ 50% reduction in target lesion at this initial assessment (Fig. 3A). Representative examples of response to cCRT + canakinumab on the first response assessment are shown in Fig. 4. The confirmed objective response rate at any time point on study was 81% (95% CI, 64–93) (Fig. 3B).

Fig. 3. Treatment response rates.

Initial radiographic response assessment (A) best confirmed response (B). Data from 31 patients. Source data are provided as a Source Data file.

Fig. 4. Radiographic examples of initial response to canakinumab with concurrent chemoradiotherapy.

Representative examples of depth of response at the first response assessment after the completion of cCRT + canakinumab across 4 patients, baseline imaging (left) (A–D).

On univariable analysis, PD-L1 expression when evaluated as PDL1 ≥ 1% vs <1% was not associated with progression-free survival (p = 0.7). Similarly, age, ECOG PS and histology did not associate with PFS (p = 0.4, p = 0.4 and p = 0.3, respectively). Patients with stage IIIB/IIIC vs IIIA disease had worse PFS (p = 0.023) (Table 2).

Table 2.

Univariable Cox Analysis for Progression- Free Survival

Characteristic	N	Event N	HR (95% CI)	p-value
Age	32			0.4
≤70		4	-
>70		6	1.76 (0.49, 6.24)
ECOG Performance Status	32			0.4
0		6	—
1		4	1.71 (0.48, 6.09)
PD-L1	29			0.7
Negative		5	-
Positive		4	0.8 (0.21, 3.02)
Histology	32			0.3
Adenocarcinoma		7	—
Squamous/Other		3	0.5 (0.13, 1.95)
Stage	32			0.023a
IIIA		0	—
IIIB/IIIC		10

^alog-rank p-value.

CI confidence interval, HR hazards ratio.

Safety

A summary of the safety analysis is given in Tables 3 and 4 for the 37 patients analyzed for safety. There were no canakinumab treatment-related deaths. Grade 3–4 toxicities possibly, probably, or definitely related to canakinumab occurred more often during the cCRT phase of treatment and included grade 3 febrile neutropenia (n = 1), neutropenia (n = 4), and lymphopenia (n = 1), and grade 4 neutropenia (n = 1). Grade 3 canakinumab related toxicities occurring during durvalumab consolidation included lung infection (n = 1), fatigue (n = 1) and hypertension (n = 1). One patient who did not complete chemoradiation therapy developed grade 3 neutropenia found to be possibly related to canakinumab which may have contributed to the early discontinuation of cCRT. Canakinumab-related toxicities did not lead to the discontinuation of durvalumab consolidation. In total, 9 patients (24%) developed pneumonitis of any attribution: grade 2 (n = 7) and grade 3 (n = 2).

Table 3.

Canakinumab-Related Toxicities During Chemoradiation Phase (n = 37)

Toxicity	Grade 2	Grade 3	Grade 4
Dermatitis	1 (3%)
Diarrhea	2 (5%)
Dyspepsia	1 (3%)
Dysphagia	1 (3%)
Dyspnea	1 (3%)
Esophagitis	2 (5%)
Fatigue	2 (5%)
Febrile neutropenia		1 (3%)
Hypoxia	1 (3%)
Lymphocyte count decreased		1 (3%)
Nausea	1 (3%)
Neutrophil count decreased	6 (16%)	4 (11%)	1 (3%)
Rash maculo-papular	1 (3%)

Table 4.

Canakinumab-Related Toxicities During Chemoradiation Phase (n = 32)

Toxicity	Grade 2	Grade 3	Grade 4
Cough	1 (3%)
Dry skin	1 (3%)
Dyspnea	4 (13%)
Fatigue	1 (3%)	1 (3%)
Hypertension		1 (3%)
Hypoxia	1 (3%)
Lung infection		1 (3%)
Nausea	1 (3%)
Neutrophil count decreased	2 (6%)
Pain in extremity	1 (3%)
Pneumonitis	2 (6%)
Pruritus	1 (3%)
Urinary tract infection	2 (6%)
Weight gain	1 (3%)
Weight loss	1 (3%)
Wheezing	1 (3%)

Post-hoc analysis of imaging and ctDNA associations with disease outcomes

All patients (n = 32) had detectable ctDNA at baseline. ctDNA was assessed at three additional on-treatment timepoints. First on-treatment samples, taken a median of 3 weeks (interquartile range: 3-3.2) from treatment start, were assessed in 30 patients, of whom 10 (33%) had undetectable ctDNA. Second on-treatment samples, taken a median of 6.2 weeks (IQR 6-7) from treatment start, were assessed in 30 patients of whom 20 of 30 (66%) had undetectable ctDNA. Third on-treatment samples, taken a median of 15.2 (IQR 14.4-17.3) weeks from treatment start and 4 weeks (IQR 4-4.4) from start of durvalumab + canakinumab consolidation, were assessed in 29 patients of whom 20 (69%) had undetectable ctDNA (Fig. 5). Among the 9 patients with detectable ctDNA on the third on-treatment sample, 3 (33%) had a decreasing VAF compared to their second on-treatment sample.

Fig. 5.

Circulating tumor DNA detection at baseline and through 3 on-treatment timepoints. Solid purple circle, detectable ctDNA; Blue circle, undetectable ctDNA; Open purple circle, detectable ctDNA but decreasing VAF. Green lines, confirmed PR/CR as best imaging response; red lines, SD as best confirmed response; gray lines identify patients with non-evaluable. Number of patients at baseline: n = 32, at timepoint 2: n = 30, at timepoint 3: n = 30, at timepoint 4: n = 29.Source data are provided as a Source Data file.

Patients with a confirmed best response of CR or PR vs SD were less likely to have progressed at 24 months (p = 0.004). Detectable ctDNA on the first on-treatment sample was not associated with progression by 24 months (p > 0.9). More patients with detectable ctDNA on the third on-treatment sample progressed by 24 months (67% vs 27%), but this difference was not statistically significant (p = 0.15). All patients with detectable ctDNA on the third on-treatment sample who also had the best confirmed response of SD progressed by 24 months (p = 0.02). (Supplementary Table 2).

Translational Immune Correlates

Longitudinal immune profiling examining changes from baseline to week 3 and week 6 identified expansion across multiple T cell compartments (Supplementary Fig. 3). Increases in proliferating and activated subsets, including Ki67⁺ PD-1⁺, CD8⁺ and CD4⁺ T cells, as well as up-regulation of ICOS and CTLA-4 expression, were observed at week 3 and sustained through week 6. In contrast, expression of FOXP3, TIM-3, and LAG-3 showed only minimal change at both timepoints. Serum cytokine analysis of change from baseline to week 3 and week 6 demonstrated stable levels of IL-1β and IL-6 with a modest increase of IFN-γ at week 6 (Supplementary Fig. 4).

Multiparameter flow cytometry identified three populations with significantly different longitudinal trajectories by best overall response (FDR-adjusted q < 0.1) (Fig. 6A–C). Myeloid-derived suppressor cells (MDSCs) within the live lymphocyte/monocyte gate (q = 0.04) showed early enrichment by week 3 in patients with stable disease whereas responders demonstrated attenuated expansion across treatment. Similarly, CTLA4⁺ CD8⁺ T cells (q = 0.08) and Ki67⁺CTLA4⁺ CD8⁺ T cells (q = 0.06) demonstrated early and sustained expansion across week 3 and 6 in patients with stable disease, whereas remained attenuated across treatment in responders.

Fig. 6. Trajectorial of peripheral immune cell populations and associations with best confirmed response.

Longitudinal trajectories of MDSCs (A), CTLA4⁺ + CD8⁺ T cells (B) and KI67⁺CTLA4⁺ CD8⁺ T cells (C) stratified by best confirmed response (CR/PR vs SD). Number of patients with MDSC flow samples (A): CR/PR patients: n = 20 at baseline, n = 16 at week 3, n = 12 at week 6; SD patients: n = 3 at baseline, n = 2 at week 3, n = 2 at week 6. Number of patients with T-cell flow samples (B, C): CR/PR patients: n = 25 at baseline, n = 26 at week 3, n = 24 at week 6; SD patients: n = 5 at baseline, n = 5 at week 3, n = 4 at week 6. Data are presented as Q1-1.5*IQR, Q1, median, Q3, Q3 + 1.5*IQR in the boxplot; all points represent outliers. Q1 and Q3 correspond to the 25th and 75th percentile, respectively, and IQR (interquartile range) = Q3-Q1. P-values correspond to the interaction term between group and timepoint specified in the GEE model. P-values are two-sided and adjusted for multiple comparisons using the Benjamini-Hochberg method, which corresponds to the presented q-values. Source data are provided as a Source Data file.

To contextualize these findings, parallel immune profiling was performed in an independent, prospectively followed, cohort of patients treated with standard chemoradiation without canakinumab (n = 9) (Supplementary Figs. 5 and 6). Comparison of serum cytokine levels between cohorts from baseline to week 6 demonstrated significantly different longitudinal patterns of IL-1β and IL-6, with a rise in IL-1β at week 6 and a rise in IL-6 at week 3 seen predominantly in the cohort treated without canakinumab (Supplementary Fig. 7 A, B). Cross-cohort comparison of immune cell compartments revealed additional differences in immune dynamics. The two CD8⁺ subsets linked to response in canakinumab-treated patients (KI67⁺CTLA4⁺ CD8⁺ and CTLA4⁺ CD8⁺) also differed between cohorts, with standard-of-care patients showing an early rise at week 3, whereas these populations remained suppressed in canakinumab-treated patients (q = 0.09 for both comparisons). Furthermore, MDSCs also differed significantly between cohorts, with a distinct longitudinal pattern, showing greater accumulation in patients not treated with canakinumab (q < 0.001) (Supplementary Fig. 8 A-C).

Discussion

The primary objective of this phase I/II study was to evaluate whether the addition of IL-1β blockade to chemoradiotherapy and durvalumab consolidation could improve 2-year progression-free survival (PFS) relative to established historical benchmarks¹. The observed 2-year PFS of 67% (95% CI 52–88) surpassed the prespecified threshold of 64%, meeting the primary endpoint. Two-year OS was also favorable at 73% (95% CI 57–92), and the 12-month PFS of 75% compared well with the 56% reported in PACIFIC and the 34% observed in the control arm of COAST^2,27. Notably, these results were achieved in a biologically and clinically high-risk population, nearly half PD-L1 negative, most with stage IIIB/IIIC disease, and all with detectable ctDNA at baseline, all factors previously linked to inferior outcomes^28–30. Importantly, the regimen was well tolerated, with no appreciable excess treatment-related toxicities. Together, these findings suggest that targeting IL-1β–mediated inflammation during and after chemoradiotherapy can improve outcomes in unresectable stage III NSCLC.

In the context of more recent trials evaluating immunotherapy concurrently with cCRT or incorporating dual PD-1/CTLA-4 blockade as consolidation, which have not improved outcomes^5–7, our findings support a biologically distinct strategy targeting treatment-induced inflammatory and myeloid-suppressive pathways. Prior efforts focused on augmenting adaptive immune activation have not consistently improved disease control, underscoring the need for alternative approaches. IL-1β blockade and similar strategies may address this gap by mitigating early resistance mechanisms induced by chemoradiation and thereby enhancing the efficacy of current and emerging immunotherapy approaches.

A key observation was the occurrence of early and deep radiographic responses. The objective response was 74% at the first assessment post cCRT plus canakinumab and prior to consolidation therapy, with nearly half of patients with response achieving ≥50% reduction in target lesions. This compares favorably to historical post-cCRT response rates from PROCLAIM (ORR 33–36%) and KCSG-LU05-04 (ORR 38–43%), both of which reported best response rates achieved at any time during treatment^31,32. Although cross-trial comparisons must be interpreted with caution, the magnitude and timing of the early responses in this study suggest that IL-1β blockade with cCRT may contribute to deeper and earlier tumor regression. We hypothesized that canakinumab could mitigate counter-regulatory mechanisms triggered by chemoradiation—specifically the recruitment of myeloid-derived suppressor cells (MDSCs) and the resulting suppression of adaptive T cell responses^21,33 —thereby enhancing treatment sensitivity. Supporting this, two-thirds of patients achieved ctDNA clearance by approximately six weeks, consistent with an early systemic response.

The broader CANOPY program of canakinumab in NSCLC has yielded largely negative results³⁴. Neither adjuvant canakinumab monotherapy after resection (CANOPY-A) nor canakinumab plus docetaxel in previously treated metastatic disease (CANOPY-2) improved survival^35,36. By contrast, CANOPY-1, which evaluated canakinumab with first-line chemotherapy and pembrolizumab, demonstrated a more favorable hazard ratio for PFS (HR 0.85, 95% CI 0.67–1.09) with benefits observed in predefined subsets enriched for immunosuppressive features^19,37.

The present study differs mechanistically and clinically from prior CANOPY trials in that IL-1β blockade was administered concurrently with chemoradiotherapy. While radiotherapy elicits broad antitumor immunity, it also activates IL-1β through inflammasome signaling^12–14, promoting myeloid recruitment and inhibitory T cell expansion^17,18. Preclinical models demonstrate that radiation-induced IL-1β can trigger an early influx of MDSCs that blunt CD8⁺ effector function and promote resistance²¹. Administering IL-1β blockade concurrently with chemoradiation, therefore, offers a unique opportunity to intercept this inflammatory cascade at its source. This hypothesis aligns with biomarker analyses from CANOPY-1, where clinical benefit clustered in tumors with low T cell infiltration and immunosuppressive microenvironments¹⁹. In CANOPY-1, patients with a low T cell–inflamed gene signature experienced improved PFS with canakinumab plus pembrolizumab and chemotherapy (HR 0.53, 95% CI 0.31–0.90), an effect that was independent of PD-L1 expression and absent in CD8-rich/inflamed tumors¹⁹. These data suggest that IL-1β blockade is most effective in CD8-low or otherwise immunosuppressive contexts - biology that parallels our observation that concurrent IL-1β inhibition during chemoradiation attenuated expansion of suppressive CD8⁺ subsets and MDSCs, supporting a shared mechanistic rationale across settings.

The translational correlates observed in CHORUS further reinforce this biology. Within the canakinumab cohort, patients with response exhibited attenuated expansion of proliferative and dysfunctional CD8⁺ T cell subsets (KI67⁺CTLA4⁺ and CTLA4⁺ CD8⁺ T cells) and a blunted early rise in MDSCs, whereas these populations rose more prominently and early among patients with stable disease. These findings are consistent with prior evidence linking elevated MDSCs and neutrophilia during chemoradiation to poor outcomes^21,38. Importantly, the same immune subsets that distinguished responders also showed divergent trajectories compared with a prospectively followed standard-of-care cohort treated with chemoradiation alone, in which inhibitory CD8⁺ populations rose early, and a sharp MDSC expansion was observed at week 3. While exploratory, these results align with the hypothesized role of IL-1β in mediating radiation-induced myeloid recruitment and provide biologic plausibility to the observed clinical outcomes.

Preclinical studies have shown that attenuating MDSC activity during radiotherapy enhances radiosensitivity and restores CD8⁺ T cell function²¹. The integrated clinical and immune findings from CHORUS are consistent with this mechanism. Together, the convergence of clinical efficacy across multiple endpoints—including progression-free survival, radiographic response, ctDNA clearance, and immune signatures—supports further evaluation of IL-1β blockade as a strategy to enhance the efficacy of chemoradiation followed by immunotherapy consolidation.

This study is limited by its modest sample size and single-arm design, and was conducted at a tertiary care center, which may limit generalizability and introduce potential selection bias. Furthermore, cross-trial comparisons with studies such as PACIFIC should be interpreted with caution, given differences in patient selection, study design, and endpoint definitions. As with all oncology trials utilizing scheduled radiographic surveillance, progression-free survival is subject to interval censoring, and the timing of disease assessments may affect the exact estimation of landmark PFS rates. Additionally, this study was conducted during the COVID-19 pandemic that impacted clinical trial participation, led to treatment interruptions, and trial withdrawal, and even COVID-19-related death in some patients. Furthermore, translational correlates were assessed in peripheral blood and may not fully capture tumor-microenvironmental processes. The comparator standard-of-care correlative cohort was also limited in size (n = 9), which may reduce the robustness of comparative immune analyses. Finally, because canakinumab was administered during both chemoradiotherapy and consolidation, CHORUS cannot determine the independent contribution of IL-1β blockade during each phase. Despite these limitations, the integrated clinical, imaging, molecular, and immune findings establish proof-of-concept that targeting IL-1β–driven inflammation can reshape treatment-induced immunity and improve disease control in locally advanced NSCLC.

In this single-arm phase I/II trial, concurrent IL-1β blockade with chemoradiation followed by durvalumab consolidation achieved rapid and durable disease control and favorable survival in unresectable stage III NSCLC, without added appreciable toxicity. Canakinumab appeared to restrain myeloid-driven and inhibitory T cell responses while preserving effective immune activation. These findings support IL-1β inhibition as a rational and potentially practice-changing strategy to enhance the curative potential of chemoradiation and durvalumab consolidation in locally advanced NSCLC and warrant confirmation in a randomized phase III trial.

Methods

All research complied with relevant ethical regulations for research involving human participants. The CHORUS protocol was approved by the Memorial Sloan Kettering Cancer Center Institutional Review Board (MSK IRB #21-004), and the prospective standard-of-care biospecimen protocol was approved by the same board (MSK IRB #20-364). Both studies were conducted in accordance with the Declaration of Helsinki and the principles of Good Clinical Practice. All participants provided written informed consent before study procedures.

Patients

Key eligibility criteria included: patient age ≥ 18, histologically proven locally advanced NSCLC Stage IIIA-IIIC [as per the American Joint Commission on Cancer (AJCC) 8^th edition], disease amenable and patient fit for concurrent chemoradiotherapy, no contraindications for durvalumab consolidation, Eastern Cooperative Oncology Group Status scale score of 0 - 1, no active autoimmune disorders, and no active infection.

Study design

CHORUS (NCT04905316) was an investigator-initiated, open-label, single-arm, phase I/II, non-randomized study conducted across a multi-state, multi-site tertiary cancer center under a unified institutional protocol. As all therapies were administered at fixed, previously established doses, the study did not include a formal dose-escalation phase I component; instead, the phase I component was operationalized as prospective safety monitoring with predefined dose-limiting toxicity criteria and early stopping rules, conducted within a single continuous cohort. The protocol was reviewed and approved by the institutional review board (Memorial Sloan Kettering Cancer Center (MSK) IRB #21-004) and performed in accordance with the Principles of Good Clinical Practice (GCP) and the Declaration of Helsinki. Written informed consent was obtained from all patients. The trial was registered at ClinicalTrials.gov (NCT04905316; https://clinicaltrials.gov/study/NCT04905316; first posted 27 May 2021). Patients were enrolled between 6/14/2021 and 4/26/2023. The study schema is included in Supplementary Fig. 1. The full study protocol is included as Supplementary Information. Sex was collected from the electronic medical record. Participants of both sexes were eligible. Sex was not used as a stratification factor, and sex-specific efficacy analyses were not prespecified because of the small, single-arm sample size. Study participants received no compensation. Medidata was used for clinical trial data collection. Excel was used for data analysis.

Study procedures

Patients received canakinumab in combination with standard concurrent chemoradiotherapy. Following imaging assessment after completion of chemoradiotherapy, patients without evidence of disease progression proceeded to receive consolidation durvalumab with continued canakinumab.

Thoracic radiotherapy consisted of 60 Gy (±10%) delivered in conventional daily 2 Gy fractions. Treatment was administered using external beam radiation with intensity-modulated radiation therapy (IMRT) or volumetric-modulated arc therapy (VMAT), per institutional standards. Concurrent chemotherapy included carboplatin or cisplatin combined with etoposide, paclitaxel, or pemetrexed. Chemotherapy commenced within the first five fractions of radiotherapy (cycle 1, day 1).

Patients were assessed for durvalumab consolidation initiation 2–8 weeks after cCRT completion. Durvalumab was administered per standard of care at either 10 mg/kg intravenously every 2 weeks or a fixed dose of 1500 mg every 4 weeks. During the cCRT phase, canakinumab was administered as a 200 mg subcutaneous injection every 3 weeks for up to three cycles, beginning with fraction 1 of radiotherapy. Canakinumab was then continued concurrently with durvalumab as a 200 mg intravenous infusion every 4 weeks for up to 12 additional cycles, or until disease progression (per RECIST v1.1), unacceptable toxicity, or withdrawal of consent.

Tumor assessments were performed per RECIST v1.1²³. The first evaluation occurred after completion of cCRT + canakinumab and prior to the start of consolidation therapy, followed by imaging every 3 months thereafter. Adverse events (AEs) were graded using the Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Research blood samples were collected at baseline, and at weeks 3, 6, and 16.

Endpoints

The primary endpoint was to demonstrate an improvement in 2-year progression-free survival (PFS) compared with the historical benchmark from PACIFIC¹. To ensure methodological comparability with PACIFIC, which enrolled patients only after successful completion of cCRT, patients were deemed evaluable for the primary endpoint in CHORUS if they initiated consolidation therapy (received ≥1 cycle of durvalumab plus canakinumab)¹. Including patients who never became eligible for consolidation would introduce a population not represented in PACIFIC and preclude a valid comparison, and at the time of study initiation, no alternative historical benchmark existed. PFS was defined as the time from the start of radiotherapy to disease progression per RECIST v1.1 or death from any cause, whichever occurred first. Overall survival (OS) was defined as the time from the start of radiotherapy to death or last follow-up. Patients were censored at the last follow-up. Secondary endpoints included 2-year OS, objective response rate (ORR) per RECIST v1.1, and safety and tolerability of canakinumab in combination with cCRT and durvalumab consolidation as assessed by the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The incidence of grade ≥2 pneumonitis (per CTCAE v5.0) was also evaluated as a prespecified safety endpoint. Exploratory endpoints included biomarker correlates associated with response and toxicity.

Statistical analysis

The study was powered to show that the 2-year PFS rate exceeds the historical benchmark of 46% observed with concurrent chemoradiation and durvalumab consolidation¹. Given that PFS in the present study was measured from the start of chemoradiation, whereas in PACIFIC it was measured from the start of consolidation therapy, the 46% benchmark was prospectively selected to reflect outcomes measured from the initiation of chemoradiotherapy. We planned a one-sided design (α = 0.10) such that the lower bound of the one-sided 90% confidence interval for the Kaplan–Meier estimate at 24 months would exceed 46%, providing 80% power under an expected 2-year PFS of 64%. Simulations incorporated a 15% 2-year attrition rate, 24 months of accrual, and 24 months of follow-up. We utilized the Kaplan-Meier method to estimate progression-free and overall survival and a competing risk analysis to estimate the cumulative incidence of locoregional recurrence. Distant recurrence and death were competing events. A post hoc sensitivity analysis was additionally performed to estimate PFS and OS in the modified intention-to-treat (mITT) population, defined as all enrolled patients who initiated protocol therapy regardless of receipt of consolidation. Patients who did not initiate protocol therapy were excluded because they had no evaluable post-baseline efficacy data, including no baseline RECIST assessment. Univariable Cox proportional hazards models and the log-rank test were used to identify factors associated with progression-free survival. Imaging responses (per RECIST 1.1) and circulating tumor DNA (ctDNA) responses were associated with 24-month risk of disease progression using Fisher’s exact test. This analysis was limited to patients with progression within 24 months or with at least 24 months of follow-up (+/- 6 months). Imaging and ctDNA associations with disease outcomes were a post-hoc exploratory analysis.

Prospective standard of care cohort for correlative analyses

As a planned corollary to the CHORUS trial, a separate prospective biospecimen protocol was established for patients with stage III NSCLC treated with standard-of-care (SOC) concurrent chemoradiotherapy followed by durvalumab consolidation. This protocol was approved by the Memorial Sloan Kettering Cancer Center Institutional Review Board (MSK IRB #20-364) and conducted in accordance with the principles of Good Clinical Practice and the Declaration of Helsinki.

Eligibility criteria mirrored those of the CHORUS trial and included patients with unresectable stage III NSCLC receiving cCRT followed by durvalumab consolidation. Patients who declined participation in CHORUS or were treated after completion of its accrual were offered enrollment in this biospecimen protocol.

The primary objective was to provide a matched biological control cohort for exploratory analyses evaluating the correlatives of circulating and immune biomarkers with response and toxicity. Research blood samples were collected at baseline and at weeks 3, 6, and 16, using identical timepoints and processing procedures as in CHORUS. Baseline characteristics of patients enrolled in protocol 20-364 are summarized in Supplementary Table 1.

ctDNA analyses

Circulating cell-free DNA was extracted from collected blood samples and analyzed for somatic tumor circulating tumor DNA (ctDNA) alterations by Memorial Sloan Kettering–Analysis of Circulating cell-free DNA to Examine Somatic Status (MSK-ACCESS), a next-generation sequencing assay for the detection of somatic ctDNA alterations in 129 genes^24,25. MSK-ACCESS reaches a depth of coverage ≥15,000x and employs unique molecular indexes, enabling an allele frequency detection threshold of 0.1%²⁵. The sequencing data were analyzed using validated bioinformatics methods²⁵. Detected mutations were genotyped across time points to determine their allele frequencies. Variant allele frequency (VAF) represents the proportion of mutant alleles at a particular genetic locus²⁶. An undetectable ctDNA level was classified as VAF of 0. ctDNA analyses were predefined.

Immunologic correlative analyses

Predefined exploratory analyses were performed to characterize the immune profile of patients during cCRT. Flow cytometry was performed on peripheral blood mononuclear cells (PBMCs) to quantify the T cell activation and exhaustion markers (including PD-1, CTLA-4, TIM-3, and Ki-67) as well as monocytic myeloid-derived suppressor cell (MDSC) populations. Plasma cytokine profiling included key proinflammatory mediators (e.g., IL-1β, IL-6, IL-8, TNFα, and IFNγ). Additional details on assay panels and sample processing are provided in the Supplementary Materials.

Statistical analysis of correlative data

T cell subpopulations were defined a priori based on expression or co-expression of functional markers on key parent populations to characterize T cell activation and exhaustion. The key parent populations investigated were CD3 + , CD4+, and CD8 + T cells. Other parent populations investigated in the T cell data included: CD4 + PD1 + , CD8 + KI67+, and CD8 + PD1 + . MDSCs were calculated as the percentage of MDSC cells within all live lymphocytes and monocytes of the corresponding sample. Because most flow samples were duplicated (2 samples per patient at a given time point), cell percentages for each subpopulation are averaged across duplicates for analysis.

Longitudinal patterns in T cell and MDSC subpopulations, and cytokine concentration levels during cCRT were compared between 1) patients in the CHORUS trial with the best confirmed response of CR/PR vs SD (RECIST response vs no response) and 2) patients treated on the CHORUS trial vs. the standard of care cohort (20-364). Subpopulations with differing longitudinal patterns by response on the CHORUS trial (percent MDSC of lymphocytes and monocytes, Ki67 + CTLA4+ of CD8 + , CTLA4+ of CD8 + ) were compared between patients treated on CHORUS vs the standard of care cohort. For each T cell and MDSC subpopulation, the percentages are folded root transformed and center-scaled and modeled via a GEE model with exchangeable working correlation structure and factors for group, timepoint (baseline, weeks 3 and 6), and their interaction. For each cytokine, the values were log-transformed and modeled via the same GEE model specification. We tested the longitudinal patterns between groups via the interaction term specified in the model. P-values are FDR-adjusted (Benjamini-Hochberg method) to account for false discovery rate. All analyses were performed in R 4.4.1, and statistical significance was defined by a two-sided p-value < 0.05 and q-value < 0.1 if FDR-adjusted.

Immunologic correlative analyses

Sample collection

Peripheral blood mononuclear cells (PBMC) were separated from whole blood collected in sodium heparin CPT tubes (BD) by standard Ficoll density gradient centrifugation. Plasma supernatants from spun blood samples were collected and frozen at -80 °C in 1.5 ml aliquots. Isolated PBMCs were washed several times to minimize platelets, counted, and cryopreserved in the vapor phase of liquid nitrogen at 5–10 million cells per ml per vial in cell-freezing medium (90% FBS, 10% DMSO). Samples were retrieved and thawed in batches when ready for experimental analysis.

Multiplex cytokine measurements

Cytokines were quantified following manufacturer instructions for the V-PLEX Human Proinflammatory Panel 1 (IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IFNγ, TNFα, IL-1β, and IL-13) purchased from Meso Scale Diagnostics (MSD, Cat #K15049D-1 and Cat #K15198D-1). All reagents were provided with the kit. The standards were reconstituted in the assay diluent provided. Frozen plasma samples were thawed, clarified by brief centrifugation to remove any particulate materials, and diluted two-fold in assay diluent. Diluted samples, controls, and standards were added at 50 μl per well into the MSD assay plates pre-coated with 10 capture antibodies per well against the cytokines of interest. The plate was sealed and incubated for 2 h at room temperature on an orbital shaker (600 rpm). At the end of the incubation, the wells were washed three times using 150 μl wash buffer (PBS + 0.05% Tween 20). Detection antibodies conjugated to electrochemiluminescence labels were added at 25 μl per well, and the plate was sealed and incubated for 2 h at room temperature on an orbital shaker (600 rpm). At the end of the incubation, the plate was washed three times as before. 150 μl of the MSD Read Buffer was added to each well, and the plates were read on the MSD QuickPlex SQ 120 imager. The raw data were measured as light intensity detected by the instrument's photodetectors upon application of electricity to the plate electrodes. Data was analyzed using the MSD Discovery Workbench software. A 4-parameter logistic fit calibration curve was generated for each analyte using the standards and used to calculate the concentration of each analyte in the tested samples. The upper (ULOQ) and lower limits of quantification (LLOQ) were defined by the highest and lowest concentrations of calibrator run on each plate that exhibited <20% CV of duplicate wells and 80-120% recovery of target values when back-calculated by the standard curve regression algorithm.

T cell activation/exhaustion flow panel

Human PBMC samples were thawed, washed, counted, and stained with a fixable Aqua viability dye (Invitrogen) and a cocktail of antibodies to the following surface markers: CD8-Qdot605 (Invitrogen, 3B5), CD4-Qdot 655 (Invitrogen, S3.5), PD-1-PE (BD, MIH4), LAG-3-FITC (Enzo, 17B4), ICOS-PE-Cy7 (eBioscience, ISA-3), TIM-3-APC (R&D Systems, 344823). Cells were next fixed and permeabilized with the FoxP3/Ki-67 Fixation/Permeabilization Concentrate and Diluent (eBioscience). Cells were subsequently stained intracellularly with CD3-BV570 (Biolegend, UCHT1), Ki-67-AlexaFluor700 (BD, B56), FoxP3-eFluor450 (eBioscience, PCH101), and CTLA-4-PerCP-eFluor710 (eBioscience, 14D3). Stained cells were acquired on a BD Biosciences LSRFortessa and analyzed using FlowJo software (FlowJo, LLC). Isotype control stains were used for establishing positivity gates for PD-1, LAG-3, ICOS, TIM-3, FoxP3, and CTLA-4. Gating strategy included in Supplementary Figs. 9, 10.

Myeloid-derived suppressor cell flow panel

Human PBMC samples were thawed and stained with a fixable Aqua viability dye (Invitrogen) and a cocktail of antibodies to the following surface markers: CD14-PerCP-Cy5.5 (BD Biosciences, M5E2), HLA-DR-ECD (Beckman Colter, Immu-357), Lineage cocktail – CD3/CD16/CD19/CD20/CD56-FITC (BD Biosciences, SK7/3G8/SJ2 5C1/L27/NC AM16.2). Stained cells were acquired on a BD Biosciences LSRFortessa and analyzed using FlowJo software (FlowJo, LLC). CD14 + HLA-DRlo monocytic MDSC frequencies were derived objectively by gating on live, lineage-negative CD14+ monocytes and exporting this population to a computational algorithm to estimate MDSC frequency based on the monocyte HLA-DR mean fluorescence intensity coefficient of variation and interpolation from MDSC frequencies obtained from the HLA-DR CV spread of CD14+ monocytes of healthy human donors.

Reporting summary

Further information on research design is available in the Nature Portfolio Reporting Summary linked to this article.

Author contributions

Conceptualization: N.S., M.O., and J.E.C. Methodology: N.S., M.O., J.E.C., Z.Z., N.Y.L., R.S., P.W., R.S., and M.B. Formal analysis: Z.Z., P.W., N.T., J.L., and K.C. Investigation: N.S., M.O., K.C., D.Y.G., F.C.S., A.F.S., R.G., B.M., J.Y.S., A.J.W., C.B.S. II, A.R., M.S.G., H.Y., B.D., M.G.K., I.P., P.P.k, J.E., A.I., and K.N. Data curation: N.T., J.L. and K.C.. Writing – original draft: N.S. and J.E.C. Writing – review and editing: all authors. Supervision: N.S., J.E.C., and D.R.G.

Peer review

Peer review information

Nature Communications thanks the anonymous reviewer(s) for their contribution to the peer review of this work. A peer review file is available.

Funding

This study was supported in part by the National Cancer Institute Cancer Center Core Grant (P30 CA008748) and by Novartis.

Data availability

De-identified patient-level data generated during the current study are available under restricted access for proprietary reasons. Requests to access data for academic, nonprofit purposes can be sent to the corresponding author. All requests will be reviewed by the corresponding author and study team, and if necessary, the MSK institutional review board, to evaluate the merit of the research proposed, the availability of the data, the intended use of the data, and the presence of conflicts of interest. All requests will be responded to within a time-frame of 90 days. The study protocol is available in the Supplementary Information file. The remaining data are available in the Article, its Supplementary Information and Source Data. Source data are provided with this paper.

Competing interests

N.S.: Grant/research funding; Novartis, Amgen, AstraZeneca, Humanetics Corporation. M.O.: Grant/research funding; LUNGevity, Druckenmiller Foundation. Honoraria: Pfizer, MJH Associates, ASTRO, Jazz Pharmaceuticals. Uncompensated; Mesothelioma Applied Research Foundation. Professional Services and Activities: Mesothelioma Applied Research Foundation. N.T.: None. J.L.: None. K.C.: None. D.G.: None. F.S.: Compensation/Payment; Bayer. A.F.S.: Stock; ArcellX, Doximity. R.G.: None. B.M.: None. J.Y.S.: None. A.J.W.: None. C.B.S. II: leadership or fiduciary role for the American Society for Radiation Oncology, Proton Collaborative Group, American Radium Society, and the Particle Therapy Co-Operative Group. A.R.: Grant/research funding; Varian Medical Systems, Boehringer Ingelheim, AstraZeneca, Merck, Pfizer. Honoraria: AstraZeneca, Merck. Board Member; International Mesothelioma Interest Group. Vice President of ITMIG; International Thymic Malignancies Interest Group. N.Y.L.: Advisory boards of Merck, Merck Serono, Nanotiotix, Galera, LEO SAB, GSK She has stock options from LEO SAB. M.S.G.: None H.Y: consultant or advisor for AbbVie, AstraZeneca, Black Diamond Therapeutics, Blueprint Medicines, C4 Therapeutics, Cullinan Oncology, Daiichi Sankyo, Janssen, Novocure, and Taiho Oncology; has received research funding (institution) from Astellas Pharma, AstraZeneca, Black Diamond Therapeutics, Blueprint Medicines, Cullinan Oncology, Daiichi Sankyo, Erasca, Janssen, Lilly, Novartis, Pfizer, and Systimmune; and reports other relationships with Astellas Pharma B.D.: stock and other ownerships with CVS Health, Lilly, Roche/Genentech; consulting or advisory role with Varian Medical Systems and I-MAB Biopharma M.G.K.: Compensation/Payment; i3 Health, Merus, MJH Associates. consulting fees; AstraZeneca, BerGenBio, Pfizer, Daiichi-Sankyo, Sanofi, Novartis. I.P.: None. P.P.: Grant/research funding; Boehringer Ingelheim, Novartis. advisory/consulting fee; Takeda, AstraZeneca, Janssen, CrownBio, Bicara, Mirati, EMD Serono. J.E.: None. A.I.: None. K.N.: None. M.B.: Compensation/Payment; AstraZeneca, Paige.AI, Inc. Intellectual Property Rights; SOPHiA GENETICS S.A. R. Shah: None. R. Shen: None. P.W.: None. Z.Z.: None. D.R.G.: Compensation/Payment; AstraZeneca, Grail, Johnson & Johnson, Medtronic, Varian Medical Systems. J.C.: Grant/research funding; AstraZeneca, Bristol-Myers Squibb, Merck, Genentech, Novartis, Beigene. consulting fees; AstraZeneca, Bristol-Myers Squibb, Merck, Genentech, Regeneron/Sanofi, Guardant Health, Janssen, Lilly, Hoffmann-La Roche Ltd.

Supplementary information

The online version contains supplementary material available at https://doi.org/10.1038/s41467-026-77415-1.