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

Girard, Nicolas; Bar, Jair; Garrido, Pilar; Garassino, Marina Chiara; McDonald, Fiona; Mornex, F.; Filippi, Andrea Riccardo; Smit, Hans; Peters, Solange; Field, John K.; Christoph, Daniel C.; Sibille, Anne; Fietkau, Rainer; Haakensen, Vilde Drageset; Chouaïd, C.; Markman, Ben; Hiltermann, T. Jeroen N.; Taus, Álvaro; Sawyer, William T.; Allen, A.; Chander, Pratibha; Licour, Muriel; Solomon, Benjamin

doi:10.1016/j.jtho.2022.10.003

Cited by 105 publications

(72 citation statements)

References 47 publications

(72 reference statements)

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“…After a median follow-up of 23.5 months, durvalumab achieved a median rwPFS of 21.7 months and 3-year OS rate of 63.2%. In line with the results of Gemstone-301, survival benefit could also be achieved in patients treated with sequential chemoradiotherapy, with a median rwPFS of 19.3 months; rwPFS was longer in patients with PD-L1 expression ≥ 1% versus < 1% (22.4 vs. 15.6 months) [ 58 ].…”

Section: Localized Nsclcmentioning

confidence: 82%

Emerging evidence and treatment paradigm of non-small cell lung cancer

et al. 2023

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Research on biomarker-driven therapy and immune check-point blockade in non-small cell lung cancer (NSCLC) is rapidly evolving. The width and depth of clinical trials have also dramatically improved in an unprecedented speed. The personalized treatment paradigm evolved every year. In this review, we summarize the promising agents that have shifted the treatment paradigm for NSCLC patients across all stages, including targeted therapy and immunotherapy using checkpoint inhibitors. Based on recent evidence, we propose treatment algorithms for NSCLC and propose several unsolved clinical issues, which are being explored in ongoing clinical trials. The results of these trials are likely to impact future clinical practice.

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Section: Localized Nsclcmentioning

confidence: 82%

Emerging evidence and treatment paradigm of non-small cell lung cancer

et al. 2023

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“…In the PACIFIC trial, both patients who had PD-L1 expression of less than 25% and 25% or greater derived a PFS and OS benefit from durvalumab following chemoradiation . While a more recent analysis from the PACIFIC-R study found improved disease control in patients with PD-L1 expression of 1% or greater vs less than 1%, other multicenter studies have not demonstrated associations of PD-L1–negative and PD-L1–low status with disease control . TMB has been found to be a biomarker for sensitivity to PD-1/PD-L1 inhibition across PD-L1 expression subgroups, highlighting the potential for TMB to serve as a biomarker independent of PD-L1 expression levels in the setting of locally advanced NSCLC.…”

Section: Discussionmentioning

confidence: 99%

“…We identified 81 consecutive patients with stage III NSCLC treated with definitive-intent cCRT and durvalumab, of whom 46 (57%) were male patients and 77 (95%) were prior or current smokers (Table 1). The median (IQR) follow-up was 26 (21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36) months. The median (range) patient age was 67 years, 44 patients (54%) had ECOG performance status of 0, and 56 (69%) had adenocarcinoma histology.…”

Section: Patient and Treatment Characteristicsmentioning

confidence: 99%

Analysis of Tumor Mutational Burden, Progression-Free Survival, and Local-Regional Control in Patients with Locally Advanced Non–Small Cell Lung Cancer Treated With Chemoradiation and Durvalumab

et al. 2023

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ImportanceThe addition of consolidative durvalumab to chemoradiation has improved disease control and survival in locally advanced non–small cell lung cancer (NSCLC). However, there remains a need to identify biomarkers for response to this therapy to allow for risk adaptation and personalization.ObjectivesTo evaluate whether TMB or other variants associated with radiation response are also associated with outcomes following definitive chemoradiation and adjuvant durvalumab among patients with locally advanced unresectable NSCLC.Design, Setting, and ParticipantsThis cohort study included consecutive patients with unresectable locally advanced NSCLC treated with chemoradiation and adjuvant durvalumab between November 2013 and March 2020 who had prospective comprehensive genomic profiling. This study was completed at a multisite tertiary cancer center. The median (IQR) follow-up time was 26 (21-36) months. Statistical analysis was conducted from April to October 2022.ExposuresPatients were grouped into TMB-high (≥10 mutations/megabase [mt/Mb]) and TMB-low (&lt;10 mt/Mb) groups and were additionally evaluated by the presence of somatic alterations associated with radiation resistance (KEAP1/NFE2L2) or radiation sensitivity (DNA damage repair pathway).Main Outcomes and MeasuresThe primary outcomes were 24-month local-regional failure (LRF) and progression-free survival (PFS).ResultsIn this cohort study of 81 patients (46 [57%] male patients; median [range] age, 67 [45-85] years), 36 patients (44%) had TMB-high tumors (≥10 mt/Mb). Patients with TMB-high vs TMB-low tumors had markedly lower 24-month LRF (9% [95% CI, 0%-46%] vs 51% [95% CI, 36%-71%]; P = .001) and improved 24-month PFS (66% [95% CI, 54%-84%] vs 27% [95% CI, 13%-40%]; P = .003). The 24-month LRF was 52% (95% CI, 25%-84%) among patients with KEAP1/NFE2L2-altered tumors compared with 27% (95% CI, 17%-42%) among patients with KEAP1/NFE2L2-wildtype tumors (P = .05). On Cox analysis, only TMB status was associated with LRF (hazard ratio [HR], 0.17; 95% CI, 0.03-0.64; P = .02) and PFS (HR, 0.45; 95% CI, 0.21-0.90; P = .03). Histology, disease stage, Eastern Cooperative Oncology Group status, programmed cell death ligand 1 expression, and pathogenic KEAP1/NFE2L2, KRAS, and DNA damage repair pathway alterations were not significantly associated with LRF or PFS.Conclusions and RelevanceIn this cohort study, TMB-high status was associated with improved local-regional control and PFS after definitive chemoradiation and adjuvant durvalumab. TMB status may facilitate risk-adaptive radiation strategies in unresectable locally advanced NSCLC.

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“…Additionally, in the observational PACIFIC-R study, in which the real-world effectiveness of durvalumab was assessed in patients from an early access program, as expected, real-world PFS was higher among patients who received cCT-RT versus sCT-RT and patients with higher PD-L1 expression [ 34 ]…”

Section: Discussionmentioning

confidence: 99%

The Multidisciplinary Approach in Stage III Non-Small Cell Lung Cancer over Ten Years: From Radiation Therapy Optimisation to Innovative Systemic Treatments

Ferro

Sepulcri

Schiavon

et al. 2022

Cancers

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Background: About 30% of new non-small cell lung cancer (NSCLC) cases are diagnosed at a locally advanced stage, which includes a highly heterogeneous group of patients with a wide spectrum of treatment options. The management of stage III NSCLC involves a multidisciplinary team, adequate staging, and a careful patient selection for surgery or radiation therapy integrated with systemic treatment. Methods: This is a single-center observational retrospective and prospective study including a consecutive series of stage III NSCLC patients who were referred to the Veneto Institute of Oncology and University Hospital of Padova (Italy) between 2012 and 2021. We described clinico-pathological characteristics, therapeutic pathways, and treatment responses in terms of radiological response in the entire study population and in terms of pathological response in patients who underwent surgery after induction therapy. Furthermore, we analysed survival outcomes in terms of relapse-free survival (RFS) and overall survival (OS). Results: A total of 301 patients were included. The majority of patients received surgical multimodality treatment (N = 223, 74.1%), while the remaining patients (N = 78, 25.9%) underwent definitive CRT followed or not by durvalumab as consolidation therapy. At data cut-off, 188 patients (62.5%) relapsed and the median RFS (mRFS) of the entire population was 18.2 months (95% CI: 15.83–20.57). At the time of analyses 140 patients (46.5%) were alive and the median OS (mOS) was 44.7 months (95% CI: 38.4–51.0). A statistically significant difference both in mRFS (p = 0.002) and in mOS (p < 0.001) was observed according to the therapeutic pathway in the entire population, and selecting patients treated after 2018, a significant difference in mRFS (p = 0.006) and mOS (p < 0.001) was observed according to treatment modality. Furthermore, considering only patients diagnosed with stage IIIB-C (N = 131, 43.5%), there were significant differences both in mRFS (p = 0.047) and in mOS (p = 0.022) as per the treatment algorithm. The mRFS of the unresectable population was 16.3 months (95% CI: 11.48–21.12), with a significant difference among subgroups (p = 0.030) in favour of patients who underwent the PACIFIC-regimen; while the mOS was 46.5 months (95% CI: 26.46–66.65), with a significant difference between two subgroups (p = 0.003) in favour of consolidation immunotherapy. Conclusions: Our work provides insights into the management and the survival outcomes of stage III NSCLC over about 10 years. We found that the choice of radical treatment impacts on outcome, thus suggesting the importance of appropriate staging at diagnosis, patient selection, and of the multidisciplinary approach in the decision-making process. Our results confirmed that the PACIFIC trial and the following introduction of durvalumab as consolidation treatment may be considered as a turning point for several improvements in the diagnostic-therapeutic pathway of stage III NSCLC patients.

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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

Cited by 105 publications

References 47 publications

Emerging evidence and treatment paradigm of non-small cell lung cancer

Emerging evidence and treatment paradigm of non-small cell lung cancer

Analysis of Tumor Mutational Burden, Progression-Free Survival, and Local-Regional Control in Patients with Locally Advanced Non–Small Cell Lung Cancer Treated With Chemoradiation and Durvalumab

The Multidisciplinary Approach in Stage III Non-Small Cell Lung Cancer over Ten Years: From Radiation Therapy Optimisation to Innovative Systemic Treatments

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