Predicting factors of symptomatic radiation pneumonitis induced by durvalumab following concurrent chemoradiotherapy in locally advanced non-small cell lung cancer

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Abstract

Background

Concurrent chemoradiotherapy (CCRT) followed by durvalumab is the standard of care for unresectable locally-advanced non-small cell carcinoma (LA-NSCLC). However, a major concern about administration of durvalumab after CCRT is whether the incidence of symptomatic radiation pneumonitis (RP) may increase or not. In the present analysis, we report the initial results of CCRT followed by durvalumab in patients with LA-NSCLC in a real-world setting with focus on predicting factors for symptomatic RP.

Methods

Patients who were pathologically diagnosed as NSCLC and initiated treatment with CCRT followed by durvalumab between July 2018 to December 2019 were eligible for this study. Patients were included if they completed the planned CRT course and administered at least one course of durvalumab. We retrospectively investigated the preliminary survival outcome and incidence and predicting factors for symptomatic RP.

Results

Of the 67 patients who planned CCRT, 63 patients completed the entire CCRT course. Of these, 56 patients proceeded to consolidation with durvalumab. The median time to eternal discontinuation of durvalumab was 9.7 months. The cumulative proportion of the patients who exhibited symptomatic RP was 30, 40 and 44% at 3, 6 and 12 months, respectively. In multivariate analyses, pulmonary fibrosis score and lung V40 were significant predictive factors for symptomatic RP ( p < 0.001, HR: 7.83, 95% CI: 3.38–18.13, and p = 0.034, HR: 3.17, 95% CI: 1.09–9.19, respectively).

Conclusions

Pulmonary fibrosis sore and lung V40 were significant predictive factors for symptomatic RP. We should be cautious about the administration of durvalumab for patients having subclinical pulmonary fibrosis. To our best knowledge, this is one of the first report showing the predictive value of high dose volumes to the lung in patients with LA-NSCLC who received CCRT followed by durvalumab.

Supplementary Information

The online version contains supplementary material available at 10.1186/s13014-021-01979-z.

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Most cited references 40

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The blockade of immune checkpoints in cancer immunotherapy.

Drew M Pardoll (2012)

Among the most promising approaches to activating therapeutic antitumour immunity is the blockade of immune checkpoints. Immune checkpoints refer to a plethora of inhibitory pathways hardwired into the immune system that are crucial for maintaining self-tolerance and modulating the duration and amplitude of physiological immune responses in peripheral tissues in order to minimize collateral tissue damage. It is now clear that tumours co-opt certain immune-checkpoint pathways as a major mechanism of immune resistance, particularly against T cells that are specific for tumour antigens. Because many of the immune checkpoints are initiated by ligand-receptor interactions, they can be readily blocked by antibodies or modulated by recombinant forms of ligands or receptors. Cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) antibodies were the first of this class of immunotherapeutics to achieve US Food and Drug Administration (FDA) approval. Preliminary clinical findings with blockers of additional immune-checkpoint proteins, such as programmed cell death protein 1 (PD1), indicate broad and diverse opportunities to enhance antitumour immunity with the potential to produce durable clinical responses.

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Durvalumab after Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer.

Scott J Antonia, Augusto Villegas, Davey Daniel … (2017)

Background Most patients with locally advanced, unresectable, non-small-cell lung cancer (NSCLC) have disease progression despite definitive chemoradiotherapy (chemotherapy plus concurrent radiation therapy). This phase 3 study compared the anti-programmed death ligand 1 antibody durvalumab as consolidation therapy with placebo in patients with stage III NSCLC who did not have disease progression after two or more cycles of platinum-based chemoradiotherapy. Methods We randomly assigned patients, in a 2:1 ratio, to receive durvalumab (at a dose of 10 mg per kilogram of body weight intravenously) or placebo every 2 weeks for up to 12 months. The study drug was administered 1 to 42 days after the patients had received chemoradiotherapy. The coprimary end points were progression-free survival (as assessed by means of blinded independent central review) and overall survival (unplanned for the interim analysis). Secondary end points included 12-month and 18-month progression-free survival rates, the objective response rate, the duration of response, the time to death or distant metastasis, and safety. Results Of 713 patients who underwent randomization, 709 received consolidation therapy (473 received durvalumab and 236 received placebo). The median progression-free survival from randomization was 16.8 months (95% confidence interval [CI], 13.0 to 18.1) with durvalumab versus 5.6 months (95% CI, 4.6 to 7.8) with placebo (stratified hazard ratio for disease progression or death, 0.52; 95% CI, 0.42 to 0.65; P<0.001); the 12-month progression-free survival rate was 55.9% versus 35.3%, and the 18-month progression-free survival rate was 44.2% versus 27.0%. The response rate was higher with durvalumab than with placebo (28.4% vs. 16.0%; P<0.001), and the median duration of response was longer (72.8% vs. 46.8% of the patients had an ongoing response at 18 months). The median time to death or distant metastasis was longer with durvalumab than with placebo (23.2 months vs. 14.6 months; P<0.001). Grade 3 or 4 adverse events occurred in 29.9% of the patients who received durvalumab and 26.1% of those who received placebo; the most common adverse event of grade 3 or 4 was pneumonia (4.4% and 3.8%, respectively). A total of 15.4% of patients in the durvalumab group and 9.8% of those in the placebo group discontinued the study drug because of adverse events. Conclusions Progression-free survival was significantly longer with durvalumab than with placebo. The secondary end points also favored durvalumab, and safety was similar between the groups. (Funded by AstraZeneca; PACIFIC ClinicalTrials.gov number, NCT02125461 .).

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Overall Survival with Durvalumab after Chemoradiotherapy in Stage III NSCLC

Scott J Antonia, Augusto Villegas, Davey Daniel … (2018)

An earlier analysis in this phase 3 trial showed that durvalumab significantly prolonged progression-free survival, as compared with placebo, among patients with stage III, unresectable non-small-cell lung cancer (NSCLC) who did not have disease progression after concurrent chemoradiotherapy. Here we report the results for the second primary end point of overall survival.

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Author and article information

Contributors

Hiroshi Mayahara:

ORCID: http://orcid.org/0000-0001-6378-4437

mayahara@k-mcc.net

Journal

Journal ID (nlm-ta): Radiat Oncol

Journal ID (iso-abbrev): Radiat Oncol

Title: Radiation Oncology (London, England)

Publisher: BioMed Central (London )

ISSN (Electronic): 1748-717X

Publication date (Electronic): 15 January 2022

Publication date PMC-release: 15 January 2022

Publication date Collection: 2022

Volume: 17

Electronic Location Identifier: 7

Affiliations

[1 ]Department of Radiation Oncology, Kobe Minimally-invasive Cancer Center, 8-5-1, Minatojima-Nakamachi, Chuo-Ku, Kobe, Hyogo 650-0046 Japan

[2 ]GRID grid.31432.37, ISNI 0000 0001 1092 3077, Division of Radiation Oncology, , Kobe University Graduate School of Medicine, ; 7-5-2, Kusunoki-Cho, Chuo-Ku, Kobe, Hyogo Japan

[3 ]Department of Respiratory Medical Oncology, Kobe Minimally-invasive Cancer Center, 8-5-1, Minatojima-Nakamachi, Chuo-Ku, Kobe, Hyogo Japan

[4 ]Department of Diagnostic Radiology, Kobe Minimally-invasive Cancer Center, 8-5-1, Minatojima-Nakamachi, Chuo-Ku, Kobe, Hyogo Japan

Author information

Hiroshi Mayahara http://orcid.org/0000-0001-6378-4437

Article

Publisher ID: 1979

DOI: 10.1186/s13014-021-01979-z

PMC ID: 8760798

PubMed ID: 35033139

SO-VID: 1a979c58-ac7c-41d1-9c2f-207a2e28914f

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Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 24 August 2021

Date accepted : 28 December 2021

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ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: locally advanced non-small cell lung cancer,concurrent chemoradiotherapy,radiation pneumonitis,dosimetric factor,durvalumab

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ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: locally advanced non-small cell lung cancer, concurrent chemoradiotherapy, radiation pneumonitis, dosimetric factor, durvalumab

Predicting factors of symptomatic radiation pneumonitis induced by durvalumab following concurrent chemoradiotherapy in locally advanced non-small cell lung cancer

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Cancer Immunotherapy

Most cited references 40

The blockade of immune checkpoints in cancer immunotherapy.

Durvalumab after Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer.

Overall Survival with Durvalumab after Chemoradiotherapy in Stage III NSCLC

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