Improved survival outcome with not-delayed radiotherapy and immediate PD-1/PD-L1 inhibitor for non-small-cell lung cancer patients with brain metastases

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Abstract

Purpose

To investigate the impact of radiotherapy (RT) and immune checkpoint inhibitor (ICI) sequence on the survival outcome in NSCLC patients with brain metastasis, and decide the best time to initiate RT.

Methods

Patients were managed with delayed RT (ICI delivered over 2 weeks prior to RT), concurrent RT (ICI delivered within 2 weeks prior to or after RT), or upfront RT (RT delivered over 2 weeks prior to ICI). Overall survival (OS), intracranial local progression-free survival (iLPFS), and intracranial distant progression-free survival (iDPFS) were assessed. A meta-analysis was performed to analyze the association between survival outcome and RT/ICI sequence.

Results

A total of 73 NSCLC patients were identified with a median follow-up of 13.9 months. Patients who receive delayed RT demonstrated shorter iLPFS (P = 0.0029), iDPFS (P = 0.016), and OS (P < 0.001). A meta-analysis was conducted and a total of 4 studies, 254 patients were included. The HR was 0.44 for iDPFS (P = 0.03), 0.41 for OS (P < 0.01) when compared concurrent with delayed RT, 0.21 for iDPFS (P < 0.01), 0.32 for OS (P < 0.01) when compared upfront with delayed RT, consistent with our conclusion that delayed RT brought with worst iDPFS and OS. More importantly, the best overall response rate (BOR) decreased in cases with longer RT and ICI intervals. Patients who receive intervals of RT and ICI within 7 days achieve the best median BOR of − 53%.

Conclusions

Delayed RT brought poor survival outcomes including iLPFS, iDPFS, and OS in NSCLC patients. The shorter interval of RT and ICI is associated with better BOR.

Supplementary Information

The online version contains supplementary material available at 10.1007/s11060-023-04459-4.

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Most cited references 40

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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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Radiation and Dual Checkpoint Blockade Activates Non-Redundant Immune Mechanisms in Cancer

Christina Victor, Andrew J. Rech, Amit Maity … (2015)

Immune checkpoint inhibitors 1 result in impressive clinical responses 2–5 but optimal results will require combination with each other 6 and other therapies. This raises fundamental questions about mechanisms of non-redundancy and resistance. Here, we report major tumor regressions in a subset of patients with metastatic melanoma treated with an anti-CTLA4 antibody (anti-CTLA4) and radiation (RT) and reproduced this effect in mouse models. Although combined treatment improved responses in irradiated and unirradiated tumors, resistance was common. Unbiased analyses of mice revealed that resistance was due to upregulation of PD-L1 on melanoma cells and associated with T cell exhaustion. Accordingly, optimal response in melanoma and other cancer types requires RT, anti-CTLA4, and anti-PD-L1/PD-1. Anti-CTLA4 predominantly inhibits T regulatory cells (Tregs) to increase the CD8 T cell to Treg (CD8/Treg) ratio. RT enhances the diversity of the T cell receptor (TCR) repertoire of intratumoral T cells. Together, anti-CTLA4 promotes expansion of T cells, while RT shapes the TCR repertoire of the expanded peripheral clones. Addition of PD-L1 blockade reverses T cell exhaustion to mitigate depression in the CD8/Treg ratio and further encourages oligo-clonal T cell expansion. Similar to results from mice, patients on our clinical trial with melanoma showing high PD-L1 did not respond to RT + anti-CTLA4, demonstrated persistent T cell exhaustion, and rapidly progressed. Thus, PD-L1 on melanoma cells allows tumors to escape anti-CTLA4-based therapy, and the combination of RT, anti-CTLA4, and anti-PD-L1 promotes response and immunity through distinct mechanisms.

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Five-Year Outcomes With Pembrolizumab Versus Chemotherapy for Metastatic Non–Small-Cell Lung Cancer With PD-L1 Tumor Proportion Score ≥ 50%

Martin Reck, Delvys Rodriguez-Abreu, Andrew G Robinson … (2021)

PURPOSE We report the first 5-year follow-up of any first-line phase III immunotherapy trial for non–small-cell lung cancer (NSCLC). KEYNOTE-024 (ClinicalTrials.gov identifier: NCT02142738) is an open-label, randomized controlled trial of pembrolizumab compared with platinum-based chemotherapy in patients with previously untreated NSCLC with a programmed death ligand-1 (PD-L1) tumor proportion score of at least 50% and no sensitizing EGFR or ALK alterations. Previous analyses showed pembrolizumab significantly improved progression-free survival and overall survival (OS). METHODS Eligible patients were randomly assigned (1:1) to pembrolizumab (200 mg once every 3 weeks for up to 35 cycles) or platinum-based chemotherapy. Patients in the chemotherapy group with progressive disease could cross over to pembrolizumab. The primary end point was progression-free survival; OS was a secondary end point. RESULTS Three hundred five patients were randomly assigned: 154 to pembrolizumab and 151 to chemotherapy. Median (range) time from randomization to data cutoff (June 1, 2020) was 59.9 (55.1-68.4) months. Among patients initially assigned to chemotherapy, 99 received subsequent anti–PD-1 or PD-L1 therapy, representing a 66.0% effective crossover rate. Median OS was 26.3 months (95% CI, 18.3 to 40.4) for pembrolizumab and 13.4 months (9.4-18.3) for chemotherapy (hazard ratio, 0.62; 95% CI, 0.48 to 0.81). Kaplan-Meier estimates of the 5-year OS rate were 31.9% for the pembrolizumab group and 16.3% for the chemotherapy group. Thirty-nine patients received 35 cycles (ie, approximately 2 years) of pembrolizumab, 82.1% of whom were still alive at data cutoff (approximately 5 years). Toxicity did not increase with longer treatment exposure. CONCLUSION Pembrolizumab provides a durable, clinically meaningful long-term OS benefit versus chemotherapy as first-line therapy for metastatic NSCLC with PD-L1 tumor proportion score of at least 50%.

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Author and article information

Contributors

Hao Jiang: byyfyjh@bbmc.edu.cn

Qichun Wei: qichun_wei@zju.edu.cn

Journal

Journal ID (nlm-ta): J Neurooncol

Journal ID (iso-abbrev): J Neurooncol

Title: Journal of Neuro-Oncology

Publisher: Springer US (New York )

ISSN (Print): 0167-594X

ISSN (Electronic): 1573-7373

Publication date (Electronic): 17 October 2023

Publication date PMC-release: 17 October 2023

Publication date (Print): 2023

Volume: 165

Issue: 1

Pages: 127-137

Affiliations

[1 ]Department of Radiation Oncology (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences, Zhejiang Province, China), The Second Affiliated Hospital, Zhejiang University School of Medicine, ( https://ror.org/059cjpv64) Hangzhou, Zhejiang China

[2 ]Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences, Zhejiang Province, China), The Second Affiliated Hospital, Zhejiang University School of Medicine, ( https://ror.org/059cjpv64) Hangzhou, Zhejiang China

[3 ]Zhejiang Provincial Clinical Research Center for Cancer, Cancer Center of Zhejiang University, ( https://ror.org/00a2xv884) Hangzhou, China

[4 ]Department of Radiotherapy, Lishui Municipal Central Hospital, Lishui, China

[5 ]Anhui Campus of the Second Affiliated Hospital, Zhejiang University School of Medicine, ( https://ror.org/059cjpv64) Bengbu, 233000 China

[6 ]Department of Radiation Oncology, The First Affiliated Hospital of Bengbu Medical College, ( https://ror.org/04v043n92) Bengbu, 233000 China

Article

Publisher ID: 4459

DOI: 10.1007/s11060-023-04459-4

PMC ID: 10638122

PubMed ID: 37848757

SO-VID: c22c0d50-2057-46aa-9320-fe15885c50c0

License:

Open Access This 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/.

History

Date received : 9 August 2023

Date accepted : 20 September 2023

Funding

Funded by: the National Natural Science Foundation of China

Award ID: Grant No. 82103498

Award Recipient : Haiyan Chen

Funded by: CSCO-Roche research funding

Award ID: Y-Roche2019/2-0088

Award Recipient : Haiyan Chen

Custom metadata

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: non-small-cell lung cancer,brain metastasis,radiotherapy,immunotherapy,sequencing

Data availability:

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: non-small-cell lung cancer, brain metastasis, radiotherapy, immunotherapy, sequencing

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Improved survival outcome with not-delayed radiotherapy and immediate PD-1/PD-L1 inhibitor for non-small-cell lung cancer patients with brain metastases

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Abstract

Purpose

Methods

Results

Conclusions

Supplementary Information

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Karger: Oncology

Most cited references 40

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

Radiation and Dual Checkpoint Blockade Activates Non-Redundant Immune Mechanisms in Cancer

Five-Year Outcomes With Pembrolizumab Versus Chemotherapy for Metastatic Non–Small-Cell Lung Cancer With PD-L1 Tumor Proportion Score ≥ 50%

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