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Improved survival and disease control following pembrolizumab-induced immune-related adverse events in high PD-L1 expressing non-small cell lung cancer with brain metastases

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Abstract

Introduction

Immune checkpoint inhibitors have become standard of care for many patients with non-small cell lung cancer (NSCLC). These agents often cause immune-related adverse events (IRAEs), which have been associated with increased overall survival (OS). Intracranial disease control and OS for patients experiencing IRAEs with metastatic NSCLC and brain metastases have not yet been described.

Methods

We performed a single-institution, retrospective review of patients with NSCLC and existing diagnosis of brain metastasis, who underwent pembrolizumab treatment and developed any grade IRAE. The primary outcome of the study was intracranial time to treatment failure (TTF), defined from time of pembrolizumab initiation to new intracranial disease progression or death. Kaplan–Meier and Cox proportional hazard analyses were performed.

Results

A total of 63 patients with NSCLC brain metastasis were identified, and 24 developed IRAEs. Patients with any grade IRAEs had longer OS (21 vs. 10 months, p = 0.004), systemic TTF (15 vs. 4 months, p < 0.001) and intracranial TTF (14 vs. 5 months, p = 0.001), relative to patients without IRAEs. Presence of IRAEs and high PD-L1 (≥ 50%), but not absent/moderate PD-L1 (0–49%), had a positive association for OS, systemic TTF, and intracranial TTF. Following multivariable analysis, IRAE experienced on pembrolizumab was an independent predictor of OS, systemic TTF, and intracranial TTF.

Conclusions

In our series of patients with NSCLC and brain metastases treated with pembrolizumab, IRAE presence was associated with a significant increase in OS, systemic TTF, and intracranial TTF. Future studies with increased cohorts will clarify how IRAEs should be interpreted among molecular subtypes.

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Funding

No funding was received for the production of this study. MZ receives research funding from the National Institutes of Health (5T32CA009695-27, MPI). SGS receives research funding from Novocure. JWN receives research funding from Adaptimmune Therapeutics plc, Boehringer Ingelheim, Exelixis, Genentech/Roche, GlaxoSmithKline, Merck & Co., Nektar Therapeutics, Novartis, and Takeda Pharmaceuticals. SKP receives research funding from Bayer, Boehringer Ingelheim, and EpicentRx. HW receives research funding from Arrys Therapeutics, Bristol Myers Squibb, Celgene, Clovis Oncology, Eli Lilly and Company, Exelixis, Genentech/Roche, Merck and Co., Novartis, and Pfizer. GL receives research support from Bristol Myers Squibb and Novocure.

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Author notes

  1. Michael Zhang and Adrian J. Rodrigues have been contributed equally to this work.

Authors and Affiliations

  1. Department of Neurosurgery, Stanford Medical Center, Palo Alto, CA, 94304, USA

    Michael Zhang, Adrian J. Rodrigues, Steven D. Chang, Michael Lim, Melanie Hayden Gephart & Gordon Li

  2. Department of Radiation Oncology, Stanford Medical Center, Palo Alto, CA, 94304, USA

    Erqi L. Pollom, Iris C. Gibbs, Scott G. Soltys & Steven L. Hancock

  3. Department of Medicine, Stanford Medical Center, Palo Alto, CA, 94304, USA

    Joel W. Neal, Sukhmani K. Padda, Kavitha J. Ramchandran & Heather A. Wakelee

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  1. Michael Zhang
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Contributions

Conceptualization: MZ and GL. Methodology: MZ, AJR, SGS, JWN, HW and GL. Formal analysis and investigation: MZ, AJR, SGS, JWN, HW and GL. Writing—original draft preparation: MZ. Writing—review and editing: MZ, AJR, ELP, ICG, SGS, SLH, JWN, SKP, KR, HW and GL Funding acquisition: not applicable. Resources: SGS, SLH, JWN, KR, HW, SDC, ML, MHG and GL. Supervision: GL.

Corresponding author

Correspondence to Gordon Li.

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Conflict of interest

SGS is a consultant for Inovio Pharmaceuticals, Inc. and speaker for Zap Surgical Systems, Inc. SKP is an advisor for AstraZeneca, Blueprint Medicines, and G1 Therapeutics, Inc. KR is an advisor for Dhristi, Inc. and Varian Medical Systems. HW is an advisor for AstraZeneca, Blueprint Medicines, Cellworks Group, Inc., Genentech/Roche, Helsinn Healthcare SA, Mirati Therapeutics, Inc., and the International Thymic Malignancy Interest Group. JWN receives royalties from UpToDate. GL is an advisor for Medtronic, a speaker for DePuy Synthes/Johnson&Johnson, and own stock in Abbott, Biogen, BioMarin Pharmaceutical, Inc., Bristol Myers Squibb, Exact Sciences, GlaxoSmithKline, Gilead Sciences, Inc., Merck & Co., Pfizer, and Stryker.

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11060_2020_3686_MOESM7_ESM.docx

Supplementary file7 (DOCX 21 KB) Supplementary Fig. 1A–C: Survival curves for (A) overall survival, (B) systemic time to treatment failure, and (C) intracranial time to treatment failure, stratified by EGFR mutation status.

11060_2020_3686_MOESM8_ESM.docx

Supplementary file8 (DOCX 25 KB) Supplementary Fig. 2A–C: Survival curves for (A) overall survival, (B) systemic time to treatment failure, and (C) intracranial time to treatment failure, stratified by history of radiation treatment within 14 days before initiating pembrolizumab.

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Zhang, M., Rodrigues, A.J., Pollom, E.L. et al. Improved survival and disease control following pembrolizumab-induced immune-related adverse events in high PD-L1 expressing non-small cell lung cancer with brain metastases. J Neurooncol 152, 125–134 (2021). https://doi.org/10.1007/s11060-020-03686-3

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