Intracranial response to nivolumab in NSCLC patients with untreated or progressing CNS metastases

doi:10.1016/j.lungcan.2016.05.031

Lung Cancer

Volume 98, August 2016, Pages 114-117

https://doi.org/10.1016/j.lungcan.2016.05.031 Get rights and content

Highlights

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Data regarding the intracranial activity of nivolumab in NSCLC are lacking.
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Five NSCLC patients with new/progressing brain metastases were treated with nivolumab.
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One complete and one partial response were observed.
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Systemic responses and intracranial responses were largely concordant.
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No treatment-related or disease-related grade ≥ 3 adverse events were seen.

Abstract

Central nervous system (CNS) metastases occur in 30% of patients with advanced non-small cell lung cancer (NSCLC). Localized treatments targeting CNS metastases result in delays in systemic therapy administration and are associated with neurocognitive impairment. Nivolumab is an immune check-point inhibitor that is approved as a second-line treatment of NSCLC. Data regarding the intracranial activity of nivolumab is lacking.

We retrospectively reviewed the efficacy and safety of nivolumab in five patients with advanced NSCLC and new/progressing intracranial metastases. Intracranial response was assessed by magnetic resonance imaging (MRI) using mRECIST v. 1.1 criteria.

All patients had parenchymal brain metastases; two patients had leptomeningeal carcinomatosis diagnosed according to radiological criteria. All patients were asymptomatic and did not require corticosteroids or immediate local therapy. We observed one complete and one partial response in the brain. Stabilization of leptomeningeal carcinomatosis for 10 weeks was achieved in one additional patient. Two patients progressed in the CNS. Time-to-response comprised 5 weeks and 9 weeks; both responses are still ongoing at the time of the report (24+ and 28+ weeks since start of treatment). Systemic responses and intracranial responses were largely concordant. No treatment-related or CNS metastases-related grade ≥ 3 adverse events were observed.

Nivolumab might have intracranial activity and favorable safety profile in patients with CNS metastases secondary to NSCLC. Nivolumab CNS activity warrants further evaluation.

Introduction

Central nervous system (CNS) metastases occur in 24–44% of patients with advanced non-small cell lung cancer (NSCLC) [1]. The prognosis for patients with CNS metastases depends on several factors, such as age, performance status, number of brain metastases, systemic disease control, and presence of neurological symptoms [2], [3]. However, the outlook is generally poor with median overall survival time of approximately 7 months [3].

The standard approaches to the treatment of brain metastases are primarily local comprising of surgery and radiation. The main shortcoming of these strategies is the necessity to delay systemic treatment which can be crucial in patients with rapidly progressive disease. In fact, 15% of patients do not receive further systemic therapy following whole brain radiation therapy (WBRT) administration due to early death or poor performance status [4]. Additionally, WBRT often results in long-term cognitive decline [5].

According to current guidelines developed by the European Society of Medical Oncology, systemic therapy as opposed to local brain therapy can be used in patients with brain metastases who are asymptomatic or experience only minimal neurological symptoms [6]. This recommendation is supported by the results of several clinical trials evaluating the role of chemotherapy and bevacizumab in the treatment of brain metastases [4], [7], [8]. Importantly, the deferral of radiotherapy until development of symptoms did not appear to have any detrimental effect [4], [7].

Most recently, significant advances have been made in the field of immune check-point blockade. Two such agents, nivolumab and pembrolizumab have been approved for use in patients with NSCLC. Nivolumab is a fully human IgG4 anti-PD-1 antibody which was approved for the second line treatment of advanced NSCLC based on the results of two clinical trials demonstrating a superior survival with nivolumab compared to docetaxel [9], [10]. Data regarding the CNS activity of nivolumab are lacking.

Section snippets

Materials and methods

We reviewed the medical charts of 85 patients with advanced NSCLC treated with intravenous nivolumab 3 mg/kg q2weeks between February 2015 and December 2015 at two tertiary medical centers in Israel. We selected patients with new/progressing intracranial metastases which were detected before or within one month after starting nivolumab. Patients with neurological symptoms, who required steroid administration and/or local therapy (i.e., surgery or radiation), were excluded from the analysis. Thus

Results

Five patients with newly diagnosed or progressing intracranial disease meeting the above criteria were identified (Table 1). Two intracranial responses were observed, including one complete response of parenchymal brain metastases and one partial response of leptomeningeal carcinomatosis (Fig. 1, Fig. 2). Stabilization of leptomeningeal disease which lasted 10 weeks was achieved in one additional patient. Two patients progressed in the brain and systemically 4 and 12 weeks since start of

Discussion

The recent FDA approval of nivolumab and pembrolizumab, anti-PD-1 immune check-point inhibitors, for the second line treatment of NSCLC has changed the treatment paradigm. These agents provide an effective and tolerable alternative to second-line chemotherapy [9], [11]. Additionally, several anti-programmed cell death ligand-1 (PD-L1) immune check-point inhibitors (e.g., atezolizumab, avelumab and durvalumab) are currently being evaluated in ongoing clinical trials. Data regarding intracranial

Conclusions

Overall, our data suggest that nivolumab might have intracranial activity in patients with NSCLC and untreated/progressing CNS metastases. These findings should be explored further in a prospective clinical trial. Future research should involve determination of predictive biomarkers along with characterization of pseudo-progression and clarification of the mechanism of action of anti-PD-1/anti-PD-L1 agents in the CNS.

Conflict of interest

Nir Peled – honoraria for lectures, consultant and advisor for BMS; Shlomit Yust-Katz – honoraria for lectures paid by BMS. Other authors declared no conflicts of interest.

Funding

No research funding was received; nivolumab was provided by Bristol-Myers Squibb (BMS). BMS was not involved in collection or interpretation of data, manuscript drafting or submission.

Acknowledgements

We are grateful to BMS pharmaceutical company for providing nivolumab to all the treated patients. We are grateful to Hiba Reches, RN for her assistance in patient management and data collection.

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¹: The authors equally contributed to the preparation of the manuscript.

View full text

Intracranial response to nivolumab in NSCLC patients with untreated or progressing CNS metastases

Highlights

Abstract

Introduction

Section snippets

Materials and methods

Results

Discussion

Conclusions

Conflict of interest

Funding

Acknowledgements

Int. J. Radiat. Oncol. Biol. Phys.

Ann. Oncol.

Ann. Oncol.

Ann. Oncol.

Epidemiology of brain metastases

Curr. Oncol. Rep.

Summary report on the graded prognostic assessment: an accurate and facile diagnosis-specific tool to estimate survival for patients with brain metastases

J. Clin. Oncol.

Primary chemotherapy for newly diagnosed nonsmall cell lung cancer patients with synchronous brain metastases compared with whole-brain radiotherapy administered first: result of a randomized pilot study

Cancer