- Email: [email protected]
Real-world Efficacy and Safety of Nivolumab for Advanced Non–Small-cell Lung Cancer: A Retrospective Multicenter Analysis
Accepted Manuscript Real-world efficacy and safety of nivolumab for advanced non-small cell lung cancer: a retrospective multicenter analysis Keigo Kobayashi, M.D, Ichiro Nakachi, M.D., Ph.D., Katsuhiko Naoki, M.D., Ph.D., Ryosuke Satomi, M.D., Morio Nakamura, M.D., Ph.D., Takashi Inoue, M.D., Ph.D., Hiroki Tateno, M.D., Ph.D., Fumio Sakamaki, M.D., Ph.D., Koichi Sayama, M.D., Ph.D., Takeshi Terashima, M.D., Ph.D., Hidefumi Koh, M.D., Ph.D., Takayuki Abe, Ph.D., Makoto Nishino, M.D., Daisuke Arai, M.D., Ph.D., Hiroyuki Yasuda, M.D., Ph.D., Ichiro Kawada, M.D., Ph.D., Kenzo Soejima, M.D., Ph.D., Tomoko Betsuyaku, M.D., Ph.D. PII:
S1525-7304(18)30001-9
DOI:
10.1016/j.cllc.2018.01.001
Reference:
CLLC 737
To appear in:
Clinical Lung Cancer
Received Date: 10 July 2017 Revised Date:
20 December 2017
Accepted Date: 1 January 2018
Please cite this article as: Kobayashi K, Nakachi I, Naoki K, Satomi R, Nakamura M, Inoue T, Tateno H, Sakamaki F, Sayama K, Terashima T, Koh H, Abe T, Nishino M, Arai D, Yasuda H, Kawada I, Soejima K, Betsuyaku T, On behalf of the Keio Lung Oncology Group (KLOG), Real-world efficacy and safety of nivolumab for advanced non-small cell lung cancer: a retrospective multicenter analysis, Clinical Lung Cancer (2018), doi: 10.1016/j.cllc.2018.01.001. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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ORIGINAL STUDY
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Real-world efficacy and safety of nivolumab for advanced non-small cell lung
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cancer: a retrospective multicenter analysis
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Keigo Kobayashi1, M.D., Ichiro Nakachi2, M.D., Ph.D., Katsuhiko Naoki1, M.D., Ph.D.,
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Ryosuke Satomi3, M.D., Morio Nakamura4, M.D., Ph.D., Takashi Inoue5, M.D., Ph.D.,
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Hiroki Tateno6, M.D., Ph.D., Fumio Sakamaki7, M.D., Ph.D., Koichi Sayama8, M.D.,
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Ph.D., Takeshi Terashima9, M.D., Ph.D., Hidefumi Koh10, M.D., Ph.D., Takayuki Abe11,
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Ph.D., Makoto Nishino1, M.D., Daisuke Arai2, M.D., Ph.D., Hiroyuki Yasuda1, M.D.,
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Ph.D., Ichiro Kawada1, M.D., Ph.D., Kenzo Soejima1, M.D., Ph.D., Tomoko
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Betsuyaku1, M.D., Ph.D. On behalf of the Keio Lung Oncology Group (KLOG)
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Medicine
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35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
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911-1 Takebayashimachi, Utsunomiya, Tochigi, 321-0974, Japan
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2-5-1 Higashigaoka, Meguro-ku, Tokyo, 152-8902, Japan
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Division of Pulmonary Medicine, Department of Medicine, Keio University School of
Pulmonary Division, Internal Medicine, Saiseikai Utsunomiya Hospital
National Hospital Organization Tokyo Medical Center
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1-4-17 Mita, Minato-ku, Tokyo, 108-0073, Japan
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1728 Horigomecho, Sano, Tochigi, 327-8511, Japan
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2460 Mimuro, Midori-ku, Saitama, 336-8522, Japan
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1838 Ishikawacho, Hachioji, Tokyo, 192-0032, Japan
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12-1 Shinkawadori, Kawasaki-ku, Kawasaki 210-0013, Japan
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5-11-13 Sugano, Ichikawashi, Chiba, 272-8513, Japan
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4-2-22 Nishikimachi, Tachikawa, 190-8531, Japan
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Medicine
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35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
Tokyo Saiseikai Central Hospital
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Tokyo Dental College Ichikawa General Hospital
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Department of Preventive Medicine and Public Health, Keio University School of
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35 Corresponding author:
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Ichiro Nakachi, M.D., Ph.D.
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Pulmonary division, Internal medicine, Saiseikai Utsunomiya Hospital, 911-1
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Takebayashimachi, Utsunomiya, Tochigi, 321-0974, Japan
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Telephone number: +81-28-626-5500
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Fax number: +81-28-626-5573
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E-mail address: [email protected]
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Abstract
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Objectives: Nivolumab, an immune checkpoint inhibitor, is now a standard treatment
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for previously treated advanced non-small cell lung cancer based on Phase III clinical
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trials. We aimed to evaluate the real-world efficacy and safety of nivolumab in a
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non-selective population and identify clinical characteristics that influence efficacy.
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Materials and methods: One hundred and forty-two patients with advanced non-small
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cell lung cancer who were administered nivolumab at Keio University and affiliated
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hospitals in Japan between January and July 2016 were enrolled. Treatment efficacy and
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adverse events were retrospectively reviewed and clinical characteristics associated with
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nivolumab responses were evaluated using univariate and stratified analyses and the
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Cochran-Mantel-Haenszel test.
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Results: The objective response rate (ORR) was 17.0% (95.0% confidence interval [CI],
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12.0−24.0), and the median progression-free survival (PFS) was 58 days (95% CI, 50-
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67), while the proportion of patients with adverse events (AEs) of any grade was 45.0%.
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EGFR/ALK mutation status was inversely associated with treatment response (P < 0.05),
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and the PFS for the mutation positive versus negative showed a significant difference
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(49 vs. 63 days; hazard ratio, 1.9; 95% CI, 1.1-5.2, P = 0.029). Prior radiotherapy also
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exhibited a positive association with treatment response (P = 0.012).
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Conclusion: The ORR, the PFS and the AE profiles were comparable to those observed
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in previous clinical trials. EGFR/ALK mutation-negative status and prior radiotherapy
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might be key clinical characteristics that are associated with a positive treatment
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response. Our findings may aid in the efficient immunotherapeutic management of lung
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cancer.
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Micro Abstract
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We evaluated the real-world efficacy and safety of nivolumab in 142 advanced
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non-small cell lung cancer patients in Japan, and identified clinical characteristics that
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influence the efficacy. Negative EGFR/ALK mutation status and prior radiotherapy were
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statistically associated with treatment response. These findings may aid in the efficient
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immunotherapeutic management of lung cancer.
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Clinical Practice Points
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The efficacy and safety of nivolumab treatment for advanced non-small cell lung
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cancers are based on results from phase III clinical trials conducted in carefully selected
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patient populations.
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In this retrospective multicenter study recruiting 142 advanced non-small cell lung
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cancer patients, we evaluated the real-world efficacy and safety of nivolumab, and
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clinical characteristics associated with nivolumab responses.
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The objective response rate was 17.0%, and the median progression-free survival was 58 days, while the proportion of patients with adverse events of any grade was 45.0%.
EGFR/ALK mutation status was inversely associated with treatment response, and the
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PFS for the mutation positive versus negative showed a significant difference. Prior
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radiotherapy also exhibited a positive association with treatment response.
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characteristics that are associated with a positive treatment response.
These findings may aid in the efficient immunotherapeutic management of advanced non-small cell lungs cancer.
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1. Introduction Lung cancer is the leading cause of cancer-related deaths worldwide. The majority
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of advanced cancer patients relapse with chemotherapy-resistant disease after the
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administration of conventional cytotoxic agents. Today, immune checkpoint inhibitors
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have revolutionized cancer therapy and are recognized as a novel treatment option for
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patients with advanced cancers
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antagonist antibody to programmed cell death protein 1, is now approved as a standard
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treatment for patients with advanced non-small cell lung cancer (NSCLC) who have
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experienced disease progression during or after initial therapy with platinum-based
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doublet chemotherapy 3, 4.
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. Nivolumab, an immunoglobulin G4 monoclonal
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The efficacy and safety of nivolumab are based on results from clinical trials
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conducted in carefully selected patient populations. These clinical trials enrolled
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relatively young patients with a good Eastern Cooperative Oncology Group (ECOG)
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performance status (PS) and excluded patients with complicated comorbidities, such as
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interstitial pneumonia (IP), autoimmune disease, and symptomatic central nervous
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system (CNS) metastases. The real-world efficacy and safety of nivolumab in
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non-selective populations remain unclear. Herein, we conducted a retrospective
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multicenter analysis of 142 non-selective advanced NSCLC patients in Japan. We
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aimed to evaluate the real-world efficacy and safety of nivolumab in a non-selective
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population and identify clinical characteristics that influence efficacy.
2. Materials and methods
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2.1. Study population
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In total, 142 previously treated advanced NSCLC patients, who were administered
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nivolumab at Keio University and its 13 affiliated hospitals (the Keio Lung Oncology
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Group) between January and July 2016, were enrolled. Patients with a histological or
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cytological diagnosis of NSCLC, who experienced disease progression during or after
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initial treatment, were eligible for this study. In addition to patients with Stage IIIB−IV
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disease and postoperative recurrence, patients with Stage IIIA disease who met the
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following criteria were also included: (1) a diagnosis of non-resectable or progressive
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disease (PD) after initial chemotherapy and (2) concomitant radiotherapy. Data on the
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clinical characteristics, previous treatments, and outcomes were extracted from patients’
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medical records. Patients were treated intravenously with nivolumab at a dose of 3.0
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mg/kg of bodyweight every 2 weeks (a licensed dose and administration in Japan). The
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study was approved by the Ethical Review Board Committee of Keio University and its
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affiliated hospitals. This study was received ethical approval for the use of an opt out
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style. Research was conducted in accordance with the 1964 Declaration of Helsinki, as
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revised in 2013.
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2.2. Target lesion assessment
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The baseline sizes of the target lesions were measured in advance by imaging (e.g.,
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chest radiography, computed tomography, or magnetic resonance imaging). Clinical
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responses to nivolumab were evaluated using the same imaging modalities as well as
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the Response Evaluation Criteria in Solid Tumors (version 1.1) 5. Tumor responses to
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nivolumab were defined as follows: a complete response (CR; the disappearance of all
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target lesions), a partial response (PR; ≥30.0% reduction in the sum of the diameters of
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the target lesions), PD (≥20.0% increase in the sum of the diameters of the target
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lesions), and stable disease (SD; insufficient shrinkage or expansion to qualify as a PR
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or PD). In the absence of measurable disease, unequivocal progression was defined as
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that required to declare clinically PD as PD. The objective response rate (ORR) was
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defined as the proportion of patients who had achieved a CR or a PR, while the disease
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control rate was defined as the proportion of patients who had achieved a CR, a PR, or
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SD. Adverse events (AEs) related to nivolumab treatment were reported according to
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the Common Terminology Criteria for Adverse Events (version 4.0).
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2.3.
Clinical characteristics
The following clinical characteristics were included in our analyses: age, sex,
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ECOG PS, histological subtype, EGFR/ALK mutation status, the presence or absence of
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CNS metastases, smoking status, the number of previous lines of treatment, and the
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presence or absence of previous irradiation.
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2.4. Statistical analyses
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Statistical analyses using the Pearson’s chi-square test, Fisher’s exact test, and
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student’s t-test test were used to evaluate the clinical characteristics associated with the
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efficacy of nivolumab. A two-sided P < 0.05 was considered statistically significant for
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all tests. Variables selected from those exhibiting a significant association with P < 0.05
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were entered into the stratification analysis using the Cochran-Mantel-Haenszel test. All
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statistical analyses were conducted using JMP software (version 13; SAS Institute, Cary,
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NC, USA). Data were visualized using Easy R (Saitama Medical Center, Jichi Medical
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University, Saitama, Japan), which is a graphical user interface for R (The R
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Foundation for Statistical Computing, Vienna, Austria) 6.
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3.1. Clinical characteristics of the study population
In total, 142 patients with Stage IIIA−IV disease and postoperative recurrence were
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enrolled. The baseline clinical characteristics of the patients are summarized in Table 1.
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The median age was 67 (range, 34−85) years, with thirty-eight patients (26.8%) ≥75
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years of age. One hundred and six patients (74.6%) were men and 36 patients (25.4%)
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were women. The ECOG PS was 0 in 43 (30.3%), 1 in 76 (53.5%), 2 in 15 (10.6%), and
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3 in 8 (5.6%) patients, respectively. Histological subtypes included adenocarcinoma (n
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= 83 patients; 58.5%), squamous cell carcinoma (n = 41 patients; 28.9%), and other (n =
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18 patients; 12.7%). Sixteen patients (11.3%) had an EGFR mutation-positive status and
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3 patients (2.1%) had an ALK mutation-positive status. Twenty-seven patients (19.0%)
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had baseline CNS metastases. Seven patients were irradiated in their brains
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(Supplementary Table S2). One hundred and thirteen patients (79.6%) were current or
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ex-smokers and 29 patients (20.4%) were non-smokers. Fifty-seven patients (40.1%)
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were treated with second-line and 85 patients (59.9%) were treated with third-line (or
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higher) nivolumab. Forty-five patients (31.7%) had received prior radiotherapy. Our
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study included patients with the following complications: diabetes (n = 21; 14.8%),
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thyroid disease (n = 11; 7.7%), IP (n = 10; 7.0%), autoimmune disease (n = 3; 2.1%),
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and prior oral steroid treatment (≥10.0 mg prednisolone equivalent) (n = 2; 1.4%). As
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for autoimmune disease, two patients had rheumatoid arthritis (RA), and one had
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autoimmune hemolytic anemia. One of RA patients was administrated 5 mg of
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prednisolone a day.
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3.2. Objective clinical responses and progression-free survival
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Patients underwent radiographic evaluation 6.8 ± 2.5 (mean ± standard deviation)
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weeks after commencing treatment. The ORR was 17.0% (95.0% CI: 12.0−24.0%) with
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all PRs, and the disease control rate was 62.0% (95.0% CI: 54.0−70.0%) (Figure 1A).
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The median progression-free survival (PFS) was 58 days in all patients (95% CI, 50-
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67) (Figure 1B).
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3.3. Clinical characteristics and treatment responses
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Age, sex, ECOG PS, histological subtype, the presence or absence of CNS
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metastases, smoking status, and the number of previous lines of treatment were not
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statistically associated with a response to nivolumab (Table 2). Among the patients’
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baseline clinical characteristics listed in Table 1, EGFR/ALK mutation status and prior
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radiotherapy were significantly associated with responses to nivolumab (Fisher’s exact
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test; P < 0.05 and P = 0.012, respectively). With respect to gene mutation status, none of
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the 19 EGFR/ALK mutation-positive patients exhibited a PR (PD [n = 10 patients] and
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SD [n = 9 patients]). None of the target lesions in the EGFR/ALK mutation-positive
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patients exhibited sufficient tumor size reduction to qualify as a PR at initial response
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evaluation (Figure 2). Regarding radiotherapy, patients treated with prior radiotherapy
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were more likely to respond to nivolumab than those without. The median interval
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between radiotherapy and nivolumab treatment was 323.0 (interquartile range,
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199.5−764.0) days. The most frequently irradiated site was the thorax (n = 37 [82.2%]
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of 45 patients), 7 were irradiated for whole brain, and one was for oropharynx.
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Stratification analysis using the Cochran-Mantel-Haenszel test revealed that an
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EGFR/ALK mutation-negative status and prior radiotherapy were independently
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associated with a positive response to nivolumab treatment (odds ratio: not available [P
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< 0.05] and 0.31 [P < 0.01], respectively) (Supplementary Table S1). A significant
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difference was observed in the comparison of the PFS between EGFR/ALK mutation
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positive and negative status (49 versus 63 days; hazard ratio [HR], 1.9; 95% CI, 1.1-5.2;
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P = 0.029; Figure 3A). In the comparison between patients with and without prior
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radiation, a longer median PFS was observed in the former (82 versus 52 days,
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respectively), which, however, did not reach at significance (HR, 0.77; 95% CI,
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0.49-1.2; P = 0.25; Figure 3B).
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Although no significant difference was observed between current/ex-smokers and
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non-smokers (Pearson’s chi-square test; P > 0.05), a subgroup analysis revealed
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smoking status in pack-years (PYs) to be significantly higher in responders than
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non-responders (Student’s t-test; P < 0.05) (Supplementary Figure S1).
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3.4. Effect of nivolumab on central nervous system metastases
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In an analysis of 27 patients with CNS metastases, no significant difference in
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systemic response was observed between patients with and without CNS metastases (P
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> 0.05; Table 2). Additionally, none of the patients with systemic response to treatment
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(n = 5) exhibited any change in CNS metastases (Supplementary Table S2). While no
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positive intracranial responses to nivolumab treatment were observed, CNS lesions from
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14 patients (51.9%) were stable.
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3.5. Adverse events
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The AE profile observed in response to nivolumab treatment is shown in Table 3.
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Sixty-four patients (45.1%) experienced AEs of any grade in this study. AEs of any
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grade that were observed in ≥5.0% of patients included: anorexia (n = 21, 14.8%),
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hypothyroidism (n = 15, 10.6%), a rash (n = 10, 7.0%), and IP (n = 8, 5.6%; one patient
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had a history of IP). AEs of grade 3−4 occurred in 13.3% of patients. AEs of grade 3−4
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that were observed in 2.0−5.0% of patients included anorexia (n = 6, 4.2%) and IP (n =
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3, 2.1%). Two treatment-related deaths occurred, which were caused by acute
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exacerbation of IP and disseminated intravascular coagulation, respectively.
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4. Discussion
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In this retrospective multicenter study of advanced NSCLC patients (n = 142) we
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demonstrate the real-world efficacy and safety of nivolumab, a newly approved immune
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checkpoint inhibitor. We also identify clinical characteristics that are significantly
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associated with objective response. In the CheckMate 017 (squamous NSCLC)
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CheckMate 057 (non-squamous NSCLC)
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19.0%, and the median PFS was 3.5 and 2.3 months, respectively. Although our study
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population was heterogeneous and relatively small, the ORR (17.0%) was comparable
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to those observed in the CheckMate clinical trials. This suggests that we may be able to
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estimate the proportion of advanced NSCLC patients that will benefit practically from
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this novel immune checkpoint inhibitor.
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clinical trials, the ORR was 20.0% and
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Among the clinical characteristics analyzed, an EGFR/ALK mutation-positive status
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was statistically associated with response to nivolumab treatment. Whether the efficacy
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of nivolumab is influenced by gene mutation status has been assessed in only a limited
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number of clinical studies. Gainor et al.
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advanced NSCLC patients treated with programmed cell death protein 1/programmed
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death-ligand 1 inhibitors that there was only one responder among 28 patients with an
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EGFR/ALK mutation-positive status. Lee et al.
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trials (CheckMate 057 3, Keynote 010 9, and POPLAR
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immune checkpoint inhibitors (nivolumab, pembrolizumab, and atezolizumab) in
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EGFR-mutated advanced NSCLC. The authors
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inhibitors may not improve overall survival compared with docetaxel in EGFR-mutated
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advanced NSCLC patients. Rizvi et al.
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checkpoint inhibitor efficacy from a genomic viewpoint and suggested that the higher
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mutation burden observed in NSCLC patients was a better prognostic factor for immune
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checkpoint inhibitors. Rozenblum et al. 12 revealed patients carrying driver oncogenes
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had lower mean mutation burden than those not carrying any treatment-associated
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drivers.
performed a meta-analysis of three 10
) to evaluate the role of
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concluded that immune checkpoint
elucidated potential mechanisms of immune
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Therefore, EGFR-mutated or ALK-positive NSCLC patients are less likely to
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respond to immune checkpoint inhibitors, because they are considered to harbor only a
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low mutation burden from genome-wide analysis by next-generation sequencing 13, 14.
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Our study indicated a positive association between prior radiotherapy and the
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efficacy of nivolumab. As an effective utility of immune checkpoint inhibitors, the
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potential benefit of combining immune checkpoint inhibitors with radiotherapy now
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becomes clinically evident
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radiotherapy 18-25. Shaverdian et al reported that previous treatment with radiotherapy in
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patients with advanced NSCLC resulted in longer PFS and overall survival with
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pembrolizumab treatment than that seen in patients who did not have previous
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radiotherapy26. Meanwhile, no significant difference in the PFS between the presence
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and absence of prior radiotherapy was observed in our nivolumab treatment study.
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Accordingly, further clinical trials investigating the combination of nivolumab and
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radiotherapy are needed to determine the optimal protocols for irradiation (dose, number
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of irradiation, sequential or simultaneous use with nivolumab and appropriate target
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lesions).
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. Tumor immunogenicity may be augmented by
It is also known that cigarette smoking positively correlates with a high
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genome-wide mutation burden in NSCLC
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study demonstrated that nivolumab was more effective in heavy smokers (56 ± 6.3 PYs)
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(mean ± standard deviation) compared to light or non-smokers (35 ± 2.9 PYs) (mean ±
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standard deviation). The mechanisms under which heavy smokers benefit from
17
. Subsequent statistical analysis in our
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nivolumab treatment better than light or non-smokers may also be explained in the
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context of mutation burden described above. One of the unique characteristics of our study is that patients aged ≥75 years
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account for 26.8% of the study population, which is a higher proportion than in the
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CheckMate 017 4 (11.0%) or CheckMate 057 3 (7.0%) studies. In a comparison between
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patients aged ≥75 years and those aged <75 years, no statistically significant difference
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in ORR was observed (P > 0.05; Table 2). Furthermore, no difference in the efficacy of
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nivolumab was observed between patients with early (second) and late (third or higher)
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treatment lines (P > 0.05; Table 2). However, several previous studies 3, 29 indicated that
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an early line of treatment was associated with the efficacy of nivolumab. Meanwhile, no
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significant differences in the frequencies of AEs of any grade were observed between
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patients aged ≥75 years and those aged <75 (37.0% vs. 48.0%, respectively) or between
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patients with early and late treatment lines (44.0% vs. 46.0%, respectively). Taken
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together, these findings suggest that nivolumab may be effective and safe regardless of
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age or the number of previous lines of treatment.
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While no CNS metastases responded to nivolumab, even in patients exhibiting a
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systemic response, a large number of CNS lesions remained stable (n = 14 [51.9%] of
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27 lesions). Dudnik et al.
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reported the efficacy of nivolumab in 5 patients with
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advanced NSCLC and progressing CNS metastases (CR [n = 1], PR [n = 1], SD [n = 1],
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and PD [n = 2]). In the first prospective study evaluating the efficacy of pembrolizumab
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in NSCLC patients with brain metastases 31, the ORR in CNS metastases was 33.0% (n
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= 6 of 18 patients). The systemic ORR was also 33.0%. These findings are different
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from ours and are encouraging for the future management of patients with metastatic
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NSCLC. However, it should be noted that the Johanns et al. 32 study was performed on a
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limited number of highly selected patients (n = 18). Therefore, the real-world efficacy of
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nivolumab for CNS metastases has not yet been elucidated and further studies are
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urgently required.
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frequently with nivolumab compared to conventional second-line treatment (e.g., with
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docetaxel). The proportion of patients in the present study with common AEs of grade
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3−4 or 5 were 13.3% and 1.4%, respectively, suggesting that nivolumab is safe for use
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in clinical trials.
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The major limitations of our retrospective study include the small sample size and
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relatively short follow-up period. Further accumulation of cases with longer follow-up
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periods, including overall survival data, or a mutation-positive status, CNS metastases,
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and available programmed death-ligand 1 immunohistochemistry data is necessary.
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However, we believe that the heterogeneous patient population in our study may well
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reflect the real-world efficacy and safety of nivolumab treatment.
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5. Conclusions
In our retrospective analysis of 142 non-selective patients with advanced NSCLC,
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we demonstrate the real-world efficacy and safety of nivolumab. EGFR/ALK mutation
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status and prior radiotherapy are key clinical characteristics that are statistically
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associated with the efficacy of nivolumab. Nivolumab may be more effective in patients
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with an EGFR/ALK mutation-negative status or prior radiotherapy and be safe
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regardless of age or the number of previous lines of treatment. Our findings may aid in
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the efficient immunotherapeutic management of patients with advanced NSCLC.
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Acknowledgements
We wish to thank Kazumi Nishio (Kawasaki City Ida Hospital, Kanagawa, Japan),
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Fumitake Saito (Eiju General Hospital, Tokyo, Japan), Yusuke Suzuki (Kitasato Institute
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Hospital, Tokyo, Japan), and Akira Umeda (International Medical Welfare College
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Shioya Hospital, Tochigi, Japan) for assisting in data collection, and all members of the
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Keio Lung Oncology Group who participated in this study. This study was funded by
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Ono Pharmaceutical Co., Ltd. and Chugai Pharmaceutical Co., Ltd.
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344 Disclosure
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K Soejima has received honoraria from Chugai, Ono, Eli Lilly, AstraZeneca, Boehringer
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Ingelheim and Shionogi. The remaining authors declare that they have no competing interests.
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References
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1.
2.
353
Therapy: Clinical Efficacy and Safety. Curr Cancer Drug Targets 15 (2015) 452−62. 3.
354 355
Borghaei H, Paz-Ares L, Horn L, et al: Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med 373 (2015) 1627−39.
4.
356
Brahmer J, Reckamp KL, Baas P, et al: Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med 373 (2015) 123−35.
5.
Therasse P, Arbuck SG, Eisenhauer EA, et al: New guidelines to evaluate the
TE D
357
SC
352
Azoury SC, Straughan DM, Shukla V: Immune Checkpoint Inhibitors for Cancer
M AN U
351
FEBS Lett 588 (2014) 368−76.
RI PT
350
Kyi C, Postow MA: Checkpoint blocking antibodies in cancer immunotherapy.
response to treatment in solid tumors. European Organization for Research and
359
Treatment of Cancer, National Cancer Institute of the United States, National
360
Cancer Institute of Canada. J Natl Cancer Inst 92 (2000) 205−16. 6.
362 363
AC C
361
EP
358
Kanda Y: Investigation of the freely available easy-to-use software 'EZR' for medical statistics. Bone Marrow Transplant 48 (2013) 452−8.
7.
Gainor JF, Shaw AT, Sequist LV, et al: EGFR Mutations and ALK Rearrangements
364
Are Associated with Low Response Rates to PD-1 Pathway Blockade in Non-Small
365
Cell Lung Cancer: A Retrospective Analysis. Clin Cancer Res 22 (2016) 4585−93.
22
ACCEPTED MANUSCRIPT
8.
367 368
Lee CK, Man J, Lord S, et al: Checkpoint Inhibitors in Metastatic EGFR-Mutated Non-Small Cell Lung Cancer-A Meta-Analysis. J Thorac Oncol 12 (2017) 403−7.
9.
Herbst RS, Baas P, Kim DW, et al: Pembrolizumab versus docetaxel for previously
RI PT
366
treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a
370
randomised controlled trial. Lancet 387 (2016) 1540−50.
SC
369
10. Fehrenbacher L, Spira A, Ballinger M, et al: Atezolizumab versus docetaxel for
372
patients with previously treated non-small-cell lung cancer (POPLAR): a
373
multicentre, open-label, phase 2 randomised controlled trial. Lancet 387 (2016)
374
1837−46.
M AN U
371
11. Rizvi NA, Hellmann MD, Snyder A, et al: Cancer immunology. Mutational
376
landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer.
377
Science 348 (2015) 124−8.
379 380
EP
12. Rozenblum AB, Ilouze M, Dudnik E, et al: Clinical Impact of Hybrid
AC C
378
TE D
375
Capture-Based Next-Generation Sequencing on Changes in Treatment Decisions in
Lung Cancer. J Thorac Oncol. 12(2) (2017) 258-268
381
13. Spigel DR, Schrock AB, Fabrizio D, et al: Total mutation burden (TMB) in lung
382
cancer (LC) and relationship with response to PD-1/PD-L1 targeted therapies. J
383
Clin Oncol 34 (2016) (suppl; abstr 9017).
23
ACCEPTED MANUSCRIPT
14. Kazandjian D, Suzman DL, Blumenthal G, et al: FDA Approval Summary:
385
Nivolumab for the Treatment of Metastatic Non-Small Cell Lung Cancer With
386
Progression On or After Platinum-Based Chemotherapy. Oncologist 21 (2016)
387
634−42.
RI PT
384
15. Gerber DE, Urbanic JJ, Langer C, et al: Treatment Design and Rationale for a
389
Randomized Trial of Cisplatin and Etoposide Plus Thoracic Radiotherapy Followed
390
by Nivolumab or Placebo for Locally Advanced Non-Small-Cell Lung Cancer
391
(RTOG 3505). Clin Lung Cancer S1525−7304 (2016) 30352−7.
393
M AN U
16. Herter-Sprie GS, Koyama S, Korideck H. et al. Synergy of radiotherapy and PD-1 blockade in Kras-mutant lung cancer. JCI Insight. (2016) ; 1(9): e87415.
TE D
392
SC
388
17. Twyman-Saint Victor C, Rech AJ, Maity A. et al. Radiation and dual checkpoint
395
blockade activate non-redundant immune mechanisms in cancer. Nature. (2015)
396
520(7547): 373-7.
AC C
EP
394
397
18. Iyengar P, Kavanagh BD, Wardak Z, et al: Phase II trial of stereotactic body
398
radiation therapy combined with erlotinib for patients with limited but progressive
399 400 401
metastatic non-small-cell lung cancer. J Clin Oncol 32 (2014) 3824−30. 19. Formenti SC, Demaria S. Radiation therapy to convert the tumor into an in situ vaccine. Int J Radiat Oncol Biol Phys. (2012) 84(4):879-80.
24
ACCEPTED MANUSCRIPT
403 404
20. Demaria S, Golden EB, Formenti SC. et al. Role of Local Radiation Therapy in Cancer Immunotherapy. JAMA Oncol. (2015) 1(9):1325-32. 21. Reits EA, Hodge JW, Herberts CA. et al. Radiation modulates the peptide repertoire, enhances
MHC
class
I
expression,
and
induces
406
immunotherapy. J Exp Med. (2006) 203(5):1259-71.
successful
antitumor
SC
405
RI PT
402
22. Sharabi AB, Lim M, DeWeese TL. et al. Radiation and checkpoint blockade
408
immunotherapy: radiosensitisation and potential mechanisms of synergy. Lancet
409
Oncol. (2015) 16(13):e498-509.
M AN U
407
23. Sharabi AB, Nirschl CJ, Kochel CM. et al. Stereotactic Radiation Therapy
411
Augments Antigen-Specific PD-1-Mediated Antitumor Immune Responses via
412
Cross-Presentation of Tumor Antigen. Cancer Immunol Res. (2015) 3(4):345-55.
413
24. Gupta A, Probst HC, Vuong V. et al. Radiotherapy promotes tumor-specific effector
EP
CD8+ T cells via dendritic cell activation. J Immunol. (2012) 189(2):558-66.
AC C
414
TE D
410
415
25. Liao YP, Wang CC, Butterfield LH. et al. Ionizing radiation affects human MART-1
416
melanoma antigen processing and presentation by dendritic cells. J Immunol.
417
(2004) 173(4):2462-9.
418
26. Shaverdian N, Lisberg AE, Bornazyan K: Previous radiotherapy and the clinical
419
activity and toxicity of pembrolizumab in the treatment of non-small-cell lung
25
ACCEPTED MANUSCRIPT
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cancer: a secondary analysis of the KEYNOTE-001 phase 1 trial. Lancet Oncol
421
(2017)18(7): 895-903.
423
27. Gibbons DL, Byers LA, Kurie JM: Smoking, p53 mutation, and lung cancer. Mol
RI PT
422
Cancer Res 12 (2014) 3−13.
28. Gupta A, Srivastava S, Prasad R, et al: Smoking intensity, oxidative stress and
425
chemotherapy in nonsmall cell lung cancer: a correlated prognostic study. Biosci
426
Trends 3 (2009) 191−9.
M AN U
SC
424
29. Rizvi NA, Mazières J, Planchard D, et al: Activity and safety of nivolumab, an
428
anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory
429
squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial.
430
Lancet Oncol 16 (2015) 257−65.
TE D
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30. Dudnik E, Yust-Katz S, Nechushtan H, et al: Intracranial response to nivolumab in
432
NSCLC patients with untreated or progressing CNS metastases. Lung Cancer 98
AC C
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EP
431
(2016) 114−7.
434
31. Goldberg SB, Gettinger SN, Mahajan A, et al: Pembrolizumab for patients with
435
melanoma or non-small-cell lung cancer and untreated brain metastases: early
436
analysis of a non-randomised, open-label, phase 2 trial. Lancet Oncol 17 (2016)
437
976−83.
26
ACCEPTED MANUSCRIPT
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32. Johanns T, Waqar SN, Morgensztern D: Immune checkpoint inhibition in patients with brain metastases. Ann Transl Med 4 (2016) S9. 33. Huang J, Zhang Y, Sheng J, et al: The efficacy and safety of
nivolumab in
RI PT
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previously treated advanced non-small-cell lung cancer: a meta-analysis of
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prospective clinical trials. Onco Targets Ther 9 (2016) 5867−74.
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Figure legends
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Figure 1. The overall response and the progression free survival for all patients
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(A) Clinical responses to nivolumab. CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease.
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(B) Kaplan–Meier plot of progression-free survival (n = 142).
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Figure 2.
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Waterfall plot of the percentage change in target lesion size at initial response evaluation.
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EGFR/ALK mutation-positive patients (n = 19; 13.4%) are represented in black
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(asterisks denote EGFR mutation-positive patients [n = 16] and daggers denote ALK
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mutation-positive patients [n = 3]), EGFR/ALK mutation-negative patients (n = 94;
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66.2%) are represented in white, and patients with unknown genetic mutations are
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represented in gray (n = 22; 15.5%); 7 patients (4.9%) had no measurable lesions.
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Figure 3. Progression-free survival in EGFR/ALK mutation and prior radiation
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status
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(A) Kaplan-Meier plot for EGFR/ALK positive and negative patients. HR, hazard ratio;
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CI, confidence interval. Dotted line; EGFR/ALK positive, solid line; EGFR/ALK
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(B) Kaplan-Meier plot for the patients with prior radiation and non-prior radiation. HR,
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hazard ratio; CI, confidence interval. Dotted line; non-prior radiation group, solid
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line; prior radiation group
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Supplementary Figure S1.
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Subgroup analysis of the association between clinical responses to nivolumab and
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smoking status in pack-years in all 142 patients
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Table 1. Baseline characteristics, stratification factors, and prior therapy Characteristic Patients (n = 142) Age (years), n (%) median (range) 67 (34−85) ≥75 38 (26.8) Sex, n (%) M 106 (74.6) F 36 (25.4) Disease stage, n (%) IIIA 19 (13.3) IIIB 21 (14.8) IV 85 (59.9) Postoperative recurrence 17 (12.0) ECOG PS, n (%) 0 43 (30.3) 1 76 (53.5) 2 15 (10.6) 3 8 (5.6) 4 0 (0.0) Histology, n (%) ADC 83 (58.5) SCC 41 (28.9) NSCLC (NOS) 9 (6.3) LCNEC 4 (2.8) ASC 2 (1.4) PC 2 (1.4) LELC 1 (0.7) Genetic mutation, n (%) EGFR 16 (11.3) ALK 3 (2.1) None 98 (69.0) Unknown 25 (17.6) CNS metastasis, n (%) Y 27 (19.0) N 115 (81.0) Smoking status, n (%) Current or ex-smoker 113 (79.6) Non-smoker 29 (20.4) Treatment line, n (%) Second-line 57 (40.1) Third-line or higher 85 (59.9) Prior radiotherapy, n (%) Y N Diabetes, n (%) Y
45 (31.7) 97 (68.3) 21 (14.8)
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N Thyroid disease, n (%) Y N Interstitial pneumonia, n (%) Y N Autoimmune disease, n (%) Y N Prior oral steroid treatment, n (%) Y N
11 (7.7) 131 (92.3)
3 (2.1) 139 (97.9) 2 (1.4) 140 (98.6)
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ADC, adenocarcinoma; ASC, adenosquamous carcinoma; CNS, central nervous system; ECOG, Eastern Cooperative Oncology Group; F, female; LCNEC, large cell neuroendocrine carcinoma; LELC, lymphoepithelioma-like carcinoma; M, male; N, no; NOS, not otherwise specified; NSCLC, non-small cell lung cancer; PC, pleomorphic carcinoma; PS, performance status; SCC, squamous cell carcinoma; Y, yes
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0.77
1 (Ref.) 0.54 (0.15−1.60)
0.28
1 (Ref.) 0.19 (0.02-1.48)
0.13
1 (Ref.) 2.65 (0.98-7.30)
0.055
13 (72.2)
3.16 (0.86-10.79)
0.081
19 98
0 (0.0) 18 (18.4)
19 (100.0) 80 (81.6)
− Ν/Α
0.041*
27 115
2 (7.4) 22 (19.1)
25 (92.6) 93 (80.9)
1 (Ref.) 3.00 (0.80−19.0)
0.25
113 29 57 85 45 97
*
22 (19.5) 2 (6.9)
91 (80.5) 27 (93.1)
1 (Ref.) 0.31 (0.05−1.13)
0.08
9 (15.8) 15 (17.6)
48 (84.2) 70 (82.4)
1 (Ref.) 1.10 (0.47−2.90)
0.57
13 (28.9) 11 (11.3)
32 (71.1) 86 (88.7)
1 (Ref.) 0.31 (0.13−0.77)
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1 (Ref.) 1.16 (0.41-2.96)
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P -value
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OR (95.0% CI)
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Table 2. Relationship between patients’ clinical characteristics and treatment responses Characteristic Patients (n = 142) Responders, n Non-responders, n (%) Age (years) <75 104 17 (16.3) 87 (83.7) ≥75 38 7 (18.4) 31 (81.6) Sex M 106 20 (18.9) 86 (81.1) F 36 4 (11.1) 32 (88.9) ECOG PS 119 23 (19.3) 96 (80.7) 0−1 2--3 23 1 (4.3) 22 (95.7) Histology ADC 83 9 (10.8) 74 (89.2) SCC 41 10 (24.4) 31 (75.6)
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No stable estimate was obtained for the OR as all EGFR /ALK mutation-positive patients were non-responders ADC, adenocarcinoma; CI, confidence interval; CNS, central nervous system; ECOG, Eastern Cooperative Oncology Group; F, female; M, male; N, no; N/A, not available; OR, odds ratio; PS, performance status; SCC, squamous cell carcinoma; Y, yes
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Constipation Diarrhea/colitis DIC Dysgeusia Encephalitis Hepatic dysfunction Hypacusis Hypoglycemia
6 (4.2)
0 (0.0)
5 (3.5) 4 (2.8) 1 (0.7) 1 (0.7) 1 (0.7) 6 (4.2) 1 (0.7) 1 (0.7)
0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 2 (1.4) 0 (0.0) 0 (0.0)
0 (0.0) 0 (0.0) 1 (0.7) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
15 (10.6)
1 (0.7)
0 (0.0)
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Table 3. Treatment-related adverse events Grade, n (%) Event Any 3--4 5 Adrenal insufficiency 1 (0.7) 0 (0.0) 0 (0.0) Anemia 4 (2.8) 0 (0.0) 0 (0.0)
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Interstitial pneumonia 8 (5.6) 3 (2.1) 1 (0.7) Intestinal perforation 1 (0.7) 1 (0.7) 0 (0.0) PE/DVT 2 (1.4) 1 (0.7) 0 (0.0) Pericarditis 1 (0.7) 1 (0.7) 0 (0.0) Peripheral neuropathy 3 (2.1) 1 (0.7) 0 (0.0) Pleural effusion 2 (1.4) 0 (0.0) 0 (0.0) Proteinuria 3 (2.1) 0 (0.0) 0 (0.0) Rash 10 (7.0) 2 (1.4) 0 (0.0) Reduced WBC count 2 (1.4) 0 (0.0) 0 (0.0) Renal dysfunction 4 (2.8) 1 (0.7) 0 (0.0) Thrombocytopenia 1 (0.7) 0 (0.0) 0 (0.0) Vertigo 1 (0.7) 0 (0.0) 0 (0.0) DIC, disseminated intravascular coagulation; DVT, deep
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Highlights
Practical efficacy and safety in nivolumab treatment for lung cancer is revealed
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Nivolumab may be less effective in patients with an EGFR/ALK mutation-positive
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Nivolumab is safe regardless of age or the number of previous lines of treatment
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ACCEPTED MANUSCRIPT Supplementary Table S1. Stratified analysis of clinical characteristics according to the Cochran-MantelCharacteristic OR (95.0% CI) P -valuea EGFR /ALK mutation status (positive vs. N/A 0.031* b negative) Prior radiotherapy (negative vs. positive) 0.31 (0.13−0.77) <0.01* *
P < 0.05 EGFR /ALK mutation status was stratified by the presence of prior radiotherapy (P = 0.031) and vice b No stable estimate was obtained for the OR as all EGFR /ALK mutation-positive patients were nonCI, confidence interval; N/A, not available; OR, odds ratio
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Supplementary Table S2. Systemic and intracranial responses in patients (n = 27) with central nervous system (CNS) metastases RT for Systemic CNS CNS # Sex Age (y) response response metastase s 1 M 66 PR SD − 2 M 50 PR SD − 3 F 74 PR SD − 4 M 75 PR SD − 5 F 70 PR SD − 6 M 59 SD SD − 7 M 66 SD SD − 8 M 76 SD SD + 9 M 66 SD SD + 10 M 74 SD SD − 11 M 61 SD PD + 12 M 63 PD SD + 13 M 51 PD SD − 14 M 75 PD SD − 15 M 68 PD SD − 16 F 45 PD SD + 17 M 73 PD PD − 18 M 50 PD PD − 19 M 62 PD PD − 20 F 48 PD PD − 21 M 56 PD PD − 22 F 62 PD PD + 23 M 64 PD PD − 24 M 64 PD PD − 25 M 48 PD PD − a F 68 PD NE + 26 M 85 PD NE − 27a Nivolumab treatment was discontinued before CNS metastatic lesions were evaluated F, female; M, male; NE, not evaluable; PD, progressive disease; PR, partial response; RT, radiotherapy; SD, stable disease; y, year
S1525-7304(18)30001-9
DOI:
10.1016/j.cllc.2018.01.001
Reference:
CLLC 737
To appear in:
Clinical Lung Cancer
Received Date: 10 July 2017 Revised Date:
20 December 2017
Accepted Date: 1 January 2018
Please cite this article as: Kobayashi K, Nakachi I, Naoki K, Satomi R, Nakamura M, Inoue T, Tateno H, Sakamaki F, Sayama K, Terashima T, Koh H, Abe T, Nishino M, Arai D, Yasuda H, Kawada I, Soejima K, Betsuyaku T, On behalf of the Keio Lung Oncology Group (KLOG), Real-world efficacy and safety of nivolumab for advanced non-small cell lung cancer: a retrospective multicenter analysis, Clinical Lung Cancer (2018), doi: 10.1016/j.cllc.2018.01.001. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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ORIGINAL STUDY
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Real-world efficacy and safety of nivolumab for advanced non-small cell lung
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cancer: a retrospective multicenter analysis
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Keigo Kobayashi1, M.D., Ichiro Nakachi2, M.D., Ph.D., Katsuhiko Naoki1, M.D., Ph.D.,
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Ryosuke Satomi3, M.D., Morio Nakamura4, M.D., Ph.D., Takashi Inoue5, M.D., Ph.D.,
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Hiroki Tateno6, M.D., Ph.D., Fumio Sakamaki7, M.D., Ph.D., Koichi Sayama8, M.D.,
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Ph.D., Takeshi Terashima9, M.D., Ph.D., Hidefumi Koh10, M.D., Ph.D., Takayuki Abe11,
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Ph.D., Makoto Nishino1, M.D., Daisuke Arai2, M.D., Ph.D., Hiroyuki Yasuda1, M.D.,
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Ph.D., Ichiro Kawada1, M.D., Ph.D., Kenzo Soejima1, M.D., Ph.D., Tomoko
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Betsuyaku1, M.D., Ph.D. On behalf of the Keio Lung Oncology Group (KLOG)
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Medicine
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35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
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911-1 Takebayashimachi, Utsunomiya, Tochigi, 321-0974, Japan
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2-5-1 Higashigaoka, Meguro-ku, Tokyo, 152-8902, Japan
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Division of Pulmonary Medicine, Department of Medicine, Keio University School of
Pulmonary Division, Internal Medicine, Saiseikai Utsunomiya Hospital
National Hospital Organization Tokyo Medical Center
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1-4-17 Mita, Minato-ku, Tokyo, 108-0073, Japan
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1728 Horigomecho, Sano, Tochigi, 327-8511, Japan
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2460 Mimuro, Midori-ku, Saitama, 336-8522, Japan
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1838 Ishikawacho, Hachioji, Tokyo, 192-0032, Japan
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12-1 Shinkawadori, Kawasaki-ku, Kawasaki 210-0013, Japan
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5-11-13 Sugano, Ichikawashi, Chiba, 272-8513, Japan
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4-2-22 Nishikimachi, Tachikawa, 190-8531, Japan
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Medicine
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35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
Tokyo Saiseikai Central Hospital
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Sano Kousei General Hospital
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Tokyo Dental College Ichikawa General Hospital
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Department of Preventive Medicine and Public Health, Keio University School of
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35 Corresponding author:
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Ichiro Nakachi, M.D., Ph.D.
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Pulmonary division, Internal medicine, Saiseikai Utsunomiya Hospital, 911-1
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Takebayashimachi, Utsunomiya, Tochigi, 321-0974, Japan
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Telephone number: +81-28-626-5500
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Fax number: +81-28-626-5573
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E-mail address: [email protected]
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Abstract
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Objectives: Nivolumab, an immune checkpoint inhibitor, is now a standard treatment
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for previously treated advanced non-small cell lung cancer based on Phase III clinical
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trials. We aimed to evaluate the real-world efficacy and safety of nivolumab in a
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non-selective population and identify clinical characteristics that influence efficacy.
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Materials and methods: One hundred and forty-two patients with advanced non-small
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cell lung cancer who were administered nivolumab at Keio University and affiliated
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hospitals in Japan between January and July 2016 were enrolled. Treatment efficacy and
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adverse events were retrospectively reviewed and clinical characteristics associated with
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nivolumab responses were evaluated using univariate and stratified analyses and the
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Cochran-Mantel-Haenszel test.
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Results: The objective response rate (ORR) was 17.0% (95.0% confidence interval [CI],
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12.0−24.0), and the median progression-free survival (PFS) was 58 days (95% CI, 50-
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67), while the proportion of patients with adverse events (AEs) of any grade was 45.0%.
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EGFR/ALK mutation status was inversely associated with treatment response (P < 0.05),
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and the PFS for the mutation positive versus negative showed a significant difference
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(49 vs. 63 days; hazard ratio, 1.9; 95% CI, 1.1-5.2, P = 0.029). Prior radiotherapy also
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exhibited a positive association with treatment response (P = 0.012).
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Conclusion: The ORR, the PFS and the AE profiles were comparable to those observed
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in previous clinical trials. EGFR/ALK mutation-negative status and prior radiotherapy
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might be key clinical characteristics that are associated with a positive treatment
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response. Our findings may aid in the efficient immunotherapeutic management of lung
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cancer.
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Micro Abstract
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We evaluated the real-world efficacy and safety of nivolumab in 142 advanced
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non-small cell lung cancer patients in Japan, and identified clinical characteristics that
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influence the efficacy. Negative EGFR/ALK mutation status and prior radiotherapy were
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statistically associated with treatment response. These findings may aid in the efficient
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immunotherapeutic management of lung cancer.
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The efficacy and safety of nivolumab treatment for advanced non-small cell lung
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cancers are based on results from phase III clinical trials conducted in carefully selected
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patient populations.
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In this retrospective multicenter study recruiting 142 advanced non-small cell lung
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cancer patients, we evaluated the real-world efficacy and safety of nivolumab, and
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clinical characteristics associated with nivolumab responses.
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The objective response rate was 17.0%, and the median progression-free survival was 58 days, while the proportion of patients with adverse events of any grade was 45.0%.
EGFR/ALK mutation status was inversely associated with treatment response, and the
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PFS for the mutation positive versus negative showed a significant difference. Prior
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radiotherapy also exhibited a positive association with treatment response.
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characteristics that are associated with a positive treatment response.
These findings may aid in the efficient immunotherapeutic management of advanced non-small cell lungs cancer.
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1. Introduction Lung cancer is the leading cause of cancer-related deaths worldwide. The majority
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of advanced cancer patients relapse with chemotherapy-resistant disease after the
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administration of conventional cytotoxic agents. Today, immune checkpoint inhibitors
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have revolutionized cancer therapy and are recognized as a novel treatment option for
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patients with advanced cancers
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antagonist antibody to programmed cell death protein 1, is now approved as a standard
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treatment for patients with advanced non-small cell lung cancer (NSCLC) who have
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experienced disease progression during or after initial therapy with platinum-based
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doublet chemotherapy 3, 4.
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The efficacy and safety of nivolumab are based on results from clinical trials
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conducted in carefully selected patient populations. These clinical trials enrolled
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relatively young patients with a good Eastern Cooperative Oncology Group (ECOG)
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performance status (PS) and excluded patients with complicated comorbidities, such as
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interstitial pneumonia (IP), autoimmune disease, and symptomatic central nervous
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system (CNS) metastases. The real-world efficacy and safety of nivolumab in
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non-selective populations remain unclear. Herein, we conducted a retrospective
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multicenter analysis of 142 non-selective advanced NSCLC patients in Japan. We
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aimed to evaluate the real-world efficacy and safety of nivolumab in a non-selective
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population and identify clinical characteristics that influence efficacy.
2. Materials and methods
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2.1. Study population
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In total, 142 previously treated advanced NSCLC patients, who were administered
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nivolumab at Keio University and its 13 affiliated hospitals (the Keio Lung Oncology
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Group) between January and July 2016, were enrolled. Patients with a histological or
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cytological diagnosis of NSCLC, who experienced disease progression during or after
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initial treatment, were eligible for this study. In addition to patients with Stage IIIB−IV
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disease and postoperative recurrence, patients with Stage IIIA disease who met the
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following criteria were also included: (1) a diagnosis of non-resectable or progressive
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disease (PD) after initial chemotherapy and (2) concomitant radiotherapy. Data on the
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clinical characteristics, previous treatments, and outcomes were extracted from patients’
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medical records. Patients were treated intravenously with nivolumab at a dose of 3.0
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mg/kg of bodyweight every 2 weeks (a licensed dose and administration in Japan). The
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study was approved by the Ethical Review Board Committee of Keio University and its
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affiliated hospitals. This study was received ethical approval for the use of an opt out
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style. Research was conducted in accordance with the 1964 Declaration of Helsinki, as
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revised in 2013.
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2.2. Target lesion assessment
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The baseline sizes of the target lesions were measured in advance by imaging (e.g.,
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chest radiography, computed tomography, or magnetic resonance imaging). Clinical
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responses to nivolumab were evaluated using the same imaging modalities as well as
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the Response Evaluation Criteria in Solid Tumors (version 1.1) 5. Tumor responses to
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nivolumab were defined as follows: a complete response (CR; the disappearance of all
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target lesions), a partial response (PR; ≥30.0% reduction in the sum of the diameters of
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the target lesions), PD (≥20.0% increase in the sum of the diameters of the target
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lesions), and stable disease (SD; insufficient shrinkage or expansion to qualify as a PR
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or PD). In the absence of measurable disease, unequivocal progression was defined as
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that required to declare clinically PD as PD. The objective response rate (ORR) was
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defined as the proportion of patients who had achieved a CR or a PR, while the disease
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control rate was defined as the proportion of patients who had achieved a CR, a PR, or
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SD. Adverse events (AEs) related to nivolumab treatment were reported according to
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the Common Terminology Criteria for Adverse Events (version 4.0).
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2.3.
Clinical characteristics
The following clinical characteristics were included in our analyses: age, sex,
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ECOG PS, histological subtype, EGFR/ALK mutation status, the presence or absence of
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CNS metastases, smoking status, the number of previous lines of treatment, and the
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presence or absence of previous irradiation.
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2.4. Statistical analyses
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Statistical analyses using the Pearson’s chi-square test, Fisher’s exact test, and
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student’s t-test test were used to evaluate the clinical characteristics associated with the
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efficacy of nivolumab. A two-sided P < 0.05 was considered statistically significant for
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all tests. Variables selected from those exhibiting a significant association with P < 0.05
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were entered into the stratification analysis using the Cochran-Mantel-Haenszel test. All
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statistical analyses were conducted using JMP software (version 13; SAS Institute, Cary,
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NC, USA). Data were visualized using Easy R (Saitama Medical Center, Jichi Medical
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University, Saitama, Japan), which is a graphical user interface for R (The R
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Foundation for Statistical Computing, Vienna, Austria) 6.
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3.1. Clinical characteristics of the study population
In total, 142 patients with Stage IIIA−IV disease and postoperative recurrence were
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enrolled. The baseline clinical characteristics of the patients are summarized in Table 1.
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The median age was 67 (range, 34−85) years, with thirty-eight patients (26.8%) ≥75
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years of age. One hundred and six patients (74.6%) were men and 36 patients (25.4%)
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were women. The ECOG PS was 0 in 43 (30.3%), 1 in 76 (53.5%), 2 in 15 (10.6%), and
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3 in 8 (5.6%) patients, respectively. Histological subtypes included adenocarcinoma (n
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= 83 patients; 58.5%), squamous cell carcinoma (n = 41 patients; 28.9%), and other (n =
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18 patients; 12.7%). Sixteen patients (11.3%) had an EGFR mutation-positive status and
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3 patients (2.1%) had an ALK mutation-positive status. Twenty-seven patients (19.0%)
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had baseline CNS metastases. Seven patients were irradiated in their brains
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(Supplementary Table S2). One hundred and thirteen patients (79.6%) were current or
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ex-smokers and 29 patients (20.4%) were non-smokers. Fifty-seven patients (40.1%)
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were treated with second-line and 85 patients (59.9%) were treated with third-line (or
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higher) nivolumab. Forty-five patients (31.7%) had received prior radiotherapy. Our
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study included patients with the following complications: diabetes (n = 21; 14.8%),
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thyroid disease (n = 11; 7.7%), IP (n = 10; 7.0%), autoimmune disease (n = 3; 2.1%),
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and prior oral steroid treatment (≥10.0 mg prednisolone equivalent) (n = 2; 1.4%). As
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for autoimmune disease, two patients had rheumatoid arthritis (RA), and one had
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autoimmune hemolytic anemia. One of RA patients was administrated 5 mg of
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prednisolone a day.
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3.2. Objective clinical responses and progression-free survival
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Patients underwent radiographic evaluation 6.8 ± 2.5 (mean ± standard deviation)
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weeks after commencing treatment. The ORR was 17.0% (95.0% CI: 12.0−24.0%) with
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all PRs, and the disease control rate was 62.0% (95.0% CI: 54.0−70.0%) (Figure 1A).
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The median progression-free survival (PFS) was 58 days in all patients (95% CI, 50-
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67) (Figure 1B).
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3.3. Clinical characteristics and treatment responses
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Age, sex, ECOG PS, histological subtype, the presence or absence of CNS
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metastases, smoking status, and the number of previous lines of treatment were not
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statistically associated with a response to nivolumab (Table 2). Among the patients’
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baseline clinical characteristics listed in Table 1, EGFR/ALK mutation status and prior
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radiotherapy were significantly associated with responses to nivolumab (Fisher’s exact
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test; P < 0.05 and P = 0.012, respectively). With respect to gene mutation status, none of
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the 19 EGFR/ALK mutation-positive patients exhibited a PR (PD [n = 10 patients] and
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SD [n = 9 patients]). None of the target lesions in the EGFR/ALK mutation-positive
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patients exhibited sufficient tumor size reduction to qualify as a PR at initial response
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evaluation (Figure 2). Regarding radiotherapy, patients treated with prior radiotherapy
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were more likely to respond to nivolumab than those without. The median interval
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between radiotherapy and nivolumab treatment was 323.0 (interquartile range,
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199.5−764.0) days. The most frequently irradiated site was the thorax (n = 37 [82.2%]
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of 45 patients), 7 were irradiated for whole brain, and one was for oropharynx.
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Stratification analysis using the Cochran-Mantel-Haenszel test revealed that an
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EGFR/ALK mutation-negative status and prior radiotherapy were independently
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associated with a positive response to nivolumab treatment (odds ratio: not available [P
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< 0.05] and 0.31 [P < 0.01], respectively) (Supplementary Table S1). A significant
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difference was observed in the comparison of the PFS between EGFR/ALK mutation
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positive and negative status (49 versus 63 days; hazard ratio [HR], 1.9; 95% CI, 1.1-5.2;
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P = 0.029; Figure 3A). In the comparison between patients with and without prior
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radiation, a longer median PFS was observed in the former (82 versus 52 days,
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respectively), which, however, did not reach at significance (HR, 0.77; 95% CI,
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0.49-1.2; P = 0.25; Figure 3B).
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Although no significant difference was observed between current/ex-smokers and
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non-smokers (Pearson’s chi-square test; P > 0.05), a subgroup analysis revealed
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smoking status in pack-years (PYs) to be significantly higher in responders than
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non-responders (Student’s t-test; P < 0.05) (Supplementary Figure S1).
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3.4. Effect of nivolumab on central nervous system metastases
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In an analysis of 27 patients with CNS metastases, no significant difference in
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systemic response was observed between patients with and without CNS metastases (P
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> 0.05; Table 2). Additionally, none of the patients with systemic response to treatment
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(n = 5) exhibited any change in CNS metastases (Supplementary Table S2). While no
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positive intracranial responses to nivolumab treatment were observed, CNS lesions from
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14 patients (51.9%) were stable.
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3.5. Adverse events
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The AE profile observed in response to nivolumab treatment is shown in Table 3.
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Sixty-four patients (45.1%) experienced AEs of any grade in this study. AEs of any
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grade that were observed in ≥5.0% of patients included: anorexia (n = 21, 14.8%),
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hypothyroidism (n = 15, 10.6%), a rash (n = 10, 7.0%), and IP (n = 8, 5.6%; one patient
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had a history of IP). AEs of grade 3−4 occurred in 13.3% of patients. AEs of grade 3−4
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that were observed in 2.0−5.0% of patients included anorexia (n = 6, 4.2%) and IP (n =
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3, 2.1%). Two treatment-related deaths occurred, which were caused by acute
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exacerbation of IP and disseminated intravascular coagulation, respectively.
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4. Discussion
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In this retrospective multicenter study of advanced NSCLC patients (n = 142) we
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demonstrate the real-world efficacy and safety of nivolumab, a newly approved immune
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checkpoint inhibitor. We also identify clinical characteristics that are significantly
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associated with objective response. In the CheckMate 017 (squamous NSCLC)
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CheckMate 057 (non-squamous NSCLC)
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19.0%, and the median PFS was 3.5 and 2.3 months, respectively. Although our study
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population was heterogeneous and relatively small, the ORR (17.0%) was comparable
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to those observed in the CheckMate clinical trials. This suggests that we may be able to
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estimate the proportion of advanced NSCLC patients that will benefit practically from
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this novel immune checkpoint inhibitor.
3
4
and
clinical trials, the ORR was 20.0% and
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Among the clinical characteristics analyzed, an EGFR/ALK mutation-positive status
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was statistically associated with response to nivolumab treatment. Whether the efficacy
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of nivolumab is influenced by gene mutation status has been assessed in only a limited
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number of clinical studies. Gainor et al.
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advanced NSCLC patients treated with programmed cell death protein 1/programmed
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death-ligand 1 inhibitors that there was only one responder among 28 patients with an
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EGFR/ALK mutation-positive status. Lee et al.
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trials (CheckMate 057 3, Keynote 010 9, and POPLAR
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immune checkpoint inhibitors (nivolumab, pembrolizumab, and atezolizumab) in
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EGFR-mutated advanced NSCLC. The authors
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inhibitors may not improve overall survival compared with docetaxel in EGFR-mutated
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advanced NSCLC patients. Rizvi et al.
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checkpoint inhibitor efficacy from a genomic viewpoint and suggested that the higher
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mutation burden observed in NSCLC patients was a better prognostic factor for immune
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checkpoint inhibitors. Rozenblum et al. 12 revealed patients carrying driver oncogenes
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had lower mean mutation burden than those not carrying any treatment-associated
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drivers.
performed a meta-analysis of three 10
) to evaluate the role of
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concluded that immune checkpoint
elucidated potential mechanisms of immune
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Therefore, EGFR-mutated or ALK-positive NSCLC patients are less likely to
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respond to immune checkpoint inhibitors, because they are considered to harbor only a
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low mutation burden from genome-wide analysis by next-generation sequencing 13, 14.
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Our study indicated a positive association between prior radiotherapy and the
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efficacy of nivolumab. As an effective utility of immune checkpoint inhibitors, the
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potential benefit of combining immune checkpoint inhibitors with radiotherapy now
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becomes clinically evident
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radiotherapy 18-25. Shaverdian et al reported that previous treatment with radiotherapy in
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patients with advanced NSCLC resulted in longer PFS and overall survival with
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pembrolizumab treatment than that seen in patients who did not have previous
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radiotherapy26. Meanwhile, no significant difference in the PFS between the presence
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and absence of prior radiotherapy was observed in our nivolumab treatment study.
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Accordingly, further clinical trials investigating the combination of nivolumab and
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radiotherapy are needed to determine the optimal protocols for irradiation (dose, number
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of irradiation, sequential or simultaneous use with nivolumab and appropriate target
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lesions).
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. Tumor immunogenicity may be augmented by
It is also known that cigarette smoking positively correlates with a high
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27, 28
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genome-wide mutation burden in NSCLC
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study demonstrated that nivolumab was more effective in heavy smokers (56 ± 6.3 PYs)
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(mean ± standard deviation) compared to light or non-smokers (35 ± 2.9 PYs) (mean ±
289
standard deviation). The mechanisms under which heavy smokers benefit from
17
. Subsequent statistical analysis in our
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nivolumab treatment better than light or non-smokers may also be explained in the
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context of mutation burden described above. One of the unique characteristics of our study is that patients aged ≥75 years
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account for 26.8% of the study population, which is a higher proportion than in the
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CheckMate 017 4 (11.0%) or CheckMate 057 3 (7.0%) studies. In a comparison between
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patients aged ≥75 years and those aged <75 years, no statistically significant difference
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in ORR was observed (P > 0.05; Table 2). Furthermore, no difference in the efficacy of
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nivolumab was observed between patients with early (second) and late (third or higher)
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treatment lines (P > 0.05; Table 2). However, several previous studies 3, 29 indicated that
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an early line of treatment was associated with the efficacy of nivolumab. Meanwhile, no
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significant differences in the frequencies of AEs of any grade were observed between
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patients aged ≥75 years and those aged <75 (37.0% vs. 48.0%, respectively) or between
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patients with early and late treatment lines (44.0% vs. 46.0%, respectively). Taken
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together, these findings suggest that nivolumab may be effective and safe regardless of
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age or the number of previous lines of treatment.
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While no CNS metastases responded to nivolumab, even in patients exhibiting a
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systemic response, a large number of CNS lesions remained stable (n = 14 [51.9%] of
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27 lesions). Dudnik et al.
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reported the efficacy of nivolumab in 5 patients with
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advanced NSCLC and progressing CNS metastases (CR [n = 1], PR [n = 1], SD [n = 1],
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and PD [n = 2]). In the first prospective study evaluating the efficacy of pembrolizumab
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in NSCLC patients with brain metastases 31, the ORR in CNS metastases was 33.0% (n
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= 6 of 18 patients). The systemic ORR was also 33.0%. These findings are different
312
from ours and are encouraging for the future management of patients with metastatic
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NSCLC. However, it should be noted that the Johanns et al. 32 study was performed on a
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limited number of highly selected patients (n = 18). Therefore, the real-world efficacy of
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nivolumab for CNS metastases has not yet been elucidated and further studies are
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urgently required.
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frequently with nivolumab compared to conventional second-line treatment (e.g., with
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docetaxel). The proportion of patients in the present study with common AEs of grade
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3−4 or 5 were 13.3% and 1.4%, respectively, suggesting that nivolumab is safe for use
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in clinical trials.
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The major limitations of our retrospective study include the small sample size and
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relatively short follow-up period. Further accumulation of cases with longer follow-up
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periods, including overall survival data, or a mutation-positive status, CNS metastases,
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and available programmed death-ligand 1 immunohistochemistry data is necessary.
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However, we believe that the heterogeneous patient population in our study may well
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reflect the real-world efficacy and safety of nivolumab treatment.
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5. Conclusions
In our retrospective analysis of 142 non-selective patients with advanced NSCLC,
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we demonstrate the real-world efficacy and safety of nivolumab. EGFR/ALK mutation
332
status and prior radiotherapy are key clinical characteristics that are statistically
333
associated with the efficacy of nivolumab. Nivolumab may be more effective in patients
334
with an EGFR/ALK mutation-negative status or prior radiotherapy and be safe
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regardless of age or the number of previous lines of treatment. Our findings may aid in
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the efficient immunotherapeutic management of patients with advanced NSCLC.
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Acknowledgements
We wish to thank Kazumi Nishio (Kawasaki City Ida Hospital, Kanagawa, Japan),
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Fumitake Saito (Eiju General Hospital, Tokyo, Japan), Yusuke Suzuki (Kitasato Institute
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Hospital, Tokyo, Japan), and Akira Umeda (International Medical Welfare College
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Shioya Hospital, Tochigi, Japan) for assisting in data collection, and all members of the
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Keio Lung Oncology Group who participated in this study. This study was funded by
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Ono Pharmaceutical Co., Ltd. and Chugai Pharmaceutical Co., Ltd.
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344 Disclosure
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K Soejima has received honoraria from Chugai, Ono, Eli Lilly, AstraZeneca, Boehringer
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Ingelheim and Shionogi. The remaining authors declare that they have no competing interests.
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References
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1.
2.
353
Therapy: Clinical Efficacy and Safety. Curr Cancer Drug Targets 15 (2015) 452−62. 3.
354 355
Borghaei H, Paz-Ares L, Horn L, et al: Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med 373 (2015) 1627−39.
4.
356
Brahmer J, Reckamp KL, Baas P, et al: Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med 373 (2015) 123−35.
5.
Therasse P, Arbuck SG, Eisenhauer EA, et al: New guidelines to evaluate the
TE D
357
SC
352
Azoury SC, Straughan DM, Shukla V: Immune Checkpoint Inhibitors for Cancer
M AN U
351
FEBS Lett 588 (2014) 368−76.
RI PT
350
Kyi C, Postow MA: Checkpoint blocking antibodies in cancer immunotherapy.
response to treatment in solid tumors. European Organization for Research and
359
Treatment of Cancer, National Cancer Institute of the United States, National
360
Cancer Institute of Canada. J Natl Cancer Inst 92 (2000) 205−16. 6.
362 363
AC C
361
EP
358
Kanda Y: Investigation of the freely available easy-to-use software 'EZR' for medical statistics. Bone Marrow Transplant 48 (2013) 452−8.
7.
Gainor JF, Shaw AT, Sequist LV, et al: EGFR Mutations and ALK Rearrangements
364
Are Associated with Low Response Rates to PD-1 Pathway Blockade in Non-Small
365
Cell Lung Cancer: A Retrospective Analysis. Clin Cancer Res 22 (2016) 4585−93.
22
ACCEPTED MANUSCRIPT
8.
367 368
Lee CK, Man J, Lord S, et al: Checkpoint Inhibitors in Metastatic EGFR-Mutated Non-Small Cell Lung Cancer-A Meta-Analysis. J Thorac Oncol 12 (2017) 403−7.
9.
Herbst RS, Baas P, Kim DW, et al: Pembrolizumab versus docetaxel for previously
RI PT
366
treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a
370
randomised controlled trial. Lancet 387 (2016) 1540−50.
SC
369
10. Fehrenbacher L, Spira A, Ballinger M, et al: Atezolizumab versus docetaxel for
372
patients with previously treated non-small-cell lung cancer (POPLAR): a
373
multicentre, open-label, phase 2 randomised controlled trial. Lancet 387 (2016)
374
1837−46.
M AN U
371
11. Rizvi NA, Hellmann MD, Snyder A, et al: Cancer immunology. Mutational
376
landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer.
377
Science 348 (2015) 124−8.
379 380
EP
12. Rozenblum AB, Ilouze M, Dudnik E, et al: Clinical Impact of Hybrid
AC C
378
TE D
375
Capture-Based Next-Generation Sequencing on Changes in Treatment Decisions in
Lung Cancer. J Thorac Oncol. 12(2) (2017) 258-268
381
13. Spigel DR, Schrock AB, Fabrizio D, et al: Total mutation burden (TMB) in lung
382
cancer (LC) and relationship with response to PD-1/PD-L1 targeted therapies. J
383
Clin Oncol 34 (2016) (suppl; abstr 9017).
23
ACCEPTED MANUSCRIPT
14. Kazandjian D, Suzman DL, Blumenthal G, et al: FDA Approval Summary:
385
Nivolumab for the Treatment of Metastatic Non-Small Cell Lung Cancer With
386
Progression On or After Platinum-Based Chemotherapy. Oncologist 21 (2016)
387
634−42.
RI PT
384
15. Gerber DE, Urbanic JJ, Langer C, et al: Treatment Design and Rationale for a
389
Randomized Trial of Cisplatin and Etoposide Plus Thoracic Radiotherapy Followed
390
by Nivolumab or Placebo for Locally Advanced Non-Small-Cell Lung Cancer
391
(RTOG 3505). Clin Lung Cancer S1525−7304 (2016) 30352−7.
393
M AN U
16. Herter-Sprie GS, Koyama S, Korideck H. et al. Synergy of radiotherapy and PD-1 blockade in Kras-mutant lung cancer. JCI Insight. (2016) ; 1(9): e87415.
TE D
392
SC
388
17. Twyman-Saint Victor C, Rech AJ, Maity A. et al. Radiation and dual checkpoint
395
blockade activate non-redundant immune mechanisms in cancer. Nature. (2015)
396
520(7547): 373-7.
AC C
EP
394
397
18. Iyengar P, Kavanagh BD, Wardak Z, et al: Phase II trial of stereotactic body
398
radiation therapy combined with erlotinib for patients with limited but progressive
399 400 401
metastatic non-small-cell lung cancer. J Clin Oncol 32 (2014) 3824−30. 19. Formenti SC, Demaria S. Radiation therapy to convert the tumor into an in situ vaccine. Int J Radiat Oncol Biol Phys. (2012) 84(4):879-80.
24
ACCEPTED MANUSCRIPT
403 404
20. Demaria S, Golden EB, Formenti SC. et al. Role of Local Radiation Therapy in Cancer Immunotherapy. JAMA Oncol. (2015) 1(9):1325-32. 21. Reits EA, Hodge JW, Herberts CA. et al. Radiation modulates the peptide repertoire, enhances
MHC
class
I
expression,
and
induces
406
immunotherapy. J Exp Med. (2006) 203(5):1259-71.
successful
antitumor
SC
405
RI PT
402
22. Sharabi AB, Lim M, DeWeese TL. et al. Radiation and checkpoint blockade
408
immunotherapy: radiosensitisation and potential mechanisms of synergy. Lancet
409
Oncol. (2015) 16(13):e498-509.
M AN U
407
23. Sharabi AB, Nirschl CJ, Kochel CM. et al. Stereotactic Radiation Therapy
411
Augments Antigen-Specific PD-1-Mediated Antitumor Immune Responses via
412
Cross-Presentation of Tumor Antigen. Cancer Immunol Res. (2015) 3(4):345-55.
413
24. Gupta A, Probst HC, Vuong V. et al. Radiotherapy promotes tumor-specific effector
EP
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25. Liao YP, Wang CC, Butterfield LH. et al. Ionizing radiation affects human MART-1
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melanoma antigen processing and presentation by dendritic cells. J Immunol.
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(2004) 173(4):2462-9.
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26. Shaverdian N, Lisberg AE, Bornazyan K: Previous radiotherapy and the clinical
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activity and toxicity of pembrolizumab in the treatment of non-small-cell lung
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cancer: a secondary analysis of the KEYNOTE-001 phase 1 trial. Lancet Oncol
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(2017)18(7): 895-903.
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27. Gibbons DL, Byers LA, Kurie JM: Smoking, p53 mutation, and lung cancer. Mol
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Cancer Res 12 (2014) 3−13.
28. Gupta A, Srivastava S, Prasad R, et al: Smoking intensity, oxidative stress and
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chemotherapy in nonsmall cell lung cancer: a correlated prognostic study. Biosci
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Trends 3 (2009) 191−9.
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29. Rizvi NA, Mazières J, Planchard D, et al: Activity and safety of nivolumab, an
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anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory
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squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial.
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Lancet Oncol 16 (2015) 257−65.
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30. Dudnik E, Yust-Katz S, Nechushtan H, et al: Intracranial response to nivolumab in
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NSCLC patients with untreated or progressing CNS metastases. Lung Cancer 98
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(2016) 114−7.
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31. Goldberg SB, Gettinger SN, Mahajan A, et al: Pembrolizumab for patients with
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melanoma or non-small-cell lung cancer and untreated brain metastases: early
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analysis of a non-randomised, open-label, phase 2 trial. Lancet Oncol 17 (2016)
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32. Johanns T, Waqar SN, Morgensztern D: Immune checkpoint inhibition in patients with brain metastases. Ann Transl Med 4 (2016) S9. 33. Huang J, Zhang Y, Sheng J, et al: The efficacy and safety of
nivolumab in
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previously treated advanced non-small-cell lung cancer: a meta-analysis of
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prospective clinical trials. Onco Targets Ther 9 (2016) 5867−74.
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Figure legends
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Figure 1. The overall response and the progression free survival for all patients
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(A) Clinical responses to nivolumab. CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease.
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(B) Kaplan–Meier plot of progression-free survival (n = 142).
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Figure 2.
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Waterfall plot of the percentage change in target lesion size at initial response evaluation.
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EGFR/ALK mutation-positive patients (n = 19; 13.4%) are represented in black
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(asterisks denote EGFR mutation-positive patients [n = 16] and daggers denote ALK
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mutation-positive patients [n = 3]), EGFR/ALK mutation-negative patients (n = 94;
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66.2%) are represented in white, and patients with unknown genetic mutations are
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represented in gray (n = 22; 15.5%); 7 patients (4.9%) had no measurable lesions.
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Figure 3. Progression-free survival in EGFR/ALK mutation and prior radiation
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status
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(A) Kaplan-Meier plot for EGFR/ALK positive and negative patients. HR, hazard ratio;
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CI, confidence interval. Dotted line; EGFR/ALK positive, solid line; EGFR/ALK
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(B) Kaplan-Meier plot for the patients with prior radiation and non-prior radiation. HR,
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hazard ratio; CI, confidence interval. Dotted line; non-prior radiation group, solid
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line; prior radiation group
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Supplementary Figure S1.
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Subgroup analysis of the association between clinical responses to nivolumab and
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smoking status in pack-years in all 142 patients
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Table 1. Baseline characteristics, stratification factors, and prior therapy Characteristic Patients (n = 142) Age (years), n (%) median (range) 67 (34−85) ≥75 38 (26.8) Sex, n (%) M 106 (74.6) F 36 (25.4) Disease stage, n (%) IIIA 19 (13.3) IIIB 21 (14.8) IV 85 (59.9) Postoperative recurrence 17 (12.0) ECOG PS, n (%) 0 43 (30.3) 1 76 (53.5) 2 15 (10.6) 3 8 (5.6) 4 0 (0.0) Histology, n (%) ADC 83 (58.5) SCC 41 (28.9) NSCLC (NOS) 9 (6.3) LCNEC 4 (2.8) ASC 2 (1.4) PC 2 (1.4) LELC 1 (0.7) Genetic mutation, n (%) EGFR 16 (11.3) ALK 3 (2.1) None 98 (69.0) Unknown 25 (17.6) CNS metastasis, n (%) Y 27 (19.0) N 115 (81.0) Smoking status, n (%) Current or ex-smoker 113 (79.6) Non-smoker 29 (20.4) Treatment line, n (%) Second-line 57 (40.1) Third-line or higher 85 (59.9) Prior radiotherapy, n (%) Y N Diabetes, n (%) Y
45 (31.7) 97 (68.3) 21 (14.8)
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N Thyroid disease, n (%) Y N Interstitial pneumonia, n (%) Y N Autoimmune disease, n (%) Y N Prior oral steroid treatment, n (%) Y N
11 (7.7) 131 (92.3)
3 (2.1) 139 (97.9) 2 (1.4) 140 (98.6)
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ADC, adenocarcinoma; ASC, adenosquamous carcinoma; CNS, central nervous system; ECOG, Eastern Cooperative Oncology Group; F, female; LCNEC, large cell neuroendocrine carcinoma; LELC, lymphoepithelioma-like carcinoma; M, male; N, no; NOS, not otherwise specified; NSCLC, non-small cell lung cancer; PC, pleomorphic carcinoma; PS, performance status; SCC, squamous cell carcinoma; Y, yes
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1 (Ref.) 0.54 (0.15−1.60)
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1 (Ref.) 0.19 (0.02-1.48)
0.13
1 (Ref.) 2.65 (0.98-7.30)
0.055
13 (72.2)
3.16 (0.86-10.79)
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19 98
0 (0.0) 18 (18.4)
19 (100.0) 80 (81.6)
− Ν/Α
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27 115
2 (7.4) 22 (19.1)
25 (92.6) 93 (80.9)
1 (Ref.) 3.00 (0.80−19.0)
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22 (19.5) 2 (6.9)
91 (80.5) 27 (93.1)
1 (Ref.) 0.31 (0.05−1.13)
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9 (15.8) 15 (17.6)
48 (84.2) 70 (82.4)
1 (Ref.) 1.10 (0.47−2.90)
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13 (28.9) 11 (11.3)
32 (71.1) 86 (88.7)
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P -value
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OR (95.0% CI)
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Table 2. Relationship between patients’ clinical characteristics and treatment responses Characteristic Patients (n = 142) Responders, n Non-responders, n (%) Age (years) <75 104 17 (16.3) 87 (83.7) ≥75 38 7 (18.4) 31 (81.6) Sex M 106 20 (18.9) 86 (81.1) F 36 4 (11.1) 32 (88.9) ECOG PS 119 23 (19.3) 96 (80.7) 0−1 2--3 23 1 (4.3) 22 (95.7) Histology ADC 83 9 (10.8) 74 (89.2) SCC 41 10 (24.4) 31 (75.6)
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Constipation Diarrhea/colitis DIC Dysgeusia Encephalitis Hepatic dysfunction Hypacusis Hypoglycemia
6 (4.2)
0 (0.0)
5 (3.5) 4 (2.8) 1 (0.7) 1 (0.7) 1 (0.7) 6 (4.2) 1 (0.7) 1 (0.7)
0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 2 (1.4) 0 (0.0) 0 (0.0)
0 (0.0) 0 (0.0) 1 (0.7) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
15 (10.6)
1 (0.7)
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Table 3. Treatment-related adverse events Grade, n (%) Event Any 3--4 5 Adrenal insufficiency 1 (0.7) 0 (0.0) 0 (0.0) Anemia 4 (2.8) 0 (0.0) 0 (0.0)
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Highlights
Practical efficacy and safety in nivolumab treatment for lung cancer is revealed
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Nivolumab is effective in patients with prior radiotherapy
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Nivolumab may be less effective in patients with an EGFR/ALK mutation-positive
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ACCEPTED MANUSCRIPT Supplementary Table S1. Stratified analysis of clinical characteristics according to the Cochran-MantelCharacteristic OR (95.0% CI) P -valuea EGFR /ALK mutation status (positive vs. N/A 0.031* b negative) Prior radiotherapy (negative vs. positive) 0.31 (0.13−0.77) <0.01* *
P < 0.05 EGFR /ALK mutation status was stratified by the presence of prior radiotherapy (P = 0.031) and vice b No stable estimate was obtained for the OR as all EGFR /ALK mutation-positive patients were nonCI, confidence interval; N/A, not available; OR, odds ratio
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Supplementary Table S2. Systemic and intracranial responses in patients (n = 27) with central nervous system (CNS) metastases RT for Systemic CNS CNS # Sex Age (y) response response metastase s 1 M 66 PR SD − 2 M 50 PR SD − 3 F 74 PR SD − 4 M 75 PR SD − 5 F 70 PR SD − 6 M 59 SD SD − 7 M 66 SD SD − 8 M 76 SD SD + 9 M 66 SD SD + 10 M 74 SD SD − 11 M 61 SD PD + 12 M 63 PD SD + 13 M 51 PD SD − 14 M 75 PD SD − 15 M 68 PD SD − 16 F 45 PD SD + 17 M 73 PD PD − 18 M 50 PD PD − 19 M 62 PD PD − 20 F 48 PD PD − 21 M 56 PD PD − 22 F 62 PD PD + 23 M 64 PD PD − 24 M 64 PD PD − 25 M 48 PD PD − a F 68 PD NE + 26 M 85 PD NE − 27a Nivolumab treatment was discontinued before CNS metastatic lesions were evaluated F, female; M, male; NE, not evaluable; PD, progressive disease; PR, partial response; RT, radiotherapy; SD, stable disease; y, year