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Retrospective review of safety and efficacy of programmed cell death-1 inhibitors in refractory high grade gliomas

Retrospective review of safety and efficacy of programmed cell death-1 inhibitors in refractory... Background: Programmed cell death ligand-1 (PD-L1) expression has been reported in up to 61% of high grade gliomas (HGG). The purpose of this study was to describe safety and efficacy of PD-1 inhibition in patients with refractory HGGs. Methods: This Institutional Review Board approved single center retrospective study included adult patients with pathologically confirmed HGG who received a PD-1 inhibitor from 9/2014–10/2016 outside of a clinical trial at Memorial Sloan Kettering Cancer Center. Results: Twenty five HGG patients received pembrolizumab as part of a compassionate use program. Median age was 50 years (range 30–72); 44% were men; 13 had glioblastoma (52%), 7 anaplastic astrocytoma (28%), 2 anaplastic oligodendroglioma (8%), 2 unspecified HGG (8%), and 1 gliosarcoma (4%). Median prior lines of treatments were 4 (range 1–9). Nineteen (76%) previously failed bevacizumab. Median KPS was 80 (range 50–100). Concurrent treatment included bevacizumab in 17 (68%) or bevacizumab and temozolomide in 2 (8%) patients. Median number of doses administered was 3 (range 1–14). Outcomes were assessed in 24 patients. PD-1 inhibitor related adverse events included LFT elevations, hypothyroidism, diarrhea, myalgias/arthralgias, and rash. Best radiographic response was partial response (n =2), stable disease (n = 5), and progressive disease (n = 17). Median progression free survival (PFS) was 1.4 months (range 0.2–9.4) and median overall survival (OS) was 4 months (range 0.5–13.8). Three-month PFS was 12% and 6-month OS was 28%. Conclusion: While response rates are low, a few patients had a prolonged PFS. Pembrolizumab was tolerated with few serious toxicities, even in patients receiving concomitant therapy. Keywords: Glioblastoma, Immune checkpoint, High-grade glioma, PD-1, PD-L1, Pembrolizumab Background grade III and grade IV tumors is 39 and 30 weeks, respect- High grade malignant gliomas, including anaplastic ively [3]. Progression free survival at 26 weeks is 28% for oligodendrogliomas, anaplastic astrocytoma (grade III) and grade III tumors and 16% for grade IV tumors. Non- glioblastomas (grade IV), are the most common primary surgical treatment options for recurrent or progressive high malignant brain tumors diagnosed in adults [1]. Despite grade gliomas are limited. FDA approved treatment options advancements in understanding the underlying pathogen- for recurrent glioblastoma include an anti-vascular esis, overall survival remains limited with a median survival endothelial growth factor (VEGF) agent, bevacizumab, and for glioblastoma, the most aggressive high grade glioma low-intensity alternating electric fields (TTFields); neither (HGG), between 16 and 19 months [1]. Upfront therapy for treatment has been shown to significantly improve overall glioblastoma consists of maximal safe resection followed by survival [4–6]. Other treatment options include conven- radiation with concurrent temozolomide and adjuvant tem- tional chemotherapy such as temozolomide in different dos- ozolomide [2]. Median survival for patients with recurrent ing schedules, carboplatin, irinotecan, and nitrosoureas [7]. Checkpoint inhibitors have advanced treatment for metastatic melanoma, non-small cell lung cancer, renal * Correspondence: reisss@mskcc.org cell carcinoma, Non-Hodgkin Lymphoma and other ma- Department of Pharmacy, Memorial Sloan Kettering Cancer Center, 1275 lignancies [8, 9]. For patients diagnosed with non-small York Ave, New York, NY 10065, USA Full list of author information is available at the end of the article © The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Reiss et al. Journal for ImmunoTherapy of Cancer (2017) 5:99 Page 2 of 7 cell lung cancer, the level of programmed cell death and OS; patients were censored at the last follow up date if ligand-1 (PD-L1) expression has been associated with an event did not occur. improved outcomes to PD-1 inhibitors [8, 10, 11]. The presence of tumor infiltrating lymphocytes and PD-L1 Results expression has been reported in up to 61% of high grade Patient characteristics gliomas and therefore this checkpoint is a viable target for Twenty-nineneuro-oncologypatientsreceived a PD-1 treatment [12, 13]. PD-1 inhibitors block the interaction inhibitor between September 2014 and October 2016. Four between PD-L1 and its receptor thereby overcoming T-cell patients were excluded; 3 patients received previous inhibition and promoting an immune response against the checkpoint inhibitor therapy as part of a clinical trial and 1 tumor. Developing effective treatment options for patient did not have a high grade glioma. Baseline character- malignant high grade gliomas has proven difficult due to istics are described in Table 1. The median age was 49 years the inability of many medications to cross the blood brain (range: 30–72 years), 11 patients were male (44%), and the barrier. Data evaluating the penetration of checkpoint in- majority of patients were Caucasian (88%). All patients re- hibitors across the blood brain barrier is limited. However, ceived pembrolizumab as PD-1 inhibitor for treatment of the activity of immunotherapy for brain metastasis from HGG through a compassionate use program. Thirteen pa- melanoma and lung cancer has been reported and is tients had pathology confirmed glioblastoma (52%), 7 ana- promising [14]. Additionally, there have been case reports plasticastrocytoma(28%), 2anaplasticoligodendroglioma of prolonged response after checkpoint inhibitors in (8%), 2 unspecified HGG (8%), and 1 gliosarcoma (4%). Four patients with glioblastoma [15, 16]. Currently, there are an patients (16%) were MGMT methylated, 12 (48%) were abundance of clinical trials evaluating checkpoint inhibitors MGMT unmethylated and 9 (36%) were unknown. Ten pa- of patients with glioblastoma. Unfortunately, many patients tients (40%) had tumors that harbored an IDH1 mutation, 9 with high grade gliomas are excluded due to previous treat- (36%) were IDH1 wild type, and 6 (24%) were unknown. ments, performance status, or tumor histology [12, 17, 18]. Median mutational load was 7 with a range of 3–58 At our institution, many patients with high grade gliomas (Table 2). None of the patients were considered to have a that do not qualify for clinical trial receive off label check- hypermutator phenotype, defined as 100 or more mutations, point inhibitors. The purpose of this retrospective study is by MSK-Impact. Patients were heavily pretreated, receiving to describe efficacy and safety of PD-1 inhibitors in patients a median of 4 prior lines of therapy (range 1–9) and 19 pa- with refractory malignant high grade gliomas. tients (76%) previously progressed on bevacizumab treat- ment. Median KPS at initiation of pembrolizumab was 80 (range 50–100). Concurrent treatment with pembrolizumab Methods included bevacizumab in 17 (68%) or bevacizumab and tem- Study design ozolomide in 2 (8%) patients. Out of the 19 patients who This was an Institutional Review Board approved single- previously failed bevacizumab, 17 continued on bevacizu- center observational retrospective study performed at mab with pembrolizumab therapy. Of the six patients who Memorial Sloan Kettering Cancer Center evaluating did not previously receive bevacizumab therapy, two were patients with pathology confirmed high grade malignant started on bevacizumab in combination with pembrolizu- glioma who received a PD-1 inhibitor outside of a clinical mab. Median number of doses of pembrolizumab adminis- trial. Patients were identified through the pharmacy data- tered was 3 (range 1–14). Fourteen patients (56%) were on base and electronic medical records. Inclusion criteria dexamethasone during their first treatment dose and 19 pa- consisted of patients who were 18 years of age or older and tients (79%) received dexamethasone at some point during had received a PD-1 inhibitor between September 2014 and the course of treatment with pembrolizumab. Out of the October 2016. Patients were excluded if they received a 105 total doses of pembrolizumab administered, 34 doses PD-1 inhibitor as part of a clinical trial. (32%) were administered with concomitant dexamethasone for treatment of disease related neurologic symptoms. Endpoints and assessments The primary objective of this study was to describe overall Efficacy response rate (ORR) on contrast enhanced MRI. Secondary Treatment response and toxicity was evaluable in 24 patients. objectives included characterizing toxicities according to One patient was excluded from evaluation of response and the Common Terminology Criteria for Adverse Events toxicity because they transitioned to hospice less than one (CTCAE) version 4.03 as well as describing progression free week after their first and only dose of pembrolizumab; there- survival (PFS) and overall survival (OS). Frequencies and fore, imaging and toxicity data is not available. This patient percentages were used to describe categorical variables and was included in survival analysis. Best radiographic response medians and ranges were used to describe continuous vari- was partial response (n=2,8%),stabledisease (n = 5, 21%), ables. Kaplan-Meier methods were used to visualize PFS and progressive disease (n = 17, 71%) (Table 3). Both of the Reiss et al. Journal for ImmunoTherapy of Cancer (2017) 5:99 Page 3 of 7 Table 1 Baseline Characteristics greater than 200 days. One of these patients received beva- cizumab plus pembrolizumab after failing 9 prior treat- Characteristic All patients (n = 25) ments including bevacizumab containing regimens. The Age, year (range) 49 (30–72) other patient received pembrolizumab monotherapy after failing 2 prior lines of therapy. The first patient was on Gender: male, no. (%) 11 (44) dexamethasone only during their first dose of pembrolizu- Race mab. The second patient did not receive dexamethasone Caucasian, no. (%) 22 (88) during treatment with pembrolizumab. Of note, 7 of the 18 Asian, no. (%) 1 (4) patients without a clinical response did not require steroids Black, no. (%) 0 (0) at treatment initiation. The median mutation load was 6 in Latino/Hispanic, no. (%) 1 (4) patients with partial response and stable disease compared to 7 in those who did not respond. Median progression free Other, no. (%) 1 (4) survival (PFS) was 1.4 months (range 0.2–9.4) and median Diagnosis overall survival (OS) was 4 months (range 0.5–13.8) (Fig. 3). Glioblastoma, no. (%) 13 (52) Six month PFS was 12% and 6 month OS was 28%. Anaplastic astrocytoma, no. (%) 7 (28) Anaplastic oligodendroglioma, no. (%) 2 (8) Toxicity Unspecified high grade glioma, no. (%) 2 (8) All toxicities are listed in Table 4. The most common adverse events reported were fatigue (grade 3–4: 4%; grade 1–2: Gliosarcoma, no. (%) 1 (4) 75%), headache (grade 3–4: 4%; grade 1–2: 43%), nausea Performance status, KPS (range) 80 (50–100) (grade 3–4: 4%; grade 1–2: 37.5%), diarrhea (grade 3–4: 0%; Number of prior therapies, median (range) 4 (1–9) grade 1–2: 17%), seizures (grade 3–4: 4%; grade 1–2: 17%), Previously received bevacizumab, no. (%) 19 (76) vomiting (grade 3–4: 4%; grade 1–2: 17%), myalgias/arthral- MGMT status gia (grade 3–4: 0%; grade 1–2: 13%), and rash (grade 3–4: Methylated, no. (%) 4 (16) 0%; grade 1–2: 8%). The most common laboratory abnormal- ities recorded were hyperglycemia (grade 1–2: 79%), Unmethylated, no. (%) 12 (48) thrombocytopenia (grade 1–2: 50%), leukopenia (grade 1–2: Unknown, no. (%) 9 (36) 37.5%), ALT elevations (grade 1–2: 33%), AST elevations IDH1 Status (grade 1–2: 29%), bilirubin elevations (grade 1–2: 21%), neu- IDH1 Mutated, no. (%) 10 (40) tropenia (grade 1–2: 21%), and hypothyroidism (grade 1–2: IDH1 Wild Type, no. (%) 9 (36) 17%). Additionally, 74% of patients (n = 14) who experienced Unknown, no. (%) 6 (24) hyperglycemia were receiving dexamethasone. One patient with a history of epilepsy was admitted for a grade 3 seizure. Number of mutations by MSK-Impact, median (range) 7 (3–58) The second patient who experienced grade 3 adverse events, PD-1 inhibitor specifically nausea, vomiting, and headache, was admitted for Pembrolizumab, no. (%) 25 (100) symptoms of increased intracranial pressure due to pathology Number of doses administered, median (range) 3 (1–14) confirmed recurrent glioblastoma. Lastly, one patient experi- Concomitant therapy enced grade 4 cerebral edema requiring emergent surgery Pembrolizumab monotherapy, no. (%) 6 (24) 7 days after their first and only dose of pembrolizumab. Path- ology confirmed edema was due to rapid tumor progression. Bevacizumab, no. (%) 17 (68) No patients discontinued pembrolizumab due to toxicity. Cytotoxic chemotherapy + bevacizumab, no. (%) 2 (8) Receiving dexamethasone at time of first dose, no. (%) 14 (56%) Discussion Our study demonstrated that heavily pretreated patients patients with a partial response received concomitant bevaci- with malignant high grade gliomas have low response rates zumab, and one patient was bevacizumab-naïve. These two to pembrolizumab. To our knowledge, this is the first study patients received pembrolizumab plus bevacizumab in the to investigate PD-1 inhibitioningrade IIIgliomas.Garber second and third line setting for treatment of glioblastoma and colleagues found that PD-L1 expression was only and anaplastic astrocytoma, respectively. Both patients re- present on grade IV gliomas, where as it was not present in ceived dexamethasone for management of disease related the 33 anaplastic astrocytomas or 9 oligodendrogliomas. symptoms, one at initiation of pembrolizumab treatment. [19] There is no current data correlating PD-L1 expression Duration of therapy, best radiographic response, previous and clinical outcomes outside of pembrolizumab use in bevacizumab, and concomitant bevacizumab can be visual- non-small cell lung cancer. In our grade III glioma cohort, ized in Figs. 1 and 2. Two patients had stable disease 1 patient had a partial response to pembrolizumab and 2 Reiss et al. Journal for ImmunoTherapy of Cancer (2017) 5:99 Page 4 of 7 Table 2 Patient Characteristics, Response and Steroid Dose Pt Grade OR KPS # of cycles MGMT Status IDH 1p/ ML Steroids at Steroid dose at initiation # of cycles Con Prev # of pembro Status 19q initiation (in prednisone equivalence) with steroids Bev Bev 0 <20 ≥20 1 III PR 90 4 unmethylated WT N/A 6 N X 2 Y Y 2 IV PR 80 4 unmethylated N/A N/A 6 Y X 1 Y N 3 III SD 90 14 methylated WT intact 6 N X 0 N N 4 III SD 70 10 unmethylated MUT N/A 3 Y X 1 Y Y 5 IV SD 90 14 unmethylated WT N/A 12 N X 5 Y Y 6 IV SD 100 4 methylated N/A N/A 13 N X 0 N Y 7 IV SD 100 1 N/A WT N/A N/A Y X 1 Y Y 8 III PD 90 6 N/A MUT co-del 5 Y X 1 N N 9 III PD 60 5 N/A MUT co-del 58 Y X 0 Y Y 10 III PD 60 3 unmethylated MUT N/A 7 N X 2 N N 11 III PD 70 3 unmethylated WT N/A 5 Y X 3 Y Y 12 III PD 90 2 unmethylated WT intact 15 Y X 2 Y N 13 III PD 90 2 unmethylated MUT N/A 7 Y X 2 Y Y 14 III PD N/A 1 methylated MUT N/A 5 N X 0 N Y 15 IV PD 90 5 methylated MUT N/A 11 Y X 2 N N 16 IV PD 60 5 unmethylated WT intact 10 Y X 2 Y Y 17 IV PD 50 4 N/A N/A N/A N/A N X 0 Y Y 18 IV PD 90 3 N/A MUT N/A 9 Y X 3 Y Y 19 IV PD 90 3 unmethylated N/A N/A 4 Y X 1 Y Y 20 IV PD 90 3 N/A N/A N/A N/A N X 1 Y Y 21 IV PD 70 2 unmethylated WT N/A 13 Y X 2 Y Y 22 IV PD 80 2 unmethylated MUT N/A 5 N X 0 Y Y 23 IV PD 80 2 N/A WT N/A N/A N X 1 Y Y 24 N/A PD 70 2 N/A N/A N/A N/A N X 1 Y Y 25 IV N/A 60 1 N/A MUT intact 19 Y X 1 Y Y Abbreviations: Pt: Patient; OR: Objective response; CR: Complete response; PR: Partial response; SD: Stable disease; PD: Progressive disease; KPS: Karnofsky performance score; Pembro: pembrolizumab; N/A: not applicable or unknown; MGMT methylated: methylated; MGMT unmethylated: unmethylated; IDH mutant: MUT; IDH wild type: WT; 1p19q intact: intact; 1p19q codeleted: Co-del; ML: mutational load by MSK impact; Y: yes; N: no; X: indicates steroid dose at initiation; Con Bev: Concomitant bevacizumab; Prev Bev: previously progressed on bevacizumab treatment patients had prolonged progression free survival with having PD-L1 expression ≥1%, bevacizumab naïve, and pembrolizumab. unable to receive standard treatment. Median PFS and OS Pembrolizumab monotherapy for recurrent glioblast- were reported as 2.8 months and 14.4 months, respect- oma was studied in the KEYNOTE-028 trial. [20] Patients ively. CheckMate-143 compared nivolumab monotherapy were included if they were diagnosed with glioblastoma to bevacizumab monotherapy in glioblastoma in patients with first recurrence. Median OS was 9.8 months with Table 3 Clinical Response nivolumab and 10 months with bevacizumab, PFS was Characteristic All evaluable 1.5 months with nivolumab and 3.5 months with bevaci- patients (n = 24) zumab, demonstrating no improvement in overall survival. Best radiographic response [21] We observed a shorter PFS and OS most likely be- Complete response (CR), no. (%) 0 (0) cause patients that failed bevacizumab were also included. Partial response (PR), no. (%) 2 (8) Pembrolizumab was well tolerated in our cohort; toxicities were similar compared to those reported with other malig- Stable disease (SD), no. (%) 5 (21) nancies. [8, 9] Very few serious adverse events occurred dur- Progressive disease (PD), no. (%) 17 (71) ing treatment. Serious adverse events, cerebral edema, Median PFS, days (range) 42 (7–282) seizures and headaches could be related to disease progres- Median OS, days (range) 121 (15–415) sion or checkpoint inhibition. Reiss et al. Journal for ImmunoTherapy of Cancer (2017) 5:99 Page 5 of 7 Fig. 1 Best Radiographic Response in Grade III Glioma Patients. BEV = bevacizumab. The X axis represents the number of doses of pembrolizumab that was received. The color represents the best radiographic response each patient had. 3 patients continue on Fig. 3 Overall Survival and Progression Free Survival. Median pembrolizumab at the end of data collection. 6 patients previously progression free survival (PFS) was 1.4 months (range 0.2–9.4) and progressed on bevacizumab; of those patients 5 continued bevacizumab median overall survival (OS) was 4 months (range 0.5–13.8). Six with pembrolizumab. 4 patients never received bevacizumab, of those 1 month PFS was 12% and 6 month OS was 28%. Two patients had started on bevacizumab with pembrolziumab. One patient had a partial stable disease greater than 200 days response; 2 had stable disease; and the rest had progressive disease Our study had several limitations. Firstly, it was a retrospect- ive study with a small sample size. Second, many patients re- ceived pembrolizumab in combination with other treatment modalities such as bevacizumab, making it difficult to evaluate the effectiveness of pembrolizumab monotherapy in high Table 4 Adverse events - incidence and grading according to grade glioma patients. Additionally, we included patients with CTCAE v 4.03 both WHO grade III and IV gliomas, making it difficult to Toxicity Overall incidence, Grade 1 and Grade 3 and compare these results to published data that includes only no. (%) 2, no. (%) 4, no. (%) glioblastoma patients. Many of our patients were excluded Hyperglycemia 19 (79) 19 (79) Fatigue 19 (79) 18 (75) 1 (4) Thrombocytopenia 12 (50) 12 (50) Headache 11 (46) 10 (43) 1 (4) Nausea 10 (42) 9 (38) 1 (4) Leukopenia 9 (38) 9 (38) ALT elevations 8 (33) 8 (33) AST elevations 7 (29) 7 (29) Bilirubin elevations 5 (21) 5 (21) Neutropenia 5 (21) 5 (21) Anemia 5 (21) 4 (17) 1 (4) Seizures 5 (21) 4 (17) 1 (4) Vomiting 5 (21) 4 (17) 1 (4) Thyroid toxicity 4 (17) 4 (17) Fig. 2 Best Radiographic Response in Grade IV Glioma Patients. BEV Diarrhea 4 (17) 4 (17) = bevacizumab. The X axis represents the number of doses of pembrolizumab that was received by each patient. The color Myalgias/Arthralgias 3 (13) 3 (13) represents the best radiographic response each patient had. One Rash 2 (8) 2 (8) patient continue on pembrolizumab at the end of data collection. Pyrexia 2 (8) 2 (8) Eleven patients previously progressed on bevacizumab; of those patients 10 continued bevacizumab with pembrolizumab. 2 patients Lipase 1 (4) 1 (4) never received bevacizumab and, of those, one started on Amylase 1 (4) 1 (4) bevacizumab with pembrolziumab. One patient had a partial response; 3 had stable disease; and the rest had progressive disease Mucositis 1 (4) 1 (4) Reiss et al. Journal for ImmunoTherapy of Cancer (2017) 5:99 Page 6 of 7 from participation in clinical trials for checkpoint inhibitors Ethics approval and consent to participate This study was approved by the Memorial Sloan Kettering Cancer Center due to their WHO grade, previoustreatment with bevacizu- Institutional Review Board and consent was waived due to the retrospective mab, and poor KPS. This patient population differs from pre- nature of this study. viously reported clinical observations using checkpoint Consent for publication inhibitors as it includes grade III and IV gliomas. The observed N/A response rate and survival data might be biased due to the poor prognostics factors in our population (heavily pretreated, Competing interests bevacizumab-resistance, low KPS performance status). How- The authors declare that they have no competing interests. ever, these patients are frequently encountered in the clinical setting with little literature to guide treatment decisions. Publisher’sNote We also did not account for baseline abnormalities and Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. due to the retrospective nature of this study were unable to differentiate between treatment related toxicity and disease Author details related adverse events. Lastly, we did not assess PD-L1 Department of Pharmacy, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10065, USA. Department of Neurology, Memorial expression to correlate clinical response to PD-L1 status. Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10065, USA. Pembrolizumab requires further studies to confirm a benefit for patients with refractory high grade glioma as monother- Received: 24 July 2017 Accepted: 8 November 2017 apy or in combination with chemotherapy or bevacizumab. References 1. Wen PY, Kesari S. Malignant gliomas in adults. N Engl J Med. 2008;359:492– Conclusions Patients with pathology confirmed refractory high grade gli- 2. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, omas have low response rates to pembrolizumab. However, Belanger K, Brandes AA, Marosi C, Bogdahn U, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. a small number of patients have a prolonged progression free 2005;352:987–96. survival. Pembrolizumab was tolerated with few serious ad- 3. Lamborn KR, Yung WK, Chang SM, Wen PY, Cloughesy TF, DeAngelis LM, verse events, even in patients receiving concomitant therapy. Robins HI, Lieberman FS, Fine HA, Fink KL, et al. Progression-free survival: an important end point in evaluating therapy for recurrent high-grade gliomas. Pembrolizumab requires further study to confirm a benefit Neuro-Oncology. 2008;10:162–70. for patients with refractory high grade glioma as monother- 4. Stupp R, Wong ET, Kanner AA, Steinberg D, Engelhard H, Heidecke V, Kirson apy or in combination with chemotherapy or bevacizumab. ED, Taillibert S, Liebermann F, Dbaly V, et al. NovoTTF-100A versus physician's choice chemotherapy in recurrent glioblastoma: a randomised phase III trial of a novel treatment modality. Eur J Cancer. 2012;48:2192–202. Abbreviations 5. Friedman HS, Prados MD, Wen PY, Mikkelsen T, Schiff D, Abrey LE, Yung WK, Bev: Bevacizumab; co-del: 1p19q codeleted; Con Bev: Concomitant bevacizumab; Paleologos N, Nicholas MK, Jensen R, et al. Bevacizumab alone and in CR: Complete response; CTCAE: Common Terminology Criteria for Adverse Events; combination with irinotecan in recurrent glioblastoma. J Clin Oncol. 2009; HGG: high grade gliomas; intact: 1p19q intact; KPS: Karnofsky performance score; 27:4733–40. methylated:MGMTmethylated; ML:mutationalloadbyMSK impact;MUT:IDH 6. AVASTIN (bevacizumab) [package insert]. Genentech, Inc, San Francisco, CA; mutant; N: no; N/A: not applicable or unknown; OR: Objective response; 2016. [https://www.gene.com/download/pdf/avastin_prescribing.pdf]. ORR: Overall response rate; OS: Overall survival; PD: progressive disease; PD- 7. Chamberlain MC. Salvage therapy with lomustine for temozolomide 1: Programmed cell death protein-1; PD-L1: Programmed cell death ligand-1; refractory recurrent anaplastic astrocytoma: a retrospective study. J Neuro- Pembro: pembrolizumab; PFS: Progression free survival; PR: Partial response; Prev Oncol. 2015;122:329–38. Bev: previously progressed on bevacizumab treatment; Pt: Patient; SD: stable 8. KEYTRUDA (pembrolizumab) [package insert]. Merck & Co., Inc. Whitehouse disease; unmethylated: MGMT unmethylated; VEGF: vascular endothelial growth Station, NJ; 2016. [http://www.merck.com/product/usa/pi_circulars/k/ factor; WT: IDH wild type; Y: yes keytruda/keytruda_pi.pdf]. 9. OPDIVO (nivolumab) [package insert]. Bristol-Myers Squibb Company, Princeton, NJ; 2017. [http://packageinserts.bms.com/pi/pi_opdivo.pdf]. Acknowledgements 10. Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried not applicable. M, Peled N, Tafreshi A, Cuffe S, et al. Pembrolizumab versus chemotherapy for PD-L1–positive non–small-cell lung cancer. N Engl J Med. 2016;375: Funding 1823–33. This study was funded by Memorial Sloan Kettering Cancer Center Support/ 11. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Core Grant (P30 CA008748). Powderly JD, Carvajal RD, Sosman JA, Atkins MB, et al. Safety, activity, and immune correlates of anti–PD-1 antibody in cancer. N Engl J Med. 2012;366: 2443–54. Availability of data and materials 12. Berghoff AS, Kiesel B, Widhalm G, Rajky O, Ricken G, Wohrer A, Dieckmann N/A K, Filipits M, Brandstetter A, Weller M, et al. Programmed death ligand 1 expression and tumor-infiltrating lymphocytes in glioblastoma. Neuro- Authors’ contributions Oncology. 2015;17:1064–75. SNR participated in conceiving the study, obtaining data, interpreting the 13. Nduom EK, Wei J, Yaghi NK, Huang N, Kong LY, Gabrusiewicz K, Ling X, results, and writing the manuscript; PY participated in obtaining data and Zhou S, Ivan C, Chen JQ, et al. PD-L1 expression and prognostic impact in reviewing the manuscript; LM participated in obtaining data and reviewing glioblastoma. Neuro-Oncology. 2016;18:195–205. the manuscript; CG participated in conceiving the study, performing 14. Goldberg SB, Gettinger SN, Mahajan A, Chiang AC, Herbst RS, Sznol M, statistical analysis, interpreting the results, and writing the manuscript. All Tsiouris AJ, Cohen J, Vortmeyer A, Jilaveanu L, et al. Pembrolizumab for authors have read and approved the final manuscript. patients with melanoma or non-small-cell lung cancer and untreated brain Reiss et al. Journal for ImmunoTherapy of Cancer (2017) 5:99 Page 7 of 7 metastases: early analysis of a non-randomised, open-label, phase 2 trial. Lancet Oncol. 2016;17:976–83. 15. Roth P, Valavanis A, Weller M. Long-term control and partial remission after initial pseudoprogression of glioblastoma by anti-PD-1 treatment with nivolumab. Neuro-Oncology. 2016; 16. Bouffet E, Larouche V, Campbell BB, Merico D, de Borja R, Aronson M, Durno C, Krueger J, Cabric V, Ramaswamy V, et al. Immune checkpoint inhibition for Hypermutant glioblastoma Multiforme resulting from germline Biallelic mismatch repair deficiency. J Clin Oncol. 2016;34:2206–11. 17. Reardon DA, DeGroot JF, Colman H, Jordan JT, Daras M, Clarke JL, Nghiemphu PL, Gaffey SC, Peters KB. Safety of pembrolizumab in combination with bevacizumab in recurrent glioblastoma (rGBM). J Clin Oncol. 2016;34 18. Ampie L, Woolf EC, Dardis C. Immunotherapeutic advancements for glioblastoma. Front Oncol. 2015;5:12. 19. Garber ST, Hashimoto Y, Weathers SP, Xiu J, Gatalica Z, Verhaak RG, Zhou S, Fuller GN, Khasraw M, de Groot J, et al. Immune checkpoint blockade as a potential therapeutic target: surveying CNS malignancies. Neuro-Oncology. 2016;18:1357–66. 20. TM RDAK, Frenel JS, Santoro A, et al. ATIM-35. Results of the Phase IB KEYNOTE-028 Multi-Cohort Trial of Pembrolizumab Monotherapy in Patietns with Recurrent PD-L1 Positive Glioblastoma Multiforme (GBM). Neuro Oncol. 2016;18:vi25–6. 21. Reardon DA, Omuro A, Brandes AA, et al. Randomized phase 3 study evaluating the efficacy and safety of Nivolumab vs bevacizumab in patients with recurrent glioblastoma: CheckMate 143. Neuro-Oncology. 2017;19:iii21. https://academic.oup.com/neuro-oncology/article/19/suppl_3/iii21/3743874#. Submit your next manuscript to BioMed Central and we will help you at every step: • We accept pre-submission inquiries � Our selector tool helps you to find the most relevant journal � We provide round the clock customer support � Convenient online submission � Thorough peer review � Inclusion in PubMed and all major indexing services � Maximum visibility for your research Submit your manuscript at www.biomedcentral.com/submit http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal for ImmunoTherapy of Cancer Springer Journals

Retrospective review of safety and efficacy of programmed cell death-1 inhibitors in refractory high grade gliomas

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Springer Journals
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Copyright © 2017 by The Author(s).
Subject
Medicine & Public Health; Oncology; Immunology
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2051-1426
DOI
10.1186/s40425-017-0302-x
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29254497
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Abstract

Background: Programmed cell death ligand-1 (PD-L1) expression has been reported in up to 61% of high grade gliomas (HGG). The purpose of this study was to describe safety and efficacy of PD-1 inhibition in patients with refractory HGGs. Methods: This Institutional Review Board approved single center retrospective study included adult patients with pathologically confirmed HGG who received a PD-1 inhibitor from 9/2014–10/2016 outside of a clinical trial at Memorial Sloan Kettering Cancer Center. Results: Twenty five HGG patients received pembrolizumab as part of a compassionate use program. Median age was 50 years (range 30–72); 44% were men; 13 had glioblastoma (52%), 7 anaplastic astrocytoma (28%), 2 anaplastic oligodendroglioma (8%), 2 unspecified HGG (8%), and 1 gliosarcoma (4%). Median prior lines of treatments were 4 (range 1–9). Nineteen (76%) previously failed bevacizumab. Median KPS was 80 (range 50–100). Concurrent treatment included bevacizumab in 17 (68%) or bevacizumab and temozolomide in 2 (8%) patients. Median number of doses administered was 3 (range 1–14). Outcomes were assessed in 24 patients. PD-1 inhibitor related adverse events included LFT elevations, hypothyroidism, diarrhea, myalgias/arthralgias, and rash. Best radiographic response was partial response (n =2), stable disease (n = 5), and progressive disease (n = 17). Median progression free survival (PFS) was 1.4 months (range 0.2–9.4) and median overall survival (OS) was 4 months (range 0.5–13.8). Three-month PFS was 12% and 6-month OS was 28%. Conclusion: While response rates are low, a few patients had a prolonged PFS. Pembrolizumab was tolerated with few serious toxicities, even in patients receiving concomitant therapy. Keywords: Glioblastoma, Immune checkpoint, High-grade glioma, PD-1, PD-L1, Pembrolizumab Background grade III and grade IV tumors is 39 and 30 weeks, respect- High grade malignant gliomas, including anaplastic ively [3]. Progression free survival at 26 weeks is 28% for oligodendrogliomas, anaplastic astrocytoma (grade III) and grade III tumors and 16% for grade IV tumors. Non- glioblastomas (grade IV), are the most common primary surgical treatment options for recurrent or progressive high malignant brain tumors diagnosed in adults [1]. Despite grade gliomas are limited. FDA approved treatment options advancements in understanding the underlying pathogen- for recurrent glioblastoma include an anti-vascular esis, overall survival remains limited with a median survival endothelial growth factor (VEGF) agent, bevacizumab, and for glioblastoma, the most aggressive high grade glioma low-intensity alternating electric fields (TTFields); neither (HGG), between 16 and 19 months [1]. Upfront therapy for treatment has been shown to significantly improve overall glioblastoma consists of maximal safe resection followed by survival [4–6]. Other treatment options include conven- radiation with concurrent temozolomide and adjuvant tem- tional chemotherapy such as temozolomide in different dos- ozolomide [2]. Median survival for patients with recurrent ing schedules, carboplatin, irinotecan, and nitrosoureas [7]. Checkpoint inhibitors have advanced treatment for metastatic melanoma, non-small cell lung cancer, renal * Correspondence: reisss@mskcc.org cell carcinoma, Non-Hodgkin Lymphoma and other ma- Department of Pharmacy, Memorial Sloan Kettering Cancer Center, 1275 lignancies [8, 9]. For patients diagnosed with non-small York Ave, New York, NY 10065, USA Full list of author information is available at the end of the article © The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Reiss et al. Journal for ImmunoTherapy of Cancer (2017) 5:99 Page 2 of 7 cell lung cancer, the level of programmed cell death and OS; patients were censored at the last follow up date if ligand-1 (PD-L1) expression has been associated with an event did not occur. improved outcomes to PD-1 inhibitors [8, 10, 11]. The presence of tumor infiltrating lymphocytes and PD-L1 Results expression has been reported in up to 61% of high grade Patient characteristics gliomas and therefore this checkpoint is a viable target for Twenty-nineneuro-oncologypatientsreceived a PD-1 treatment [12, 13]. PD-1 inhibitors block the interaction inhibitor between September 2014 and October 2016. Four between PD-L1 and its receptor thereby overcoming T-cell patients were excluded; 3 patients received previous inhibition and promoting an immune response against the checkpoint inhibitor therapy as part of a clinical trial and 1 tumor. Developing effective treatment options for patient did not have a high grade glioma. Baseline character- malignant high grade gliomas has proven difficult due to istics are described in Table 1. The median age was 49 years the inability of many medications to cross the blood brain (range: 30–72 years), 11 patients were male (44%), and the barrier. Data evaluating the penetration of checkpoint in- majority of patients were Caucasian (88%). All patients re- hibitors across the blood brain barrier is limited. However, ceived pembrolizumab as PD-1 inhibitor for treatment of the activity of immunotherapy for brain metastasis from HGG through a compassionate use program. Thirteen pa- melanoma and lung cancer has been reported and is tients had pathology confirmed glioblastoma (52%), 7 ana- promising [14]. Additionally, there have been case reports plasticastrocytoma(28%), 2anaplasticoligodendroglioma of prolonged response after checkpoint inhibitors in (8%), 2 unspecified HGG (8%), and 1 gliosarcoma (4%). Four patients with glioblastoma [15, 16]. Currently, there are an patients (16%) were MGMT methylated, 12 (48%) were abundance of clinical trials evaluating checkpoint inhibitors MGMT unmethylated and 9 (36%) were unknown. Ten pa- of patients with glioblastoma. Unfortunately, many patients tients (40%) had tumors that harbored an IDH1 mutation, 9 with high grade gliomas are excluded due to previous treat- (36%) were IDH1 wild type, and 6 (24%) were unknown. ments, performance status, or tumor histology [12, 17, 18]. Median mutational load was 7 with a range of 3–58 At our institution, many patients with high grade gliomas (Table 2). None of the patients were considered to have a that do not qualify for clinical trial receive off label check- hypermutator phenotype, defined as 100 or more mutations, point inhibitors. The purpose of this retrospective study is by MSK-Impact. Patients were heavily pretreated, receiving to describe efficacy and safety of PD-1 inhibitors in patients a median of 4 prior lines of therapy (range 1–9) and 19 pa- with refractory malignant high grade gliomas. tients (76%) previously progressed on bevacizumab treat- ment. Median KPS at initiation of pembrolizumab was 80 (range 50–100). Concurrent treatment with pembrolizumab Methods included bevacizumab in 17 (68%) or bevacizumab and tem- Study design ozolomide in 2 (8%) patients. Out of the 19 patients who This was an Institutional Review Board approved single- previously failed bevacizumab, 17 continued on bevacizu- center observational retrospective study performed at mab with pembrolizumab therapy. Of the six patients who Memorial Sloan Kettering Cancer Center evaluating did not previously receive bevacizumab therapy, two were patients with pathology confirmed high grade malignant started on bevacizumab in combination with pembrolizu- glioma who received a PD-1 inhibitor outside of a clinical mab. Median number of doses of pembrolizumab adminis- trial. Patients were identified through the pharmacy data- tered was 3 (range 1–14). Fourteen patients (56%) were on base and electronic medical records. Inclusion criteria dexamethasone during their first treatment dose and 19 pa- consisted of patients who were 18 years of age or older and tients (79%) received dexamethasone at some point during had received a PD-1 inhibitor between September 2014 and the course of treatment with pembrolizumab. Out of the October 2016. Patients were excluded if they received a 105 total doses of pembrolizumab administered, 34 doses PD-1 inhibitor as part of a clinical trial. (32%) were administered with concomitant dexamethasone for treatment of disease related neurologic symptoms. Endpoints and assessments The primary objective of this study was to describe overall Efficacy response rate (ORR) on contrast enhanced MRI. Secondary Treatment response and toxicity was evaluable in 24 patients. objectives included characterizing toxicities according to One patient was excluded from evaluation of response and the Common Terminology Criteria for Adverse Events toxicity because they transitioned to hospice less than one (CTCAE) version 4.03 as well as describing progression free week after their first and only dose of pembrolizumab; there- survival (PFS) and overall survival (OS). Frequencies and fore, imaging and toxicity data is not available. This patient percentages were used to describe categorical variables and was included in survival analysis. Best radiographic response medians and ranges were used to describe continuous vari- was partial response (n=2,8%),stabledisease (n = 5, 21%), ables. Kaplan-Meier methods were used to visualize PFS and progressive disease (n = 17, 71%) (Table 3). Both of the Reiss et al. Journal for ImmunoTherapy of Cancer (2017) 5:99 Page 3 of 7 Table 1 Baseline Characteristics greater than 200 days. One of these patients received beva- cizumab plus pembrolizumab after failing 9 prior treat- Characteristic All patients (n = 25) ments including bevacizumab containing regimens. The Age, year (range) 49 (30–72) other patient received pembrolizumab monotherapy after failing 2 prior lines of therapy. The first patient was on Gender: male, no. (%) 11 (44) dexamethasone only during their first dose of pembrolizu- Race mab. The second patient did not receive dexamethasone Caucasian, no. (%) 22 (88) during treatment with pembrolizumab. Of note, 7 of the 18 Asian, no. (%) 1 (4) patients without a clinical response did not require steroids Black, no. (%) 0 (0) at treatment initiation. The median mutation load was 6 in Latino/Hispanic, no. (%) 1 (4) patients with partial response and stable disease compared to 7 in those who did not respond. Median progression free Other, no. (%) 1 (4) survival (PFS) was 1.4 months (range 0.2–9.4) and median Diagnosis overall survival (OS) was 4 months (range 0.5–13.8) (Fig. 3). Glioblastoma, no. (%) 13 (52) Six month PFS was 12% and 6 month OS was 28%. Anaplastic astrocytoma, no. (%) 7 (28) Anaplastic oligodendroglioma, no. (%) 2 (8) Toxicity Unspecified high grade glioma, no. (%) 2 (8) All toxicities are listed in Table 4. The most common adverse events reported were fatigue (grade 3–4: 4%; grade 1–2: Gliosarcoma, no. (%) 1 (4) 75%), headache (grade 3–4: 4%; grade 1–2: 43%), nausea Performance status, KPS (range) 80 (50–100) (grade 3–4: 4%; grade 1–2: 37.5%), diarrhea (grade 3–4: 0%; Number of prior therapies, median (range) 4 (1–9) grade 1–2: 17%), seizures (grade 3–4: 4%; grade 1–2: 17%), Previously received bevacizumab, no. (%) 19 (76) vomiting (grade 3–4: 4%; grade 1–2: 17%), myalgias/arthral- MGMT status gia (grade 3–4: 0%; grade 1–2: 13%), and rash (grade 3–4: Methylated, no. (%) 4 (16) 0%; grade 1–2: 8%). The most common laboratory abnormal- ities recorded were hyperglycemia (grade 1–2: 79%), Unmethylated, no. (%) 12 (48) thrombocytopenia (grade 1–2: 50%), leukopenia (grade 1–2: Unknown, no. (%) 9 (36) 37.5%), ALT elevations (grade 1–2: 33%), AST elevations IDH1 Status (grade 1–2: 29%), bilirubin elevations (grade 1–2: 21%), neu- IDH1 Mutated, no. (%) 10 (40) tropenia (grade 1–2: 21%), and hypothyroidism (grade 1–2: IDH1 Wild Type, no. (%) 9 (36) 17%). Additionally, 74% of patients (n = 14) who experienced Unknown, no. (%) 6 (24) hyperglycemia were receiving dexamethasone. One patient with a history of epilepsy was admitted for a grade 3 seizure. Number of mutations by MSK-Impact, median (range) 7 (3–58) The second patient who experienced grade 3 adverse events, PD-1 inhibitor specifically nausea, vomiting, and headache, was admitted for Pembrolizumab, no. (%) 25 (100) symptoms of increased intracranial pressure due to pathology Number of doses administered, median (range) 3 (1–14) confirmed recurrent glioblastoma. Lastly, one patient experi- Concomitant therapy enced grade 4 cerebral edema requiring emergent surgery Pembrolizumab monotherapy, no. (%) 6 (24) 7 days after their first and only dose of pembrolizumab. Path- ology confirmed edema was due to rapid tumor progression. Bevacizumab, no. (%) 17 (68) No patients discontinued pembrolizumab due to toxicity. Cytotoxic chemotherapy + bevacizumab, no. (%) 2 (8) Receiving dexamethasone at time of first dose, no. (%) 14 (56%) Discussion Our study demonstrated that heavily pretreated patients patients with a partial response received concomitant bevaci- with malignant high grade gliomas have low response rates zumab, and one patient was bevacizumab-naïve. These two to pembrolizumab. To our knowledge, this is the first study patients received pembrolizumab plus bevacizumab in the to investigate PD-1 inhibitioningrade IIIgliomas.Garber second and third line setting for treatment of glioblastoma and colleagues found that PD-L1 expression was only and anaplastic astrocytoma, respectively. Both patients re- present on grade IV gliomas, where as it was not present in ceived dexamethasone for management of disease related the 33 anaplastic astrocytomas or 9 oligodendrogliomas. symptoms, one at initiation of pembrolizumab treatment. [19] There is no current data correlating PD-L1 expression Duration of therapy, best radiographic response, previous and clinical outcomes outside of pembrolizumab use in bevacizumab, and concomitant bevacizumab can be visual- non-small cell lung cancer. In our grade III glioma cohort, ized in Figs. 1 and 2. Two patients had stable disease 1 patient had a partial response to pembrolizumab and 2 Reiss et al. Journal for ImmunoTherapy of Cancer (2017) 5:99 Page 4 of 7 Table 2 Patient Characteristics, Response and Steroid Dose Pt Grade OR KPS # of cycles MGMT Status IDH 1p/ ML Steroids at Steroid dose at initiation # of cycles Con Prev # of pembro Status 19q initiation (in prednisone equivalence) with steroids Bev Bev 0 <20 ≥20 1 III PR 90 4 unmethylated WT N/A 6 N X 2 Y Y 2 IV PR 80 4 unmethylated N/A N/A 6 Y X 1 Y N 3 III SD 90 14 methylated WT intact 6 N X 0 N N 4 III SD 70 10 unmethylated MUT N/A 3 Y X 1 Y Y 5 IV SD 90 14 unmethylated WT N/A 12 N X 5 Y Y 6 IV SD 100 4 methylated N/A N/A 13 N X 0 N Y 7 IV SD 100 1 N/A WT N/A N/A Y X 1 Y Y 8 III PD 90 6 N/A MUT co-del 5 Y X 1 N N 9 III PD 60 5 N/A MUT co-del 58 Y X 0 Y Y 10 III PD 60 3 unmethylated MUT N/A 7 N X 2 N N 11 III PD 70 3 unmethylated WT N/A 5 Y X 3 Y Y 12 III PD 90 2 unmethylated WT intact 15 Y X 2 Y N 13 III PD 90 2 unmethylated MUT N/A 7 Y X 2 Y Y 14 III PD N/A 1 methylated MUT N/A 5 N X 0 N Y 15 IV PD 90 5 methylated MUT N/A 11 Y X 2 N N 16 IV PD 60 5 unmethylated WT intact 10 Y X 2 Y Y 17 IV PD 50 4 N/A N/A N/A N/A N X 0 Y Y 18 IV PD 90 3 N/A MUT N/A 9 Y X 3 Y Y 19 IV PD 90 3 unmethylated N/A N/A 4 Y X 1 Y Y 20 IV PD 90 3 N/A N/A N/A N/A N X 1 Y Y 21 IV PD 70 2 unmethylated WT N/A 13 Y X 2 Y Y 22 IV PD 80 2 unmethylated MUT N/A 5 N X 0 Y Y 23 IV PD 80 2 N/A WT N/A N/A N X 1 Y Y 24 N/A PD 70 2 N/A N/A N/A N/A N X 1 Y Y 25 IV N/A 60 1 N/A MUT intact 19 Y X 1 Y Y Abbreviations: Pt: Patient; OR: Objective response; CR: Complete response; PR: Partial response; SD: Stable disease; PD: Progressive disease; KPS: Karnofsky performance score; Pembro: pembrolizumab; N/A: not applicable or unknown; MGMT methylated: methylated; MGMT unmethylated: unmethylated; IDH mutant: MUT; IDH wild type: WT; 1p19q intact: intact; 1p19q codeleted: Co-del; ML: mutational load by MSK impact; Y: yes; N: no; X: indicates steroid dose at initiation; Con Bev: Concomitant bevacizumab; Prev Bev: previously progressed on bevacizumab treatment patients had prolonged progression free survival with having PD-L1 expression ≥1%, bevacizumab naïve, and pembrolizumab. unable to receive standard treatment. Median PFS and OS Pembrolizumab monotherapy for recurrent glioblast- were reported as 2.8 months and 14.4 months, respect- oma was studied in the KEYNOTE-028 trial. [20] Patients ively. CheckMate-143 compared nivolumab monotherapy were included if they were diagnosed with glioblastoma to bevacizumab monotherapy in glioblastoma in patients with first recurrence. Median OS was 9.8 months with Table 3 Clinical Response nivolumab and 10 months with bevacizumab, PFS was Characteristic All evaluable 1.5 months with nivolumab and 3.5 months with bevaci- patients (n = 24) zumab, demonstrating no improvement in overall survival. Best radiographic response [21] We observed a shorter PFS and OS most likely be- Complete response (CR), no. (%) 0 (0) cause patients that failed bevacizumab were also included. Partial response (PR), no. (%) 2 (8) Pembrolizumab was well tolerated in our cohort; toxicities were similar compared to those reported with other malig- Stable disease (SD), no. (%) 5 (21) nancies. [8, 9] Very few serious adverse events occurred dur- Progressive disease (PD), no. (%) 17 (71) ing treatment. Serious adverse events, cerebral edema, Median PFS, days (range) 42 (7–282) seizures and headaches could be related to disease progres- Median OS, days (range) 121 (15–415) sion or checkpoint inhibition. Reiss et al. Journal for ImmunoTherapy of Cancer (2017) 5:99 Page 5 of 7 Fig. 1 Best Radiographic Response in Grade III Glioma Patients. BEV = bevacizumab. The X axis represents the number of doses of pembrolizumab that was received. The color represents the best radiographic response each patient had. 3 patients continue on Fig. 3 Overall Survival and Progression Free Survival. Median pembrolizumab at the end of data collection. 6 patients previously progression free survival (PFS) was 1.4 months (range 0.2–9.4) and progressed on bevacizumab; of those patients 5 continued bevacizumab median overall survival (OS) was 4 months (range 0.5–13.8). Six with pembrolizumab. 4 patients never received bevacizumab, of those 1 month PFS was 12% and 6 month OS was 28%. Two patients had started on bevacizumab with pembrolziumab. One patient had a partial stable disease greater than 200 days response; 2 had stable disease; and the rest had progressive disease Our study had several limitations. Firstly, it was a retrospect- ive study with a small sample size. Second, many patients re- ceived pembrolizumab in combination with other treatment modalities such as bevacizumab, making it difficult to evaluate the effectiveness of pembrolizumab monotherapy in high Table 4 Adverse events - incidence and grading according to grade glioma patients. Additionally, we included patients with CTCAE v 4.03 both WHO grade III and IV gliomas, making it difficult to Toxicity Overall incidence, Grade 1 and Grade 3 and compare these results to published data that includes only no. (%) 2, no. (%) 4, no. (%) glioblastoma patients. Many of our patients were excluded Hyperglycemia 19 (79) 19 (79) Fatigue 19 (79) 18 (75) 1 (4) Thrombocytopenia 12 (50) 12 (50) Headache 11 (46) 10 (43) 1 (4) Nausea 10 (42) 9 (38) 1 (4) Leukopenia 9 (38) 9 (38) ALT elevations 8 (33) 8 (33) AST elevations 7 (29) 7 (29) Bilirubin elevations 5 (21) 5 (21) Neutropenia 5 (21) 5 (21) Anemia 5 (21) 4 (17) 1 (4) Seizures 5 (21) 4 (17) 1 (4) Vomiting 5 (21) 4 (17) 1 (4) Thyroid toxicity 4 (17) 4 (17) Fig. 2 Best Radiographic Response in Grade IV Glioma Patients. BEV Diarrhea 4 (17) 4 (17) = bevacizumab. The X axis represents the number of doses of pembrolizumab that was received by each patient. The color Myalgias/Arthralgias 3 (13) 3 (13) represents the best radiographic response each patient had. One Rash 2 (8) 2 (8) patient continue on pembrolizumab at the end of data collection. Pyrexia 2 (8) 2 (8) Eleven patients previously progressed on bevacizumab; of those patients 10 continued bevacizumab with pembrolizumab. 2 patients Lipase 1 (4) 1 (4) never received bevacizumab and, of those, one started on Amylase 1 (4) 1 (4) bevacizumab with pembrolziumab. One patient had a partial response; 3 had stable disease; and the rest had progressive disease Mucositis 1 (4) 1 (4) Reiss et al. Journal for ImmunoTherapy of Cancer (2017) 5:99 Page 6 of 7 from participation in clinical trials for checkpoint inhibitors Ethics approval and consent to participate This study was approved by the Memorial Sloan Kettering Cancer Center due to their WHO grade, previoustreatment with bevacizu- Institutional Review Board and consent was waived due to the retrospective mab, and poor KPS. This patient population differs from pre- nature of this study. viously reported clinical observations using checkpoint Consent for publication inhibitors as it includes grade III and IV gliomas. The observed N/A response rate and survival data might be biased due to the poor prognostics factors in our population (heavily pretreated, Competing interests bevacizumab-resistance, low KPS performance status). How- The authors declare that they have no competing interests. ever, these patients are frequently encountered in the clinical setting with little literature to guide treatment decisions. Publisher’sNote We also did not account for baseline abnormalities and Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. due to the retrospective nature of this study were unable to differentiate between treatment related toxicity and disease Author details related adverse events. Lastly, we did not assess PD-L1 Department of Pharmacy, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10065, USA. Department of Neurology, Memorial expression to correlate clinical response to PD-L1 status. Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10065, USA. Pembrolizumab requires further studies to confirm a benefit for patients with refractory high grade glioma as monother- Received: 24 July 2017 Accepted: 8 November 2017 apy or in combination with chemotherapy or bevacizumab. References 1. Wen PY, Kesari S. Malignant gliomas in adults. N Engl J Med. 2008;359:492– Conclusions Patients with pathology confirmed refractory high grade gli- 2. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, omas have low response rates to pembrolizumab. However, Belanger K, Brandes AA, Marosi C, Bogdahn U, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. a small number of patients have a prolonged progression free 2005;352:987–96. survival. Pembrolizumab was tolerated with few serious ad- 3. Lamborn KR, Yung WK, Chang SM, Wen PY, Cloughesy TF, DeAngelis LM, verse events, even in patients receiving concomitant therapy. 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Journal for ImmunoTherapy of Cancer – Springer Journals

Published: Dec 19, 2017

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