Supplementary appendix

Size: px

Start display at page:

Download "Supplementary appendix"

Martin Rodney Cole
5 years ago
Views:

1 Supplementary appendix This appendix formed part of the original submission and has been peer reviewed. We post it as supplied by the authors. Supplement to: Younes A, Santoro A, Shipp M, et al. Nivolumab for classical Hodgkin s lymphoma after failure of both autologous stem-cell transplantation and brentuximab vedotin: a multicentre, multicohort, single-arm phase 2 trial. Lancet Oncol 2016; published online July 20.

2 Supplementary Appendix This appendix has been provided by the authors to give readers additional information about their work. Supplement to: Younes A, Santoro A, Shipp M, et al. Nivolumab for classical Hodgkin lymphoma after autologous stem-cell transplantation and brentuximab vedotin failure: a phase 2 study CONTENTS Investigator list page 2 Additional methods page 3 4 Tables S1 S5 page 5 10 Figures S1 S5 page

3 Study Sites and Investigators Site - country Site number Investigator Site - institution Patients treated (N=80) Germany 0033 Andreas Engert University Hospital of Cologne 16 United States 0040 Anas Younes Memorial Sloan Kettering Cancer Center 10 United States 0008 Voravit Ratanatharathorn Barbara Ann Karmanos Cancer Institute 9 Italy 0019 Pier Luigi Zinzani Institute of Hematology L. e A. Seràgnoli, University of Bologna 7 United States 0009 John Timmerman UCLA Medical Center 6 United States 0003 Stephen Ansell Mayo Clinic 5 Italy 0035 Armando Santoro Humanitas Cancer Center, Humanitas University 5 United States 002 Philippe Armand Dana Farber Cancer Institute 2 United States 0007 Michelle Fanale University of Texas MD Anderson Cancer Center 4 Canada 042 John Kuruvilla Princess Margaret Cancer Centre 4 United States 0001 Jonathon Cohen Winship Cancer Institute, Emory University Canada 0046 Kerry Savage British Columbia Cancer Agency 2 United Kingdom 0026 Graham Collins Churchill Hospital 2 Germany 0034 Michaela Feuring-Buske University Hospital Ulm 1 Netherlands 0016 Jan Paul De Boer NKI AVL, Amsterdam 1 United Kingdom 0013 David Cunningham Royal Marsden Hospital 1 United States 0005 Lisa Giulini Roth Weill Cornell Medical College 1 United States 0006 Suresh Nair Lehigh Valley Hospital 1 3 2

4 ADDITIONAL METHODS Eligibility criteria At study entry, one lesion had to measure greater than 15 mm in the longest diameter on cross-sectional imaging and be measurable in two perpendicular dimensions on computed tomography or magnetic resonance imaging and 18 F-fluoro-deoxyglucose avid by positron-emission tomography (FDG-PET). Pathological confirmation of classical Hodgkin lymphoma was required. Screening laboratory values had to meet the following criteria and to be obtained within 14 days before the first treatment dose: absolute neutrophil count 750/µL ( 0 75 x 10 9 /L; no white blood cell growth factors for prior 14 days); platelets 50 x 10 3 /µl ( 50 x 10 9 /L; no platelet transfusions for prior 14 days); haemoglobin 8 5 g/dl ( 85 g/l; no red blood cell transfusions for prior 7 days); serum creatinine 1 5 times the upper limit of normal or creatinine clearance 40 ml/minute (0 04 L; measured using the Cockcroft-Gault formula); aspartate aminotransferase/alanine aminotransferase levels 3 times the upper limit of normal; total bilirubin 1 5 times the upper limit of normal. Exclusion criteria Key exclusion criteria were known central nervous system lymphoma; nodular lymphocyte-predominant Hodgkin lymphoma, active interstitial pneumonitis, autoimmune disease, known history of testing positive for human immunodeficiency virus or known AIDS, any positive test for hepatitis B or C indicating acute or chronic infection, a condition requiring systemic treatment with corticosteroids (>10 mg daily prednisone equivalent), or other immunosuppressive medications within 14 days of nivolumab administration; autologous stem-cell transplantation no more than 90 days prior to the first dose of nivolumab; radiation therapy within 3 weeks, or chest radiation no more than 24 weeks prior to the first dose of nivolumab; carmustine (BCNU) 600 mg/m² received as part of the pretransplant conditioning regimen; and a previous malignancy active within the previous 3 years, except for locally curable cancers that have been cured. Protocol amendment Under the original discontinuation criteria, patients stopped the study drug when investigator assessment determined disease progression using the 2007 International Working Group criteria. An amendment permitted patients to continue on the study drug beyond investigator-assessed disease progression in certain cases. Interventions For grade 1 nivolumab-related infusion reactions, infusion interruption or intervention was not indicated; however, prophylactic premedications (diphenhydramine 50 mg [or equivalent] and/or paracetamol [acetaminophen] mg) were recommended for future infusions at least 30 minutes before additional nivolumab administrations. For grade 2 symptoms, nivolumab infusion was stopped and an intravenous infusion of normal saline was initiated. The patient was treated with diphenhydramine 50 mg intravenously (or equivalent) and/or paracetamol (acetaminophen) mg, and, if appropriate, corticosteroid or bronchodilator therapy. Nivolumab infusion was stopped immediately and permanently discontinued in the case of grade 3/4 infusion reactions, and an intravenous infusion of normal saline was initiated. The patient was treated with bronchodilators, epinephrine mg of a 1:1000 solution for subcutaneous administration or mg of a 1: solution injected slowly for intravenous administration, and/or diphenhydramine 50 mg intravenously with methylprednisolone 100 mg intravenously (or equivalent), as needed. Assessments Patients were evaluated for safety if they had received any study drug. Toxicity assessments were continuous during the treatment phase. During the safety follow-up phase, toxicity assessments were done in person. Once patients reached the survival follow-up phase, safety could be done in person or via documented telephone calls. Patient-reported general health status and quality of life were assessed using the EQ-5D and the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire Core 36 (EORTC QLQ- C30). Quality-of-life assessments were performed on day 1 of cycle 1 and then every four cycles for the first 17 cycles (day 1 [prior to dosing] of cycles 5, 9, 13, and 17), and then every six cycles thereafter (cycles 23, 29, 35+). EQ-5D records the patient s self-rated health state on a 100-point vertical visual analogue scale (VAS; 0=worst imaginable health state; 100=best imaginable health state). EORTC QLQ-C30 is a 30-item questionnaire comprised of five functional scales, three symptom scales, and a global health/quality-of-life scale. Scale score rages from 0 100, with higher scores representing a better response level for functional and global health/quality-of-life scales and lower scores representing a better response level for symptom scales. 3

5 Fluorescence in situ hybridization was performed using the bacterial artificial chromosome (BAC) clones (CHORI; RP11-599H20 and RP11-635N21, which both map to 9p24 1 and include CD274 (encoding PD-L1, labelled with Spectrum Orange) and PDCD1LG2 (encoding PD-L2, labelled with Spectrum Green), respectively. As a control, the centromeric probe Spectrum Aqua labelled CEP9 (Abbott Molecular) that maps to 9p11-q11 was hybridised per manufacturer s recommendations. Immunohistochemical staining was performed using an automated staining system (BOND-III, Leica Biosystems). A double-staining technique for PD-L1 (405 9A11) and PAX5 (24/Pax-5, BD Biosciences), and for PD-L2 (366C 9E5) and phosphorylated STAT3 (pstat3; D3A7, Cell Signaling Technology) was used. For PD-L1 immunohistochemical evaluation, 50 Reed-Sternberg cells were scored per case unless <50 Reed-Sternberg cells were present, and then all Reed-Sternberg cells were evaluated for positive and negative staining. The H-score (0 300) was calculated by multiplying the percentage of malignant cells with positive staining (0 100%) and average intensity of positive staining in the malignant cells (1, 2, or 3+). Statistical analysis The planned sample size was 60. Eighty patients were enrolled due to high demand from investigators and also to account for the possibility of a high rate of screening failures. Safety was assessed using National Cancer Institute Common Terminology Criteria for Adverse Events, version 4 0, and adverse events were coded using the Medical Dictionary for Regulatory Activities (MedDRA), version Descriptive statistics of on-study adverse events were tabulated using worst grade by system organ class and MedDRA preferred term. Descriptive statistics were used to evaluate mean change in EORTC QLQ-C30 and EQ-5D scores from baseline to week 33. EQ-5D VAS was summarised using descriptive statistics at each assessment time point, and analyses evaluating mean score changes from baseline using the EORTC QLQ-C30 were performed in all treated patients who had an assessment at baseline and at least one subsequent assessment. Associations between variables were evaluated post-hoc using the Kruskal-Wallis rank-sum tests for continuous data comparing two or more groups. The modified H-score for PD- L1 and PD-L2 protein expression was divided into four equally sized groups (quartiles). 4

6 Table S1: Previous systemic cancer therapy Therapy Patients (N = 80) Immunotherapy by monoclonal antibody 80 (100%) Brentuximab vedotin 80 (100%) Investigational antineoplastic 4 (5%) Rituximab 14 (18%) Steroid 45 (56%) Dexamethasone 31 (39%) Methylprednisolone 8 (10%) Prednisolone 11 (14%) Prednisone 18 (23%) Chemotherapy (other than anthracyclines) 80 (100%) Bendamustine 26 (33%) Bleomycin 77 (96%) Busulfan 1 (1%) Carboplatin 37 (46%) Carmustine 5 (6%) Chlorambucil 4 (5%) Cisplatin 40 (50%) Cyclophosphamide 22 (28%) Cytarabine 28 (35%) Dacarbazine 72 (90%) Etoposide 65 (81%) Fludarabine 1 (1%) Gemcitabine 54 (68%) Ifosfamide 59 (74%) Irinotecan 1 (1%) Lomustine 1 (1%) Melphalan 10 (13%) Methotrexate 2 (3%) Nitrogen mustard 5 (6%) Oxaliplatin 3 (4%) Paclitaxel 1 (1%) Procarbazine 23 (29%) Thiotepa 2 (3%) Trofosfamide 1 (1%) Vinblastine 72 (90%) Vincristine 24 (30%) Vinorelbine 39 (49%) Chemotherapy (anthracyclines) 80 (100%) Doxorubicin 79 (99%) Doxorubicin liposomal 12 (15%) Epirubicin 4 (5%) Mitoxantrone 1 (1%) Kinase inhibitors 5 (6%) Idelalisib 1 (1%) Investigational antineoplastic 2 (3%) Sorafenib 2 (3%) 5

7 Immunomodulary derivatives 10 (13%) Arsenic trioxide 1 (1%) Lenalidomide 7 (9%) Thalidomide 2 (3%) Radioimmunotherapy 1 (1%) Investigational antineoplastic 1 (1%) Other 21 (26%) Bortezomib 1 (1%) Everolimus 15 (19%) Investigational antineoplastic 8 (10%) Investigational immunomodulating agent 1 (1%) Investigational immunotherapy 1 (1%) Mesna 1 (1%) Sirolimus 1 (1%) T-cell infusion 1 (1%) Vorinostat 2 (3%) Data are n (%). 6

8 Table S2: Best overall response by 9p24 1 genetic alterations and PD-L1 H-score Best overall response 9p24 1 genetic alteration PD-L1 H-score* Polysomy Copy gain Amplification Q1 Q2 Q3 Q4 Progressive disease Stable disease Partial response Complete response *p=0 013, Kruskal-Wallis test. Two patients with stable disease and 9p24 1 copy gain and one patient with partial response and 9p24 1 copy gain did not have enough material for assessment of PD-L1 protein expression. 7

9 Table S3: Serious adverse events.* Event Patients with adverse event (N=80) Any grade Grade 3 4 Grade 5 Total patients with an event 20 (25%) 10 (13%) 1 (1%) Pyrexia 3 (4%) 1 (1%) 0 Malignant neoplasm progression 2 (3%) 2 (3%) 0 Pneumonia 2 (3%) 1 (1%) 0 Arrhythmia 2 (3%) 1 (1%) 0 Meningitis 2 (3%) 1 (1%) 0 Infusion-related reaction 2 (3%) 0 0 Data are number (%). *Listed are serious adverse events that were reported in at least 2% of patients. Includes events reported between the first dose and 30 days after the last dose of study therapy. Multi-organ failure. Includes progression of Hodgkin lymphoma. 8

10 Table S4: QLQ-C30 Completion rate Assessment time point QLQ-C30 completion rate * Week 1 (baseline) 94% Week 9 83% Week 17 85% Week 25 82% Week 33 88% * Proportion of evaluable patients with a completed PRO at the study visit. 9

11 Table S5: EORTC-QLQ-C30 functional and symptom scale summary Mean (SD) score Mean change from baseline (SD) Baseline (n=75) Week 9 (n=64) Week 17 (n=60) Week 25 (n=51) Week 33 (n=44) Global health and functional subscales* Global health status 65.2 (25.2) 9.8 (19.0) 4.2 (20.9) 9.4 (21.5) 6.7 (24.2) Physical functioning 77.6 (24.9) 7.5 (17.6) 5.5 (16.8) 7.1 (19.9) 4.9 (13.3) Role functioning 69.8 (33.1) 10.7 (29.0) 5.1 (22.2) 7.1 (22.3) 6.1 (20.7) Emotional functioning 78.1 (21.6) 4.4 (18.3) 0.6 (20.4) 5.7 (20.6) 4.9 (11.9) Cognitive functioning 87.1 (17.9) 0.6 (17.5) 2.4 (19.7) 1.0 (20.2) 0.0 (15.8) Social Functioning 72.7 (28.6) 7.1 (24.8) 2.7 (26.9) 4.8 (27.2) 10.6 (23.5) Symptom subscales Fatigue 27.0 (28.9) 8.1 (26.0) 6.9 (23.3) 9.8 (23.9) 7.6 (20.1) Nausea and vomiting 4.4 (14.3) 2.0 (14.9) 0.0 (14.9) 1.7 (16.0) 0.4 (19.9) Pain 18.4 (21.5) 8.2 (20.6) 6.3 (22.6) 7.8 (25.7) 4.5 (22.4) Dyspnea 23.1 (30.0) 9.0 (23.0) 4.8 (20.5) 6.8 (24.5) 4.1 (20.0) Insomnia 29.8 (32.2) 5.7 (28.5) 4.2 (31.2) 4.9 (27.5) 12.2 (25.6) Appetite loss 21.8 (30.3) 9.0 (24.6) 6.6 (25.0) 7.5 (25.7) 7.3 (26.4) Constipation 11.6 (22.9) 1.1 (30.9) 3.0 (25.6) 2.7 (28.7) 8.1 (20.8) Diarrhea 10.7 (25.2) 0.0 (24.8) 3.0 (26.4) 2.0 (22.0) 0.8 (19.0) Financial difficulties 35.6 (36.1) 8.5 (31.9) 3.0 (32.6) 5.4 (36.2) 5.7 (27.8) * Higher scores indicate higher health-related quality of life; positive changes indicate improvement in health-related quality of life from baseline. Lower scores equal better symptom status; negative change scores indicate improvement in symptoms compared with baseline. 10

12 Figure S1: Study design *Includes patients who responded to brentuximab vedotin and later experienced disease progression. 11

13 Figure S2: CONSORT patient disposition flow diagram *Autoimmune hepatitis, increased alanine aminotransferase, increased aspartate aminotransferase, and multiorgan failure. Six patients proceeded to stem-cell transplantation (one additional patient underwent stem-cell transplantation after data cut-off date); one patient discontinued because of lack of response (investigator s decision). Note: total number of patients with progression, n=23 12

14 Figure S3: Change in tumour burden Shown are the results for change in tumour burden in patients treated beyond progression per investigator assessment. 13

Figure S4: PD-L1/PD-L2 alterations and PD-1 ligand expression in tumour biopsies from trial patients: representative patient specimens Row 1: representative FISH images (PD-L1, red; PD-L2, green;

15 Figure S4: PD-L1/PD-L2 alterations and PD-1 ligand expression in tumour biopsies from trial patients: representative patient specimens Row 1: representative FISH images (PD-L1, red; PD-L2, green; centromeric probe, aqua) from patients with: polysomy (left), three green red fusion signals and three centromeric signals; copy gain (middle), five green red fusion signals and three centromeric signals; and amplification (right), aggregates of multiple red green fusion signals and two centromeric signals. Row 2: expression of PD-L1 protein by Reed-Sternberg cells for corresponding cases in row 1 (positive staining = brown). PD-L1 was evaluated in conjunction with PAX5 to identify Reed-Sternberg cell nuclei (positive staining = red). Row 3: expression of PD-L2 by Reed-Sternberg cells for corresponding cases shown in Row 1 (positive staining = brown). Phosphorylated signal transducer and activator of transcription 3 (pstat3), which reflects Janus kinase-stat activation in Reed-Sternberg cells, was assessed on the same slide (positive staining = red). Images were acquired with 1000 magnification. Scale bars indicate 50 µm. See appendix p 7. 14

16 Figure S5: Best change from baseline in target lesion Shown are the results for best change from baseline in target lesion for all response-evaluable patients per IRRC (panel A) and investigator (panel B), where crosses denote ongoing response. IRRC=independent radiologic review committee. 15

Presented at the 59th American Society of Hematology (ASH) Annual Meeting & Exposition; December 9 12, 2017; Atlanta, GA, USA

Presented at the 59th American Society of Hematology (ASH) Annual Meeting & Exposition; December 9 12, 2017; Atlanta, GA, USA 65 Nivolumab Treatment Beyond Investigator-Assessed Progression: Outcomes in Patients With Relapsed/Refractory Classical Hodgkin Lymphoma From the Phase 2 CheckMate 25 Study Jonathon B. Cohen, 1 Andreas