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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: Overman MJ, McDermott R, Leach JL, et al. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate ): an open-label, multicentre, phase study. Lancet Oncol 07; published online July 9.

2 Supplementary Appendix Contents Supplementary methods Table S: Study sites and investigators Table S: Concordance between local and central assessments of dmmr/msi-h status Table S: Summary of patients with discrepancies between local and central assessments of dmmr/msi-h status Table S: Objective response rate, best overall response, and disease control rate in patients with non MSI-H and microsatellite status not reported metastatic or recurrent colorectal cancer per central assessment of MSI-H status 6 Table S: Summary of time to and duration of response per BICR assessment 7 Table S6: Best overall response per BICR assessment in biomarker-defined patient populations 8 Table S7: Completion rates for patient-reported outcome measures 9 Table S8: EORTC QLQ-C0: number (%) of patients with 0-point deterioration from baseline 0 Table S9: EQ-D: Number (%) of patients reporting health problems Table S0: Selected treatment-related adverse events reported in patients treated with nivolumab Figure S: Plots of change from baseline in target lesion size over time and PFS per BICR assessment in patients with metastatic or recurrent colorectal cancer locally assessed as dmmr/msi-h Figure S: Event charts per BICR assessment for patients with metastatic or recurrent colorectal cancer locally assessed as dmmr/msi-h who responded to treatment or with stable disease 6 Figure S: Changes in CEA levels correlated with response per investigator assessment 7 Figure S: Patient-reported changes per EORTC QLQ-C0 8 Figure S: Patient-reported changes per EQ-D VAS and Utility Index 0

3 Supplementary methods Criteria for treatment delay Criteria for treatment delay include any grade non skin- (except grade fatigue or laboratory abnormalities) or grade skin-related adverse event (AE); any grade laboratory abnormality, except asymptomatic grade amylase or lipase abnormalities, or grade (if levels were normal at baseline) or (if grade at baseline) alanine aminotransferase (ALT) or aspartate aminotransferase (AST) or total bilirubin abnormalities; and any AE, laboratory abnormality, or intercurrent illness that was considered to warrant a delay by the investigator. Criteria for treatment discontinuation Criteria for treatment discontinuation include disease progression, any grade treatment-related uveitis, eye pain, or blurred vision that does not respond to topical therapy and does not improve to grade within the retreatment period or requires systemic treatment; any grade non skin treatment related AE lasting >7 days (exceptions include grade treatment-related uveitis, pneumonitis, bronchospasm, diarrhoea, colitis, neurological toxicity, hypersensitivity reaction, or infusion reaction of any duration that requires discontinuation; for grade endocrinopathy AEs such as adrenal insufficiency, adrenocorticotropic hormone deficiency, hyperthyroidosis or hypothyroidosis, or glucose intolerance that resolve or are adequately controlled with physiological hormone replacement [steroids, thyroid hormones] or glucose-controlling agents do not require treatment discontinuation; grade drug-related laboratory abnormalities do not require treatment discontinuation except for grade treatmentrelated thrombocytopenia lasting >7 days [associated with bleeding requires discontinuation]; and any treatmentrelated liver function test abnormality that meets the criteria [AST or ALT >8 upper limit of normal (ULN), total bilirubin > ULN, or concurrent AST or ALT > ULN and total bilirubin > ULN require discontinuation]); any grade treatment-related AE or laboratory abnormality, except asymptomatic grade amylase or lipase abnormalities, isolated grade electrolyte imbalances/abnormalities that are not associated with clinical sequelae and are corrected with supplementation/appropriate management within 7 hours of their onset; any dosing interruption lasting >6 weeks from the last dose except interruptions for prolonged steroid tapers to manage treatment-related AEs and interruptions >6 weeks from the last dose that occur for non treatment-related reasons; and any AE, laboratory abnormality, or intercurrent illness that in the judgement of the investigator presents a substantial clinical risk to the patient receiving continued nivolumab.

4 Table S: Study sites and investigators Site country Site number Investigator Site institution Patients treated (N=7) USA 000 Eunice L. Kwak, MD Massachusetts General Hospital, Boston, MA USA 000 Michael J. Overman, MD The University of Texas MD Anderson Cancer, Houston, TX USA 000 Heinz-Josef Lenz, MD USC Norris Comprehensive Cancer Center, Los Angeles, CA USA 0006 Emily Chan, MD Vanderbilt-Ingram Cancer Center, Nashville, TN USA 0008 Bassel El-Rayes, MD Emory University, Atlanta, GA Spain 000 Antonio Cubillo Gracian, Hospital de Madrid, Norte Sanchinarro, MD Madrid Spain 00 Pilar Garcia, MD Hospital General Universitario Gregorio, Maranon USA 00 James J. Lee, MD UPMC Cancer Pavilion, Pittsburgh, PA Canada 006 Albiruni Razak, MBBCh Mount Sinai Hospital, Toronto, ON Belgium 008 Bart Neyns, MD Universitair Ziekenhuis Brussel, Jette Belgium 009 Alain Hendlisz, MD Institut Jules Bordet, Brussels Belgium 000 Eric Van Cutsem, MD Universitaire Ziekenhuizen Leuven, Gasthuisberg Ireland 00 Ray Mcdermott, MBBCh St Vincent s University Hospital, Dublin USA 00 Michael Morse, MD Duke University Medical Center, Durham, NC France 00 Thierry André, MD Hopital Saint Antoine, Paris USA 008 Tomislav Dragovich, MD MD Anderson Cancer Center, Houston, TX USA 009 Franklin L. Chen, MD Novant Health Oncology Specialists, Winston-Salem, NC Italy 000 Massimo Aglietta, MD IRCC, Candiolo Italy 00 Vittorina Zagonel, MD Istituto Oncologico Veneto IRCCS, Padua USA 00 Joseph W. Leach, MD Allina Health, Virginia Piper Cancer Institute, Minneapolis, MN Italy 00 Gabriele Luppi, MD Azienda Ospedaliera Universitaria di Modena 9 USA 006 Eunice L. Kwak, MD Massachusetts General Hospital, Boston, MD Australia 007 Jayesh Desai, MBBS Royal Melbourne Hospital, Parkville, VIC Australia 009 Andrew G. Hill, MD Tasman Oncology Research Pty Ltd, Southport, QLD Australia 000 Ka Yeung Mark Wong, MBBS Westmead Hospital, Westmead, NSW

5 Table S: Concordance between local and central assessments of dmmr/msi-h status dmmr/msi-h per local assessment Patients, n (%) N=7 MSI per central assessment MSI-H (7) Non MSI-H* (9) No result 7 (9) Reasons for missing central MSI assessment H&E processing No tumour identified () No viable tumour identified () PCR processing Tumour and control DNA low/no amplification () Tumour DNA low/no amplification () Local method used for concordant patients n= IHC only 7 () PCR only 7 () IHC and PCR 9 (7) Local method used for discordant patients n= IHC only 0 (7) PCR only () IHC and PCR () dmmr/msi-h=dna mismatch repair deficient/microsatellite instability high. H&E, hematoxylin and eosin. IHC=immunohistochemistry. PCR=polymerase chain reaction. *Includes patients with microsatellite stable and MSI-low tumours.

6 Table S: Summary of patients with discrepancies between local and central assessments of dmmr/msi-h status Local laboratory Clinical history Patient Method Result Central laboratory result of Lynch syndrome* IHC dmmr MSI-L Unknown IHC dmmr MSS No IHC dmmr MSS Yes IHC dmmr MSS Yes # IHC/ PCR pmmr (IHC)/ MSI-H (PCR) MSS 6 IHC dmmr MSS Yes 7 IHC dmmr MSS No 8 PCR MSI-H MSS Yes 9 IHC/ PCR dmmr (IHC)/ MSI-H (PCR) MSS 0 IHC dmmr MSS No IHC dmmr MSS Unknown PCR MSI-H MSS Unknown IHC dmmr MSI-L Unknown IHC dmmr MSS Unknown dmmr=dna mismatch repair deficient. IHC=immunohistochemistry. MSI-H=microsatellite instability high. MSI- L=microsatellite instability low. MSS=microsatellite stable. PCR=polymerase chain reaction. pmmr=dna mismatch repair proficient. *Lynch syndrome designation was based on the clinical records of the patients at sites in countries where this reporting was permitted (excluded Italy). MSI-L, categorized as MSS. Patient had two primary tumours, one of which was assessed as dmmr per local laboratory; a metastatic tumour from a lymph node was assessed as MSS per central laboratory. # Patient had results from local testing: MSS by IHC and MSI-H by PCR; central test result is MSS, discordant from the local PCR test result. No Yes

7 Table S: Objective response rate, best overall response, and disease control rate in patients with non MSI-H and microsatellite status not reported metastatic or recurrent colorectal cancer per central assessment of MSI-H status Microsatellite status Patients, n (%) Non MSI-H per central assessment (n=)* not reported per central assessment (n=7) Investigator BICR Investigator BICR Objective response rate [9% CI] Best overall response Complete response Partial response Stable disease Progressive disease Not determined Disease control for weeks [9% CI] () [ ] 0 () (6) (6) (7) 8 (7) [9 8] () [ ] 0 () () 7 (0) (7) (6) [ 6] () [0 8] 0 () () () 0 (7) [8 90] (9) [ 7] () () () (9) (7) [9 96] BICR=blinded independent central review. MSI-H=microsatellite instability high. *Includes patients with microsatellite stable and MSI-low tumours. 6

8 Table S: Summary of time to and duration of response per BICR assessment Parameter All treated patients (N=7) Median time to response (IQR), months.8 (. 8.) Median duration of response (range), months NE (.+, 6.+) Duration months (9% CI), %* 9% (68 99) The + indicates censored values. BICR=blinded independent central review. MSI-H=microsatellite instability high. ORR=objective response rate. *Kaplan-Meier - month event rate. 7

9 Table S6: Best overall response per BICR assessment in biomarker-defined patient populations Objective response rate, n (%) [9%CI] Disease control rate Tumour cell PD-L expression % (n=) 7 () [ 7] (.) [0 7] <% (n=7) (8) [6 ] (66) [0 79] Rare (n=) () [7 ] () [ 7] dmmr/msi-h metastatic colorectal cancer per local assessment (N=7) Immune cell PD-L expression Intermediate (n=) () [8 7] (67) [ 8] Numerous (n=) 0 () [ 6] (6) [ 8] BRAF mutant (n=) () [0 6] Mutation status KRAS mutant (n=6) 8 () [ ] BRAF and KRAS wild type (n=9) 9 () [ ] Clinical history of Lynch syndrome* Yes (n=7) 8 (0) [ 0] No (n=8) 0 (6) [9 6] NA NA NA NA NA dmmr/msi-h=dna mismatch repair deficient/microsatellite instability high. NA, not available. PD-L=programmed death ligand. *Lynch syndrome designation was based on the clinical records of the patients at sites in countries where this reporting was permitted (excluded Italy). 8

10 Table S7: Completion rates for patient-reported outcome measures n/n (%) Baseline EORTC QLQ-C0 70/7 (9) 9/6 (9) 0/ (9) /8 (90) /6 (9) 8/ (88) / (8) 8/ (68) 6/ (8) 0/ (8) /7 (76) /6 (88) /6 (88) /6 (9) /6 (8) / (80) / (00) EQ-D 66/7 (89) 9/6 (9) 9/ (9) /8 (88) /6 (9) 8/ (88) 6/ (88) EORTC=European Organisation for Research and Treatment of Cancer. n/n, number of patients who completed questionnaire/number of patients on study. 7/ (66) / (78) 7/ (7) /7 (76) /6 (8) /6 (88) /6 (9) /6 (8) / (80) / (00) 9

11 Table S8: EORTC QLQ-C0: patients with 0-point deterioration from baseline Physical functioning Role functioning Emotional functioning Cognitive functioning Social functioning 7 (n=7) (n=8) 9 (n=) (n=) (n=7) 7 (n=) (n=8) 9 (n=6) 8 () (6) (7) (0) () (6) () (8) () NA () () (7) (8) (7) () () 6 () 7 (7) () (8) (9) () () (6) () (6) () (0) () () () 7 () () (7) (7) () (6) () NA () (8) () () () (8) (7) () 6 (8) 9 (9) 8 (9) 6 () (0) 6 (8) (7) (9) () () 7 (0) () () () () (8) (9) () 6 () 7 (7) 6 (6) (9) () () () () (9) () (0) () () () (n=9) 6 (n=) 67 (n=) 7 (n=) 79 (n=) 8 (n=) 9 (n=) 97 (n=) Fatigue () 0 () 0 () () 8 () () (8) () (6) (8) () (6) () () () () Nausea and vomiting (9) () (7) (0) () (6) (7) () () NA NA NA (7) () (8) (8) Pain 9 (6) (8) 7 (7) (0) 6 (6) (9) () () () (8) () (9) (0) () () () Dyspnea 7 () (6) (0) (7) () () () NA () (8) () () (7) () (8) () Insomnia 6 () 7 () 9 () 6 () () (6) () (8) () NA () (7) NA (8) (7) NA Appetite loss 0 (8) (8) (7) () () (6) (7) () () NA (7) () (7) () () (8) Constipation (9) (6) (0) () () NA () (8) () NA (7) (7) (7) (8) (8) NA Diarrhea () 0 () (0) 7 (7) () 6 (8) (7) () (6) (8) NA (9) (7) () (8) () Financial difficulties (9) 6 () 7 (7) 6 () 7 (9) () () () () () () () (0) () (7) () Quality of (9) () 6 () (0) () () () () () NA () () (7) () () () life Data are in n (%). EORTC=European Organisation for Research and Treatment of Cancer. NA, not available. 0

12 Table S9: EQ-D: patients reporting health problems Data are in n (%). *n=66 patients at baseline. Baseline (n=67) 7 (n=9) (n=9) 9 (n=) (n=) (n=8) 7 (n=6) (n=7) 9 (n=) (n=7) 6 (n=) 67 (n=) 7 (n=) 79 (n=) 8 (n=) 9 (n=) 97 (n=) Mobility* () () 9 (8) () () (8) (8) 6 () (0) () () () (7) () () () () Self-care 8 () 7 () (6) () () (8) () () (8) () () () () () () (7) () Usual activities (6) 8 (0) (6) 6 () 0 () 8 () 9 () 6 () (0) () () () (6) 7 (7) (8) () () Pain 8 (7) 6 () () (9) (6) () 8 () 8 (0) 9 (6) () () () (6) () () () () Anxiety 9 () () () (6) (6) 6 () 9 () 8 (0) 6 () () () () (6) (7) () (8) ()

13 Table S0: Selected treatment-related adverse events reported in patients treated with nivolumab dmmr/msi-h (N=7) Selected adverse event category Any grade Grade or Skin Pruritus 0 () 0 Rash 8 () 0 Maculopapular rash (7) () Dry skin () 0 Gastrointestinal Diarrhoea 6 () () Nausea 7 (0) 0 Stomatitis () () Abdominal pain () () Colitis () () Oesophagitis () () Gastritis () () Endocrine Hyperthyroidism () 0 Hypothyroidism () 0

14 Adrenal insufficiency () () Hepatic Lipase increase 9 () 6 (8) Aspartate aminotransferase increase (7) 0 Alanine aminotransferase increase () () Amylase increase () () Gamma-glutamyl transferase increase () () Hypersensitivity/infusion Hypersensitivity () 0 Infusion-related reaction () 0 Renal Creatinine increase () () Acute kidney injury () () Data are in n (%). dmmr/msi-h=dna mismatch repair deficient/microsatellite instability high.

Figure S: Plots of change from baseline in target lesion size over time and PFS per BICR assessment in patients with metastatic or recurrent colorectal cancer locally assessed as dmmr/msi-h

15 Figure S: Plots of change from baseline in target lesion size over time and PFS per BICR assessment in patients with metastatic or recurrent colorectal cancer locally assessed as dmmr/msi-h BICR=blinded independent central review. dmmr/msi-h=dna mismatch repair deficient/microsatellite instability high. PFS=progression-free survival. Percentage change from baseline in the sum of tumour burden for target lesions over time per BICR for evaluable patients treated with nivolumab. Triangles indicate complete or partial response per Response Evaluation Criteria In Solid Tumors v., plus signs indicate the first occurrence of a new lesion, and squares indicate percentage change truncated to 00%. (B) Kaplan-Meier curve for PFS per BICR in patients treated with nivolumab. Triangles indicate censored observations. A.

16 B.

17 Figure S: Event charts per BICR assessment for patients with metastatic or recurrent colorectal cancer locally assessed as dmmr/msi-h who responded to treatment or with stable disease BICR=blinded independent central review. dmmr/msi-h=dna mismatch repair deficient/microsatellite instability high. Characteristics of response (top panel) or stable disease (bottom panel) evaluated per BICR by Response Evaluation Criteria In Solid Tumors v.. Triangles indicate censored observations, plus signs indicate first responses, open circles indicate the last nivolumab doses, closed circles indicate the last nivolumab doses when off treatment, and hash signs indicate death. 6

18 Figure S: Changes in CEA levels correlated with response per investigator assessment CEA=carcinoembryonic antigen. CEA levels (September database lock) were measured at baseline and on day of week 7 (day [range 8 8]). (A) Percentage change from baseline in patients with complete responses or partial responses and patients with stable disease for weeks. (B) Percentage change from baseline in patients with disease control for weeks and patients with stable disease or progressive disease for < weeks; a significant difference in the percentage change in CEA levels was observed between these groups by Kruskal-Wallis test (p=0 08). Circles represent individual patients, plus sign indicates mean percentage change, and black lines indicate median percentage change. A. B. 7

19 Figure S: Patient-reported outcomes: EORTC QLQ-C0 Patient-reported outcomes were evaluated by the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C0 and the -level EQ-D.,6 The EORTC QLQ-C0 assesses functioning, symptoms, and quality of life on scales ranging from 0 to 00, with higher scores indicating better functioning, quality of life, or worsening symptoms, including fatigue, appetite loss, and pain. 8

20 9

21 Figure S: Patient-reported outcomes: EQ-D VAS and Utility Index Patient-reported outcomes were evaluated by the European Organisation for Research and Treatment of Cancer QLQ-C0 and the -level EQ-D.,6 The EQ-D assesses the proportion of patients reporting health problems and consists of a visual analogue scale (VAS) evaluating self-reported health on a scale from 0 to 00, with higher scores indicating better health status. 0

Bristol-Myers Squibb, Braine-l Alleud, Belgium; 12 MD Anderson Cancer Center, Houston, TX, USA

Bristol-Myers Squibb, Braine-l Alleud, Belgium; 12 MD Anderson Cancer Center, Houston, TX, USA 3531 Combination of nivolumab (NIVO) + ipilimumab (IPI) in the treatment of patients (pts) with deficient DNA mismatch repair (dmmr)/high microsatellite instability (MSI-H) metastatic colorectal cancer