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Jon Ker 2018
Jon Ker 2018
Jon Ker 2018
Summary
Background Napabucasin is a first-in-class cancer stemness inhibitor that targets STAT3, which is a poor prognostic Lancet Gastroenterol Hepatol
factor in colorectal cancer. This study aimed to test napabucasin in advanced colorectal cancer. 2018
Published Online
January 31, 2018
Methods This study was a double-blind randomised phase 3 trial done at 68 centres in Canada, Australia, New Zealand,
http://dx.doi.org/10.1016/
and Japan. Patients with advanced colorectal cancer with a good Eastern Cooperative Oncology Group (ECOG) S2468-1253(18)30009-8
performance status (0–1) for whom all available standard therapies had failed were eligible for the study. Patients were Department of Medicine,
randomly assigned (1:1) to receive placebo or napabucasin through a web-based system with a permuted block method, Division of Medical Oncology,
after stratification by ECOG performance status, KRAS status, previous VEGF inhibitor treatment, and time from Ottawa Hospital Research
Institute, University of Ottawa,
diagnosis of metastatic disease. Napabucasin 480 mg or matching placebo was taken orally every 12 h. All patients
Ottawa, ON, Canada
received best supportive care. The primary endpoint was overall survival assessed in an intention-to-treat analysis. (D J Jonker MD, M M Vickers MD);
This is the final analysis of this trial, which is registered at ClinicalTrials.gov, number NCT01830621. Medical Oncology, Royal
Hobart Hospital, Hobart,
Australia (L Nott MBBS);
Findings Accrual began on April 15, 2013, and was stopped for futility on May 23, 2014, at which point 282 patients had
Department of
undergone randomisation (138 assigned to the napabucasin group and 144 to the placebo group). Overall survival did Gastroenterology &
not differ significantly between groups: median overall survival was 4·4 months (95% CI 3·7–4·9) in the napabucasin Gastrointestinal Oncology,
group and 4·8 months (4·0–5·3) in the placebo group (adjusted hazard ratio [HR] 1·13, 95% CI 0·88–1·46, p=0·34). National Cancer Center
Hospital East, Chiba, Japan
The safety population included 136 patients in the napabucasin group and 144 patients in the placebo group. More
(T Yoshino MD); Department of
patients who received napabucasin had any grade of treatment-related diarrhoea (108 [79%] of 136 patients), nausea Medicine, Division of Medical
(69 [51%]), and anorexia (52 [38%]) than did patients who received placebo (28 [19%] of 144 patients, 35 [24%], and Oncology, British Columbia
23 [16%], respectively). The most common severe (grade 3 or worse) treatment-related adverse events were abdominal Cancer Agency, University of
British Columbia, Vancouver,
pain (five [4%] patients receiving napabucasin vs five [3%] receiving placebo), diarrhoea (21 [15%] vs one [1%]), fatigue
BC, Canada (S Gill MD);
(14 [10%] vs eight [6%]), and dehydration (six [4%] vs one [1%]). 251 (89%) patients had data on pSTAT3 expression, of Department of Oncology,
whom 55 (22%) had pSTAT3-positive tumours (29 in the napabucasin group, 26 in the placebo group). In a prespecified Cabrini Hospital, Melbourne,
biomarker analysis of pSTAT3-positive patients, overall survival was longer in the napabucasin group than in the Australia (J Shapiro MBBS);
Department of
placebo group (median 5·1 months [95% CI 4·0–7·5] vs 3·0 months [1·7–4·1]; HR 0·41, 0·23–0·73, p=0·0025). Gastroenterology and
Gastrointestinal Oncology,
Interpretation Although there was no difference in overall survival between groups in the overall unselected National Cancer Center
population, STAT3 might be an important target for the treatment of colorectal cancer with elevated pSTAT3 Hospital East, Kashiwa, Japan
(Prof A Ohtsu MD); School of
expression. Nevertheless, these results require validation. Public Health & Preventive
Medicine, Monash University,
Funding Canadian Cancer Society Research Institute and Boston Biomedical. Melbourne, Australia
(Prof J Zalcberg MBBS); Division
of General Surgery, Princess
Introduction feature of colorectal cancer stem cells.8 Elevated Margaret Cancer Centre,
Colorectal cancer is a leading cause of death from cancer, expression of phosphorylated STAT3 (pSTAT3) is University of Toronto, Toronto,
with a fatality rate nearing 50%.1,2 When unresectable, associated with poor prognosis.9 ON, Canada (A C Wei MD);
standard treatments include chemotherapy (eg, fluoro- Napabucasin (BBI608, Boston Biomedical Inc/1Globe Clinical Development, Boston
Biomedical, Boston, MA, USA
pyrimidines, irinotecan, and oxaliplatin) and agents Health Institutes) is a small molecule inhibitor of (Y Gao PhD, M Hitron MD,
targeting EGFR (eg, cetuximab and panitumumab) and STAT3 and has been shown to block self-renewal and W Li PhD, Y Li MD); 1Globe
VEGF (eg, bevacizumab, aflibercept, ramucirumab, and induce death in cancer stem cells from colorectal Health Institute, Norwood,
regorafenib).3–7 However, no new biological pathways cancer and other types of cancer in preclinical studies.10 MA, USA (C J Li MD), Boston
Biomedical, Cambridge, MA,
have successfully been targeted in randomised trials for Results from early trials of napabucasin alone and USA; Department of
more than a decade. combined with chemotherapy in colorectal cancer Mathematics and Statistics
Cancer stem cells, or cancer cells with stemness suggest promising activity.11–13 The Canadian Cancer (Prof D Tu PhD) and
Department of Public Health
phenotype, have self-renewal capability and are respon- Trials Group (CCTG), the Australasian Gastrointestinal
Sciences
sible for malignant growth, recurrence, drug resistance, Trials Group (AGITG), and investigators from Japan (Prof C J O’Callaghan PhD),
and metastasis. Cancer stem cells are resistant to did this trial to compare napabucasin with placebo in Canadian Cancer Trials Group
chemotherapies and existing targeted agents. STAT3 is patients receiving best supportive care for refractory (N M Magoski MSc), Queens
University, Kingston, ON,
aberrantly activated in many cancers, and is a key advanced colorectal cancer.
Patient-reported quality of life was assessed at baseline with Kaplan-Meier plots. The primary comparisons of
and at weeks 4, 8, 12, 16, and 24 after randomisation15 the treatment groups were done with the stratified log-
by use of the European Organisation for Research and rank test adjusted for stratification factors. HRs with
Treatment of Cancer (EORTC) quality-of-life questionnaire 95% CIs were calculated from stratified Cox regression
(QLQ-C30) version 3.0 and Health Utilities Index (HUI3). models with treatment group as the single factor.16 For
QLQ-C30, scores for the primary quality-of-life domains
Outcomes of interest (physical function and global health status)
The primary endpoint was overall survival. Secondary were standardised to range from 0 to 100, with higher
endpoints included progression-free survival, objective scores representing better quality of life. Deterioration
response rate, disease control (ie, the proportion of in quality of life was defined a priori as a decline of
patients achieving complete remission, partial remission, 10 points or more from baseline. Discrete variables were
or stable disease), quality of life, and adverse events. compared with Fisher’s exact test and continuous and
Other secondary endpoints, which are not reported here, ordinal categorical variables were compared with the
were health utilities, health economics evaluation, and Wilcoxon test. Exploratory analyses of the effect of other
the exposure-response relationship of napabucasin. The potential prognostic factors that were specified a priori
protocol also prespecified that biomarker analyses would were done via a multivariable Cox regression model
be done for pSTAT3 expression by immunohistochemistry stratified by ECOG performance status at randomisation.
in formalin-fixed, paraffin-embedded archival tissue by All p values were two-sided, and no adjustment was
Clarient (Aliso Viejo, CA, USA), masked to treatment made for multiple comparisons. Statistical analyses
allocation (appendix p 1). In this report, pSTAT3-positivity were done with SAS version 9.4. This study is registered See Online for appendix
was defined as cancer cell nuclear staining of 5% with ClinicalTrials.gov, number NCT01830621.
or greater plus a stroma staining score of at least 2.
Two additional biomarker analyses were also prespecified: Role of the funding source
pSTAT3-positivity defined only by cancer cell nuclear The study was designed by members of the CCTG and
staining of 5% or greater and nuclear β-catenin and these the AGITG. Napabucasin and placebo were supplied by
will be reported separately. Adverse events were assessed Boston Biomedical. Pretrial biomarker development
in accordance with the Common Terminology Criteria was done by Boston Biomedical (CJL, YG, YL, WL). The
for Adverse Events version 3.0. CCTG collected, managed, and analysed the data. CCTG
maintains full unrestricted rights to publication of the
Statistical analysis study data. The first draft of the manuscript was written
Our a-priori estimates showed that 650 accrued patients by DJJ then submitted to all authors (including CJL, MH,
over 26 months with 12 months of additional follow-up YG, YL, and WL associated with Boston Biomedical) for
would yield 615 overall survival events, providing comment and revision. DT, CJO’C, NMM, and DJJ had
90% power, with a two-sided α of 5%, to detect a 23% full access to the raw data and DJJ had final responsibility
reduction in the risk of death (hazard ratio [HR] 0·77), for the decision to submit for publication.
corresponding to an increase in median survival from
4·6 to 6·0 months. Results
Two interim analyses were planned. An interim Accrual began on April 15, 2013, and was stopped for
futility analysis was planned for 10 weeks after the futility on May 23, 2014, following DSMC review of the
96th patient had been randomised and was based on first interim analysis, at which point 282 patients had
the proportion of patients who had achieved disease undergone randomisation (138 assigned to receive
control. An independent data safety monitoring napabucasin and 144 assigned to receive placebo).
committee (DSMC) would stop the trial if both the ratio Patients were unmasked and removed from study
of the difference in disease control between napabucasin therapy unless they were deriving benefit in the opinion
and placebo over the disease control in placebo group of the investigator and the patient. The final analysis
was less than 30% and the absolute difference in used cleaned data observed on or before the prespecified
disease control between the groups was less than 10%. clinical cutoff, Aug 26, 2015. At that time, the median
A second interim analysis for futility and superiority of follow-up was 19·4 months (IQR 17·8–21·6) and
overall survival was planned after 50% of required 258 patients had died. Because of the premature trial
deaths (308 deaths) had been observed. closure, the second interim analysis plan was modified
All patients who underwent randomisation were to include data up to a clinical cutoff of May 23, 2014,
included in the efficacy analysis in their assigned group from patients enrolled on or before March 28, 2014.
(ie, analysis by intention to treat). The safety analysis This analysis was intended to assess the efficacy in
was done on an on-treatment basis, with comparisons patients who had the opportunity for 2 months of
of patients who received at least one dose of exposure to study therapy before the DSMC decision.
napabucasin with those who received at least one dose The final analysis was modified to be done when 90% of
of placebo. Time-to-event variables were summarised the events (195 deaths in patients who underwent
Adverse events are reported at the worst grade that they occurred. Table shows all adverse events occurring in ≥10% in either study group and all grade 3–5 events.
Table 2: Adverse events deemed at least possibly related to napabucasin or placebo by investigator
cancer is warranted in these patients. Additionally, 5 Goldberg RM, Sargent DJ, Morton RF, et al. A randomized
STAT3 is a mediator of chemotherapy resistance,18–22 and controlled trial of fluorouracil plus leucovorin, irinotecan, and
oxaliplatin combinations in patients with previously untreated
napabucasin in combination with chemotherapy has metastatic colorectal cancer. J Clin Oncol 2004; 22: 23–30.
shown signs of anticancer activity irrespective of pSTAT3 6 Van Cutsem E, Peeters M, Siena S, et al. Open-label phase III trial
status.23 As such, further study of napabucasin in of panitumumab plus best supportive care with best supportive care
alone in patients with chemotherapy-refractory metastatic colorectal
combination with chemotherapy is underway in phase 3 cancer. J Clin Oncol 2007; 25: 1658–64.
trials in all patients with advanced colorectal cancer 7 Jonker DJ, O’Callaghan CJ, Karapetis CS, et al. Cetuximab for the
(NCT02753127). treatment of colorectal cancer. N Engl J Med 2007; 357: 2040–48.
8 Lin L, Liu A, Peng Z, Lin HJ, Li PK, Lin J. STAT3 is necessary for
Contributions proliferation and survival in colon cancer-initiating cells.
DJJ, CJO’C, CJL, and DT conceived and designed the study. DJJ, LN, TY, Cancer Res 2011; 71: 7226–37.
SG, JSh, AO, JZ, MMV, ACW, YG, NCT, BM, TE, SK, TP, and JSi 9 Morikawa T, Baba Y, Yamauchi M, et al. STAT3 expression,
recruited patients. CJL, YL, YG, and WL contributed to the biomarker molecular features, inflammation patterns, and prognosis in a
development. DT, CJO’C, and NMM collected and assembled the data. database of 724 colorectal cancers. Clin Cancer Res 2011; 17: 1452–62.
All authors contributed to the data analysis and interpretation and 10 Li Y, Rogoff HA, Keates S, et al. Suppression of cancer relapse and
manuscript writing, and approved the final manuscript. metastasis by inhibiting cancer stemness. Proc Natl Acad Sci USA
2015; 112: 1839–44.
Declaration of interests
11 Ciombor KK, Edenfield WJ, Hubbard JM, et al. A phase 1b/2 study
WL and MH are employees of, and hold intellectual property with,
of cancer stemness inhibitor BBI608 administered with
Boston Biomedical. YL and YG were employees at the time of the study
panitumumab in KRAS wild-type patients with metastatic colorectal
of, and have intellectual property with, Boston Biomedical and are cancer. Proc Am Soc Clin Oncol 2015; 33 (suppl): abstr 3617.
current employees of 1Globe Health Institute. CJL was an employee of 12 Hubbard JM, Jonker DJ, O’Neil BH, et al. A phase 1b study of
Boston Biomedical at the time of the study and is an employee of and first-in-class cancer stemness inhibitor BBI608 in combination with
holds patents with 1Globe Health Institute. TP reports non-financial FOLFIRI with and without Bevacizumab in patients with advanced
support from Roche and Merck and grants from Amgen. SG has colorectal cancer. Proc Am Soc Clin Oncol 2015;
received honoraria from Amgen, Bristol-Myers Squibb, and Taiho 33 (suppl): abstr 3616.
Pharmaceuticals. JSh has received travel, accommodation, or other 13 Jonker DJ, Stephenson J, Edenfield WJ, et al. A phase I extension
expenses from Amgen and Merck. TY has received grants from study of BBI608, a first-in-class cancer stem cell (CSC) inhibitor, in
GlaxoSmithKline KK and Nippon Boehringer Ingelheim and honoraria patients with advanced solid tumors. Proc Am Soc Clin Oncol 2014;
from Taiho, Chugai, and Eli Lilly. AO reports grants from Bristol-Myers 32 (suppl): abstr 2546.
Squibb. JZ has received personal fees from Bayer, Roche, Amgen, Pfizer, 14 Eisenhauer E, Therasse P, Bogaerts J, et al. New response
Specialized Therapeutics, and Merck Serono, travel support from Merck evaluation criteria in solid tumors: revised RECIST guideline
Serono and Ipsen, and grants from Bayer, Roche, Amgen, Pfizer, Merck (version 1.1). Eur J Cancer 2009; 45: 228–47.
Serono, Novartis, Bristol-Myers Squibb, AstraZeneca, and Shire. 15 Aaronson NK, Ahmedzai S, Bergman B, et al. The European
NCT has received honoraria from Merck Serono, Amgen, and Roche. organization for research and treatment of cancer QLQC30:
ACW has received honoraria from Sanofi, Celgene, and Shire. SK has a quality-of-life instrument for use in international clinical trials in
oncology. J Natl Cancer Inst 1993; 85: 365–76.
received honoraria from Celgene. MMV has had advisory roles with
Ipsen, Celgene, and Amgen. TE has received honoraria from Chugai 16 Klein JP, Moeschberger ML. Survival analysis: techniques for
censored and truncated data. New York: Springer, 1997.
Pharma, Eli Lilly, Taiho Pharmaceutical, Merck Serono, Ono
Pharmaceutical, Nihon Kayahu, and Eisai and institutional funding from 17 Yokom D, Sud S, Marginean H, et al. Signal transducer and
activator of transcription-3 (STAT3) expression concordance in
Eli Lilly, Taiho Pharmaceutical, Merck Serono, Novartis, Daiichi Sankyo,
paired primary and metastatic colorectal cancers (mCRC)
Dainippon Sumitomo Pharma, AstraZeneca, Boehringer Ingelheim,
Ann Oncol 2016; 27 (suppl 6): 123.
MSD, Pfizer, and GlaxoSmithKline. JSi, DJJ, DT, NMM, CJO’C, LN, and
18 Zhao C, Li H, Lin HJ, Yang S, Lin J, Liang G. Feedback activation of
BM declare no competing interests. STAT3 as a cancer drug-resistance mechanism. Trends Pharmacol Sci
Acknowledgments 2016; 37: 47–61.
Funding for this study was supported by the Canadian Cancer Society 19 Kim BH, Yi EH, Ye SK. Signal transducer and activator of
Research Institute and Boston Biomedical. A list of additional transcription 3 as a therapeutic target for cancer and the tumor
participating investigators is available in the appendix. microenvironment. Arch Pharm Res 2016; 39: 1085–99.
20 Spitzner M, Ebner R, Wolff HA, Ghadimi BM, Wienands J,
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