- Email: [email protected]
Tipiracil and Regorafenib
Accepted Manuscript Real-World Treatment Patterns Among Patients With Colorectal Cancer Treated With Trifluridine/Tipiracil And Regorafenib Anuj K. Patel, MD, Mei S. Duh, MPH, ScD, Victoria Barghout, MSPH, Mihran A. Yenikomshian, MBA, Yongling Xiao, PhD, Willy Wynant, PhD, Majid Tabesh, MD, PhD, Charles S. Fuchs, MD, MPH PII:
S1533-0028(18)30009-4
DOI:
10.1016/j.clcc.2018.04.002
Reference:
CLCC 459
To appear in:
Clinical Colorectal Cancer
Received Date: 12 January 2018 Revised Date:
11 April 2018
Accepted Date: 16 April 2018
Please cite this article as: Patel AK, Duh MS, Barghout V, Yenikomshian MA, Xiao Y, Wynant W, Tabesh M, Fuchs CS, Real-World Treatment Patterns Among Patients With Colorectal Cancer Treated With Trifluridine/Tipiracil And Regorafenib, Clinical Colorectal Cancer (2018), doi: 10.1016/ j.clcc.2018.04.002. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT 4/11/2018
Confidential
REAL-WORLD TREATMENT PATTERNS AMONG PATIENTS WITH COLORECTAL CANCER TREATED WITH TRIFLURIDINE/TIPIRACIL AND REGORAFENIB
Dana-Farber Cancer Institute, Boston, MA Analysis Group, Inc., Boston, MA 3 VEB HealthCare LLC, Morristown, NJ 4 Groupe d'analyse, Ltée, Montréal, QC, Canada 5 Strategic Global Medical Affairs LLC, Chicago, IL 6 Yale Cancer Center, New Haven, CT 2
M AN U
Disclosures: Research Funding
SC
1
RI PT
Anuj K Patel, MD1; Mei S Duh, MPH, ScD2; Victoria Barghout, MSPH3; Mihran A Yenikomshian, MBA2; Yongling Xiao, PhD4; Willy Wynant, PhD4; Majid Tabesh, MD, PhD5;Charles S Fuchs, MD, MPH1,6
This study is funded by Taiho Oncology, Inc.
Declaration of Conflicts of Interest/Other Relationships
EP
TE D
Research funding was provided to Analysis Group, Inc. by Taiho Oncology, Inc. Dana-Farber Cancer Institute received a research fund from Analysis Group. AK Patel is an employee of the Dana-Farber Cancer Institute and has not received any consultation fee from Analysis Group, Inc., or Taiho Oncology, Inc. for this study. MS Duh and MA Yenikomshian are employees of Analysis Group, Inc. V Barghout is an employee of VEB HealthCare LLC. and has received a consultant fee from Taiho Oncology. Y Xiao and W Wynant are employees of Groupe d’analyse, Ltée. M Tabesh is an employee of Strategic Global Medical Affairs LLC. and has received a consultant fee from Taiho Oncology. CS Fuchs was an employee of the Dana-Farber Cancer Institute at the start of the study and is an employee with Yale Cancer Center. CS Fuchs has received consultation fees from Analysis Group, Inc. for this study.
AC C
Acknowledgments: The authors are grateful for the writing assistance provided by Erin McDonnell, formerly of Analysis Group, Inc. Corresponding author: Mihran Yenikomshian Mailing address: Analysis Group, Inc., 111 Huntington Ave, 14th Floor, Boston, MA 02199 Phone: 617-425-8158 Fax number: 617-425-8001 Email: [email protected] RUNNING HEAD: TRIFLURIDINE/TIPIRACIL AND REGORAFENIB TREATMENT PATTERNS
1
ACCEPTED MANUSCRIPT 4/11/2018
Confidential
MicroAbstract (Range= 40-60 words, current word count=51 words)
RI PT
Real-world data comparing treatment patterns of trifluridine/tipiracil (FTD/TPI) and regorafenib (REG) in refractory metastatic colorectal cancer patients are lacking/insufficient. This study evaluated real-world treatment patterns using a large-scale nationally-representative US claims database. Our results suggest that mCRC patients initiating on FTD/TPI have better adherence and compliance than patients initiating on REG. Structured Abstract (250 word limit, current word count = 250 words)
SC
BACKGROUND: Trifluridine/tipiracil (FTD/TPI) and regorafenib (REG) prolong survival in refractory metastatic colorectal cancer (mCRC) and have similar indications with different side effect profiles. This study compares real-world treatment patterns with FTD/TPI and REG for mCRC in a large, representative US claims database.
M AN U
METHODS: Retrospective data from the US Symphony Health Solutions’ Integrated Dataverse (IDV®) database were analyzed for adult mCRC patients receiving FTD/TPI or REG (10/20147/2016). The index date was first FTD/TPI or REG prescription date. The observation period spanned from index date to end of data, end of continuous clinical activity, or treatment switch. Adherence was assessed using medication possession ratio (MPR) and proportion of days covered (PDC) at 3 months. Time to discontinuation were assessed over the observation period with gaps of 45, 60, or 90 days. Outcomes were compared between cohorts using logistic regression and Cox proportional hazards models adjusting for baseline characteristic differences.
EP
TE D
RESULTS: A total of 1,630 FTD/TPI patients and 1,425 REG patients were identified. FTD/TPI patients were 80% more likely to have a MPR≥0.80 compared to REG patients (Odds Ratio [OR]= 1.80, p<0.001) and more than twice as likely to have a PDC≥0.80 (OR= 2.66, p<0.001) at 3 months. FTD/TPI patients were 37% less likely to discontinue their treatment compared to REG patients when using 60-day gaps (Hazard Ratio= 0.63, p<0.001). Similar results were found using 45- and 90-day gaps. CONCLUSIONS: mCRC patients on FTD/TPI were significantly more likely to adhere and comply with therapy compared to those on REG.
AC C
KEYWORDS: (five keywords should be listed at the bottom of the abstract page) Colorectal cancer, drug adherence, treatment patterns, trifluridine/tipiracil, regorafenib
2
ACCEPTED MANUSCRIPT 4/11/2018
Confidential
BACKGROUND Colorectal cancer (CRC) is the fourth most common type of cancer diagnosed in the United States (US) and represents 8.0% of all new cancer cases nationwide1,2 An estimated 135,430 new cases will be diagnosed and 50,260 deaths attributed to CRC in 20172,3 with approximately
RI PT
50%-60% of patients developing metastatic disease.4 The 5-year survival rate of metastatic CRC (mCRC) is 14%.4 Long term survival for mCRC has improved gradually over the last 30 years, likely representative of advancements in treatments and new agents active against this disease.4
SC
Survival and disease progression highly depend on patient medication adherence.5–7 A recent study of mCRC concluded that 28% of chemotherapy regimens were associated with an adherence rate of less than 80%.8 Multiple studies have demonstrated that most cancer patients
M AN U
prefer oral treatment over IV treatment for reasons such as convenience, environment while receiving treatment, and problems with IV administration.9 However, mCRC patients are actually less adherent to oral chemotherapies.8 Reasons for lack of adherence to these preferred therapies include less frequent interactions with care providers for education and counseling, simply forgetting doses, disliking aspects of the medication, and management of adverse events.10
TE D
In refractory mCRC, two approved oral agents, trifluridine/tipiracil (FTD/TPI) (Lonsurf®;Taiho Pharmaceutical, Tokyo, Japan) and regorafenib (REG) (Stivarga®; Bayer Pharma AG, Berlin, Germany), have been proven to prolong survival in randomized, multicenter phase III clinical trials. Both agents are indicated for the treatment of patients with mCRC who have been
EP
previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, as well as with anti-VEGF therapy and anti-EGFR therapy, if RAS wild type.11,12 REG is a multikinase inhibitor with activity in multiple pathways, including those involved in angiogenesis,
AC C
tumor microenvironment, and oncogenesis.11 FTD/TPI is a combination of trifluridine, a nucleoside metabolic inhibitor, and tipiracil, a thymidine phosphorylase inhibitor.12 In the RECOURSE study, FTD/TPI showed significant improvement in median overall survival compared to placebo (7.1 vs. 5.3 months; HR 0.68; 95% CI 0.58-0.81; p<0.001).13 In the CORRECT study, REG showed significant improvement in median overall survival compared to placebo (6.4 vs. 5.0 months; HR 0.77; 95% confidence interval [CI] 0.64-0.94; p=0.0052). 14 Despite similar indications and oral administration, FTD/TPI and REG have not been compared head-to-head in a clinical trial. Although a recent real-world retrospective analysis was conducted to compare the two treatments in patients with refractory mCRC showing that the two 3
ACCEPTED MANUSCRIPT 4/11/2018
Confidential
treatments had similar efficacy but different side effect profiles, this study was conducted in Japan based on data collected from only two cancer centers, and thus had a very small sample size.15 In addition, the generalizability of the study results to the US population may be also limited.15 Moreover, while FTD/TPI gained FDA-approval in September 2015, real-world data on treatment patterns of these therapies are lacking.16 While both agents are administered orally,
RI PT
they possess distinct side effect profiles. Dose reductions or treatment interruptions may be considered in real-world clinical practice, with the aim of reducing or avoiding adverse reactions. This study aims to evaluate real-world treatment patterns following initiation of FTD/TPI or REG for mCRC through the investigation of a large, nationally-representative US claims database.
SC
METHODS
M AN U
Data Sources
This study uses the Symphony Health Solutions’ (SHS) Integrated Dataverse (IDV®) database. The SHS database is a nationally-representative longitudinal de-identified claims database, which captures prescription and medical claims for over 220 million people across the US and covers all payment types. Data collected from October 2014 to July 2016 were used in this study.
TE D
Study Design and Patient Selection
A retrospective longitudinal cohort design was used to conduct this study. Patients diagnosed with CRC (ICD-9-CM: 153.x, 154.0x, 154.1x, 154.8x; ICD-10-CM: C18.x, C19.x, C20.x, C21.8) who received either FTD/TPI (Generic Product Identifier [GPI]: 2199000275) or REG (GPI:
EP
2153305000) between October 2014 and July 2016 were included in the study population. The index date was defined as the earliest date of the first FTD/TPI or REG claim; the index therapy
AC C
was the therapy (FTD/TPI or REG) supplied on the index date. Patients were included in the study if they were 18 years or older, had at least one diagnosis of CRC, did not have a diagnosis of gastric cancer or gastrointestinal stromal tumor, and had continuous clinical activity for at least 3 months both before and after the index date. The baseline period corresponded to the 3-month period prior to the index date used to assess baseline characteristics, except for baseline healthcare resource utilization variables that were assessed over the entire period prior to the index date. Patients were classified into two study cohorts based on the treatment they received at the index date: the FTD/TPI and REG cohorts. The observation period spanned from the index date 4
ACCEPTED MANUSCRIPT 4/11/2018
Confidential
to the earliest date among the switch to another mCRC treatment, the end of continuous clinical activity, or the end of data availability. Outcomes and Statistical Analysis Treatment patterns for the index therapy, including duration of treatment (DOT), medication
RI PT
adherence, and persistence, were assessed for each cohort. DOT was calculated over the observation period as the difference between the index date and the last day of supply of the last prescription. Medication adherence was assessed using medication possession ratio (MPR) and proportion of days covered (PDC). MPR was calculated by dividing total number of days of
SC
medication supplied by total number of days between the first prescription and the last day of supply of the last prescription among patients with at least 2 prescriptions. PDC was defined as the number of unique days with medication divided by the length of a fixed time interval. For
M AN U
both MPR and PDC, proportions of patients having a threshold equal to or over 0.8 and 0.9 were also reported.17,18 Persistence was defined as continuous use of the index therapy over a fixed time interval, with a specified allowable gap (i.e., 45 or 60 days) between two consecutive prescriptions or in the period between the last day of supply of the last prescription and the end of the assessment period. Both PDC and persistence were evaluated at 3 and 6 months after the index date among patients with at least 3 and 6 months of follow-up, respectively. In
TE D
addition, time to discontinuation (TTD) was assessed over the entire observation period using three allowable gap thresholds (i.e., 45, 60, or 90 days). Patients who never discontinued the index therapy were censored at the end of the observation period. Dosing patterns for the index therapy were evaluated over the observation period using dose
EP
intensity (DI) and relative dose intensity (RDI). DI was used to measure the amount of drug delivered per unit of time, calculated by dividing the sum of strength (in milligrams) of all prescriptions for the index therapy by DOT, multiplying by a factor of 2.8 for FTD/TPI (28 days of
AC C
a cycle divided by 10 dosing days) and 1.3 for REG (28 days of a cycle divided by 21 dosing days). The choice of the factors was determined based on the labeled recommended doses for FTD/TPI and REG.11,12 The recommended dose for FTD/TPI is 35 mg/m2/dose twice daily on days 1 through 5 and days 8 through 12 of each 28-day cycle;12 the recommended dose for REG is 160 mg once daily for the first 21 days of each 28-day cycle.11 This analysis assumed two distinct recommended daily doses of FTD/TPI to reflect the variability in body mass surface area (BSA). Doses of 120 mg and 130 mg were chosen based on previously reported 95% confidence limits of 1.81 to 1.84 m2 for mean BSA among adjuvant CRC patients,19 which corresponds to recommended daily doses of 126.7 mg to 128.8 mg. Daily dosages of FTD/TPI 5
ACCEPTED MANUSCRIPT 4/11/2018
Confidential
were rounded to account for the two available dosage strengths of tablets. RDI was calculated as the ratio of the DI of the administered regimen to the DI of the recommended regimen as noted in the prescribing information (i.e., 160 mg/day for REG and 120 mg/day or 130 mg/day for FTD/TPI per BSA described above). While the patient was on index therapy, both DI and RDI were estimated from the population-level perspective using the median number of claims,
RI PT
mode of drug quantity, mode of drug strength, and mean DOT obtained from the SHS claims data. To account for data errors in the quantity field of the claims data, patients were excluded from these calculations if they had at least one prescription for the study drugs with a quantity of less than 20 pills (approximately <25% of the labeled recommended doses).
SC
Descriptive statistics were reported for patient and clinical characteristics at baseline as well as for treatment patterns during the observation period. Means, standard deviations (SDs), and
M AN U
medians were used to describe continuous variables; frequencies and percentages were reported for categorical variables. Differences in baseline demographics and clinical characteristics between cohorts were assessed using Chi-square tests for categorical variables and Wilcoxon rank sum tests for continuous variables. Kaplan-Meier survival analyses were conducted to illustrate the differences in treatment discontinuation between the two cohorts. Multivariate regression models were used to estimate the adjusted differences in treatment
TE D
patterns between cohorts. The baseline covariates adjusted for in the models included age, gender, region, insurance plan, Charlson Comorbidity Index (CCI), individual comorbidities and baseline treatments/medications that significantly differed between cohorts (p-value<0.05), allcause baseline prescription drug costs, all-cause baseline medical costs, number of all-cause
EP
baseline IP visits, and number of all-cause baseline ER visits. Cox proportional hazards models were used to estimate hazard ratios and their corresponding 95% confidence intervals (CIs) for TTD. Linear regression models were used to estimate mean differences and their corresponding
AC C
95% CIs for continuous PDC and MPR. Logistic regression models were used to estimate odds ratios (OR) and their corresponding 95% CIs for dichotomized PDC, MPR, and persistence. RESULTS
Baseline Characteristics
1,630 FTD/TPI patients and 1,425 REG patients were included in the study (see Figure 1). Table 1 summarizes the baseline demographic and clinical characteristics of each cohort. FTD/TPI patients were younger compared to those on REG (mean age: 61.0 vs. 62.8, p<0.001). FTD/TPI patients had started their treatment more recently compared to those on REG 6
ACCEPTED MANUSCRIPT 4/11/2018
Confidential
(initiation in 2015: 46.3% vs. 83.2%, p<0.001; initiation in 2016: 53.7% vs. 16.0%, p<0.001). During the 3-month baseline period, the mean CCI was similar between the two cohorts (FTD/TPI vs. REG: 3.8 vs. 3.9, p=0.422). Treatment adherence
RI PT
Table 2 compares adherence to the index therapy among FTD/TPI patients versus REG during the observation period (mean duration of observation period, FTD/TPI vs. REG: 160.8 days vs. 211.7 days, p<0.001). The mean MPR was significantly higher for FTD/TPI patients compared to those on REG (mean MPR: 0.91 vs. 0.87, p<0.001). Consistently, the proportion of patients
SC
with MPR ≥0.80 and ≥0.90 were also higher for FTD/TPI patients compared to REG patients (84.5% vs. 74.0% and 71.2% vs. 55.1%, respectively, p<0.001). The mean PDC at 3 months and 6 months were significantly higher for FTD/TPI patients compared to REG patients (mean
M AN U
PDC at 3 months: 0.71 vs. 0.59, p<0.001; mean PDC at 6 months: 0.57 vs. 0.45, p<0.001). The proportion of patients with a PDC ≥0.8 were also significantly higher in the FTD/TPI cohort compared to the REG cohort (at 3 months of follow-up: 50.8% vs. 29.2%, p<0.001; at 6 months of follow-up: 23.6% vs. 12.6%, p<0.001).
After adjusting for the baseline covariates, medication adherence remained significantly higher for FTD/TPI patients compared to those on REG (Table 3). Specifically, FTD/TPI patients were
TE D
80% more likely to have a MPR ≥0.80 compared to those on REG (OR: 1.80, p<0.001) and were more than twice as likely to have a PDC ≥0.80 at 3 and 6 months (OR at 3 months: 2.66, p<0.001; OR at 6 months: 2.31, p<0.001) (Table 3).
EP
Treatment persistence and TTD
The mean TTD was significantly longer for FTD/TPI patients compared to those on REG,
AC C
regardless of whether discontinuation was defined as a gap in treatment of 45, 60, or 90 days (95.3 vs. 82.4 days, p<0.001; 101.1 vs. 88.2 days, p<0.001; and 116.1 vs. 105.3, p<0.001, respectively) (Table 2). Kaplan-Meier survival curves showed that the proportion of patients discontinuing therapy (when defined as no gaps in treatment ≥60 days) was significantly higher for REG patients compared to those on FTD/TPI over the follow-up time (log-rank test p<0.001) (Figure 2). For example, 6 months after the index date, 77.7% of the patients on REG discontinued their therapy compared to only 61.6% of the patients on FTD/TPI (p<0.001). Similar Kaplan-Meier curves were generated as a sensitivity analysis that defined discontinuation as gaps ≥45 days and ≥ 90 days (data not shown).
7
ACCEPTED MANUSCRIPT 4/11/2018
Confidential
After adjusting for the baseline covariates, FTD/TPI patients were 37% less likely to discontinue their treatment compared to those on REG, when defining discontinuation as having a gap of ≥60 days (HR: 0.63, p<0.001) (Table 3). Similarly, FTD/TPI patients were 36% and 40% less likely to discontinue their treatment compared to those on REG when defining discontinuation as having a gap of ≥45 days and 90 days, respectively (HR: 0.64, p<0.001 and HR: 0.60, p<0.001,
RI PT
respectively) (Table 3). Dosing patterns
FTD/TPI patients had a higher number of claims during the observation period compared to
SC
those on REG (3.2 vs. 2.9, p<0.001; data not shown). The mean DI for FTD/TPI was 106.1 mg/day, while it was 102.7 mg/day for REG (data not shown). FTD/TPI patients had a mean
patients had a mean RDI of 64%. DISCUSSION
M AN U
RDI of 88% or 82% when using presumed doses of 120 mg daily or 130 mg, respectively; REG
This retrospective claims data analysis assessed the real-world medication utilization of FTD/TPI and REG in mCRC patients and consistently showed that FTD/TPI was associated with better drug adherence and compliance than REG. After multivariable adjustment, the
TE D
proportion of patients with MPR higher than 80% was nearly doubled among patients initiated on FTD/TPI compared to those initiated on REG. Moreover, the proportion of patients with PDC higher than 80% was more than two times higher among FTD/TPI patients compared to REG patients.
EP
The adherence rates of FTD/TPI and REG in the analysis are similar to past findings from international single-center studies using self-reported treatment diaries to evaluate adherence.
AC C
One study showed a 95.0%-98.2% adherence rate for FTD/TPI, which agrees with our reported mean MPR of 0.91.20 In that study, reasons for lack of adherence included nausea/vomiting, abdominal pain, neutropenia, ileus, diarrhea, and missed doses. Our reported mean MPR of 0.87 for REG over a mean duration of 87 days was also consistent with the findings from other studies of adherence for this drug. A recently presented study found that REG adherence increased from 64.4% to 83.8% between cycles 1 and 3, citing hand-foot skin reaction (HFSR) and liver dysfunction as the main reasons for lack of adherence.21 A second study reported 86% adherence to REG using patient diaries, physician interview, and pill counts.22 A third study classified REG patients as adherent if they both self-reported adherence on a questionnaire and had an MPR of 80% or higher. The resulting adherence rate in this population was 82%. In that 8
ACCEPTED MANUSCRIPT 4/11/2018
Confidential
analysis, predictors of poor adherence to REG included higher Eastern Cooperative Oncology Group (ECOG) status, lower education level, lower level of REG acceptance, and use of many concomitant oral therapies.23 Our analysis showed that FTD/TPI patients had delayed TTD and higher persistence at 3 and 6
RI PT
months than those on REG, regardless of the duration of the gap used in the assessment of TTD. Only 40% of FTD/TPI patients discontinued treatment at 90 days (based on a 60-day duration of gap) following initiation of therapy, compared to 57% of REG patients. These rates, although much higher, are proportional to the rates of treatment discontinuation from clinical trials. In the RECOURSE trial,13 8% of FTD/TPI patients discontinued treatment for reasons not
SC
related to progression or death, compared to 12% of REG patients in the CORRECT trial.14 Note that there is no tumor progression information in claims databases, this analysis cannot
M AN U
estimate rates of discontinuation specifically for reasons other than progression or death, which may explain the higher rates in this analysis. In real-world data, TTD or time to next treatment can sometimes serve as a proxy for time to tumor progression.24–27
DI was closer to label recommendations for FTD/TPI compared to REG. This is consistent with prior international RDI reports of 92.9% and 57.6% for FTD/TPI28 and REG,21 respectively. The vast deviation from the recommended dose of REG may be attributable to toxicities, most
TE D
commonly hand-foot skin reactions.29 A retrospective single-center study of REG patients found that 43.8% of patients required dose reductions or interruptions, and 24% discontinued therapy altogether because of toxicities.30
The use of claims data is valuable due to their large scale, but they are subject to limitations.
EP
First, dosing instructions are not available in claims databases, therefore measures of adherence and persistence cannot account for any physician-instructed medication use that
AC C
deviates from the dosage provided in pharmacy dispensing claims records. Second, reasons for drug discontinuation are not observable in the claims data and thus cannot be assessed. Finally, residual confounding may exist if confounders remained uncontrolled due to the limits of data collection and potential claims data inaccuracies.31 Specifically, line of therapy could not be identified due to a combination of the 1) limited period of the dataset (October 2014-July 2016), which may truncate a patient's medical and drug utilization history and 2) lack of cancer-specific information in claims data such as date of first mCRC diagnosis. As for limitations specific to this study, the SHS database must employ a matching algorithm to link records across different health care facilities and pharmacies, linking on patient identifiable information. Non-matches/mismatches of patient records may occur if a patient received care 9
ACCEPTED MANUSCRIPT 4/11/2018
Confidential
from multiple doctors at different networks. Furthermore, the SHS database lacks eligibility files, meaning that patients must have incurred clinical services in order to be included in this study. A limitation of this study is the substantial proportion of patients with only one claim of their index agent due to the limited follow-up related to these drugs’ market availability. Also, since FTD/TPI was approved later than REG (September 2015 vs. September 2012),16,32 the limited
RI PT
follow-up time would have the tendency to bias the results against FTD/TPI and may artificially produce shorter DOT and lower adherence than the actuality. Finally, the SHS database does not include data on overall survival and progression free survival. However, the focus of this manuscript was on adherence and compliance in the real-world setting.
SC
Conclusions
This analysis of a large nationally-representative claims database indicates that FTD/TPI is
M AN U
associated with longer DOT and approximately two to three times better drug adherence than REG in patients with mCRC. Further research is needed to assess clinical and economic implications of better adherence and persistence for mCRC patients on FTD/TPI and REG in the real-world setting as well as understanding the reasons for discontinuations and nonadherence.
•
TE D
Clinical Practice Points
FTD/TPI and REG both prolong survival in refractory metastatic colorectal cancer and have similar indications with different side effect profiles. FTD/TPI patients are much more likely to adhere to therapy than REG patients
•
REG patients discontinue therapy faster than FTP/TPI patients
•
Real-world treatment patterns should be considered when selecting between FTD/TPI
EP
•
AC C
and REG therapy
10
ACCEPTED MANUSCRIPT 4/11/2018
Confidential
National Cancer Institute; Surveillance, Epidemiology and ERP. Cancer Stat Facts: Colon and Rectum Cancer. https://seer.cancer.gov/statfacts/html/colorect.html. Accessed March 28, 2017.
2.
Siegel R, Miller K, Jemal A. Cancer statistics, 2017 . CA Cancer J Clin. 2017;67(1):7-30.
3.
American Cancer Society. Cancer Facts & Figures 2017. Atlanta, GA; 2017.
4.
Siegel RL, Miller KD, Fedewa SA, et al. Colorectal cancer statistics , 2017. 2017;67(3):177-193. doi:10.3322/caac.21395.
5.
Ganesan P, Sagar TG, Dubashi B, et al. Nonadherence to imatinib adversely affects event free survival in chronic phase chronic myeloid leukemia. Am J Hematol. 2011;86(6):471-474. doi:10.1002/ajh.22019.
6.
Hershman DL, Shao T, Kushi LH, et al. Early discontinuation and non-adherence to adjuvant hormonal therapy are associated with increased mortality in women with breast cancer. Breast Cancer Res Treat. 2011;126(2):529-537. doi:10.1007/s10549-010-1132-4.
7.
Ibrahim AR, Eliasson L, Apperley JF, et al. Poor adherence is the main reason for loss of CCyR and imatinib failure for chronic myeloid leukemia patients on long-term therapy. Blood. 2011;117(14):3733-3736. doi:10.1182/blood-2010-10-309807.
8.
Seal BS, Anderson S, Shermock KM. Factors associated with adherence rates for oral and intravenous anticancer therapy in commercially insured patients with metastatic colon cancer. J Manag Care Spec Pharm. 2016;22(3):227-235. doi:10.18553/jmcp.2016.22.3.227.
9.
Liu G, Franssen E, Fitch M, Warner E. Patient preferences for oral versus intravenous palliative chemotherapy. J Clin Oncol. 1997;15(1):110-115. doi:10.1200/JCO.1997.15.1.110.
10.
Ruddy K, Mayer E, Partridge A. Patient adherence and persistence with oral anticancer treatment. 2009;59(1):56-66. doi:10.3322/caac.20004.
11.
Stivarga (regorafenib) prescribing information. Wayne, New Jersey: Bayer HealthCare Pharmaceuticals Inc.
12.
Lonsurf (trifluridine and tipiracil) prescribing information. Princeton, New Jersey: Taiho Pharmaceutical Co., Ltd.;
13.
14.
EP
TE D
M AN U
SC
RI PT
1.
AC C
References
Mayer RJ, Van Cutsem E, Falcone A, et al. Randomized Trial of TAS-102 for Refractory Metastatic Colorectal Cancer. N Engl J Med. 2015;372(20):1909-1919. doi:10.1056/NEJMoa1414325.
Grothey A, Van Cutsem E, Sobrero A, et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): An international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381(9863):303-312. doi:10.1016/S0140-6736(12)61900-X.
15.
Masuishi T, Taniguchi H, Hamauchi S, et al. Regorafenib Versus Trifluridine/Tipiracil for Refractory Metastatic Colorectal Cancer: A Retrospective Comparison. Clin Colorectal Cancer. 2017;16(2):e15-e22. doi:10.1016/j.clcc.2016.07.019.
16.
US Food and Drug Administration Center for Drug Evaluation and Research. Lonsurf NDA 207981 Approval Letter, September 22, 2015. 11
ACCEPTED MANUSCRIPT 4/11/2018
Confidential
Campagna EJ, Muser E, Parks J, Morrato EH. Methodological Considerations in Estimating Adherence and Persistence for a Long-Acting Injectable Medication. J Manag Care Spec Pharm. 2014;20(7):756-766.
18.
Watanabe JH, Bounthavong M, Chen T. Revisiting the medication possession ratio threshold for adherence in lipid management. Curr Med Res Opin. 2013;29(3):175-180. doi:10.1185/03007995.2013.766164.
19.
Sacco JJ, Botten J, Macbeth F, Bagust A, Clark P. The average body surface area of adult cancer patients in the UK: A multicentre retrospective study. PLoS One. 2010;5(1):1-6. doi:10.1371/journal.pone.0008933.
20.
Sugita K, Kawakami K, Yokokawa T, et al. Self-reported adherence to trifluridine and tipiracil hydrochloride for metastatic colorectal cancer: A retrospective cohort study. Oncol. 2016;91(4):224-230. doi:10.1159/000448717.
21.
Kawakami K, Suenaga M, Soejima A, et al. Self-reported adherence to regorafenib for metastatic colorectal cancer: A retrospective cohort study. J Clin Oncol. 2017;35:supp 4S; abstract 783.
22.
Del Prete S, Addeo R, Montesarchio V, et al. Adherence to regorafenib therapy in patients with previously treated metastatic colorectal cancer: STI observational multicenter study. J Clin Oncol. 2015;33(suppl; abstr e17529).
23.
Del Prete S, Cennamo G, Leo L, et al. Adherence and safety of regorafenib for patients with metastatic colorectal cancer: observational real-life study. Futur Oncol. 2017;13(5):415-423. doi:10.2217/fon-2016-0421.
24.
Chen C-C, Parikh K, Abouzaid S, et al. Real-world treatment patterns, time to next treatment, and economic outcomes in relapsed or refractory multiple myeloma patients treated with pomalidomide or carfilzomib. J Manag Care Spec Pharm. 2017;23(2):236246. doi:10.18553/jmcp.2017.23.2.236.
25.
Blommestein HM, Franken MG, Uyl-de Groot CA. A practical guide for using registry data to inform decisions about the cost effectiveness of new cancer drugs: Lessons learned from the PHAROS registry. Pharmacoeconomics. 2015;33(6):551-560. doi:10.1007/s40273-015-0260-4.
26.
National Institute for Health and Care Excellence. Abiraterone for castration-resistant metastatic prostate cancer previously treated with a docetaxel-containing regimen. NICE Technol Apprais Guid. 259(June 2012).
27.
National Institute for Health and Care Excellence. Enzalutamide for metastatic hormonerelapsed prostate cancer previously treated with a docetaxel-containing regimen. NICE Technol Apprais Guid. 316(July 2014).
29.
SC
M AN U
TE D
EP
AC C
28.
RI PT
17.
Sugita K, Kawakami K, Yokokawa T, et al. Self-reported adherence with TAS-102. Ann Oncol. 2015;26(supp_7):vii100. Krishnamoorthy SK, Relias V, Sebastian S, Jayaraman V, Saif MW. Management of regorafenib-related toxicities: a review. Therap Adv Gastroenterol. 2015;8(5):285-297. doi:10.1177/1756283X15580743.
30.
Bugano D, Gomes D, Hassabo HM, et al. MD Anderson experience with off-study regorafenib in patients with advanced colorectal cancer. J Clin Oncol. 2014;32(suppl3; abstr 635).
31.
Johnson EK, Nelson CP. Utility and Pitfalls in the Use of Administrative Databases for Outcomes Assessment. J Urol. 2013;190(1):17-18. doi:10.1016/j.juro.2013.04.048.
32.
US Food and Drug Administration Center for Drug Evaluation and Research. Stivarga 12
ACCEPTED MANUSCRIPT 4/11/2018
Confidential
AC C
EP
TE D
M AN U
SC
RI PT
NDA 203085 Approval Letter, September 27, 2012.
13
ACCEPTED MANUSCRIPT
4/11/2018
Confidential
RI PT
Figure 1. Identification of the study population
1
≥1 diagnosis of CRC and ≥1 pharmacy dispensing of FTD-TPI or REG N = 5,500 2
3
No diagnosis of gastric cancer or gastrointestinal stromal tumors
M AN U
SC
N = 5,389 (98.0%)
FTD-TPI patients N = 2,844 (52.8%)
REG patients N = 2,545 (47.2%)
≥18 years of age at index date
N = 2,844 (100.0%)
N = 2,545 (100.0%)
EP
≥3 months continuous clinical activity prior index date N = 1,630 (88.9%)
≥3 months continuous clinical activity post index date N = 1,910 (75.0%)
AC C
≥3 months continuous clinical activity post index date N = 1,834 (64.5%)
TE D
≥18 years of age at index date
≥3 months continuous clinical activity prior index date N = 1,425 (74.6%)
Abbreviations: CRC=colorectal cancer; ICD-9-CM = International classification of diseases, ninth edition-clinical modifications; ICD-10-CM = International classification of diseases, tenth edition-clinical modifications. Notes: 1. CRC was identified using the ICD-9-CM codes 153.x, 154.0x, 154.1x, 154.8x and ICD-10-CM codes C18, C19, C20 and C21.8. 2. Gastric cancer was identified using the ICD-9-CM code 151.x and the ICD-10-CM codes C16.8 and C16.9. 3. Gastrointestinal stromal tumor was identified using the ICD-9-CM codes 171.5x, 215.5x and 238.1x and ICD-10-CM codes C49.4x, D21.4x and D48.1x.
14
ACCEPTED MANUSCRIPT
4/11/2018
Confidential
RI PT
Table 1. Baseline characteristics of FTD/TPI or REG patients
AC C
EP
TE D
M AN U
SC
Demographic characteristics, evaluated at the index date Female, N (%) Year of treatment initiation, N (%) 2014 2015 2016 Age at treatment initiation, mean ± SD [median] Age, N (%) < 35 35 – 44 45 – 54 55 – 64 65 – 74 75 + Region, N (%) South Midwest West Northeast Unknown Insurance plan at treatment initiation, N (%) Medicare Medicaid Commercial
15
FTD/TPI patients (N=1,630)
REG patients (N=1,425)
Pvalue
742 (45.5)
637 (44.7)
0.650
0 (0.0) 755 (46.3) 875 (53.7) 61.0 ± 11.0
11 (0.8) 1,186 (83.2) 228 (16.0) 62.8 ± 10.9
<0.001* <0.001* <0.001* <0.001*
22 (1.3) 94 (5.8) 353 (21.7) 517 (31.7) 445 (27.3) 199 (12.2)
14 (1.0) 65 (4.6) 248 (17.4) 408 (28.6) 463 (32.5) 227 (15.9)
0.348 0.135 0.003* 0.064 0.002* 0.003*
677 (41.5) 305 (18.7) 267 (16.4) 356 (21.8) 25 (1.5)
642 (45.1) 319 (22.4) 207 (14.5) 236 (16.6) 21 (1.5)
0.050 0.012* 0.158 <0.001* 0.892
602 (36.9) 129 (7.9) 888 (54.5)
753 (52.8) 165 (11.6) 501 (35.2)
<0.001* <0.001* <0.001*
ACCEPTED MANUSCRIPT
4/11/2018
Confidential
AC C
EP
TE D
M AN U
SC
RI PT
Other 11 (0.7) Clinical characteristics during the 3-month baseline period Charlson Comorbidity Index (CCI), mean ± SD [median] 3.8 ± 2.9 [6.0] Individual components of CCI, N (%) AIDS 2 (0.1) Cerebrovascular disease 16 (1.0) Chronic diabetes 14 (0.9) Chronic pulmonary disease 66 (4.0) Congestive heart failure 18 (1.1) Dementia 3 (0.2) Hemiplegia 2 (0.1) Liver disease 11 (0.7) Malignancy (including lymphoma and leukemia) 385 (23.6) Metastatic solid tumor 820 (50.3) Mild liver disease 93 (5.7) Mild to moderate diabetes 125 (7.7) Myocardial infarction 11 (0.7) Peripheral vascular disease 24 (1.5) Peptic ulcer disease, 5 (0.3) Renal disease 46 (2.8) Rheumatologic disease 4 (0.2) Other comorbidities, N (%) Arterial thromboembolism 2 (0.1) Cardiac dysrhythmia 21 (1.3) Coronary artery disease 48 (2.9) Hypertension 310 (19.0) Stroke 6 (0.4) Venous thromboembolism 41 (2.5) mCRC chemotherapy used in 3-month period prior to treatment initiation, N (%) Any chemotherapy 575 (35.3) 5-fluorouracil 309 (19.0) Bevacizumab 191 (11.7) 16
6 (0.4)
0.347
3.9 ± 2.9 [5.0]
0.422
3 (0.2) 15 (1.1) 24 (1.7) 59 (4.1) 22 (1.5) 0 (0.0) 1 (0.1) 8 (0.6) 401 (28.1) 707 (49.6) 101 (7.1) 120 (8.4) 10 (0.7) 27 (1.9) 2 (0.1) 35 (2.5) 4 (0.3)
0.669 0.845 0.040* 0.899 0.286 0.253 1.000 0.691 0.004* 0.702 0.118 0.445 0.928 0.363 0.460 0.530 1.000
3 (0.2) 36 (2.5) 39 (2.7) 296 (20.8) 4 (0.3) 21 (1.5)
0.669 0.012* 0.730 0.225 0.759 0.042*
575 (40.4) 306 (21.5) 177 (12.4)
0.004* 0.084 0.551
ACCEPTED MANUSCRIPT
4/11/2018
Confidential
AC C
EP
TE D
M AN U
SC
RI PT
Capecitabine 133 (8.2) 141 (9.9) 0.094 Cetuximab 71 (4.4) 78 (5.5) 0.152 Irinotecan 255 (15.6) 282 (19.8) 0.003* Leucovorin 187 (11.5) 206 (14.5) 0.014* Mitomycin 0 (0.0) 0 (0.0) Oxaliplatin 95 (5.8) 90 (6.3) 0.573 Panitumumab 56 (3.4) 59 (4.1) 0.307 Ramucirumab 8 (0.5) 4 (0.3) 0.354 Ziv-aflibercept 1 (0.1) 1 (0.1) 1.000 No chemotherapy 1,055 (64.7) 850 (59.6) 0.004* Abbreviations: FTD/TPI = Trifluridine/Tipiracil; REG = regorafenib; SD = standard deviation; mCRC = metastatic colorectal cancer * p-value<0.05
17
ACCEPTED MANUSCRIPT
4/11/2018
Confidential
REG patients (N =1,425) 211.67 ± 112.61 [181.00] 1,333 (93.5) 717 (50.3)
P-value
87.26 ± 74.94 [66.00]
<0.001*
953 (66.9) 0.87 ± 0.15 [0.92] 705 (74.0) 525 (55.1)
<0.001* <0.001* <0.001* <0.001*
RI PT
Table 2. Adherence and persistence among patients initiated on FTD/TPI and REG FTD/TPI patients (N =1,630) Length of the observation period (days), mean ± SD [median] 160.79 ± 59.43 [156.00] Patients followed for ≥ 3 months, N (%) 1,524 (93.5) Patients followed for ≥ 6 months, N (%) 554 (34.0) Duration of treatment (DOT) (days), mean ± SD [median]
94.89 ± 57.35 [84.00]
AC C
EP
TE D
M AN U
SC
Medication possession ratio (MPR) Patients with ≥ 2 claims, N (%) 1,335 (81.9) MPR, Mean ± SD [median] 0.91 ± 0.13 [0.98] MPR ≥ 0.80, N (%) 1,128 (84.5) MPR ≥ 0.90, N (%) 951 (71.2) Proportion of days covered (PDC) At 3 months, N 1,524 (93.5) PDC, mean ± SD [median] 0.71 ± 0.24 [0.81] PDC ≥ 0.80, N (%) 774 (50.8) PDC ≥ 0.90, N (%) 533 (35.0) At 6 months, N 554 (34.0) PDC, mean ± SD [median] 0.57 ± 0.25 [0.58] PDC ≥ 0.80, N (%) 131 (23.6) PDC ≥ 0.90, N (%) 67 (12.1) Persistence, N (%) At 3 months, N 1,524 (93.5) No gap ≥ 45 days 1,229 (80.6) No gap ≥ 60 days 1,269 (83.3) At 6 months, N 554 (34.0) No gap ≥ 45 days 209 (37.7) No gap ≥ 60 days 255 (46.0) Time to discontinuation, mean ± SD [median] No gap ≥ 45 days 95.33 ± 57.74 [89.00] No gap ≥ 60 days 101.10 ± 59.37 [97.00] No gap ≥ 90 days 116.06 ± 60.90 [111.00] Abbreviations: FTD/TPI = Trifluridine/Tipiracil; REG = regorafenib; SD = standard deviation * p-value<0.05 18
1,333 (93.5) 0.59 ± 0.25 [0.62] 389 (29.2) 245 (18.4) 717 (50.3) 0.45 ± 0.26 [0.43] 90 (12.6) 43 (6.0) 1,333 (93.5) 836 (62.7) 894 (67.1) 717 (50.3) 200 (27.9) 244 (34.0) 82.38 ± 68.52 [62.00] 88.17 ± 72.99 [69.00] 105.32 ± 78.92 [94.00]
<0.001* -
<0.001* <0.001* <0.001* <0.001* <0.001* <0.001* <0.001* <0.001* <0.001* <0.001* <0.001* <0.001* <0.001*
ACCEPTED MANUSCRIPT
4/11/2018
Confidential
RI PT
Figure 2. Proportion of patients discontinuing therapy (no gap ≥ 60 days) among patients initiated on FTD/TPI or REG
100% 90%
SC
FTD/TPI patients
M AN U
70% REG patients 60% 50%
TE D
40% 30%
EP
20% 10% 0% 0
30
AC C
% of patients discontinuing therapy
Log-rank test: p-value<0.001* 80%
60
90
120 Time (Days)
Abbreviations: FTD/TPI = Trifluridine/Tipiracil; REG = regorafenib * p-value<0.05
19
150
180
210
240
ACCEPTED MANUSCRIPT
4/11/2018
Confidential
Table 3. Comparison of persistence and adherence, adjusted for baseline characteristics between patients initiated on FTD/TPI and REG 1
<0.001*
P-
1.80 (1.42, 2.27)
<0.001*
RI PT
3.36 (2.09, 4.64)
Odds ratio (95% CI)3 (FTD/TPI vs. REG)
SC
Proportion of days covered PDC (%), at 3 months PDC (%), at 6 months
P-value
12.52 (10.50, 14.55) 13.91 (10.92, 16.91)
PDC ≥ 80%, at 3 months PDC ≥ 80%, at 6 months
M AN U
Medication possession ratio MPR (%) MPR ≥ 80%
Mean difference (95% CI)2 (FTD/TPI vs. REG)
Hazard ratio (95% CI)4 (FTD/TPI vs. REG)
P-value
<0.001* <0.001*
2.66 (2.24, 3.17) 2.31 (1.68, 3.19)
<0.001* <0.001*
AC C
EP
TE D
Time to discontinuation No gap ≥ 45 days 0.64 (0.59, 0.71) <0.001* No gap ≥ 60 days 0.63 (0.57, 0.70) <0.001* No gap ≥ 90 days 0.60 (0.53, 0.68) <0.001* Abbreviations: FTD/TPI = Trifluridine/Tipiracil; REG = regorafenib; CI = confidence interval * p-value<0.05 Notes: 1. All models are multivariate models adjusting for demographic covariates (i.e., age, gender, region, insurance plan), Charlson comorbidity index, individual comorbidities and baseline treatments/medications that had statistical significant differences between cohorts (p-value<0.05, Table 1), all-cause baseline prescription drug costs, all-cause baseline medical costs, number of all-cause baseline inpatient visits, and number of all-cause baseline emergency room visits. 2. Estimated using multivariable linear regression models. 3. Estimated using multivariable logistic regression models. 4. Estimated using multivariable Cox proportional hazards regression models. 20
S1533-0028(18)30009-4
DOI:
10.1016/j.clcc.2018.04.002
Reference:
CLCC 459
To appear in:
Clinical Colorectal Cancer
Received Date: 12 January 2018 Revised Date:
11 April 2018
Accepted Date: 16 April 2018
Please cite this article as: Patel AK, Duh MS, Barghout V, Yenikomshian MA, Xiao Y, Wynant W, Tabesh M, Fuchs CS, Real-World Treatment Patterns Among Patients With Colorectal Cancer Treated With Trifluridine/Tipiracil And Regorafenib, Clinical Colorectal Cancer (2018), doi: 10.1016/ j.clcc.2018.04.002. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT 4/11/2018
Confidential
REAL-WORLD TREATMENT PATTERNS AMONG PATIENTS WITH COLORECTAL CANCER TREATED WITH TRIFLURIDINE/TIPIRACIL AND REGORAFENIB
Dana-Farber Cancer Institute, Boston, MA Analysis Group, Inc., Boston, MA 3 VEB HealthCare LLC, Morristown, NJ 4 Groupe d'analyse, Ltée, Montréal, QC, Canada 5 Strategic Global Medical Affairs LLC, Chicago, IL 6 Yale Cancer Center, New Haven, CT 2
M AN U
Disclosures: Research Funding
SC
1
RI PT
Anuj K Patel, MD1; Mei S Duh, MPH, ScD2; Victoria Barghout, MSPH3; Mihran A Yenikomshian, MBA2; Yongling Xiao, PhD4; Willy Wynant, PhD4; Majid Tabesh, MD, PhD5;Charles S Fuchs, MD, MPH1,6
This study is funded by Taiho Oncology, Inc.
Declaration of Conflicts of Interest/Other Relationships
EP
TE D
Research funding was provided to Analysis Group, Inc. by Taiho Oncology, Inc. Dana-Farber Cancer Institute received a research fund from Analysis Group. AK Patel is an employee of the Dana-Farber Cancer Institute and has not received any consultation fee from Analysis Group, Inc., or Taiho Oncology, Inc. for this study. MS Duh and MA Yenikomshian are employees of Analysis Group, Inc. V Barghout is an employee of VEB HealthCare LLC. and has received a consultant fee from Taiho Oncology. Y Xiao and W Wynant are employees of Groupe d’analyse, Ltée. M Tabesh is an employee of Strategic Global Medical Affairs LLC. and has received a consultant fee from Taiho Oncology. CS Fuchs was an employee of the Dana-Farber Cancer Institute at the start of the study and is an employee with Yale Cancer Center. CS Fuchs has received consultation fees from Analysis Group, Inc. for this study.
AC C
Acknowledgments: The authors are grateful for the writing assistance provided by Erin McDonnell, formerly of Analysis Group, Inc. Corresponding author: Mihran Yenikomshian Mailing address: Analysis Group, Inc., 111 Huntington Ave, 14th Floor, Boston, MA 02199 Phone: 617-425-8158 Fax number: 617-425-8001 Email: [email protected] RUNNING HEAD: TRIFLURIDINE/TIPIRACIL AND REGORAFENIB TREATMENT PATTERNS
1
ACCEPTED MANUSCRIPT 4/11/2018
Confidential
MicroAbstract (Range= 40-60 words, current word count=51 words)
RI PT
Real-world data comparing treatment patterns of trifluridine/tipiracil (FTD/TPI) and regorafenib (REG) in refractory metastatic colorectal cancer patients are lacking/insufficient. This study evaluated real-world treatment patterns using a large-scale nationally-representative US claims database. Our results suggest that mCRC patients initiating on FTD/TPI have better adherence and compliance than patients initiating on REG. Structured Abstract (250 word limit, current word count = 250 words)
SC
BACKGROUND: Trifluridine/tipiracil (FTD/TPI) and regorafenib (REG) prolong survival in refractory metastatic colorectal cancer (mCRC) and have similar indications with different side effect profiles. This study compares real-world treatment patterns with FTD/TPI and REG for mCRC in a large, representative US claims database.
M AN U
METHODS: Retrospective data from the US Symphony Health Solutions’ Integrated Dataverse (IDV®) database were analyzed for adult mCRC patients receiving FTD/TPI or REG (10/20147/2016). The index date was first FTD/TPI or REG prescription date. The observation period spanned from index date to end of data, end of continuous clinical activity, or treatment switch. Adherence was assessed using medication possession ratio (MPR) and proportion of days covered (PDC) at 3 months. Time to discontinuation were assessed over the observation period with gaps of 45, 60, or 90 days. Outcomes were compared between cohorts using logistic regression and Cox proportional hazards models adjusting for baseline characteristic differences.
EP
TE D
RESULTS: A total of 1,630 FTD/TPI patients and 1,425 REG patients were identified. FTD/TPI patients were 80% more likely to have a MPR≥0.80 compared to REG patients (Odds Ratio [OR]= 1.80, p<0.001) and more than twice as likely to have a PDC≥0.80 (OR= 2.66, p<0.001) at 3 months. FTD/TPI patients were 37% less likely to discontinue their treatment compared to REG patients when using 60-day gaps (Hazard Ratio= 0.63, p<0.001). Similar results were found using 45- and 90-day gaps. CONCLUSIONS: mCRC patients on FTD/TPI were significantly more likely to adhere and comply with therapy compared to those on REG.
AC C
KEYWORDS: (five keywords should be listed at the bottom of the abstract page) Colorectal cancer, drug adherence, treatment patterns, trifluridine/tipiracil, regorafenib
2
ACCEPTED MANUSCRIPT 4/11/2018
Confidential
BACKGROUND Colorectal cancer (CRC) is the fourth most common type of cancer diagnosed in the United States (US) and represents 8.0% of all new cancer cases nationwide1,2 An estimated 135,430 new cases will be diagnosed and 50,260 deaths attributed to CRC in 20172,3 with approximately
RI PT
50%-60% of patients developing metastatic disease.4 The 5-year survival rate of metastatic CRC (mCRC) is 14%.4 Long term survival for mCRC has improved gradually over the last 30 years, likely representative of advancements in treatments and new agents active against this disease.4
SC
Survival and disease progression highly depend on patient medication adherence.5–7 A recent study of mCRC concluded that 28% of chemotherapy regimens were associated with an adherence rate of less than 80%.8 Multiple studies have demonstrated that most cancer patients
M AN U
prefer oral treatment over IV treatment for reasons such as convenience, environment while receiving treatment, and problems with IV administration.9 However, mCRC patients are actually less adherent to oral chemotherapies.8 Reasons for lack of adherence to these preferred therapies include less frequent interactions with care providers for education and counseling, simply forgetting doses, disliking aspects of the medication, and management of adverse events.10
TE D
In refractory mCRC, two approved oral agents, trifluridine/tipiracil (FTD/TPI) (Lonsurf®;Taiho Pharmaceutical, Tokyo, Japan) and regorafenib (REG) (Stivarga®; Bayer Pharma AG, Berlin, Germany), have been proven to prolong survival in randomized, multicenter phase III clinical trials. Both agents are indicated for the treatment of patients with mCRC who have been
EP
previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, as well as with anti-VEGF therapy and anti-EGFR therapy, if RAS wild type.11,12 REG is a multikinase inhibitor with activity in multiple pathways, including those involved in angiogenesis,
AC C
tumor microenvironment, and oncogenesis.11 FTD/TPI is a combination of trifluridine, a nucleoside metabolic inhibitor, and tipiracil, a thymidine phosphorylase inhibitor.12 In the RECOURSE study, FTD/TPI showed significant improvement in median overall survival compared to placebo (7.1 vs. 5.3 months; HR 0.68; 95% CI 0.58-0.81; p<0.001).13 In the CORRECT study, REG showed significant improvement in median overall survival compared to placebo (6.4 vs. 5.0 months; HR 0.77; 95% confidence interval [CI] 0.64-0.94; p=0.0052). 14 Despite similar indications and oral administration, FTD/TPI and REG have not been compared head-to-head in a clinical trial. Although a recent real-world retrospective analysis was conducted to compare the two treatments in patients with refractory mCRC showing that the two 3
ACCEPTED MANUSCRIPT 4/11/2018
Confidential
treatments had similar efficacy but different side effect profiles, this study was conducted in Japan based on data collected from only two cancer centers, and thus had a very small sample size.15 In addition, the generalizability of the study results to the US population may be also limited.15 Moreover, while FTD/TPI gained FDA-approval in September 2015, real-world data on treatment patterns of these therapies are lacking.16 While both agents are administered orally,
RI PT
they possess distinct side effect profiles. Dose reductions or treatment interruptions may be considered in real-world clinical practice, with the aim of reducing or avoiding adverse reactions. This study aims to evaluate real-world treatment patterns following initiation of FTD/TPI or REG for mCRC through the investigation of a large, nationally-representative US claims database.
SC
METHODS
M AN U
Data Sources
This study uses the Symphony Health Solutions’ (SHS) Integrated Dataverse (IDV®) database. The SHS database is a nationally-representative longitudinal de-identified claims database, which captures prescription and medical claims for over 220 million people across the US and covers all payment types. Data collected from October 2014 to July 2016 were used in this study.
TE D
Study Design and Patient Selection
A retrospective longitudinal cohort design was used to conduct this study. Patients diagnosed with CRC (ICD-9-CM: 153.x, 154.0x, 154.1x, 154.8x; ICD-10-CM: C18.x, C19.x, C20.x, C21.8) who received either FTD/TPI (Generic Product Identifier [GPI]: 2199000275) or REG (GPI:
EP
2153305000) between October 2014 and July 2016 were included in the study population. The index date was defined as the earliest date of the first FTD/TPI or REG claim; the index therapy
AC C
was the therapy (FTD/TPI or REG) supplied on the index date. Patients were included in the study if they were 18 years or older, had at least one diagnosis of CRC, did not have a diagnosis of gastric cancer or gastrointestinal stromal tumor, and had continuous clinical activity for at least 3 months both before and after the index date. The baseline period corresponded to the 3-month period prior to the index date used to assess baseline characteristics, except for baseline healthcare resource utilization variables that were assessed over the entire period prior to the index date. Patients were classified into two study cohorts based on the treatment they received at the index date: the FTD/TPI and REG cohorts. The observation period spanned from the index date 4
ACCEPTED MANUSCRIPT 4/11/2018
Confidential
to the earliest date among the switch to another mCRC treatment, the end of continuous clinical activity, or the end of data availability. Outcomes and Statistical Analysis Treatment patterns for the index therapy, including duration of treatment (DOT), medication
RI PT
adherence, and persistence, were assessed for each cohort. DOT was calculated over the observation period as the difference between the index date and the last day of supply of the last prescription. Medication adherence was assessed using medication possession ratio (MPR) and proportion of days covered (PDC). MPR was calculated by dividing total number of days of
SC
medication supplied by total number of days between the first prescription and the last day of supply of the last prescription among patients with at least 2 prescriptions. PDC was defined as the number of unique days with medication divided by the length of a fixed time interval. For
M AN U
both MPR and PDC, proportions of patients having a threshold equal to or over 0.8 and 0.9 were also reported.17,18 Persistence was defined as continuous use of the index therapy over a fixed time interval, with a specified allowable gap (i.e., 45 or 60 days) between two consecutive prescriptions or in the period between the last day of supply of the last prescription and the end of the assessment period. Both PDC and persistence were evaluated at 3 and 6 months after the index date among patients with at least 3 and 6 months of follow-up, respectively. In
TE D
addition, time to discontinuation (TTD) was assessed over the entire observation period using three allowable gap thresholds (i.e., 45, 60, or 90 days). Patients who never discontinued the index therapy were censored at the end of the observation period. Dosing patterns for the index therapy were evaluated over the observation period using dose
EP
intensity (DI) and relative dose intensity (RDI). DI was used to measure the amount of drug delivered per unit of time, calculated by dividing the sum of strength (in milligrams) of all prescriptions for the index therapy by DOT, multiplying by a factor of 2.8 for FTD/TPI (28 days of
AC C
a cycle divided by 10 dosing days) and 1.3 for REG (28 days of a cycle divided by 21 dosing days). The choice of the factors was determined based on the labeled recommended doses for FTD/TPI and REG.11,12 The recommended dose for FTD/TPI is 35 mg/m2/dose twice daily on days 1 through 5 and days 8 through 12 of each 28-day cycle;12 the recommended dose for REG is 160 mg once daily for the first 21 days of each 28-day cycle.11 This analysis assumed two distinct recommended daily doses of FTD/TPI to reflect the variability in body mass surface area (BSA). Doses of 120 mg and 130 mg were chosen based on previously reported 95% confidence limits of 1.81 to 1.84 m2 for mean BSA among adjuvant CRC patients,19 which corresponds to recommended daily doses of 126.7 mg to 128.8 mg. Daily dosages of FTD/TPI 5
ACCEPTED MANUSCRIPT 4/11/2018
Confidential
were rounded to account for the two available dosage strengths of tablets. RDI was calculated as the ratio of the DI of the administered regimen to the DI of the recommended regimen as noted in the prescribing information (i.e., 160 mg/day for REG and 120 mg/day or 130 mg/day for FTD/TPI per BSA described above). While the patient was on index therapy, both DI and RDI were estimated from the population-level perspective using the median number of claims,
RI PT
mode of drug quantity, mode of drug strength, and mean DOT obtained from the SHS claims data. To account for data errors in the quantity field of the claims data, patients were excluded from these calculations if they had at least one prescription for the study drugs with a quantity of less than 20 pills (approximately <25% of the labeled recommended doses).
SC
Descriptive statistics were reported for patient and clinical characteristics at baseline as well as for treatment patterns during the observation period. Means, standard deviations (SDs), and
M AN U
medians were used to describe continuous variables; frequencies and percentages were reported for categorical variables. Differences in baseline demographics and clinical characteristics between cohorts were assessed using Chi-square tests for categorical variables and Wilcoxon rank sum tests for continuous variables. Kaplan-Meier survival analyses were conducted to illustrate the differences in treatment discontinuation between the two cohorts. Multivariate regression models were used to estimate the adjusted differences in treatment
TE D
patterns between cohorts. The baseline covariates adjusted for in the models included age, gender, region, insurance plan, Charlson Comorbidity Index (CCI), individual comorbidities and baseline treatments/medications that significantly differed between cohorts (p-value<0.05), allcause baseline prescription drug costs, all-cause baseline medical costs, number of all-cause
EP
baseline IP visits, and number of all-cause baseline ER visits. Cox proportional hazards models were used to estimate hazard ratios and their corresponding 95% confidence intervals (CIs) for TTD. Linear regression models were used to estimate mean differences and their corresponding
AC C
95% CIs for continuous PDC and MPR. Logistic regression models were used to estimate odds ratios (OR) and their corresponding 95% CIs for dichotomized PDC, MPR, and persistence. RESULTS
Baseline Characteristics
1,630 FTD/TPI patients and 1,425 REG patients were included in the study (see Figure 1). Table 1 summarizes the baseline demographic and clinical characteristics of each cohort. FTD/TPI patients were younger compared to those on REG (mean age: 61.0 vs. 62.8, p<0.001). FTD/TPI patients had started their treatment more recently compared to those on REG 6
ACCEPTED MANUSCRIPT 4/11/2018
Confidential
(initiation in 2015: 46.3% vs. 83.2%, p<0.001; initiation in 2016: 53.7% vs. 16.0%, p<0.001). During the 3-month baseline period, the mean CCI was similar between the two cohorts (FTD/TPI vs. REG: 3.8 vs. 3.9, p=0.422). Treatment adherence
RI PT
Table 2 compares adherence to the index therapy among FTD/TPI patients versus REG during the observation period (mean duration of observation period, FTD/TPI vs. REG: 160.8 days vs. 211.7 days, p<0.001). The mean MPR was significantly higher for FTD/TPI patients compared to those on REG (mean MPR: 0.91 vs. 0.87, p<0.001). Consistently, the proportion of patients
SC
with MPR ≥0.80 and ≥0.90 were also higher for FTD/TPI patients compared to REG patients (84.5% vs. 74.0% and 71.2% vs. 55.1%, respectively, p<0.001). The mean PDC at 3 months and 6 months were significantly higher for FTD/TPI patients compared to REG patients (mean
M AN U
PDC at 3 months: 0.71 vs. 0.59, p<0.001; mean PDC at 6 months: 0.57 vs. 0.45, p<0.001). The proportion of patients with a PDC ≥0.8 were also significantly higher in the FTD/TPI cohort compared to the REG cohort (at 3 months of follow-up: 50.8% vs. 29.2%, p<0.001; at 6 months of follow-up: 23.6% vs. 12.6%, p<0.001).
After adjusting for the baseline covariates, medication adherence remained significantly higher for FTD/TPI patients compared to those on REG (Table 3). Specifically, FTD/TPI patients were
TE D
80% more likely to have a MPR ≥0.80 compared to those on REG (OR: 1.80, p<0.001) and were more than twice as likely to have a PDC ≥0.80 at 3 and 6 months (OR at 3 months: 2.66, p<0.001; OR at 6 months: 2.31, p<0.001) (Table 3).
EP
Treatment persistence and TTD
The mean TTD was significantly longer for FTD/TPI patients compared to those on REG,
AC C
regardless of whether discontinuation was defined as a gap in treatment of 45, 60, or 90 days (95.3 vs. 82.4 days, p<0.001; 101.1 vs. 88.2 days, p<0.001; and 116.1 vs. 105.3, p<0.001, respectively) (Table 2). Kaplan-Meier survival curves showed that the proportion of patients discontinuing therapy (when defined as no gaps in treatment ≥60 days) was significantly higher for REG patients compared to those on FTD/TPI over the follow-up time (log-rank test p<0.001) (Figure 2). For example, 6 months after the index date, 77.7% of the patients on REG discontinued their therapy compared to only 61.6% of the patients on FTD/TPI (p<0.001). Similar Kaplan-Meier curves were generated as a sensitivity analysis that defined discontinuation as gaps ≥45 days and ≥ 90 days (data not shown).
7
ACCEPTED MANUSCRIPT 4/11/2018
Confidential
After adjusting for the baseline covariates, FTD/TPI patients were 37% less likely to discontinue their treatment compared to those on REG, when defining discontinuation as having a gap of ≥60 days (HR: 0.63, p<0.001) (Table 3). Similarly, FTD/TPI patients were 36% and 40% less likely to discontinue their treatment compared to those on REG when defining discontinuation as having a gap of ≥45 days and 90 days, respectively (HR: 0.64, p<0.001 and HR: 0.60, p<0.001,
RI PT
respectively) (Table 3). Dosing patterns
FTD/TPI patients had a higher number of claims during the observation period compared to
SC
those on REG (3.2 vs. 2.9, p<0.001; data not shown). The mean DI for FTD/TPI was 106.1 mg/day, while it was 102.7 mg/day for REG (data not shown). FTD/TPI patients had a mean
patients had a mean RDI of 64%. DISCUSSION
M AN U
RDI of 88% or 82% when using presumed doses of 120 mg daily or 130 mg, respectively; REG
This retrospective claims data analysis assessed the real-world medication utilization of FTD/TPI and REG in mCRC patients and consistently showed that FTD/TPI was associated with better drug adherence and compliance than REG. After multivariable adjustment, the
TE D
proportion of patients with MPR higher than 80% was nearly doubled among patients initiated on FTD/TPI compared to those initiated on REG. Moreover, the proportion of patients with PDC higher than 80% was more than two times higher among FTD/TPI patients compared to REG patients.
EP
The adherence rates of FTD/TPI and REG in the analysis are similar to past findings from international single-center studies using self-reported treatment diaries to evaluate adherence.
AC C
One study showed a 95.0%-98.2% adherence rate for FTD/TPI, which agrees with our reported mean MPR of 0.91.20 In that study, reasons for lack of adherence included nausea/vomiting, abdominal pain, neutropenia, ileus, diarrhea, and missed doses. Our reported mean MPR of 0.87 for REG over a mean duration of 87 days was also consistent with the findings from other studies of adherence for this drug. A recently presented study found that REG adherence increased from 64.4% to 83.8% between cycles 1 and 3, citing hand-foot skin reaction (HFSR) and liver dysfunction as the main reasons for lack of adherence.21 A second study reported 86% adherence to REG using patient diaries, physician interview, and pill counts.22 A third study classified REG patients as adherent if they both self-reported adherence on a questionnaire and had an MPR of 80% or higher. The resulting adherence rate in this population was 82%. In that 8
ACCEPTED MANUSCRIPT 4/11/2018
Confidential
analysis, predictors of poor adherence to REG included higher Eastern Cooperative Oncology Group (ECOG) status, lower education level, lower level of REG acceptance, and use of many concomitant oral therapies.23 Our analysis showed that FTD/TPI patients had delayed TTD and higher persistence at 3 and 6
RI PT
months than those on REG, regardless of the duration of the gap used in the assessment of TTD. Only 40% of FTD/TPI patients discontinued treatment at 90 days (based on a 60-day duration of gap) following initiation of therapy, compared to 57% of REG patients. These rates, although much higher, are proportional to the rates of treatment discontinuation from clinical trials. In the RECOURSE trial,13 8% of FTD/TPI patients discontinued treatment for reasons not
SC
related to progression or death, compared to 12% of REG patients in the CORRECT trial.14 Note that there is no tumor progression information in claims databases, this analysis cannot
M AN U
estimate rates of discontinuation specifically for reasons other than progression or death, which may explain the higher rates in this analysis. In real-world data, TTD or time to next treatment can sometimes serve as a proxy for time to tumor progression.24–27
DI was closer to label recommendations for FTD/TPI compared to REG. This is consistent with prior international RDI reports of 92.9% and 57.6% for FTD/TPI28 and REG,21 respectively. The vast deviation from the recommended dose of REG may be attributable to toxicities, most
TE D
commonly hand-foot skin reactions.29 A retrospective single-center study of REG patients found that 43.8% of patients required dose reductions or interruptions, and 24% discontinued therapy altogether because of toxicities.30
The use of claims data is valuable due to their large scale, but they are subject to limitations.
EP
First, dosing instructions are not available in claims databases, therefore measures of adherence and persistence cannot account for any physician-instructed medication use that
AC C
deviates from the dosage provided in pharmacy dispensing claims records. Second, reasons for drug discontinuation are not observable in the claims data and thus cannot be assessed. Finally, residual confounding may exist if confounders remained uncontrolled due to the limits of data collection and potential claims data inaccuracies.31 Specifically, line of therapy could not be identified due to a combination of the 1) limited period of the dataset (October 2014-July 2016), which may truncate a patient's medical and drug utilization history and 2) lack of cancer-specific information in claims data such as date of first mCRC diagnosis. As for limitations specific to this study, the SHS database must employ a matching algorithm to link records across different health care facilities and pharmacies, linking on patient identifiable information. Non-matches/mismatches of patient records may occur if a patient received care 9
ACCEPTED MANUSCRIPT 4/11/2018
Confidential
from multiple doctors at different networks. Furthermore, the SHS database lacks eligibility files, meaning that patients must have incurred clinical services in order to be included in this study. A limitation of this study is the substantial proportion of patients with only one claim of their index agent due to the limited follow-up related to these drugs’ market availability. Also, since FTD/TPI was approved later than REG (September 2015 vs. September 2012),16,32 the limited
RI PT
follow-up time would have the tendency to bias the results against FTD/TPI and may artificially produce shorter DOT and lower adherence than the actuality. Finally, the SHS database does not include data on overall survival and progression free survival. However, the focus of this manuscript was on adherence and compliance in the real-world setting.
SC
Conclusions
This analysis of a large nationally-representative claims database indicates that FTD/TPI is
M AN U
associated with longer DOT and approximately two to three times better drug adherence than REG in patients with mCRC. Further research is needed to assess clinical and economic implications of better adherence and persistence for mCRC patients on FTD/TPI and REG in the real-world setting as well as understanding the reasons for discontinuations and nonadherence.
•
TE D
Clinical Practice Points
FTD/TPI and REG both prolong survival in refractory metastatic colorectal cancer and have similar indications with different side effect profiles. FTD/TPI patients are much more likely to adhere to therapy than REG patients
•
REG patients discontinue therapy faster than FTP/TPI patients
•
Real-world treatment patterns should be considered when selecting between FTD/TPI
EP
•
AC C
and REG therapy
10
ACCEPTED MANUSCRIPT 4/11/2018
Confidential
National Cancer Institute; Surveillance, Epidemiology and ERP. Cancer Stat Facts: Colon and Rectum Cancer. https://seer.cancer.gov/statfacts/html/colorect.html. Accessed March 28, 2017.
2.
Siegel R, Miller K, Jemal A. Cancer statistics, 2017 . CA Cancer J Clin. 2017;67(1):7-30.
3.
American Cancer Society. Cancer Facts & Figures 2017. Atlanta, GA; 2017.
4.
Siegel RL, Miller KD, Fedewa SA, et al. Colorectal cancer statistics , 2017. 2017;67(3):177-193. doi:10.3322/caac.21395.
5.
Ganesan P, Sagar TG, Dubashi B, et al. Nonadherence to imatinib adversely affects event free survival in chronic phase chronic myeloid leukemia. Am J Hematol. 2011;86(6):471-474. doi:10.1002/ajh.22019.
6.
Hershman DL, Shao T, Kushi LH, et al. Early discontinuation and non-adherence to adjuvant hormonal therapy are associated with increased mortality in women with breast cancer. Breast Cancer Res Treat. 2011;126(2):529-537. doi:10.1007/s10549-010-1132-4.
7.
Ibrahim AR, Eliasson L, Apperley JF, et al. Poor adherence is the main reason for loss of CCyR and imatinib failure for chronic myeloid leukemia patients on long-term therapy. Blood. 2011;117(14):3733-3736. doi:10.1182/blood-2010-10-309807.
8.
Seal BS, Anderson S, Shermock KM. Factors associated with adherence rates for oral and intravenous anticancer therapy in commercially insured patients with metastatic colon cancer. J Manag Care Spec Pharm. 2016;22(3):227-235. doi:10.18553/jmcp.2016.22.3.227.
9.
Liu G, Franssen E, Fitch M, Warner E. Patient preferences for oral versus intravenous palliative chemotherapy. J Clin Oncol. 1997;15(1):110-115. doi:10.1200/JCO.1997.15.1.110.
10.
Ruddy K, Mayer E, Partridge A. Patient adherence and persistence with oral anticancer treatment. 2009;59(1):56-66. doi:10.3322/caac.20004.
11.
Stivarga (regorafenib) prescribing information. Wayne, New Jersey: Bayer HealthCare Pharmaceuticals Inc.
12.
Lonsurf (trifluridine and tipiracil) prescribing information. Princeton, New Jersey: Taiho Pharmaceutical Co., Ltd.;
13.
14.
EP
TE D
M AN U
SC
RI PT
1.
AC C
References
Mayer RJ, Van Cutsem E, Falcone A, et al. Randomized Trial of TAS-102 for Refractory Metastatic Colorectal Cancer. N Engl J Med. 2015;372(20):1909-1919. doi:10.1056/NEJMoa1414325.
Grothey A, Van Cutsem E, Sobrero A, et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): An international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381(9863):303-312. doi:10.1016/S0140-6736(12)61900-X.
15.
Masuishi T, Taniguchi H, Hamauchi S, et al. Regorafenib Versus Trifluridine/Tipiracil for Refractory Metastatic Colorectal Cancer: A Retrospective Comparison. Clin Colorectal Cancer. 2017;16(2):e15-e22. doi:10.1016/j.clcc.2016.07.019.
16.
US Food and Drug Administration Center for Drug Evaluation and Research. Lonsurf NDA 207981 Approval Letter, September 22, 2015. 11
ACCEPTED MANUSCRIPT 4/11/2018
Confidential
Campagna EJ, Muser E, Parks J, Morrato EH. Methodological Considerations in Estimating Adherence and Persistence for a Long-Acting Injectable Medication. J Manag Care Spec Pharm. 2014;20(7):756-766.
18.
Watanabe JH, Bounthavong M, Chen T. Revisiting the medication possession ratio threshold for adherence in lipid management. Curr Med Res Opin. 2013;29(3):175-180. doi:10.1185/03007995.2013.766164.
19.
Sacco JJ, Botten J, Macbeth F, Bagust A, Clark P. The average body surface area of adult cancer patients in the UK: A multicentre retrospective study. PLoS One. 2010;5(1):1-6. doi:10.1371/journal.pone.0008933.
20.
Sugita K, Kawakami K, Yokokawa T, et al. Self-reported adherence to trifluridine and tipiracil hydrochloride for metastatic colorectal cancer: A retrospective cohort study. Oncol. 2016;91(4):224-230. doi:10.1159/000448717.
21.
Kawakami K, Suenaga M, Soejima A, et al. Self-reported adherence to regorafenib for metastatic colorectal cancer: A retrospective cohort study. J Clin Oncol. 2017;35:supp 4S; abstract 783.
22.
Del Prete S, Addeo R, Montesarchio V, et al. Adherence to regorafenib therapy in patients with previously treated metastatic colorectal cancer: STI observational multicenter study. J Clin Oncol. 2015;33(suppl; abstr e17529).
23.
Del Prete S, Cennamo G, Leo L, et al. Adherence and safety of regorafenib for patients with metastatic colorectal cancer: observational real-life study. Futur Oncol. 2017;13(5):415-423. doi:10.2217/fon-2016-0421.
24.
Chen C-C, Parikh K, Abouzaid S, et al. Real-world treatment patterns, time to next treatment, and economic outcomes in relapsed or refractory multiple myeloma patients treated with pomalidomide or carfilzomib. J Manag Care Spec Pharm. 2017;23(2):236246. doi:10.18553/jmcp.2017.23.2.236.
25.
Blommestein HM, Franken MG, Uyl-de Groot CA. A practical guide for using registry data to inform decisions about the cost effectiveness of new cancer drugs: Lessons learned from the PHAROS registry. Pharmacoeconomics. 2015;33(6):551-560. doi:10.1007/s40273-015-0260-4.
26.
National Institute for Health and Care Excellence. Abiraterone for castration-resistant metastatic prostate cancer previously treated with a docetaxel-containing regimen. NICE Technol Apprais Guid. 259(June 2012).
27.
National Institute for Health and Care Excellence. Enzalutamide for metastatic hormonerelapsed prostate cancer previously treated with a docetaxel-containing regimen. NICE Technol Apprais Guid. 316(July 2014).
29.
SC
M AN U
TE D
EP
AC C
28.
RI PT
17.
Sugita K, Kawakami K, Yokokawa T, et al. Self-reported adherence with TAS-102. Ann Oncol. 2015;26(supp_7):vii100. Krishnamoorthy SK, Relias V, Sebastian S, Jayaraman V, Saif MW. Management of regorafenib-related toxicities: a review. Therap Adv Gastroenterol. 2015;8(5):285-297. doi:10.1177/1756283X15580743.
30.
Bugano D, Gomes D, Hassabo HM, et al. MD Anderson experience with off-study regorafenib in patients with advanced colorectal cancer. J Clin Oncol. 2014;32(suppl3; abstr 635).
31.
Johnson EK, Nelson CP. Utility and Pitfalls in the Use of Administrative Databases for Outcomes Assessment. J Urol. 2013;190(1):17-18. doi:10.1016/j.juro.2013.04.048.
32.
US Food and Drug Administration Center for Drug Evaluation and Research. Stivarga 12
ACCEPTED MANUSCRIPT 4/11/2018
Confidential
AC C
EP
TE D
M AN U
SC
RI PT
NDA 203085 Approval Letter, September 27, 2012.
13
ACCEPTED MANUSCRIPT
4/11/2018
Confidential
RI PT
Figure 1. Identification of the study population
1
≥1 diagnosis of CRC and ≥1 pharmacy dispensing of FTD-TPI or REG N = 5,500 2
3
No diagnosis of gastric cancer or gastrointestinal stromal tumors
M AN U
SC
N = 5,389 (98.0%)
FTD-TPI patients N = 2,844 (52.8%)
REG patients N = 2,545 (47.2%)
≥18 years of age at index date
N = 2,844 (100.0%)
N = 2,545 (100.0%)
EP
≥3 months continuous clinical activity prior index date N = 1,630 (88.9%)
≥3 months continuous clinical activity post index date N = 1,910 (75.0%)
AC C
≥3 months continuous clinical activity post index date N = 1,834 (64.5%)
TE D
≥18 years of age at index date
≥3 months continuous clinical activity prior index date N = 1,425 (74.6%)
Abbreviations: CRC=colorectal cancer; ICD-9-CM = International classification of diseases, ninth edition-clinical modifications; ICD-10-CM = International classification of diseases, tenth edition-clinical modifications. Notes: 1. CRC was identified using the ICD-9-CM codes 153.x, 154.0x, 154.1x, 154.8x and ICD-10-CM codes C18, C19, C20 and C21.8. 2. Gastric cancer was identified using the ICD-9-CM code 151.x and the ICD-10-CM codes C16.8 and C16.9. 3. Gastrointestinal stromal tumor was identified using the ICD-9-CM codes 171.5x, 215.5x and 238.1x and ICD-10-CM codes C49.4x, D21.4x and D48.1x.
14
ACCEPTED MANUSCRIPT
4/11/2018
Confidential
RI PT
Table 1. Baseline characteristics of FTD/TPI or REG patients
AC C
EP
TE D
M AN U
SC
Demographic characteristics, evaluated at the index date Female, N (%) Year of treatment initiation, N (%) 2014 2015 2016 Age at treatment initiation, mean ± SD [median] Age, N (%) < 35 35 – 44 45 – 54 55 – 64 65 – 74 75 + Region, N (%) South Midwest West Northeast Unknown Insurance plan at treatment initiation, N (%) Medicare Medicaid Commercial
15
FTD/TPI patients (N=1,630)
REG patients (N=1,425)
Pvalue
742 (45.5)
637 (44.7)
0.650
0 (0.0) 755 (46.3) 875 (53.7) 61.0 ± 11.0
11 (0.8) 1,186 (83.2) 228 (16.0) 62.8 ± 10.9
<0.001* <0.001* <0.001* <0.001*
22 (1.3) 94 (5.8) 353 (21.7) 517 (31.7) 445 (27.3) 199 (12.2)
14 (1.0) 65 (4.6) 248 (17.4) 408 (28.6) 463 (32.5) 227 (15.9)
0.348 0.135 0.003* 0.064 0.002* 0.003*
677 (41.5) 305 (18.7) 267 (16.4) 356 (21.8) 25 (1.5)
642 (45.1) 319 (22.4) 207 (14.5) 236 (16.6) 21 (1.5)
0.050 0.012* 0.158 <0.001* 0.892
602 (36.9) 129 (7.9) 888 (54.5)
753 (52.8) 165 (11.6) 501 (35.2)
<0.001* <0.001* <0.001*
ACCEPTED MANUSCRIPT
4/11/2018
Confidential
AC C
EP
TE D
M AN U
SC
RI PT
Other 11 (0.7) Clinical characteristics during the 3-month baseline period Charlson Comorbidity Index (CCI), mean ± SD [median] 3.8 ± 2.9 [6.0] Individual components of CCI, N (%) AIDS 2 (0.1) Cerebrovascular disease 16 (1.0) Chronic diabetes 14 (0.9) Chronic pulmonary disease 66 (4.0) Congestive heart failure 18 (1.1) Dementia 3 (0.2) Hemiplegia 2 (0.1) Liver disease 11 (0.7) Malignancy (including lymphoma and leukemia) 385 (23.6) Metastatic solid tumor 820 (50.3) Mild liver disease 93 (5.7) Mild to moderate diabetes 125 (7.7) Myocardial infarction 11 (0.7) Peripheral vascular disease 24 (1.5) Peptic ulcer disease, 5 (0.3) Renal disease 46 (2.8) Rheumatologic disease 4 (0.2) Other comorbidities, N (%) Arterial thromboembolism 2 (0.1) Cardiac dysrhythmia 21 (1.3) Coronary artery disease 48 (2.9) Hypertension 310 (19.0) Stroke 6 (0.4) Venous thromboembolism 41 (2.5) mCRC chemotherapy used in 3-month period prior to treatment initiation, N (%) Any chemotherapy 575 (35.3) 5-fluorouracil 309 (19.0) Bevacizumab 191 (11.7) 16
6 (0.4)
0.347
3.9 ± 2.9 [5.0]
0.422
3 (0.2) 15 (1.1) 24 (1.7) 59 (4.1) 22 (1.5) 0 (0.0) 1 (0.1) 8 (0.6) 401 (28.1) 707 (49.6) 101 (7.1) 120 (8.4) 10 (0.7) 27 (1.9) 2 (0.1) 35 (2.5) 4 (0.3)
0.669 0.845 0.040* 0.899 0.286 0.253 1.000 0.691 0.004* 0.702 0.118 0.445 0.928 0.363 0.460 0.530 1.000
3 (0.2) 36 (2.5) 39 (2.7) 296 (20.8) 4 (0.3) 21 (1.5)
0.669 0.012* 0.730 0.225 0.759 0.042*
575 (40.4) 306 (21.5) 177 (12.4)
0.004* 0.084 0.551
ACCEPTED MANUSCRIPT
4/11/2018
Confidential
AC C
EP
TE D
M AN U
SC
RI PT
Capecitabine 133 (8.2) 141 (9.9) 0.094 Cetuximab 71 (4.4) 78 (5.5) 0.152 Irinotecan 255 (15.6) 282 (19.8) 0.003* Leucovorin 187 (11.5) 206 (14.5) 0.014* Mitomycin 0 (0.0) 0 (0.0) Oxaliplatin 95 (5.8) 90 (6.3) 0.573 Panitumumab 56 (3.4) 59 (4.1) 0.307 Ramucirumab 8 (0.5) 4 (0.3) 0.354 Ziv-aflibercept 1 (0.1) 1 (0.1) 1.000 No chemotherapy 1,055 (64.7) 850 (59.6) 0.004* Abbreviations: FTD/TPI = Trifluridine/Tipiracil; REG = regorafenib; SD = standard deviation; mCRC = metastatic colorectal cancer * p-value<0.05
17
ACCEPTED MANUSCRIPT
4/11/2018
Confidential
REG patients (N =1,425) 211.67 ± 112.61 [181.00] 1,333 (93.5) 717 (50.3)
P-value
87.26 ± 74.94 [66.00]
<0.001*
953 (66.9) 0.87 ± 0.15 [0.92] 705 (74.0) 525 (55.1)
<0.001* <0.001* <0.001* <0.001*
RI PT
Table 2. Adherence and persistence among patients initiated on FTD/TPI and REG FTD/TPI patients (N =1,630) Length of the observation period (days), mean ± SD [median] 160.79 ± 59.43 [156.00] Patients followed for ≥ 3 months, N (%) 1,524 (93.5) Patients followed for ≥ 6 months, N (%) 554 (34.0) Duration of treatment (DOT) (days), mean ± SD [median]
94.89 ± 57.35 [84.00]
AC C
EP
TE D
M AN U
SC
Medication possession ratio (MPR) Patients with ≥ 2 claims, N (%) 1,335 (81.9) MPR, Mean ± SD [median] 0.91 ± 0.13 [0.98] MPR ≥ 0.80, N (%) 1,128 (84.5) MPR ≥ 0.90, N (%) 951 (71.2) Proportion of days covered (PDC) At 3 months, N 1,524 (93.5) PDC, mean ± SD [median] 0.71 ± 0.24 [0.81] PDC ≥ 0.80, N (%) 774 (50.8) PDC ≥ 0.90, N (%) 533 (35.0) At 6 months, N 554 (34.0) PDC, mean ± SD [median] 0.57 ± 0.25 [0.58] PDC ≥ 0.80, N (%) 131 (23.6) PDC ≥ 0.90, N (%) 67 (12.1) Persistence, N (%) At 3 months, N 1,524 (93.5) No gap ≥ 45 days 1,229 (80.6) No gap ≥ 60 days 1,269 (83.3) At 6 months, N 554 (34.0) No gap ≥ 45 days 209 (37.7) No gap ≥ 60 days 255 (46.0) Time to discontinuation, mean ± SD [median] No gap ≥ 45 days 95.33 ± 57.74 [89.00] No gap ≥ 60 days 101.10 ± 59.37 [97.00] No gap ≥ 90 days 116.06 ± 60.90 [111.00] Abbreviations: FTD/TPI = Trifluridine/Tipiracil; REG = regorafenib; SD = standard deviation * p-value<0.05 18
1,333 (93.5) 0.59 ± 0.25 [0.62] 389 (29.2) 245 (18.4) 717 (50.3) 0.45 ± 0.26 [0.43] 90 (12.6) 43 (6.0) 1,333 (93.5) 836 (62.7) 894 (67.1) 717 (50.3) 200 (27.9) 244 (34.0) 82.38 ± 68.52 [62.00] 88.17 ± 72.99 [69.00] 105.32 ± 78.92 [94.00]
<0.001* -
<0.001* <0.001* <0.001* <0.001* <0.001* <0.001* <0.001* <0.001* <0.001* <0.001* <0.001* <0.001* <0.001*
ACCEPTED MANUSCRIPT
4/11/2018
Confidential
RI PT
Figure 2. Proportion of patients discontinuing therapy (no gap ≥ 60 days) among patients initiated on FTD/TPI or REG
100% 90%
SC
FTD/TPI patients
M AN U
70% REG patients 60% 50%
TE D
40% 30%
EP
20% 10% 0% 0
30
AC C
% of patients discontinuing therapy
Log-rank test: p-value<0.001* 80%
60
90
120 Time (Days)
Abbreviations: FTD/TPI = Trifluridine/Tipiracil; REG = regorafenib * p-value<0.05
19
150
180
210
240
ACCEPTED MANUSCRIPT
4/11/2018
Confidential
Table 3. Comparison of persistence and adherence, adjusted for baseline characteristics between patients initiated on FTD/TPI and REG 1
<0.001*
P-
1.80 (1.42, 2.27)
<0.001*
RI PT
3.36 (2.09, 4.64)
Odds ratio (95% CI)3 (FTD/TPI vs. REG)
SC
Proportion of days covered PDC (%), at 3 months PDC (%), at 6 months
P-value
12.52 (10.50, 14.55) 13.91 (10.92, 16.91)
PDC ≥ 80%, at 3 months PDC ≥ 80%, at 6 months
M AN U
Medication possession ratio MPR (%) MPR ≥ 80%
Mean difference (95% CI)2 (FTD/TPI vs. REG)
Hazard ratio (95% CI)4 (FTD/TPI vs. REG)
P-value
<0.001* <0.001*
2.66 (2.24, 3.17) 2.31 (1.68, 3.19)
<0.001* <0.001*
AC C
EP
TE D
Time to discontinuation No gap ≥ 45 days 0.64 (0.59, 0.71) <0.001* No gap ≥ 60 days 0.63 (0.57, 0.70) <0.001* No gap ≥ 90 days 0.60 (0.53, 0.68) <0.001* Abbreviations: FTD/TPI = Trifluridine/Tipiracil; REG = regorafenib; CI = confidence interval * p-value<0.05 Notes: 1. All models are multivariate models adjusting for demographic covariates (i.e., age, gender, region, insurance plan), Charlson comorbidity index, individual comorbidities and baseline treatments/medications that had statistical significant differences between cohorts (p-value<0.05, Table 1), all-cause baseline prescription drug costs, all-cause baseline medical costs, number of all-cause baseline inpatient visits, and number of all-cause baseline emergency room visits. 2. Estimated using multivariable linear regression models. 3. Estimated using multivariable logistic regression models. 4. Estimated using multivariable Cox proportional hazards regression models. 20