If you don't remember your password, you can reset it by entering your email address and clicking the Reset Password button. You will then receive an email that contains a secure link for resetting your password
If the address matches a valid account an email will be sent to __email__ with instructions for resetting your password
Trifluridine/tipiracil (FTD/TPI) and regorafenib (REG) prolong survival in refractory metastatic colorectal cancer (mCRC) and have similar indications with different side-effect profiles. The present study compared real-world treatment patterns with FTD/TPI and REG for mCRC in a large, representative US claims database.
Materials and Methods
Retrospective data from the US Symphony Health Solutions’ Integrated Dataverse database were analyzed for adult mCRC patients receiving FTD/TPI or REG from October 2014 to July 2016. The index date was the first FTD/TPI or REG prescription date. The observation period spanned from the index date to the end of data collection, end of continuous clinical activity, or treatment switch. Adherence was assessed using the medication possession ratio and proportion of days covered at 3 months. The time to discontinuation was assessed over the observation period with gaps of 45, 60, or 90 days. Outcomes were compared between the cohorts using logistic regression and Cox proportional hazards models adjusting for baseline characteristic differences.
Results
A total of 1630 FTD/TPI patients and 1425 REG patients were identified. The FTD/TPI patients were 80% more likely to have a medication possession ratio of ≥ 0.80 compared with the REG patients (odds ratio, 1.80; P < .001) and more than twice as likely to have a proportion of days covered of ≥ 0.80 (odds ratio, 2.66; P < .001) at 3 months. The FTD/TPI patients were 37% less likely to discontinue their treatment compared with the REG patients when using the 60-day gap (hazard ratio, 0.63; P < .001). Similar results were found using the 45- and 90-day gaps.
Conclusion
mCRC patients taking FTD/TPI were significantly more likely to adhere to and comply with therapy compared with those taking REG.
Colorectal cancer (CRC) is the fourth most common type of cancer diagnosed in the United States and represents 8.0% of all new cancer cases nationwide.
Long-term survival for mCRC has improved gradually over the past 30 years, likely representative of advancements in treatments and new agents active against this disease.
Multiple studies have demonstrated that most cancer patients prefer oral treatment over intravenous treatment because of convenience, environment during treatment, and problems with intravenous administration.
The reasons for the 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.
For refractory mCRC, 2 approved oral agents, trifluridine/tipiracil (FTD/TPI; Lonsurf; Taiho Pharmaceutical, Tokyo, Japan) and regorafenib (REG; Stivarga; Bayer AG, Berlin, Germany), have been proved to prolong survival in randomized, multicenter phase III clinical trials. Both agents are indicated for the treatment of patients with mCRC who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy or anti–vascular endothelial growth factor therapy and anti–epidermal growth factor receptor therapy, if RAS wild type.
In the RECOURSE study (study of FTD/TPI in patients with mCRC to standard chemotherapies), FTD/TPI showed significant improvement in median overall survival compared with placebo (7.1 vs. 5.3 months; hazard ratio [HR], 0.68; 95% confidence interval [CI], 0.58-0.81; P < .001).
In the CORRECT study (patients with mCRC treated with REG or placebo after failure of standard therapy), REG showed significant improvement in median overall survival compared with placebo (6.4 vs. 5.0 months; HR, 0.77; 95% CI, 0.64-0.94; P = .0052).
Despite their similar indications and oral administration, FTD/TPI and REG have not been compared head-to-head in a clinical trial. A recent real-world retrospective analysis was conducted to compare the 2 treatments in patients with refractory mCRC. That analysis showed that the 2 treatments had similar efficacy but different side-effect profiles. However, that study was conducted in Japan and included data collected from only 2 cancer centers and, thus, had a very small sample size.
Moreover, although FTD/TPI was approved by the Food and Drug Administration in September 2015, real-world data on the treatment patterns for these therapies are lacking.
Although both agents are administered orally, they possess distinct side-effect profiles. Dose reductions or treatment interruptions could be considered in real-world clinical practice, with the aim of reducing or avoiding adverse reactions. The present study aimed to evaluate the real-world treatment patterns after initiation of FTD/TPI or REG for mCRC through the investigation of a large, nationally representative US claims database.
Materials and Methods
Data Sources
The present study used the Symphony Health Solutions’ (SHS) Integrated Dataverse database. The SHS database is a nationally representative, longitudinal, de-identified claims database that captures prescription and medical claims for > 220 million people across the United States and covers all payment types. Data collected from October 2014 to July 2016 were used in the present study.
Study Design and Patient Selection
A retrospective longitudinal cohort design was used to conduct the present study. Patients diagnosed with CRC (International Classification of Diseases, 9th Revision, Clinical Modification, codes 153.x, 154.0x, 154.1x, 154.8x; International Classification of Diseases, 10th Revision, Clinical Modification, codes C18.x, C19.x, C20.x, C21.8) who had received either FTD/TPI (generic product identifier, 2199000275) or REG (generic product identifier, 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 was the therapy (FTD/TPI or REG) supplied on the index date. Patients were included in the present study if they were aged ≥ 18 years, had ≥ 1 diagnosis of CRC, did not have a diagnosis of gastric cancer or gastrointestinal stromal tumor, and had continuous clinical activity for ≥ 3 months both before and after the index date. The baseline period corresponded to the 3-month period before the index date and was used to assess the baseline characteristics, except for baseline healthcare resource utilization variables, which were assessed over the entire period before the index date.
Patients were grouped into 2 study cohorts according to which treatment they had received on the index date: FTD/TPI and REG. The observation period spanned from the index date to the earliest date of a switch to another mCRC treatment, the end of continuous clinical activity, or the end of data availability.
Outcomes
The treatment patterns for the index therapy, including the duration of treatment (DOT), medication adherence, and persistence, were assessed for each cohort. The 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 the medication possession ratio (MPR) and the proportion of days covered (PDC). The MPR was calculated by dividing the total number of days of medication supplied by the total number of days between the first prescription and the last day of supply of the last prescription among the patients with ≥ 2 prescriptions. The PDC was defined as the number of unique days with medication divided by the length of a fixed interval. For both MPR and PDC, the proportions of patients with a threshold of ≥ 0.8 and ≥ 0.9 were also reported.
Persistence was defined as continuous use of the index therapy for a fixed interval, with a specified allowable gap (ie, 45 or 60 days) between 2 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 for patients with ≥ 3 and 6 months of follow-up data available, respectively. In addition, the time to discontinuation (TTD) was assessed for the entire observation period using 3 allowable gap thresholds (ie, 45, 60, or 90 days). Patients who never discontinued the index therapy were censored at the end of the observation period.
The dosing patterns for the index therapy were evaluated during the observation period using the dose intensity (DI) and relative dose intensity (RDI). The DI was used to measure the amount of drug delivered per unit of time and was calculated by dividing the sum of strength (in milligrams) of all prescriptions for the index therapy by the DOT, multiplying by a factor of 2.8 for FTD/TPI (28 days of 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 factors was determined by the labeled recommended doses for FTD/TPI and REG.
The present analysis assumed 2 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 the mean BSA among adjuvant CRC patients,
which corresponds to a recommended daily dose of 126.7 to 128.8 mg. The daily dosages of FTD/TPI were rounded to account for the 2 available dosage strengths of the tablets. The 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 (ie, 160 mg/d for REG and 120 mg/d or 130 mg/d for FTD/TPI per BSA as described). While the patient was taking index therapy, the DI and RDI were both estimated from the population-level perspective using the median number of claims, 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 had ≥ 1 prescription for the study drugs with a quantity of < 20 pills (approximately < 25% of the labeled recommended dose).
Statistical Analysis
Descriptive statistics were reported for the patient and clinical characteristics at baseline and for the treatment patterns during the observation period. The mean, standard deviation, and median were used to describe the continuous variables, and frequencies and percentages were used to describe the categorical variables. Differences in the baseline demographics and clinical characteristics between the 2 cohorts were assessed using χ2 tests for the categorical variables and Wilcoxon rank sum tests for the continuous variables. Kaplan-Meier survival analyses were conducted to illustrate the differences in treatment discontinuation between the 2 cohorts.
Multivariate regression models were used to estimate the adjusted differences in treatment patterns between the 2 cohorts. The baseline covariates adjusted for in the models included age, gender, region, insurance plan, Charlson comorbidity index, individual comorbidities and baseline treatments and medications that significantly differed between the 2 cohorts (P < .05), all-cause baseline prescription drug costs, all-cause baseline medical costs, number of all-cause baseline inpatient (IP) visits, and number of all-cause baseline emergency room visits. Cox proportional hazards models were used to estimate the HRs and their corresponding 95% CIs for the TTD. Linear regression models were used to estimate the mean differences and their corresponding 95% CIs for continuous PDC and MPR. Logistic regression models were used to estimate the odds ratios (ORs) and their corresponding 95% CIs for dichotomized PDC, MPR, and persistence.
Results
Baseline Characteristics
A total of 1630 FTD/TPI patients and 1425 REG patients were included in the present study (Figure 1). The baseline demographic and clinical characteristics of each cohort are summarized in Table 1. The FTD/TPI patients were younger than the REG patients (mean age, 61.0 vs. 62.8 years; P < .001). The FTD/TPI patients had started their treatment more recently than had the REG patients (initiation in 2015, 46.3% vs. 83.2%, P < .001; initiation in 2016, 53.7% vs. 16.0%, P < .001). During the 3-month baseline period, the mean Charlson comorbidity index was similar between the 2 cohorts (FTD/TPI vs. REG, 3.8 vs. 3.9; P = .422).
Figure 1Identification of the Study Population. 1Colorectal Cancer (CRC) Was Identified Using International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM), Codes 153.x, 154.0x, 154.1x, 154.8x and International Classification of Diseases, 10th Revision, Clinical Modification (ICD-10-CM), Codes C18, C19, C20, and C21.8. 2Gastric Cancer Was Identified Using ICD-9-CM Code 151.x and ICD-10-CM Codes C16.8 and C16.9. 3Gastrointestinal Stromal Tumor Was Identified Using ICD-9-CM Codes 171.5x, 215.5x, and 238.1x and ICD-10-CM Codes C49.4x, D21.4x, and D48.1x
Adherence to the index therapy among the FTD/TPI patients and REG patients during the observation period (mean duration of observation period for FTD/TPI vs. REG, 160.8 vs. 211.7 days; P < .001) is summarized in Table 2. The mean MPR was significantly greater for the FTD/TPI patients than for the REG patients (mean MPR, 0.91 vs. 0.87; P < .001). Consistently, the proportion of patients with an MPR of ≥ 0.80 and ≥ 0.90 was also greater for the FTD/TPI patients than for the REG patients (84.5% vs. 74.0% and 71.2% vs. 55.1%, respectively; P < .001). The mean PDC at 3 and 6 months was significantly greater for the FTD/TPI patients than for the REG patients (mean PDC at 3 months, 0.71 vs. 0.59, P < .001; mean PDC at 6 months, 0.57 vs. 0.45, P < .001). The proportion of patients with a PDC of ≥ 0.8 was also significantly greater in the FTD/TPI cohort than in the REG cohort (at 3 months of follow-up, 50.8% vs. 29.2%, P < .001; at 6 months of follow-up, 23.6% vs. 12.6%, P < .001).
Table 2Adherence and Persistence Among Patients Initiating FTD/TPI and REG
After adjusting for the baseline covariates, medication adherence remained significantly greater for the FTD/TPI patients compared with the REG patients (Table 3). Specifically, the FTD/TPI patients were 80% more likely to have an MPR of ≥ 0.80 than were the REG patients (OR, 1.80; P < .001) and were more than twice as likely to have a PDC of ≥ 0.80 at 3 and 6 months (OR at 3 months, 2.66, P < .001; OR at 6 months, 2.31, P < .001; Table 3).
Table 3Comparison of Persistence and Adherence, Adjusted for Baseline Characteristics Between Patients Initiating FTD/TPI and REG
All models are multivariate models adjusting for demographic covariates (ie, age, gender, region, insurance plan), Charlson comorbidity index, individual comorbidities and baseline treatments and medications with statistically significant differences between cohorts (P < .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.
Abbreviations: CI = confidence interval; FTD/TPI = trifluridine/tipiracil; HR = hazard ratio; MPR = medication possession ratio; OR = odds ratio; PDC = proportion of days covered; REG = regorafenib; TTD = time to discontinuation.
a All models are multivariate models adjusting for demographic covariates (ie, age, gender, region, insurance plan), Charlson comorbidity index, individual comorbidities and baseline treatments and medications with statistically significant differences between cohorts (P < .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.
b Estimated using multivariable linear regression models.
c Estimated using multivariable logistic regression models.
d Estimated using multivariable Cox proportional hazards regression models.
The mean TTD was significantly longer for the FTD/TPI patients than for the REG patients, regardless of whether discontinuation was defined as a gap in treatment of 45, 60, or 90 days (95.3 vs. 82.4 days, P < .001; 101.1 vs. 88.2 days, P < .001; and 116.1 vs. 105.3 days, P < .001, respectively; Table 2). The Kaplan-Meier survival curves showed that the proportion of patients discontinuing therapy (defined as no gaps in treatment of ≥ 60 days) was significantly greater for the REG patients than for the FTD/TPI patients during the follow-up time (log-rank test, P < .001; Figure 2). For example, at 6 months after the index date, 77.7% of the REG patients had discontinued therapy compared with only 61.6% of the FTD/TPI patients (P < .001). Similar Kaplan-Meier curves were generated as a sensitivity analysis that defined discontinuation as gaps of ≥ 45 days and ≥ 90 days (data not shown).
Figure 2Proportion of Patients Discontinuing Therapy (No Gap of ≥ 60 Days) Among Patients Initiating Trifluridine/Tipiracil (FTD/TPI) or Regorafenib (REG)
After adjusting for the baseline covariates, the FTD/TPI patients were 37% less likely to discontinue their treatment than were the REG patients when defining discontinuation as a gap of ≥ 60 days (HR, 0.63; P < .001; Table 3). Similarly, the FTD/TPI patients were 36% and 40% less likely to discontinue their treatment compared with the REG patients when defining discontinuation as a gap of ≥ 45 days and ≥ 90 days, respectively (HR, 0.64, P < .001; HR, 0.60, P < .001, respectively; Table 3).
Dosing Patterns
The FTD/TPI patients had a greater number of claims during the observation period compared with the REG patients (3.2 vs. 2.9; P < .001). The mean DI for FTD/TPI was 106.1 mg/d and was 102.7 mg/d for REG (data not shown). The FTD/TPI patients had a mean RDI of 88% or 82% when using the presumed dose of 120 mg/d or 130 mg/d, respectively. The REG patients had a mean RDI of 64%.
Discussion
The present retrospective claims data analysis assessed the real-world medication usage of FTD/TPI and REG by mCRC patients and consistently showed that FTD/TPI was associated with better drug adherence and compliance than REG. After multivariable adjustment, the proportion of patients with an MPR > 80% was nearly doubled among the patients taking FTD/TPI compared with those taking REG. Moreover, the proportion of patients with a PDC > 80% was > 2 times greater among the FTD/TPI patients compared with the REG patients.
The adherence rates of FTD/TPI and REG in the analysis were similar to previous findings from international single-center studies using self-reported treatment diaries to evaluate adherence. One study showed a 95.0% to 98.2% adherence rate for FTD/TPI, which agrees with our reported mean MPR of 0.91.
In that study, the reasons for a lack of adherence included nausea/vomiting, abdominal pain, neutropenia, ileus, diarrhea, and missed doses. Our reported mean MPR of 0.87 for REG for 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 and liver dysfunction as the main reasons for the lack of adherence.
A third study classified REG patients as adherent if they both self-reported adherence on a questionnaire and had an MPR of ≥ 80%. The resulting adherence rate in that population was 82%. In that analysis, predictors of poor adherence to REG included higher Eastern Cooperative Oncology Group status, lower education level, lower level of REG acceptance, and use of many concomitant oral therapies.
Our analysis showed that FTD/TPI patients had a delayed TTD and greater persistence at 3 and 6 months compared with the REG patients, regardless of the duration of the gap used in the assessment of the TTD. Only 40% of FTD/TPI patients had discontinued treatment at 90 days (using a 60-day duration of gap) after the initiation of therapy compared with 57% of the REG patients. These rates, although much greater, are proportional to the rates of treatment discontinuation from clinical trials. In the RECOURSE trial,
Because no tumor progression information is available from claims databases, the present analysis could not estimate the rates of discontinuation specifically for reasons other than progression or death, which might explain the greater rates in our analysis. In real-world data, the TTD or time to next treatment can sometimes serve as a proxy for the time to tumor progression.
Real-world treatment patterns, time to next treatment, and economic outcomes in relapsed or refractory multiple myeloma patients treated with pomalidomide or carfilzomib.
A practical guide for using registry data to inform decisions about the cost effectiveness of new cancer drugs: lessons learned from the PHAROS registry.
Abiraterone for castration-resistant metastatic prostate cancer previously treated with a docetaxel-containing regimen. NICE Technology Appraisal Guidance TA259. June 27, 2012.
Enzalutamide for metastatic hormone-relapsed prostate cancer previously treated with a docetaxel-containing regimen. NICE Technology Appraisal Guidance TA316. July 23, 2014.
The DI was closer to label recommendations for FTD/TPI than for REG. This is consistent with previous international RDI reports of 92.9% and 57.6% for FTD/TPI
respectively. The vast deviation from the recommended dose of REG might be attributable to the occurrence of toxicities, most commonly hand-foot skin reactions.
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.
The use of claims data is valuable because of their large scale; however, they are subject to limitations. First, dosing instructions are not available from claims databases; therefore, measures of adherence and persistence cannot account for any physician-instructed medication use that deviates from the dosage provided in the pharmacy dispensing claims records. Second, the reasons for drug discontinuation are not observable in the claims data and, thus, cannot be assessed. Finally, residual confounding could exist if confounders remained uncontrolled owing to the limits of data collection and potential claims data inaccuracies.
Specifically, the line of therapy could not be identified owing to a combination of the limited period of the data set (October 2014 to July 2016), which might truncate a patient's medical and drug utilization history, and a lack of cancer-specific information in claims data such as the date of the first mCRC diagnosis.
Regarding the limitations specific to the present study, the SHS database must use a matching algorithm to link records across different health care facilities and pharmacies, linking by patient identifiable information. Nonmatches or mismatches of patient records can occur if a patient received care from multiple doctors at different networks. Furthermore, the SHS database lacks eligibility files i.e., patients must have incurred clinical services to have been included in the present study. Another limitation of the present study was the substantial proportion of patients with only 1 claim of their index agent owing to the limited follow-up data related to these drugs’ market availability. Also, because FTD/TPI was approved later than was REG (September 2015 vs. September 2012),
the limited follow-up time would have the tendency to bias the results against FTD/TPI and might have artificially produced a 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 our study was on adherence and compliance in the real-world setting.
Conclusion
The results of the present analysis of a large, nationally representative claims database indicate that FTD/TPI is associated with a longer DOT and ∼2 to 3 times better drug adherence than REG for patients with mCRC. Further research is needed to assess the clinical and economic implications of better adherence and persistence for mCRC patients taking FTD/TPI versus REG in the real-world setting and to understand the reasons for discontinuations and nonadherence.
Clinical Practice Points
•
FTD/TPI and REG both prolong survival in patients with refractory mCRC and have similar indications with different side-effect profiles.
•
FTD/TPI patients were much more likely to adhere to therapy than were REG patients.
•
REG patients discontinued therapy sooner than did FTP/TPI patients.
•
Real-world treatment patterns should be considered when selecting between FTD/TPI and REG therapy.
Acknowledgments
The present study was funded by Taiho Oncology, Inc Research funding was provided to Analysis Group, Inc by Taiho Oncology, Inc Dana-Farber Cancer Institute received a research fund from Analysis Group. The authors are grateful for the writing assistance provided by Erin McDonnell, formerly of Analysis Group, Inc.
A.K.P. is an employee of the Dana-Farber Cancer Institute and did not receive any consultation fee from Analysis Group, Inc, or Taiho Oncology, Inc, for the present study. M.S.D. and M.A.Y. are employees of Analysis Group, Inc. V.B. is an employee of VEB HealthCare LLC and received a consultation fee from Taiho Oncology. Y.X. and W.W. are employees of Groupe d’analyse, Ltée. M.T. is an employee of Strategic Global Medical Affairs LLC and received a consultation fee from Taiho Oncology. C.S.F. was an employee of the Dana-Farber Cancer Institute at the start of the study and is an employee with Yale Cancer Center and received consultation fees from Analysis Group, Inc for the present study.
References
National Cancer Institute
Surveillance, Epidemiology and ERP. Cancer Stat Facts: Colon and Rectum Cancer.
Real-world treatment patterns, time to next treatment, and economic outcomes in relapsed or refractory multiple myeloma patients treated with pomalidomide or carfilzomib.
A practical guide for using registry data to inform decisions about the cost effectiveness of new cancer drugs: lessons learned from the PHAROS registry.
Abiraterone for castration-resistant metastatic prostate cancer previously treated with a docetaxel-containing regimen. NICE Technology Appraisal Guidance TA259. June 27, 2012.
Enzalutamide for metastatic hormone-relapsed prostate cancer previously treated with a docetaxel-containing regimen. NICE Technology Appraisal Guidance TA316. July 23, 2014.
30009-4&id=gr1.jpg){kind=link}
30009-4&id=gr2.jpg){kind=link}