Tipiracil and Regorafenib

Accepted Manuscript Optimizing Treatment sequence in Late Line Metastatic Colorectal Cancer Patients using Trifluridine/Tipiracil and Regorafenib Matthias Unseld, Magdalena Drimmel, Alexander Siebenhühner, Andreas Gleiss, Daniela Bianconi, Markus Kieler, Werner Scheithauer, Thomas Winder, Gerald W. Prager PII:

S1533-0028(18)30093-8

DOI:

10.1016/j.clcc.2018.05.012

Reference:

CLCC 471

To appear in:

Clinical Colorectal Cancer

Received Date: 27 March 2018 Revised Date:

8 May 2018

Accepted Date: 31 May 2018

Please cite this article as: Unseld M, Drimmel M, Siebenhühner³ A, Gleiss A, Bianconi D, Kieler M, Scheithauer W, Winder T, Prager GW, Optimizing Treatment sequence in Late Line Metastatic Colorectal Cancer Patients using Trifluridine/Tipiracil and Regorafenib, Clinical Colorectal Cancer (2018), doi: 10.1016/j.clcc.2018.05.012. 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 COMMENTS FROM THE EDITORS AND REVIEWERS: -REVIEWER 1

re: The title should be changed because the authors do not make any clear

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statement about the optimal treatment sequence.

We changed the title according to the suggestions of the Reviewer.

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re: The paper seems to focus on TAS, but there is at least as much focus on

regorafenib.From these data, the focus should be more on regorafenib since the

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results seem to be better with the regorafenib first treatment sequence.

We optimized the abstract and the introduction according to the suggestions of the reviewer to offer more information about regorafenib. Specifically, the abstract was reformulated as the introduction already contains enough information on

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regorafenib.

re: The authors should critically discuss the reason for selecting regorafenib first and the selection bias.

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The limitations of the study were revised and added into the discussion section.

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re:Table 1 would be more informative if the characteristics would be separated by treatment selection.

Table 1 was newly created; Characteristics were seperated according to treatment selection as suggested.

Optimizing Treatment sequence in Late Line Metastatic Colorectal Cancer Patients using Trifluridine/Tipiracil and Regorafenib

ACCEPTED MANUSCRIPT Matthias Unseld1, Magdalena Drimmel1, Alexander Siebenhühner³, Andreas Gleiss2, Daniela Bianconi1, Markus Kieler1, Werner Scheithauer1, Thomas Winder3, Gerald W. Prager1

1

Department of Medicine I, Clin. Div. of Oncology, Comprehensive Cancer Center, Medical University of Vienna, Austria.

2

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Center for Medical Statistics, Informatics, and Intelligent Systems, Medical University of Vienna, Austria.

3

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Department of Oncology, University Hospital Zurich, Switzerland.

Corresponding authors:

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Gerald Prager Division of Oncology Department of Medicine I Medical University Vienna [email protected] Tel.:+4314040044450 Fax: +4314040044510 and Thomas Winder ([email protected])

ACCEPTED MANUSCRIPT Abstract Background: Treatment sequencing in refractory metastatic colorectal cancer (mCRC) patients is highly debated. The thymidine-based nucleoside trifluridine/tipiracil (TAS-102) and the multikinase inhibitor regorafenib have demonstrated clinical benefits in randomized

therapy sequence involving TAS-102 and regorafenib.

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phase III trials when compared to placebo. However, limited data exists on the most optimal

Methods/patients: In this retrospective, observational, real-life study, clinical data on mCRC

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patients treated with TAS-102 or an alternative salvage treatment at the Medical University of

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Vienna and Zurich was collected from January 2013 to December 2016.

Results: 85 patients whose disease had progressed on fluoropyrimidine-based therapy (FBT) ± antibody were included. The disease control rate (DCR) in patients treated with trifluridine/tipiracil following FBT-based treatment was 24% compared with a DCR of 35% in patients treated with regorafenib following FBT-based treatment (adjusted odds ratio: 1.75;

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95% confidence interval [CI]: 0.41−7.47; p=0.449). Progression-free survival (PFS) in patients treated with trifluridine/tipiracil was 2.8 months (quartile: 2.0−4.8 months) and overall survival (OS) was 15.9 months. When data were analyzed according to subgroups of

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patients with or without any FBT-free period, TAS-102-treated patients with a prior FBT-free interval showed a PFS of 3.1 months and OS of 17.7 months compared with a PFS of 2.2

FBT.

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months and OS of 8.1 months in patients who received trifluridine/tipiracil immediately after

Conclusion: Our study confirms the efficacy of trifluridine/tipiracil and regorafenib in the reallife setting. Treatment sequence analysis showed a tendency of longer PFS and OS in trifluridine/tipiracil-treated patients following a FBT-free interval. Prospective randomized data are needed to gain more information about the most beneficial therapy sequence in the salvage treatment of mCRC.

ACCEPTED MANUSCRIPT Introduction Colorectal cancer (CRC) is the third most common type of cancer, with an estimated 1.4 million new cases diagnosed worldwide in 20121. Depending on tumor stage, the 5-year survival rate decreases from 90% in non-metastatic patients to just 13% in patients

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diagnosed with metastatic colorectal cancer (mCRC)2. The overall survival of patients suffering from refractory metastatic CRC has been prolonged as new treatment options have become available3. Standard therapy involves well-established regimens including

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chemotherapeutic drugs such 5-fluouracil (5-FU), oxaliplatin and irinotecan combined with targeted therapy against the vascular endothelial growth factor (VEGF) or, in case of RAS-

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wild type patients, epidermal growth factor (EGFR)3. Furthermore, in 2012, the FDA approved the oral multikinase inhibitor regorafenib based on the results of the international multicenter phase III CORRECT trial which, when compared to placebo, described a significant improvement in overall survival (6.4 months versus 5.0 months, respectively; hazard ratio [HR]=0.77; p=0.0052) and progression-free survival (1.9 months versus. 1.7

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months, respectively; HR=0.49; p<.0001) in the late-line treatment of mCRC4. Although median overall survival has extended 30 months, new active drugs are available for the third and later lines of treatment to extend patient survival3.

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TAS-102 is a combination of trifluridine plus tipiracil hydrochloride, which inhibits cellular proliferation and causes cell death by incorporation of its triphosphorylated thymidine-based

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nucleoside form into the DNA5. Combined with the thymidine phosphorylase inhibitor tipiracil, trifluridine reaches adequate plasma levels for a longer time period5. In the RECOURSE trial, TAS-102 was compared with placebo in patients with mCRC refractory to standard chemotherapies5. TAS-102 was shown to significantly prolong overall survival when compared with placebo (7.1 months versus 5.3 months, respectively; HR=0.58; p<.001) and progression-free survival (2.0 months versus 1.7 months, respectively; HR=0.48; p<.001). Based on these results, regorafenib and trifluridine/tipiracil are now considered in third and later lines of treatment as salvage therapy for mCRC patients3,5,6. However, no prospective randomized clinical trial has evaluated the most effective therapy sequence involving these

ACCEPTED MANUSCRIPT agents, and it has yet to be determined which agent should be administered first. Furthermore, treatment decisions have to consider the performance status (PS) of the patient and specific side effects of each drug3. There is a limited number of retrospective studies comparing regorafenib and TAS-102 in third and later lines of treatment. In addition, these

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studies have evaluated efficacy and treatment sequence in Asian patient populations7-9 Herein, we report the first analysis of the efficacy of trifluridine/tipiracil treatment with or without a prior FBT-free interval in a real-life setting to help determine the optimal therapy

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sequence of trifluridine/tipiracil in mCRC patients.

ACCEPTED MANUSCRIPT Methods Study design The study was conducted in convention with the International Conference on Harmonization E6 requirements for Good Clinical Practice outlined in the Declaration of Helsinki and

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approved by the institutional ethics committee of the Medical University of Vienna (EC Nr.:1302/2016). Patients

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Patients who received regorafenib or trifluridine/tipiracil (TAS-102) at the Department of Oncology at the Medical University of Vienna and Zurich from January 2013 to December

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2016 were screened for inclusion. Eligible patients had a histologically-confirmed diagnosis of mCRC with a PS of ECOG 0−3 and verified tumor progression after conventional standard treatment. Measurable disease according to RECIST 1.1 criteria was also required. Other eligibility criteria at baseline included: creatinine clearance of >60 mL·min−1; adequate bone

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marrow function indicated by a leukocyte count ≥3,000 mcL−1, absolute neutrophil count ≥ 1,000 mcL−1 and platelet count ≥ 100,000 mcL−1; adequate hepatic function with a total

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bilirubin up to 1.5 x the upper reference range. Therapy was given upon informed consent.

Treatment plan and toxicity assessment

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Trifluridine/tipiracil or regorafenib was administered to patients with mCRC. Dosage reduction was allowed on the occurrence of ≥ Grade 2 adverse events (AEs). Therapy was administered until disease progression, severe AEs or patient`s withdrawal of treatment. Toxicities were graded by the National Cancer Institute Common Terminology Criteria for adverse events version 4.0. Statistical considerations The distribution of categorical variables was described by counts and percentages. Progression-free survival was defined as the time from the start of treatment until

ACCEPTED MANUSCRIPT progression according to RECIST 1.1 criteria, death from any cause or end of treatment due to side effects. Patients were censored at the date last seen if therapy was ongoing. Overall survival was defined as the time from the start of treatment until death from any cause or date of censoring. Median overall and progression-free survival as well as quartiles were

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deduced from Kaplan-Meier estimates, which were reported together with 95% confidence limits. Hazard ratios for quantifying the potential influence of predictors were calculated using Cox proportional-hazards regression models with adjustment for ECOG PS (0 versus >0). P <0.05 was considered statistically significant and all tests conducted were two-sided. Due

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to the exploratory nature of this study no correction for multiplicity was performed, and pvalues and confidence intervals were interpreted accordingly. All computations were carried

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out using SAS software Version 9.4 (SAS Institute Inc., Cary, NC, USA, 2012). For treatment sequence evaluation, patients were organized according to the therapy given first (i.e. TAS-102 first, regorafenib first), independent of the subsequent therapy given. Pvalues were calculated for comparing disease control rates and survival for TAS-102 first

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versus regorafenib first. For comparison with the published literature, we also reported descriptive results for other groupings (e.g., median survival of all patients receiving regorafenib at any point in the therapy sequence, or for patients receiving first TAS-102 with

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or without an FBT-free interval).

ACCEPTED MANUSCRIPT Results Patient characteristics Between 2013 and 2016, 85 patients, 27 women (32%) and 58 men (68%) were identified as suitable candidates for inclusion in this study (Table 1). The mean age of patients was 63.1 ±

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10 years at the beginning of salvage therapy. At the beginning of trifluridine/tipiracil therapy, 51% of patients had an ECOG PS of 0, 29% had an ECOG of 1, 8% had an ECOG PS of 2 and 6% of patients had an ECOG of 3; while ECOG PS was missing in 6% of patients. In the

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FBT-free period, 62% of patients had an ECOG PS of 0 and 28% had an ECOG PS of 1; in 10% of cases the ECOG PS was missing. Most tumors were located on the left side (74%)

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while only 21 patients (26%) had a right-sided tumor (including three colon transversum tumor patients). RAS mutations were detected in 40 patients (47%), while 43 patients (51%) had wild-type mutations; RAS status was not described in 2 patients. All patients suffered from metastatic disease; metastatic sites included the liver (77%), lung (69%) and lymph nodes (62%). In terms of prior therapies, 100% of patients had received fluoropyrimidines,

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98% had received prior oxaliplatin and 97% had received prior irinotecan. Biologicals targeting the VEGF-pathway were used in 94% of patients and antibodies targeting the

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EGFR pathway were used in 46% of patients (Table 1).

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Response rate and therapy sequence Of the 85 patients included in this analysis, 56% (n=49) received trifluridine/tipiracil and 81% (n=69)

received

regorafenib.

No

complete

responses

were

observed.

In

the

trifluridine/tipiracil group, one patient (2%) showed a partial response and 15 patients (31%) had disease stabilization, resulting in an overall response rate of 2% and disease control rate of 33% (n=16). In the regorafenib group, 9% of patients (n=6) had a partial response while 26% (n=18) had stable disease, resulting in an overall response rate of 9% and a disease control rate of 35% (n=24). 43 patients (63%) did not benefit from treatment and had progressive disease according to RECIST 1.1 (Table 2).

ACCEPTED MANUSCRIPT For treatment sequence evaluation, patients were organized dependent on the therapy given first (regorafenib first or trifluridine/tipiracil first. 86 patients (80%) were included in the regorafenib first group and 17 (20%) were included in the trifluridine/tipiracil first group (Table 3). The disease control rate in the regorafenib first group was 35% (n=24) versus 24% (n=4)

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in the TAS-102 first group. No statistically significant difference in the disease control rate was observed: odds ratio=1.77 (CI 0.52−6.04; p=0.313); also, when adjusting for ECOG PS (adjusted odds ratio=1.75; CI 0.41−7.47; p=0.449).

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Survival data

Progression free survival in all regorafenib-treated patients was 3.1 months (quartiles

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2.2−4.6) versus 2.8 months (quartile 2.0−4.8) in all trifluridine/tipiracil-treated patients, see Table 4. When patients were distributed into the regorafenib first group (n=68, 80%) and the TAS-102 first group (n=17, 20%), progression-free survival was 3.1 months (quartiles 2.1−4.6) versus 2.2 months (quartiles 1.6-3.6), respectively (Figure 1). The statistical significance of the survival advantage for patients receiving regorafenib first (HR=0.52; CI:

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0.30−0.90; p=0.020) disappeared when adjusting for ECOG PS (adjusted HR=0.61; CI: 0.33−1.15; p=0.124). Progression-free survival in the trifluridine/tipiracil first group in the subgroup of patients who had a prior FBT-free interval was 3.1 month (quartiles 2.3−5.9).

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From the start of treatment the median overall survival in patients treated with

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trifluridine/tipiracil was 15.9 months (lower quartile 6.7). trifluridine/tipiracil therapy without regorafenib or with subsequent regorafenib therapy (TAS-102 first) resulted in a median overall survival of 8.1 months (lower quartile 6.7; Figure 2). The overall survival in trifluridine/tipiracil-treated patients who previously-received regorafenib was 17.7 months (lower quartile 13.9). There was a trend towards TAS-102-treated patients without a FBT-free interval having a worse ECOG PS ≥ 2 versus those with a FBT-free interval (10% versus 25% respectively). However, subgroup analysis of patients with an ECOG PS of 0 to 1 still revealed a trend towards an overall survival benefit in patients with an FBT-free period before trifluridine/tipiracil respectively).

(median overall survival of 17.7 months versus 8.0 months,

ACCEPTED MANUSCRIPT Discussion The current study is the first report assessing the treatment sequence of trifluridine/tipiracil and regorafenib in European patients with refractory mCRC. Data were analyzed in the reallife setting and included stratification for gender, age, tumor localization, RAS status and

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ECOG PS. The disease control rate in all regorafenib-treated patients was 35% (9% partial remission, 26% stable disease) while the disease control rate in all trifluridine/tipiracil -treated patients was 33% (2% partial remission, 31% stable disease). The disease control rate of

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patients in the regorafenib first group (+/- subsequent trifluridine/tipiracil) was 35% compared with 24% in patients of the trifluridine/tipiracil first group (+/- subsequent regorafenib) without

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significant differences (95% CI: 0.41−7.47; p=0.449). Median progression-free survival for all patients who received regorafenib was 3.1 months while progression-free survival in patients treated with trifluridine/tipiracil was 2.8 months. When data were analyzed for therapy sequence, median progression-free survival in the regorafenib first group was 3.1 months compared with 2.2 months in the trifluridine/tipiracil first group, with a HR of 0.52 (95% CI:

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0.30−0.90; p=0.020) and an adjusted HR of 0.61 (95% CI: 0.33−1.15; p=0.124). There have been a limited number of real-life studies on the treatment sequence of trifluridine/tipiracil and regorafenib7-9. In 2017, Masuishi et al., evaluated 200 mCRC patients

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following trifluridine/tipiracil or regorafenib in a retrospective comparison. They reported a disease control rate of 33% in the regorafenib group versus 38% in the trifluridine/tipiracil

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group (p=0.60)7. Median progression-free survival in regorafenib-treated patients versus trifluridine/tipiracil-treated patients did not differ. Median progression-free survival for patients who received trifluridine/tipiracil with and without previous regorafenib was 2.2 months (95% CI: 1.8−3.1) and 2.1 months (95% CI, 1.8-3.1), respectively, with a HR of 1.13 (95% CI, 0.761.67; p=0.53). A further group in Japan analyzed the efficacy and safety of TAS-102 treatment in 43 patients with a median age of 63 years, and reported a disease control rate of 33%, median progression-free survival of 2.5 months and median overall survival of 2.5 months

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. When response and survival in trifluridine/tipiracil -treated patients with and

without pre-treatment with regorafenib was examined, they found a trend for longer median

ACCEPTED MANUSCRIPT progression-free survival in the regorafenib pre-treated group (4.6 versus 1.9 months, respectively) with an HR of 0.33 (95% CI: 0.15-0.68; p=0.0025). Furthermore, a higher disease control rate was reported in the regorafenib pre-treated group compared with the regorafenib-naïve group (43% versus 27%; p=0.48). In addition, a longer median overall

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survival from induction of trifluridine/tipiracil chemotherapy in the regorafenib-pretreated group compared with the regorafenib-naive group (19.3 versus 6.6 months) was observed with an HR of 0.13 (95% CI=0.03−0.41; p=0.0002). This is consistent with our observation of an overall survival of 17.7 months versus 8.1 months, respectively. However, there is a

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potential limitation of these analyses as it might lead to immortal time bias resulting from

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time-dependent events17

When compared with the original prospective clinical studies which led to approval of TAS-1025 and regorafenib4,10, response and progression-free survival data in our study showed expected results. However, this manuscript is the first analysis, which compared trifluridine/tipiracil and regorafenib treatment sequencing in a European patient population.

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We also found a tendency for a longer progression-free survival in patients who received regorafenib following trifluridine/tipiracil therapy (3.1 months, quartile 2.1−4.6) when compared with patients who were treated with TAS-102 first (2.2 month, quartile 1.6−3.6);

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however results were not significant with an HR of 0.52 (95% CI: 0.30−0.90; p=0.020) or upon stratification for ECOG PS (adjusted HR of 0.61; 95% CI: 0.33−1.15, p=0.124).

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trifluridine/tipiracil has previously been suggested to be more efficient in combination with angiogenic agents in mCRC patients15. For example, trifluridine/tipiracil treatment in combination with bevacizumab has been shown to improve survival in a phase I/II study16. The hypothesis for that study was based on a murine xenograft model which reported a higher trifluridine concentration in tumors with previous bevacizumab administration. In this context, regorafenib was suggested to be acting as a chemotherapy re-sensitizing agent for trifluridine/tipiracil due to its angiogenic effects15,16. A re-sensitizing effect of regorafenib for other treatments was also suggested in a previously presented clinical phase II trial (REVERCE), which suggested regorafenib followed by cetuximab as the preferred sequence

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. The study at hand has several limitations. As the analysis was retrospective and not

randomized, the ability to draw concise conclusions is limited. Furthermore, the majority of our patients received regorafenib first followed by trifluridine/tipiracil. Regorafenib has been longer available than trifluridine/tipiracil, which has only been approved later. A clear

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proposition relating the therapy sequence requires careful consideration. In conclusion, progression-free survival and response with trifluridine/tipiracil and regorafenib treatment in a real-world setting were comparable to results seen in phase III clinical trials

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and other retrospective studies3,4,7,12,13. In terms of therapy sequence, early treatment with regorafenib seems to bear beneficial effects and does not negatively affect the benefit upon

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trifluridine/tipiracil efficacy, however data are limited. Prospective data are therefore needed to gain more information about the most beneficial therapy sequence in the salvage treatment of mCRC patients.

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Acknowledgements

Editorial assistance was provided by Mark English, PhD of Cor2Ed.

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Conflicts of Interest

MU, MD, AG, AS, DB, MK, SD declare no conflict of interest.

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WS, TW and GP were members of advisory boards for Bayer and Servier.

ACCEPTED MANUSCRIPT References Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012.. Int J Cancer. 2015 Mar 1;136(5):E359-86. doi: 10.1002/ijc.29210. Epub 2014 Oct 9.

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Choi YJ, Chang WJ, Shin SW, et al. The prognostic role of serum C-X-X chemokine receptor type 4 in patients with metastatic or recurrent colorectal cancer. Onco. Targets. Ther., vol.9, pp. 3307-12, 2016.

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Van Cutsem E, Cervantes A, Adam R, et al. ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Ann Oncol. 2016 Aug;27(8):1386-422.

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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 Jan 26;381(9863):30312.

(5)

Mayer RJ, Van Cutsem E, Falcone A et al. Randomized Trial of TAS-102 for Refractory Metastatic Colorectal Cancer. N Engl J Med. 2015 May 14;372(20):190919.

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Kakizawa N, Suzuki K, Fukui T, et al. Clinical and molecular assessment of regorafenib monotherapy. Oncol Rep. 2017 Apr;37(4):2506-2512.

(7)

Masuishi T, Taniguchi H, Hamauchi S et al. Regorafenib Versus Trifluridine/Tipiracil for Refractory Metastatic Colorectal Cancer: A Retrospective Comparison. Clin Colorectal Cancer. 2017 Jun;16(2):e15-e22.

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Sueda T, Sakai D, Kudo T et al. Efficacy and Safety of Regorafenib or TAS-102 in Patients with Metastatic Colorectal Cancer Refractory to Standard Therapies. Anticancer Res. 2016 Aug;36(8):4299-306.

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(9) ARITA S, SHIRAKAWA T, MATSUSHITA Y. Efficacy and Safety of TAS-102 in Clinical Practice of Salvage Chemotherapy for Metastatic Colorectal Cancer. Anticancer Research2016. 36: 1959-1966.

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(10) Li J, Qin S, Xu R, et al. Regorafenib plus best supportive care versus placebo plus best supportive care in Asian patients with previously treated metastatic colorectal cancer (CONCUR): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2015 Jun;16(6):619-29. (11) Lam KO, Lee KC, Chiu J, et al. The real-world use of regorafenib for metastatic colorectal cancer: multicentre analysis of treatment pattern and outcomes in Hong Kong. Postgrad Med J. 2016 Nov 11. (12) Kopeckova K, Buchler T, Bortlicek Z, et al. Regorafenib in the Real-Life Clinical Practice: Data from the Czech Registry. Target Oncol. 2017 Feb;12(1):89-95. (13) Calcagno F, Lenoble S, Lakkis Z, Nguyen T, Limat S, Borg C, Jary M, Kim S, Nerich V. Efficacy, Safety and Cost of Regorafenib in Patients with Metastatic Colorectal Cancer in French Clinical Practice. Clin Med Insights Oncol. 2016; 4;10:59-66.

ACCEPTED MANUSCRIPT (14) Kwakman JJM, Vink G, Vestjens JH et al. Feasibility and effectiveness of trifluridine/tipiracil in metastatic colorectal cancer: real-life data from The Netherlands. Int J Clin Oncol. 2017 Dec 4. [Epub ahead of print] (15) Bertocchi P, Aroldi F, Prochilo T, et al. Chemotherapy rechallenge after regorafenib treatment in metastatic colorectal cancer: still hope after the last hope?. J Chemother. 2017 Apr;29(2):102-105.

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(16) Avallone A, Piccirillo MC, Aloj L, et al. A randomized phase 3 study on the optimization of the combination of bevacizumab with FOLFOX/OXXEL in the treatment of patients with metastatic colorectal cancer-OBELICS (Optimization of Bevacizumab schedulIng within Chemotherapy Scheme). BMC Cancer. 2016 Feb 8;16:69.

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(17) Gleiss A, Oberbauer R, Heinze G. An unjustified benefit: immortal time bias in the analysis of time-dependent events. Transpl Int. 2017 Oct 11. doi: 10.1111/tri.13081. [Epub ahead of print]

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(18) Shitara-K, Yamanaka T, Denda T et al. J Clin Oncol 36, 2018 (suppl 4S; abstr 557)

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Table 1. Patients characteristics. Trifluridine/Tipracil n=49

Gender, n (%) Female Male

19 (28) 49 (72)

15 (31) 34 (69)

Mean age, years (SD)

63 (11)

62 (10)

ECOG PS, n (%) 0 1 2 3 Missing Total

42 (62) 19 (28) 0 0 7 (10) 68 (100)

SC 25 (51) 14 (29) 4 (8) 3 (6) 3 (6) 49 (100)

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Primary site Right-sided Left-sided Rectum

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Regorafenib n=68

14 (29) 19 (39) 16 (32)

K-RAS exon 2 Wild-type Mutant Unknown

35 (51) 32 (47) 1 (2)

26 (53) 22 (45) 1 (2)

Metastatic site Liver Lung Lymph nodes Other

57 (84) 51 (75) 39 (57) 29 (43)

37 (76) 37 (76) 27 (55) 20 (41)

Prior treatment Fluoropyrimidine Oxaliplatin Irinotecan Anti-VEGF Anti-EGFR

68 (100) 67 (99) 66 (97) 64 (94) 33 (49)

49 (100) 48 (98) 48 (98) 47 (96) 25 (51)

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19 (28) 24 (35) 25 (37)

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EGFR, endothelial growth factor; SD, standard deviation; VEGF, vascular endothelial growth factor.

Table 2. Treatment response for patients receiving regorafenib or TRIFLURIDINE/TIPIRACIL independent of therapy sequence (N=85). Treatment

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Regorafenib all, n (%)

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TAS-102 all, n (%)

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Complete response Partial response Stable disease Progressive disease Unknown ORR DCR

68 (81)

̶ 6 (9) 18 (26) 43 (63) 1 (1) 6 (9) 24 (35) 49 (56)

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Complete response ̶ Partial response 1 (2) Stable disease 15 (31) Progressive disease 31 (63) Unknown 1 (2) ORR 1 (2) DCR 16(33) DCR, disease control rate = CR+PR+SD; ORR, overall response rate = CR+PR.

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Regorafenib first, n

Regorafenib only Regorafenib/TAS-102 TAS-102/regorafenib TAS-102 only

36 32 ̶ ̶

Total Disease control rate, n (%) Regorafenib all

TAS 102 all

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Regorafenib only Regorafenib/TAS-102 TAS-102/Regorafenib Regorafenib first

̶

̶ 1 16

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68 (80)

TAS-102 first, n

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Therapy sequence

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Regorafenib/TAS-102 TAS-102/regorafenib TAS-102 only TAS-102 first DCR: 35.3% for regorafenib first versus 23.5% for TAS-102 first OR=1.77; 95% CI 0.52−6.04, p=0.313) Adjusted OR*=1.75 (CI 0.41−7.47, p=0.449)

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Table 3. Treatment sequence and disease control subgroups.

OR, odds ratio; CI, confidence interval. *adjusted for ECOG PS (0 versus >0) and log(CRP).

17 (20)

24 (35) 10 14 0 24 (35) 16 (33) 12 1 3 4 (24)

Total n (%) 36 32 1 16

85 (100)

ACCEPTED MANUSCRIPT Table 4. Survival according to regorafenib and TAS-102 treatment sequence. Median overall survival, month (quartile)

Regorafenib all Regorafenib first

9.5−34.9 6.7−NR 6.7−NR

17.7

14−NR

3.1 3.1

2.2−4.6 2.1−4.6

2.8 2.2 3.1

2.0−4.8 1.6−3.6 2.3−5.9

M AN U

SC

TAS-102 all TAS-102 first TAS-102 (after regorafenib)

26.4 15.9 8.1

RI PT

Regorafenib all TAS-102 all TAS-102 first (+/- subsequent regorafenib) TAS-102 (+ prior FBT) Median progression-free survival, month (quartile)

Median PFS: regorafenib first versus TAS 102 first HR=0.52; 95% CI: 0.30−0.90; p=0.020) HR adjusted=0.61; 95% CI: 0.33−1.15; p=0.124)

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EP

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CI, confidence interval; FBT, fluoropyrimidine-based therapy; HR, hazard ratio; NR, not reached; OS, overall survival; PFS, progression-free survival. *Adjusted for ECOG PS (0 versus >0)

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

AC C

EP

TE D

Figure 1. Progression free survival in patients with regorafenib (regorafenib first: +/subsequent TAS-102) and TAS-102 (TAS-102 first: +/- subsequent regorafenib) treatment.

M AN U

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ACCEPTED MANUSCRIPT

AC C

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Figure 2. Overall survival with regorafenib (regorafenib first: +/- subsequent TAS-102) and TAS-102 (TAS-102 first: +/- subsequent regorafenib) treatment.