Refractory mCRC Research Articles

P-221 - Regorafenib or trifluridine/tipiracil in refractory metastatic colorectal cancer: The optimization of pharmacological costs

Introduction: The introduction of active new agents for refractory metastatic colorectal cancer (mCRC), such as regorafenib and trifluridine/tipiracil, is associated with a relevant increase of costs and it might be interesting to make a balance between the costs of treatment and the added value represented by the improvement of the clinical parameters of interest such as OS (overall survival). Methods: Pivotal phase III randomized controlled trials (RCTs) of regorafenib and trifluridine/tipiracil in refractory mCRC were considered. Differences in OS (expressed in months) between the different arms were calculated and compared with the pharmacological costs (at the Pharmacy of our Hospital) needed to get one month of OS. The costs of drugs are at the Pharmacy of our Hospital and are expressed in euros (€). We assumed the following costs: 2299 € for 1 month of therapy with regorafenib at dose of 160 mg daily, 1160 € for 1 month of therapy with trifluridine/tipiracil at dose of 35 mg per square meter twice daily. Calculations were based on an “ideal patient” (BSA 1.8 sqm; weight 70 Kg). The dosage of drugs were considered according to those reported in each RCT. We have subsequently applied the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS) to the above phase III RCTs. Results: Three phase III RCTs (RECOURSE, CORRECT and CONCUR trials), including 1764 patients, were considered. ESMO-MCBS reached grade 3 for the CONCUR trial, grade 2 for the RECOURSE trial and grade 1 for the CORRECT trial. Combining the costs of therapy with the measure of efficacy represented by the OS, we get the costs for obtaining the advantage in OS, for each arm of the analyzed trials. Trifluridine/tipiracil (RECOURSE trial) resulted the less expensive, with 967 € per month OS-gained towards the CONCUR trial and CORRECT trial, with 2207 € and 2956 € per month OS-gained, respectively, mainly due to the increase in OS difference compared to placebo. Conclusion: Combining pharmacological costs of drugs with the measure of efficacy represented by the OS, trifluridine/tipiracil is a cost-effective treatment for patients with refractory mCRC.

The safety of trifluridine and tipiracil for the treatment of metastatic colorectal cancer

ABSTRACTIntroduction: TAS102 is an oral thymidine-based nucleoside analog that has been approved for the treatment of patients with metastatic colorectal cancer (mCRC) previously treated with, or not candidates for, available therapies including fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapies, anti-vascular endothelial growth factor (VEGF) agents and, if RAS wild-type, anti-epidermal growth factor receptor (EGFR) therapy. The pivotal RECOURSE phase III trial demonstrated a significant improvement in disease control rate, progression-free survival (PFS), and overall survival (OS) as compared with placebo in patients with refractory mCRC.Areas covered: This manuscript aims to review the clinical development of TAS102 in CRC, with a particular focus on safety, and to provide some perspective regarding its role in clinical practice. A literature search was conducted of MEDLINE and EMBASE databases for published studies (January 2004–December 2016) using the search terms TAS102, trifluridine–tipiracil, metastatic or advanced CRC, clinical trial, toxicity, safety, pharmacology, pharmacokinetics, and therapy.Expert opinion: TAS102 significantly improves survival of patients with refractory mCRC and has manageable toxicity. An expanding role in the treatment of CRC is expected for TAS102 in the near future, as its favorable safety profile makes TAS102 a suitable drug to be combined with other cytotoxic and targeted agents.

Trifluridine/Tipiracil (TAS-102) in Refractory Metastatic Colorectal Cancer: A Multicenter Register in the Frame of the Italian Compassionate Use Program.

TAS-102 is indicated for patients with metastatic colorectal cancer (mCRC) previously treated with, or not considered candidates for, available therapies. Given the complete inefficacy in half of patients, the lack of predictive factors, the palliative setting, and the financial and clinical toxicity, optimizing the cost-benefit ratio is crucial. The "ColonLife" nomogram allows an estimate of the 12-week life expectancy of patients with refractory mCRC. We collected data from patients treated at eight Italian centers in the compassionate use program. Baseline characteristics of patients who were or were not progression free at 6 months were compared. The discriminative ability of the ColonLife nomogram was assessed. Among patients who received both TAS-102 and regorafenib, clinical outcomes of the two sequences were compared. This study included 341 patients. Six (2%) and 93 (27%) patients achieved response and disease stabilization, respectively. The median progression-free survival (PFS) was 2.4 months with an estimated 6-month PFS rate of 19%; the median overall survival (OS) was 6.2 months. An Eastern Cooperative Oncology Group performance status (ECOG PS) of 0, normal lactate dehydrogenase (LDH), and a time from the diagnosis of metastatic disease of >18 months were independently associated with higher chances of a patient being progression free at 6 months. The discriminative ability of ColonLife was confirmed. Among 121 patients who received both regorafenib and TAS-102, no differences in first or second PFS or OS were reported between the two sequences. One out of five patients achieves clinical benefit with TAS-102. ECOG PS, LDH, and time from diagnosis of metastatic disease may help to identify these patients. Excluding patients with very short life expectancy appears a reasonable approach. Improving the cost-efficacy ratio of TAS-102 in metastatic colorectal cancer is needed to spare useless toxicities in a definitely palliative setting. Eastern Cooperative Oncology Group performance status, lactate dehydrogenase levels, and time from the diagnosis of metastatic disease may help to identify patients more likely to achieve benefit. Properly designed prognostic tools (i.e., the "ColonLife" nomogram) may enable excluding from further treatments patients with very limited life expectancy.

Duration of previous treatment as a prognostic factor in metastatic colorectal cancer treated with trifluridine/tipiracil.

We herein describe the findings from the trifluridine/tipiracil (TAS-102) Compassionate Use program in Latvia, set up prior to marketing authorization for the management of pretreated patients with metastatic colorectal cancer (mCRC). The efficacy and safety of TAS-102 in patients with refractory mCRC were evaluated in the phase III trial RECOURSE. A previous report confirmed neutropenia and duration of previous treatment for mCRC as prognostic factors in TAS-102 users. The aim of the present study was to analyze possible prognostic factors, such as neutropenia, in TAS-102 responders. A retrospective analysis of 14 patients who received TAS-102 chemotherapy in two institutions in Latvia (Clinic of Oncology of Pauls Stradins Clinical University Hospital and Oncology Centre of Riga East University Hospital) was performed. Grade 3-4 neutropenia was observed in 28% of the patients. In patients with grade 3-4 neutropenia the median progression-free survival (mPFS) was 7 months, whereas in those without neutropenia the mPFS was 5 months [hazard ratio (HR)=0.24, P=0.033]. In 64% of the patients, the duration of previous treatment was >18 months. In patients treated for >18 months from the start of first-line mCRC treatment the mPFS was 7 months, whereas in those treated for ≤18 months from the start of first-line mCRC treatment the mPFS was 5 months (HR=0.15, P=0.029). Therefore, a longer time from mCRC diagnosis until disease progression may be used to select chemotherapy-refractory mCRC patients for TAS-102 treatment. Furthermore, severe neutropenia may be considered as a surrogate marker for predicting TAS-102 treatment outcomes.

A Pilot Study of Apatinib as Third-Line Treatment in Patients With Heavily Treated Metastatic Colorectal Cancer

BackgroundAntiangiogenic therapy has shown improved clinical outcome in metastatic colorectal cancer (mCRC). After the failure of standard treatments, regorafenib and TAS-102 would be recommended for patients with mCRC, however, they have not been approved in China during this study period. Patients and MethodsThis pilot study aimed to assess the efficacy and safety of apatinib, a novel oral inhibitor targeting vascular endothelial growth factor receptor 2, as third-line treatment for patients with mCRC refractory to standard therapies. In this retrospective study, all patients received apatinib treatment until progressive disease (PD), death, unacceptable toxicity, and curative surgery. The dose or treatment schedule was modified according to the physician's discretion according to the toxicity profiles. ResultsBetween March 2015 and June 2017, 36 patients were enrolled and eligible for evaluation of the safety and efficacy. One patient (2.8%) achieved complete response, 3 (8.3%) achieved partial response, 24 (66.7%) achieved stable disease, and 8 (22.2%) PD. The objective response rate and the disease control rate were 11.1% (4 of 36), and 77.8% (28 of 36), respectively. Moreover, the median overall survival (OS) since the initiation of first-line treatment was 33.2 months. The median progression-free survival (PFS) and median OS from apatinib treatment were 4.8 and 10.1 months, respectively. Intergroup analysis showed that there was no significant difference in median PFS and median OS between patients who were previously treated with and without bevacizumab. The most common Grade 3 to 4 adverse reactions were hand-foot syndrome, hypertension, and proteinuria. ConclusionOur results suggested that apatinib was active as a third-line treatment of refractory mCRC with a manageable tolerability profile. In addition, preliminary data suggested that the efficacy of apatinib would not be affected by previous bevacizumab treatment. Further prospective randomized controlled clinical trials are urgently needed.

122P - Selecting patients with metastatic colorectal cancer for treatment with temozolomide using proteomic analysis of MGMT

Background: Temozolomide (TMZ) is a standard treatment for melanoma and glioblastoma and it has shown limited but encouraging activity in patients with metastatic colorectal cancer (mCRC). In multiple cancer types, tumor expression of the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) is a marker of poor response to TMZ. MGMT promoter methylation is associated with loss of MGMT expression and response to TMZ. We hypothesized that mCRC patients whose tumors expressed quantities of MGMT protein below a pre-defined cutoff would have better outcomes on TMZ than patients with MGMT expression above the cutoff. To test our hypothesis, we assessed MGMT by mass spectrometry in the tumor samples of patients with refractory mCRC and MGMT promoter methylation who had received TMZ. Methods: Archived formalin-fixed, paraffin-embedded tissue sections were obtained from 24 patients from two phase 2 trials of TMZ. A pathologist marked the tumor areas, which were then microdissected and solubilized. In each tumor sample, multiple protein biomarkers including MGMT were quantified with selected reaction monitoring mass spectrometry. An MGMT cutoff of 200 amol/ug was based on the limit of quantitation from a concentration curve. The Mantel-Cox log-rank and the Fisher’s exact tests were used for survival comparisons. Results: MGMT protein was detected in 13 of 24 (54.2%) colorectal tumor samples (range: 229.3-784.8 amol/µg). The overall response rate was 29%. Patients with MGMT protein levels below a cutoff of 200 amol/ug (n = 11) had a notably higher response rate than patients with MGMT levels above the cutoff (64% vs. 0%; p = 0.001 Fisher’s test). Also a longer progression-free survival was observed (4.3 vs. 1.6 months, HR = 0.36, 95% CI = 0.13-1.10, p = 0.054). Results for overall survival were consistent but not statistically significant (8.9 vs 6.9 months, HR = 0.55, p = 0.221). Conclusions: Patients with mCRC whose tumors expressed low or undetectable levels of MGMT protein had better outcomes following TMZ treatment than their counterparts. Quantitative proteomic analysis of MGMT could potentially be used to select CRC patients for TMZ treatment. The results of validation studies are forthcoming. Legal entity responsible for the study: NantOmics, LLC Funding: Has not received any funding Disclosure: F. Cecchi: Employee at NantOmics

Evolution of regorafenib from bench to bedside in colorectal cancer: Is it an attractive option or merely a "me too" drug?

Colorectal cancer (CRC) is a major public health problem in the United States with an estimated 50,260 deaths in 2017. Over the past two decades, several agents have been approved by the US Food and Drug Administration (FDA) for the treatment of patients with metastatic CRC (mCRC). Regorafenib (BAY 73-4506) is a small-molecule multikinase inhibitor that was approved for the treatment of mCRC in 2012. This agent is a novel oral diphenylurea-based multikinase inhibitor that is active against several angiogenic receptor tyrosine kinases (RTKs; VEGFR-1, VEGFR-2, VEGFR-3, TIE-2), oncogenic RTKs (c-KIT, RET), stromal RTKs (PDGFR-B, FGFR-1), and intracellular signaling kinases (c-RAF/RAF-1, BRAF, BRAFV600E). Preclinical studies have documented its broad-spectrum activity against different solid tumor types including CRC. Phase I studies showed that it had an acceptable safety profile in advanced refractory mCRC. A subsequent Phase III trial (CORRECT) demonstrated significant clinical efficacy of regorafenib in patients with refractory or advanced mCRC, which eventually led to its FDA approval for the treatment of mCRC in September 2012. However, the drug was associated with significant toxicity in clinical practice when administered at the approved doses, which necessitated a thorough reassessment of its dosing schedule and toxicity profile. This review summarizes the development of regorafenib from the initial preclinical studies to the Phase III trials and critically examines the current clinical space occupied by regorafenib in the treatment of mCRC, at 5 years after its initial FDA approval.

A Polymorphism within the Vitamin D Transporter Gene Predicts Outcome in Metastatic Colorectal Cancer Patients Treated with FOLFIRI/Bevacizumab or FOLFIRI/Cetuximab.

Purpose: Vitamin D exerts its inhibitory influence on colon cancer growth by inhibiting Wnt signaling and angiogenesis. We hypothesized that SNPs in genes involved in vitamin D transport, metabolism, and signaling are associated with outcome in metastatic colorectal cancer (mCRC) patients treated with first-line FOLFIRI and bevacizumab.Experimental Design: 522 mCRC patients enrolled in the FIRE-3 (discovery cohort) and TRIBE (validation set) trials treated with FOLFIRI/bevacizumab were included in this study. 278 patients receiving FOLFIRI and cetuximab (FIRE-3) served as a control cohort. Six SNPs in 6 genes (GC, CYP24A1, CYP27B1, VDR, DKK1, CST5) were analyzed.Results: In the discovery cohort, AA carriers of the GC rs4588 SNP encoding for the vitamin D-binding protein, and treated with FOLFIRI/bevacizumab had a shorter overall survival (OS) than those harboring any C allele (15.9 vs. 25.1 months) in both univariable (P = 0.001) and multivariable analyses (P = 0.047). This association was confirmed in the validation cohort in multivariable analysis (OS 18.1 vs. 26.2 months, HR, 1.83; P = 0.037). Interestingly, AA carriers in the control set exhibited a longer OS (48.0 vs. 25.2 months, HR, 0.50; P = 0.021). This association was further confirmed in a second validation cohort comprising refractory mCRC patients treated with cetuximab ± irinotecan (PFS 8.7 vs. 3.7 months) in univariable (P = 0.033) and multivariable analyses (P = 0.046).Conclusions:GC rs4588 SNP might serve as a predictive marker in mCRC patients treated with FOLFIRI/bevacizumab or FOLFIRI/cetuximab. Whereas AA carriers derive a survival benefit with FOLFIRI/cetuximab, treatment with FOLFIRI/bevacizumab is associated with a worse outcome. Clin Cancer Res; 24(4); 784-93. ©2017 AACR.

Efficacy of Sym004 in Patients With Metastatic Colorectal Cancer With Acquired Resistance to Anti-EGFR Therapy and Molecularly Selected by Circulating Tumor DNA Analyses

Acquired resistance to anti-EGFR therapy (epidermal growth factor receptor) is frequently due to RAS and EGFR extracellular domain (ECD) mutations in metastatic colorectal cancer (mCRC). Some anti-EGFR-refractory patients retain tumor EGFR dependency potentially targetable by agents such as Sym004, which is a mixture of 2 nonoverlapping monoclonal antibodies targeting EGFR. To determine if continuous blockade of EGFR by Sym004 has survival benefit. Multicenter, phase 2, randomized, clinical trial comparing 2 regimens of Sym004 with investigator's choice from March 6, 2014, through October 15, 2015. Circulating tumor DNA (ctDNA) was analyzed for biomarker and tracking clonal dynamics during treatment. Participants had wild-type KRAS exon 2 mCRC refractory to standard chemotherapy and acquired resistance to anti-EGFR monoclonal antibodies. Participants were randomly assigned in a 1:1:1 ratio to Sym004, 12 mg/kg/wk (arm A), Sym004, 9 mg/kg loading dose followed by 6 mg/kg/wk (arm B), or investigator's choice of treatment (arm C). Overall survival (OS). Secondary end points included preplanned exploratory biomarker analysis in ctDNA. A total of 254 patients were randomized (intent-to-treat [ITT] population) (median age, 63 [range, 34-91] years; 63% male; n = 160). Median OS in the ITT population was 7.9 months (95% CI, 6.5-9.9 months), 10.3 months (95% CI, 9.0-12.9 months), and 9.6 months (95% CI, 8.3-12.2 months) for arms A, B, and C, respectively (hazard ratio [HR], 1.31; 95% CI, 0.92-1.87 for A vs C; and HR, 0.97; 95% CI, 0.68-1.40 for B vs C). The ctDNA revealed high intrapatient genomic heterogeneity following anti-EGFR therapy. Sym004 effectively targeted EGFR ECD-mutated cancer cells, and a decrease in EGFR ECD ctDNA occurred in Sym004-treated patients. However, this did not translate into clinical benefit in patients with EGFR ECD mutations, likely owing to co-occurring resistance mechanisms. A subgroup of patients was defined by ctDNA (RAS/BRAF/EGFR ECD-mutation negative) associated with improved OS in Sym004-treated patients in arm B compared with arm C (median OS, 12.8 and 7.3 months, respectively). Sym004 did not improve OS in an unselected population of patients with mCRC and acquired anti-EGFR resistance. A prospective clinical validation of Sym004 efficacy in a ctDNA molecularly defined subgroup of patients with refractory mCRC is warranted. clinicaltrialsregister.eu Identifier: 2013-003829-29.

A phase II trial of the effect of perindopril on hand foot syndrome (HFSR) incidence and severity in patients receiving regorafenib with refractory metastatic colorectal carcinoma (mCRC).

824 Background: Regorafenib is an oral multi-kinase inhibitor (MKI), with a demonstrated overall survival benefit in mCRC refractory to standard therapy ( PMID 23177514). The most common grade 3 adverse event (AE) reported in this trial was HFSR, with 47% of patients (pts) experiencing HFSR of all grades, and 17% with grade 3 severity. The pathogenesis of regorafenib-induced HFSR is not well established, but may be related to alterations in the capillary endothelium. Perindopril is an Angiotensin Converting Enzyme (ACE) Inhibitor indicated for the treatment of hypertension, and may also play a role in preventing endothelial dysfunction ( PMID 17140552). We hypothesized that perindopril may prevent or reduce the severity of regorafenib-induced HFSR. Methods: In this single center Phase II, open label trial, 34 pts with refractory mCRC were planned to be treated with regorafenib (160 mg/day) and perindopril (4 mg/day) with both agents given 3 weeks on and 1 week off. An interim analysis was planned after 10 evaluable pts. The primary objective was to assess the proportion of pts with any grade HSFR toxicity. Secondary endpoint included time to development of worst (grade 3) HSFR toxicity, proportion of all grades of hypertension and all grade toxicities, and progression free survival. All toxicities were evaluated using CTCAE v4.03. Results: 12 pts were accrued over a 9 month time period, and 10 pts were considered evaluable as they completed one cycle of treatment. Pt characteristics included (6 M/ 6F, mean age 62, ECOG PS 0 (25%)/ 1 (75%). A planned interim analysis was performed after 10 evaluable pts had completed their first cycle of study treatment. 5/10 (50%) experienced Grade 3 HFSR, and based on the statistical plan it was deemed highly unlikely that perindopril would lead to reduced levels of regorafenib induced HSFR compared with regorafenib alone thus enrolment was stopped. The most frequent other grade 3 toxicities included hypertension (16.7%), and increased AST (16.7%). Conclusions: The addition of perindopril to regorafenib did not appear to reduce HSFR incidence and severity in pts with refractory mCRC. Clinical trial information: NCT02651415.

Predictive value of tumor growth rate during previous treatment for tumor response to regorafenib (REGO) and trifluridine/tipiracil (TFTD) in metastatic colorectal cancer (mCRC).

766 Background: Although REGO and TFTD have been recognized as standard salvage treatments for patients (pts) with refractory mCRC, it is still unclear which drug should be used first. Tumor growth rate (TGR) during the pre-treatment period is associated with survival in lung and laryngeal cancer treated with chemoradiotherapy. However, little is known about the association between TGR during the pre-treatment period and tumor response to REGO and TFTD. Methods: We retrospectively analyzed the data of consecutive mCRC pts who were treated with REGO or TFTD at three institutions. We classified pts into slow-growing (SG) or rapid-growing (RG) groups according to TGR, and appearance of new lesions (NL+) or their absence (NL–) during the pre-treatment period. TGR was calculated as follows: TGR = (D1 − D0)/100D0 (CT1 − CT0), where CT1 is the date of computed tomography (CT) at progressive disease, CT0 is the date of CT before CT1, and Dn is the sum of target lesion diameters at CTn (according to RECIST version 1.1). SG was defined as NL– with a low TGR ( < 0.33), and RG was defined as NL− with a high TGR (≥0.33) or NL+, irrespective of TGR. Results: A total of 244 pts (RG/SG: 133/111, REGO/TFTD: 132/112) were eligible. The proportion of RG pts with a long duration from first-line chemotherapy and SG pts with elevated ALP was higher in the REGO group, while the proportion of SG pts with poor PS was higher in the TFTD group. The disease control rate (DCR) was similar in both groups (REGO 29% vs TFTD 23%, p = 0.556) among RG pts, while the DCR of TFTD was significantly better than REGO in SG pts In a multivariate analysis of predictive factors for DCR, drug selection was an independent factor for DCR in SG pts (odds ratio 3.51; 95% CI 1.33-9.27; p = 0.011). In RG group, DCRs of NL+ pts were worse than that of NL- pts (16% vs 36% in REGO group, p = 0.109; 9% vs. 31% in TFTD group, 0.108). Conclusions: TGR during the pre-treatment period would be helpful in selecting between REGO and TFTD, especially for pts with slow-growing tumors. Pts with appearance of new lesions may not benefit from either REGO or TFTD as salvage treatment.

Matrix metalloproteinase-related gene polymorphisms to predict efficacy of regorafenib in patients with metastatic colorectal cancer.

692 Background: Matrix metalloproteinases (MMPs) are proteolytic enzyme for extracellular matrix and involved in regulation of tumor environment including angiogenesis. MMP-2 and MMP-9 were reported to be prognostic marker of anti-angiogenic therapy. We tested whether genetic polymorphisms in the MMP family predict clinical outcomes in patients with refractory mCRC receiving regorafenib. Methods: 228 patients with mCRC receiving regorafenib were included in this pooled analysis combining two different cohorts from Italy and Japan (median age, 62 years; male, 51.5%; median follow-up time, 26.2 months; Italian/Japanese, 150/79). Six single nucleotide polymorphisms (SNPs) of five genes in MMPs ( MMP2, MMP9, MMP14, TIMP2, CD44) were analyzed by PCR-based direct sequencing. Correlations between candidate SNPs and progression-free survival (PFS) and overall survival (OS) were analyzed using Kaplan-Meier curves and log-rank test. Disease control was compared by Fisher’s exact test. Multivariable analyses were conducted using the Cox proportional hazard regression model. Results: In univariate analysis, patients carrying the G/G variant in MMP2 rs1477017 had a significantly shorter OS compared to those with any A allele (4.4 vs. 7.8 months, HR 1.85, 95%CI: 1.13-3.03, P= 0.011). The findings were confirmed in multivariable analysis (HR 1.84, 95%CI: 1.11-3.07, P= 0.019). Although the frequency of the T/T variant in MMP9 rs2274755 was considerably low, the T/T variant was associated with shorter PFS and OS compared to any G allele in univariate analysis (1.7 vs. 2.1 months, HR 2.53, 95%CI: 1.17-5.46, P= 0.011; 3.9 vs. 7.6 months, HR 2.51, 95%CI: 1.11-5.72, P= 0.021) and multivariable analysis (HR 3.04, P= 0.009; HR 5.20, P< 0.001). No significant interaction was shown between the SNPs and cohorts. Disease control was significantly infrequent in patients carrying the T/T variant in MMP9 rs2274755 ( P= 0.046). Conclusions: Our data suggest that MMPs network potentially mediates tumor angiogenesis responding to regorafenib. The MMP2 and MMP9 SNPs may predict efficacy of regorafenib in patients with refractory mCRC. However, this preliminary finding warrants further validation.

Factors associated with efficacy of TAS-102 in patients with refractory metastatic colorectal cancer (mCRC).

858 Background: TAS-102 significantly improved progression free survival (PFS) and overall survival (OS) versus placebo in patients with treatment refractory mCRC. We analyzed potential predictive and prognostic factors in patients treated with TAS-102 in real-world practice. Methods: We retrospectively evaluated the clinical data of 129 patients who received TAS-102. Different factors associated with PFS and OS were analyzed. Results: Baseline characteristics were: median age 67 (range 37-83), male 63.6%, ECOG PS 0 in 40.3% and 1 in 59.7%. Primary tumor location: right 20.2%, left 79.2%, wt RAS 45%. Median number of TAS-102 treatment line 3 (range 2-8). Prior treatment: anti-EGFR 45%, anti-VEGF 83%, and regorafenib 20.9%. Median follow-up was 9.4 months. The median number of cycles of TAS-102 was 3 (range 1-14). Best achieved response was SD in 23%. Median PFS was 3.3 months and OS was 11.1 months. Any ≥ grade 3 AE was in 45%, the most common ≥ grade 3 AEs were neutropenia (40.2%), anemia (6.2%), thrombocytopenia (4.7%), febrile neutropenia (2.3%), diarrhea (1.6%), nausea (1.6%), and asthenia (1.6%). Dose reduction was needed in 29.5% and cycle delay in 53.5%. Factors significantly associated with longer PFS were: initiation of TAS-102 treatment more than 3 months from last fluoropyrimidine therapy (p = 0.022, HR 0.633), normal baseline CRP level (p = 0.004, HR 0.479), baseline WBC < 8 × 109/L (p = 0.025, HR 0.641), monocytes < 0.5 × 109/L (p = 0.016, HR 0.522), neutropenia ≥ grade 2 during treatment (p < 0.0001, HR 0.349), TAS-102 dose reduction during treatment (p < 0.0001, HR 0.397), and TAS-102 cycle delay (p < 0.0001, HR 0.402). Factors associated with longer OS were normal CRP (p = 0.001, HR 0.295), normal LDH (p = 0.006, HR 0.422), WBC < 8 × 109/L (p = 0.0001, HR 0.357), monocytes < 0.5 × 109/L (p = 0.016, HR 0.373), neutropenia ≥ G2 during treatment (p = 0.0002, HR 0.343), TAS-102 cycle delay (p = 0.002, HR 0.421), wt RAS (p = 0.05, HR 0.578). Conclusions: This analysis confirms that TAS-102 is effective in patients with refractory mCRC treated in a real-world setting. Factors associated with better outcomes were baseline CRP, WBC, monocytes, and neutropenia, dose reduction and cycle delays during the treatment.

Prognostic value of neutrophil-to-lymphocyte ratio (NLR) on overall survival (OS), progression free survival (PFS) and disease control rate (DCR) in patients with metastatic colorectal cancer (mCRC) from the RECOURSE study.

744 Background: Elevated neutrophil-to-lymphocyte (NLR) ratios may represent markers of a suboptimal host immune response to cancer and have been shown to correlate with prognosis in multiple tumor types. Trifluridine/tipiracil (FTD/TPI also known as TAS-102) compared with placebo significantly improved OS (median: 7.1 vs.5.3 months, hazard ratio (HR) = 0.68, 95% confidence interval (CI) [0.58;0.81], p < 0.0001), PFS, and DCR in the phase 3 RECOURSE study, conducted in patients with refractory mCRC. A post-hoc analysis was conducted to assess correlation between clinical outcomes and baseline NLR (in blood) in RECOURSE. Methods: A retrospective review on 782/800 patients, with available NLR, was performed on OS, PFS, and DCR in two subgroups of patients with low ( < 3) or high (≥ 3) NLR at baseline. Based on literature, the cutoff value of 3 was chosen as the number of patients was similar in each NLR subgroup. Between-group comparison was performed using a stratified Cox’s proportional hazard model for OS and PFS, and Fisher’s Exact test for DCR. Results: The median value of NLR at baseline was similar in each group, FTD/TPI (N = 519): 4.4 ± 6.3, placebo (N = 263): 4.7 ± 6.5. Almost 60% of patients in each group had high NLR. In the low NLR vs. high NLR subgroup, there were differences at baseline for ethnic origin (Asian: 45% vs.29%), ECOG PS 0 (69% vs. 49%), and number of metastatic sites ≥ 3 (32% vs. 46%). The median OS [95 % CI] was statistically significantly higher in the low vs. high NLR subgroup: 8.4 [7.8;9.5] vs. 5.3 [4.7;5.7] months, HR = 0.49, 95% CI [0.41;0.59], p < 0.0001. Irrespective of NLR, all patients benefited from FTD/TPI vs. placebo. The results of PFS and DCR were statistically significantly better in the low NLR vs. high NLR subgroup. The multivariate Cox analysis for OS with the interaction test between treatment groups and NLR showed that NLR is not a predictive factor (p = 0.15). Conclusions: In this retrospectively analyzed mCRC population, NLR was shown to be an independent prognostic factor. Further research is warranted to assess if NLR can be a stratification factor in mCRC clinical trials. Clinical trial information: NCT01607957.

Comparison of the real-world adherence and compliance patterns with trifluridine/tipiracil (FTD/TPI) and regorafenib (REG) for the treatment of metastatic colorectal cancer (mCRC).

666 Background: FTD/TPI and REG both prolong survival in refractory 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. Methods: Retrospective data from 10/2014 to 7/2016 from the US Symphony Health Solutions’ Integrated Dataverse (IDV®) database were analyzed for patients receiving FTD/TPI or REG. The index date was the date of first FTD/TPI or REG prescription. Patients were included if: 1) age ≥18 years old, 2) ≥1 CRC diagnosis, 3) no diagnosis of gastric cancer or gastrointestinal stromal tumor, and 4) continuous clinical activity for ≥3 months before and after index date. The observation period spanned from index date to end of data, end of continuous clinical activity, or switch to another mCRC treatment. Adherence was assessed using medication possession ratio (MPR) ≥0.80 and proportion of days covered (PDC) ≥0.80 at 3 months. Compliance was assessed using time to discontinuation over the observation period using allowable gaps of 45, 60, or 90 days. Patients who never discontinued therapy were censored at the end of the observation period. Outcomes were compared between FTD/TPI and REG using multivariate logistic regression and Cox proportional hazards models, adjusting for demographic and clinical baseline characteristics. Results: A total of 1,630 FTD/TPI patients and 1,425 REG patients were identified. Mean ± standard deviation (SD) age of FTD/TPI patients was 61.0 ± 11.0 compared to 62.8 ± 10.9 for REG patients (p < 0.001). FTD/TPI patients were 80% more likely to have a MPR ≥0.80 compared to those on REG (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 those on REG when using gaps of 60 days (Hazard Ratio = 0.63, p < 0.001). Similar results were found with 45 and 90 days. Conclusions: In this retrospective study of mCRC patients, patients on FTD/TPI were significantly more likely to adhere and comply with therapy compared to those on REG.

Safety for trifluridine/tipiracil (TAS-102) with bevacizumab combination in patients with refractory metastatic colorectal cancer in real-world clinical practice: The single-institutional experience.

865 Background: Trifluridine/tipiracil (TAS-102) is an oral combination therapy approved for the treatment of patients with metastatic colorectal cancer (mCRC). Phase 1/2 C-TASK FORCE study of TAS-102 plus bevacizumab for patients with refractory mCRC demonstrated a promising efficacy results with mild toxicity profile (Kuboki Y, et al. Lancet Oncology, 2017). The retrospective single-institutional study is aiming to investigate safety of TAS-102 plus bevacizumab for patients with refractory mCRC in real-world clinical practice. Methods: MCRC patients who were refractory or intolerant to a fluoropyrimidine, irinotecan, oxaliplatin, anti-VEGF therapy, and anti-EGFR therapy (if wild-type RAS) and consecutively received TAS-102 plus bevacizumab between January 2016 and June 2017, were analyzed. Adverse events (AEs) were assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.0. Results: A total of 33 patients were identified for safety analysis. Patient characteristics were as follows; male/female, 19/14; median age, 59.0 (range 38-81); ECOG Performance Status of 0/1, 21/12; and All wild/ RAS mutant/ BRAF mutant/ unknown, 16/15/1/1. Six patients had received prior regorafenib. The relative dose intensities of TAS-102 and bevacizumab were 87% and 79%, respectively. Grade 3 or higher hematological and non-hematological AEs were follows; leucopenia, 33%; neutropenia, 42%; anemia, 9%; and proteinuria, 12%. There were no febrile neutropenia or treatment-related death. G-CSF was given in 8 patients (24%), while intravenous antibiotics was in one patient. There were four patients with emergency admission, and out of these, the two patients had intestinal perforation, and perianal abscess, which were regarded as treatment-associated; ultimately these AEs were fully recovered. Conclusions: Our findings suggested safety for TAS-102 plus bevacizumab combination in real-world clinical practice is consistent with those in clinical trial setting.

TRUSTY: A randomized multicenter phase II/III study of trifluridine/tipiracil and bevacizumab versus irinotecan, fluoropyrimidine, and bevacizumab as second-line treatment in patients with metastatic colorectal cancer progressive during or following first-line oxaliplatin-based chemotherapy.

TPS881 Background: Trifluridine/tipiracil is an oral combination preparation approved for the treatment of patients with metastatic colorectal cancer (mCRC). Trifluridine is a thymidine analog, and tipiracil is a thymidine phosphorylase inhibitor that improves the bioavailability of trifluridine. Phase I/II C-TASK FORCE study of trifluridine/tipiracil plus bevacizumab (Bev) for patients with refractory mCRC demonstrated a promising efficacy results with mild toxicity profile (Kuboki Y, et al. Lancet Oncology, 2017). Methods: We are conducting a randomized multicenter phase II/III non-inferiority study (JapicCTI-173618) to compare trifluridine/tipiracil plus Bev versus FOLFIRI plus Bev (in the control arm, S-1 can replace 5-FU) in second-line mCRC patients who have failed first-line oxaliplatin-based chemotherapy. Key eligibility criteria are a histologically confirmed colorectal adenocarcinoma, refractory to first-line chemotherapy including a fluoropyrimidine, oxaliplatin, and either Bev or an anti-EGFR antibody (if RAS wild-type), an age of 20 years or older, ECOG performance status of 0-1, and adequate oral intake. Patients are randomized in a 1:1 ratio to receive trifluridine/tipiracil plus Bev or FOLFIRI plus Bev using the minimization method stratified by RAS status, prior therapy (Bev/anti-EGFR antibody), and primary tumor sidedness. The primary endpoint is overall survival. The non-inferiority hypothesis will be achieved if the upper limit of the two-sided 95% CI of the HR is below 1.33 (as HR scale, power 0.80). If achieved, the non-inferiority hypothesis with the margin of 1.25 (as HR) and the superiority will be consequently tested. Secondary endpoints include progression-free survival, time to treatment failure, response rate, disease control rate, subsequent treatment, time to post-study treatment failure, the quality of life, and adverse events. The target sample size is 524 patients. Patients will be enrolled from October 2017. Clinical trial information: 173618.

Circulating angiogenesis-related markers as predictors of benefit from regorafenib in metastatic colorectal cancer (mCRC) patients (pts).

675 Background: Regorafenib is a treatment option for refractory mCRC pts. Considering its limited clinical benefit and the palliative setting, patients’ selection is essential to optimize the cost-effectiveness ratio. We aimed to describe the modulation of selected circulating angiogenic factors by regorafenib and to investigate their correlation with clinical outcome. Methods: IL-8, Ang-2, PDGF, bFGF, Tie-2, sVEGFR2, sVEGFR3, PlGF, VEGF-A, VEGF-B were assessed by ELISA on plasma samples collected at baseline (d1), after 15 days of treatment (d15), at the best RECIST response, at disease progression (PD) in mCRC pts treated with regorafenib, as per indication. Comparisons among concentrations of each marker at different timepoints were performed by Wilcoxon test. Markers showing significant changes were analyzed for correlation with outcome. Results: 105 pts were included. Median PFS and OS were 2.1 and 7.0 months (mos), respectively. As compared to d1, IL-8 and Ang-2 levels increased at PD. An early decrease at d15 was observed for PDGF, Tie-2, sVEGFR2 and sVEGFR3 levels, followed by an increase at PD. Conversely, PlGF levels increased at d15 and then decreased at PD. Baseline levels of Ang-2 and Tie-2 below the median value were associated with longer PFS (HR:0.61 [0.37-0.83] p = 0.006; HR:0.69 [0.43-0.95] p = 0.04, respectively) and OS (HR:0.45 [0.26-0.60] p < 0.0001; HR:0.68 [0.44-0.98] p = 0.04, respectively). With regard to Ang-2, 40 (45%) out of 89 pts with available plasma samples at d15 showed increased levels at d15 as compared to d1. Among them, 21 (53%) achieved disease control, as compared to 14 out of 49 (29%) pts with Ang-2 decreased levels (p = 0.03). Median PFS of pts with increased and decreased Ang-2 levels were 3.1 and 1.8 mos, respectively (HR:0.57 [0.33-0.78] p = 0.004). Conclusions: A dynamic modulation of plasma angiogenic factors occurs during the treatment with regorafenib. Low baseline Ang-2 and Tie-2 levels seem to be associated with good prognosis. The early modulation of Ang-2 levels may predict benefit from regorafenib. These results need validation in independent series.

Regorafenib dose optimization study (ReDOS): Randomized phase II trial to evaluate dosing strategies for regorafenib in refractory metastatic colorectal cancer (mCRC)–An ACCRU Network study.

611 Background: Regorafenib is an oral multikinase inhibitor with survival benefit in refractory mCRC patients (pts). Toxicities such as Palmar-plantar erythrodysesthesia syndrome (PPES), fatigue and hypertension (HTN) have limited its use. Despite absence of supportive data, various dosing or interval scheduling have been implemented into clinical practice. Methods: A randomized phase II study of regorafenib dose-escalation (Arm A: 80 mg/day, weekly dose escalation if no significant drug-related toxicities, up to 160 mg/day) vs. standard dose (Arm B: 160 mg/day) in pts with mCRC for 21 days of a 28-day cycle. Pts were randomized 1:1:1:1 to arms A1 and B1 (Pre-emptive Clobetasol for PPES); A2 and B2 (Reactive Clobetasol). The primary endpoint was the proportion of patients who completed 2 cycles of treatment and initiated the 3rd in Arm A (Pooled A1 + A2) vs. Arm B (Pooled B1 + B2). Superiority for Arm A was to be declared if the one-sided p-value calculated using Fisher’s exact method was less than 0.2. Results: From June 2015 to June 2017, 123 pts were randomized with 116 (A = 54, B = 62) evaluable for the primary endpoint. Demographic data were well balanced with overall median age of 61yrs (range: 29-81), M/F (61/39%) and ECOG PS 0/1 (37/63%) and KRAS MT/WT/UNK (47/44/9%).The study met its primary endpoint with 43% of pts on Arm A initiating the 3rd vs. only 25% of pts Arm B [one-sided p-value 0.028]. Median Overall Survival (OS) was improved in Arm A vs. Arm B (9.0 mos vs. 5.9 mos; p = 0.094). Median Progression Free Survival (PFS) was 2.5 mos for Arm A vs. 2.0 mos for Arm B (p=0.553). Overall rates of grade 3/4 toxicity were more favorable for Arm A vs. Arm B (% PPES 15 vs. 16, HTN 7 vs. 15 and fatigue 13 vs. 18, respectively). Multiple QOL parameters were improved in A vs. B primarily at week 2 of the first cycle. Conclusion: A strategy with weekly dose escalation of regorafenib from 80 mg to 160 mg/day was found to be superior to a starting dose of 160 mg/day. These results establish a new standard for optimizing regorafenib dosing. Further data on outcomes of preemptive vs. reactive clobetasol strategies are undergoing analysis and will be presented later. Clinical trial information: NCT02368886.

Integrated safety summary for trifluridine/tipiracil (TAS-102).

Trifluridine/tipiracil, an oral treatment combining trifluridine (an antineoplastic thymidine-based nucleoside analog) and tipiracil hydrochloride (a thymidine phosphorylase inhibitor), led to significant improvement in overall survival in metastatic colorectal cancer (mCRC) patients refractory to standard therapy in the phase III RECOURSE trial. Here, we report an integrated summary of the safety of trifluridine/tipiracil. The main safety analysis includes integrated data from the RECOURSE and J003 studies (safety data group 2) of patients with refractory mCRC receiving trifluridine/tipiracil at the recommended starting dose: 35 mg/m twice daily for 5 days with 2 days' rest for 2 weeks, followed by a 14-day rest (one cycle). Integrated data from a larger group of mCRC patients receiving trifluridine/tipiracil at the recommended starting dose (group 1) and nonintegrated data on serious adverse events (SAEs) representing all clinical experience with trifluridine/tipiracil as of the data cutoff date (group 3) are also summarized. In group 2, myelosuppressive and all-grade gastrointestinal adverse events (AEs) were more frequent in trifluridine/tipiracil patients than in placebo patients. The trifluridine/tipiracil and placebo patients had similar frequencies of AEs leading to discontinuation (9.0 vs. 11.5%) and SAEs (27.7 vs. 29.2%); fatal AEs were more frequent in placebo patients than in trifluridine/tipiracil patients (9.3 vs. 2.8%). AEs leading to interruptions/delays/reductions were more frequent in trifluridine/tipiracil patients (56.3 vs. 12.7%). Trifluridine/tipiracil was generally well tolerated, but over 50% of patients required interruptions/delays/reductions. There was a low rate of discontinuations, SAEs, and fatal AEs. This analysis confirms the safety profile observed in RECOURSE.