Refractory Colorectal Cancer Research Articles

FLT1 amplification predicts poor response in metastatic colorectal cancer patients treated with apatinib as 3rd line treatment.

e16033 Background: Apatinib, a selective vascular endothelial growth factor receptor-2 (VEGFR2) inhibitor, has demonstrated encouraging anticancer activity across a broad range of malignancies. Recent studies have shown efficacy of apatinib as a third-line treatment for patients with refractory colorectal cancer. In this study, we characterized the genomic profile and explored predictive and prognostic biomarkers in metastatic colorectal cancer (mCRC) patients treated with apatinib as the 3rd line treatment. Methods: We retrospectively recruited 19 mCRC patients, with a median age of 53, treated with apatinib as the third-line regimen. The cohort consisted of 10 female and 9 male patients with 13 and 6 patietns with left-seide and right-sided CRC, respectively. Tissue samples prior to apatinib treatment were profiled using a 520-cancer-related gene panel. Results: This cohort achieved an ORR of 16% (3/19) and DCR of 53% (10/19). The median PFS and OS were 5 and 8.7 months, respectively, comparable with published studies. The genomic profile of 19 patients showed that 57% of alterations were missense, and 18% and 12% were copy number variations (CNV) and frameshift, respectively. All 19 patients were microsatellite stable (MSS). Most frequently mutated genes were TP53 (95%), APC (53%) and KRAS (53%). Other commonly mutated genes included PI3KCA (26%), FAT3 (16%), LPR1B (16%), FLT1(16%), SAMD4 (16%), TCF7L2 (16%) and TCNNB1 (16%). Univariate Cox analysis revealed a shorter PFS in patients harboring FLT1 amplification (n = 3) versus those without (P = 0.0007). All 3 patients with FLT1 amplification had progressive diease as their best response, with an average PFS of 1.4 months. Furthermore, we also revealed that APC mutation was significantly associated with older age (P = 0.02) and lymph node metastasis (P = 0.01). Patients with pulmonary metastasis were more likely to have TP53 disruptive mutation (P = 0.02). Conclusions: Our study explored the potential predictive biomerkers for apatinib and revealed that FLT1 amplification might be a potential predictive biomarker for poor efficacy in mCRC patients treated with apatinib. FLT1 encodes VEGFR1, which could compete with VEGFR2 for binding with VEGF, potentially explaining the inferior response to apatinib observed in pateints harboring FLT1 amplification. Larger cohorts are needed to validate the finding.

An open-label, single-arm, phase I study to assess the safety, efficacy, and biomarker effects of OMT-110 in patients with refractory colorectal cancer.

e16027 Background: A metabolism modulatory anticancer durg candidate, OMT-110, has been applied for phase I clinical trial to evaluate the effect of OMT-110 on safety, efficacy, and biomarker in patients with refractory colorectal cancer resistant to standard therapies. FDG PET-CT has been suggested to be a resonable biomarker for a metabolism modulator and tested as a possible biomarker for OMT-110 in the clinical trial. Methods: The study was composed of 4 cohorts with a specified dose of 12.5, 25, 50, and 100 mg, and each cycle consisted of daily subcutaneous injections for 3 consecutive weeks and had a resting period of 1 week. 3 subjects were enrolled in each cohort in a total of 12 patients. FDG-PET/CT was utilized as a biomarker and the SUVmax was evaluated according to European Organisation for Research and Treatment of Cancer (EORTC) criteria. Results: None of the subjects permanently discontinued or reduced the dose of the investigational drug due to dose-limiting toxicity. Serious drug adverse reactions that resulted in permanent discontinuation of investigational drugs were not reported. Biomarker evaluation using FDG-PET/CT revealed that the tumor responses of 9 from total 9 subjects who completed FDG-PET/CT evaluation by Cycle 2 (8 weeks) were stable metabolic disease (SMD) or higher . In particular, four subjects showed a clear tendency for a decrease in glucose transporting and were evaluated by partial metabolic response (PMR). The result was compatible with the response of Chest CT and APCT according to RECIST. Conclusions: In the study, the results of FDG/PET-CT show OMT-110 modulates the cancer-specific metabolism and thus reduces glucose transportation. Based on the study outcome, FDG PET-CT is possibly considered as a biomarker of OMT-110 and further study is warranted.

Effect of Combined Immune Checkpoint Inhibition vs Best Supportive Care Alone in Patients With Advanced Colorectal Cancer

Single-agent immune checkpoint inhibition has not shown activities in advanced refractory colorectal cancer (CRC), other than in those patients who are microsatellite-instability high (MSI-H). To evaluate whether combining programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibition improved patient survival in metastatic refractory CRC. A randomized phase 2 study was conducted in 27 cancer centers across Canada between August 2016 and June 2017, and data were analyzed on October 18, 2018. Eligible patients had histologically confirmed adenocarcinoma of the colon or rectum; received all available standard systemic therapies (fluoropyrimidines, oxaliplatin, irinotecan, and bevacizumab if appropriate; cetuximab or panitumumab if RAS wild-type tumors; regorafenib if available); were aged 18 years or older; had adequate organ function; had Eastern Cooperative Oncology Group performance status of 0 or 1, and measurable disease. We randomly assigned patients to receive either 75 mg of tremelimumab every 28 days for the first 4 cycles plus 1500 mg durvalumab every 28 days, or best supportive care alone (BSC) in a 2:1 ratio. The primary end point was overall survival (OS) and a 2-sided P<.10 was considered statistically significant. Circulating cell-free DNA from baseline plasma was used to determine microsatellite instability (MSI) and tumor mutation burden (TMB). Of 180 patients enrolled (121 men [67.2%] and 59 women [32.8%]; median [range] age, 65 [36-87] years), 179 were treated. With a median follow-up of 15.2 months, the median OS was 6.6 months for durvalumab and tremelimumab and 4.1 months for BSC (hazard ratio [HR], 0.72; 90% CI, 0.54-0.97; P = .07). Progression-free survival was 1.8 months and 1.9 months respectively (HR, 1.01; 90% CI, 0.76-1.34). Grade 3 or 4 adverse events were significantly more frequent with immunotherapy (75 [64%] patients in the treatment group had at least 1 grade 3 or higher adverse event vs 12 [20%] in the BSC group). Circulating cell-free DNA analysis was successful in 168 of 169 patients with available samples. In patients who were microsatellite stable (MSS), OS was significantly improved with durvalumab and tremelimumab (HR, 0.66; 90% CI, 0.49-0.89; P = .02). Patients who were MSS with plasma TMB of 28 variants per megabase or more (21% of MSS patients) had the greatest OS benefit (HR, 0.34; 90% CI, 0.18-0.63; P = .004). This phase 2 study suggests that combined immune checkpoint inhibition with durvalumab plus tremelimumab may be associated with prolonged OS in patients with advanced refractory CRC. Elevated plasma TMB may select patients most likely to benefit from durvalumab and tremelimumab. Further confirmation studies are warranted. ClinicalTrials.gov Identifier: NCT02870920.

A systematic review of salvage therapies in refractory metastatic colorectal cancer.

Established that the only approved agents in previously treated metastatic colorectal cancer (CRC) are trifluoridine/tipiracil and regorafenib, we conducted a systematic review of all the published phase 2-3 trials, with the scope to evaluate the benefit of any later-line regimens in refractory metastatic CRC. Phase 2-3 studies that enrolled patients with stage IV disease receiving salvage therapies for refractory CRC were identified using electronic databases (Pubmed, EMBASE, and Cochrane Library). Clinical outcomes were pooled using a point estimates for the weighted values of median overall survival (OS), progression-free survival (PFS), response rate (ORR), stable disease rate (SD), and 6-month and 1-year OS. Overall, 7556 patients were included from 67 studies (n= 70 arms). Overall, the pooled ORR and SD were 15.4% (95% CI 13-18%) and 36.9% (95% CI 33.5-40.6%). Median PFS, 6-month and 1-year OS, and median OS were 3.2 (95% CI 2.9-3.3) months, 65.4% (95% CI 61.9-68.8%), 36% (95% CI 32.3-39.9%) and 8.8 (95% CI 8.3-9.2) months. Overall survival was different in the monochemotherapy, polychemotherapy, chemotherapy + targeted therapy, and targeted therapy alone arms (7.6, 9.5, 10.3, and 7.9months, respectively, P for difference = 0.01). Median PFS were respectively 2.3, 3.9, 3.8, and 2.6, respectively (P for difference < 0.01). Overall, combination therapy (polychemotherapy with or without targeted agents) is associated with a higher control of disease and better outcome than approved agents. Treatment, if possible, should be personalized according to the patients' conditions, physician preference and molecular profile of disease.

Is There an Optimal Choice in Refractory Colorectal Cancer? A Network Meta-Analysis

BackgroundIn the absence of head-to-head comparison studies, the present network meta-analysis evaluated and compared the efficacy of 4 therapeutic alternatives for refractory colorectal cancer. Materials and MethodsThe search focused on results from phase III randomized controlled trials. Separate (subgroup) network meta-analyses were conducted to obtain drug comparisons stratified by various patient characteristics. The principal outcome of interest was overall survival (OS). ResultsNo difference in OS was found between regorafenib and TAS-102. For a rectal primary location, TAS-102 conferred benefit versus placebo (hazard ratio [HR], 0.671), but regorafenib did not (HR, 0.950). For patients aged > 65 years, TAS-102 showed benefit versus placebo (HR, 0.579) but regorafenib did not (HR, 0.816). For patients with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 in the indirect comparison, regorafenib showed benefit versus placebo (HR, 0.687), as did TAS-102 (HR, 0.756) but with a lower advantage. For patients with RAS wild type not previously treated with anti-EGFR antibodies, panitumumab was the optimal choice for OS. ConclusionsNo differences in OS were found between regorafenib and TAS-102. Possible greater efficacy was found for TAS-102 compared with regorafenib for patients with a rectal primary location, ECOG PS > 0, and age > 65 years. In contrast, regorafenib showed possible greater effectiveness for patients with ECOG PS 0 and age < 65 years. In the RAS WT population, the anti-EGFR drug showed superiority with respect to TAS-102 and regorafenib. These results should be viewed as only exploratory, and further prospective studies are warranted to validate these data.

Relationships Between Immune Landscapes, Genetic Subtypes and Responses to Immunotherapy in Colorectal Cancer.

Colorectal cancer (CRC) is highly heterogeneous at the genetic and molecular level, which has major repercussions on the efficacy of immunotherapy. A small subset of CRCs exhibit microsatellite instability (MSI), a molecular indicator of defective DNA mismatch repair (MMR), but the majority are microsatellite-stable (MSS). The high tumor mutational burden (TMB) and neoantigen load in MSI tumors favors the infiltration of immune effector cells, and antitumor immune responses within these tumors are strong relative to their MSS counterparts. MSI has emerged as a major predictive marker for the efficacy of immune checkpoint blockade over the last few years and nivolumab or pembrolizumab targeting PD-1 has been approved for patients with MSI refractory or metastatic CRC. However, some MSS tumors show DNA polymerase epsilon (POLE) mutations that also confer a very high TMB and may also be heavily infiltrated by immune cells making them amenable to respond to immune checkpoint inhibitors (ICI). In this review we discuss the role of the different immune landscapes in CRC and their relationships with defined CRC genetic subtypes. We discuss potential reasons why immune checkpoint blockade has met with limited success for the majority of CRC patients, despite the finding that immune cell infiltration of primary non-metastatic tumors is a strong predictive, and prognostic factor for relapse and survival. We then consider in which ways CRC cells develop mechanisms to resist ICI. Finally, we address the latest advances in CRC vaccination and how a personalized neoantigen vaccine strategy might overcome the resistance of MSI and MSS tumors in patients for whom immune checkpoint blockade is not a treatment option.

A phase I/II study of Pexa-Vec oncolytic virus in combination with immune checkpoint inhibition in refractory colorectal cancer.

117 Background: The benefit of immune checkpoint inhibition is limited to the small percentage of advanced colorectal cancer (CRC) patients whose tumors present mismatch repair (MMR) gene abnormalities; immunotherapy has not shown benefit in patients with MMR proficient CRC. Oncolytic immunotherapy represents a unique therapeutic platform. This phase I trial tests the safety of the combination of pexastimogene devacirepvec (Pexa-Vec) plus durvalumab (durva) in patients with locally advanced or metastatic CRC. Methods: Eligible patients with advanced proficient mixed match repair (pMMR) CRC received intravenous infusion of Pexa-Vec at dose level 3 x 108 plaque forming units (pfu) (DL1) or at 109 pfu (DL2) every 2 weeks for 4 doses and durva 1500 mg every 28 days. Response was assessed with CT every 8 weeks. Adverse events were recorded and managed. The primary endpoint included safety, tolerability and feasibility of this combination therapy. Samples of tumor and peripheral blood were collected for assessment of immune parameters. Results: Sixteen patients (6 males and 10 females) enrolled with a median age of 52.1 years (range 39-69) from Dec, 2017 to Oct, 2018. Four patients were treated with Pexa-Vec at DL1 and durva;twelve patients were treated with Pexa-Vec at DL2 and durva.The most common treatment related adverse events (TRAE) included fever 15/16 (94 %), hypotension 12/16 (75 %), chills 12/16 (75%), fatigue 8/16 (50%), sinus tachycardia 7/16 (44%) and rash 6/16 (38%). Grade 3/4 TRAEs were reported in 8/16 (50%)patients; the most common were fever 7/16 (44 %), lymphopenia 2/16 (13%), neutropenia 1/16 (6%) and anemia 1/16 (6%). 14 patients were evaluable for response analysis; one patient 1/14 (7 %) achieved a confirmed partial response (lasting 7.1 months) and continues to receive treatment, while 13 patients had progressive disease. The median progression free survival (PFS) was 2.2 months (95% CI: 2.2-2.3 months) and the median overall survival (OS) was 7.5 months (CI: 4.9-10.1 months). Conclusions: Combination therapy of Pexa-Vec with durva ICI issafe, well tolerated and demonstrates possible activity in patients with advanced pMMR CRC. Clinical trial information: NCT03206073.

A phase II study of trifluridine/tipiracil, irinotecan, and bevacizumab in pretreated metastatic colorectal cancer (TABAsCO).

TPS275 Background: Colorectal cancer (CRC) is the second leading cause of cancer-related death in US. The majority of US patients (pts) receive first-line therapy (Rx) with FOLFOX [Folinic acid (FA), 5-fluorouracil (5-FU) and oxaliplatin (Ox)] + a biologic, making FOLFIRI [FA+ 5-FU+ irinotecan (Iri)] + bevacizumab (Bev) a common second-line Rx. This regimen has a median progression-free survival (PFS) of approximately 6 months (mo) and overall survival (OS) of 12 mo. Further gains are desperately needed. Trifluridine/tipiracil (FTD/TPI) is an oral combination Rx of a thymidine-based nucleoside analogue, FTD, and a phosphorylase inhibitor, TPI. FTD/TPI has a distinct mechanism of action from 5-FU and in preclinical models can overcome 5-FU resistance via DNA incorporation, base excision repair pathway and glycosylation responses to DNA damage. Further, there is an additive effect in combination with Iri. FTD/TPI was FDA approved for use in refractory metastatic CRC (mCRC) based on phase III RECOURSE trial. Phase I data showed combination of FTD/TPI, Iri and Bev to be safe, and an efficacy signal was seen in dose-expansion cohort (NCT01916447). A 12.5% response rate, 83.4 % disease control rate and PFS of 7.9 mo was achieved. As this study largely assessed refractory pts, one might expect a greater efficacy in Iri naïve pts. To test this hypothesis, we are conducting a multi-center phase II study of FTD/TPI, Iri and Bev as second-line Rx in mCRC pts. Methods: Eligible pts have mCRC and received first-line Ox based Rx. Rx to be given in 28-day cycles: Iri (180 mg/m2) and Bev (5 mg/kg) on D1 &amp; 15, and FTD/TPI (25 mg/m2) twice daily on D2-6 &amp; 16-20. Response assessment via CT/MRI to be done q8 wks (RECIST 1.1). Rx to continue until disease progression or unacceptable toxicity. The primary objective is to estimate PFS. Secondary objectives include ORR, OS, and safety. Final analysis to be done either 12 mo after enrollment of the final pt or once all pts have progression, whichever occurs earlier. A total of 40 pts to be accrued, and enrollment to start in January 2020. This study was approved and funded by the National Comprehensive Cancer Network (NCCN) Oncology Research Program from general research support provided by Taiho Oncology, Inc.

A phase Ib study of capecitabine and ziv-aflibercept followed by a phase II single-arm expansion cohort in chemotherapy refractory metastatic colorectal cancer

BackgroundPatients with chemotherapy refractory metastatic colorectal cancer (CRC) have a poor prognosis and limited therapeutic options. In this phase Ib/II clinical trial, we established the maximum tolerated dose (MTD) and recommended phase II dose (RPTD) for the combination of capecitabine and ziv-aflibercept, and then we evaluated the efficacy of the combination in patients with chemotherapy refractory metastatic CRC.MethodsAll patients were required to have a Karnofsky Performance Status > 70% and adequate organ function. The phase Ib dose escalation cohort included patients with advanced solid tumors who had progressed on all standard therapies. Using a standard 3 + 3 design, we identified the MTD and RPTD for the combination. Fifty patients with metastatic CRC who had progressed on or were intolerant of a fluoropyrimidine, oxaliplatin, irinotecan, and bevacizumab were then enrolled in a single-arm phase II expansion cohort, and were treated at the RPTD. Prior EGFR antibody therapy was required for subjects with RAS wildtype tumors. The primary endpoint for the expansion cohort was progression-free survival (PFS) at two months. Secondary endpoints included objective response rate (ORR) and overall survival (OS).ResultsA total of 63 patients were enrolled and evaluable for toxicity (13 dose escalation; 50 expansion). The MTD and RPTD were: capecitabine 850 mg/m2, P.O. bid, days 1–14, and ziv-aflibercept 6 mg/kg I.V., day 1, of each 21-day cycle. In the expansion cohort, 72% of patients were progression-free at two months (95% confidence interval [CI], 60–84%). Median PFS and OS were 3.9 months (95% CI, 2.3–4.5) and 7.1 months (95% CI: 5.8–10.0), respectively. Among all patients evaluable for toxicity, the most common treatment related adverse events (all grade [%]; grade ≥ 3 [%]) included palmar-plantar erythrodysesthesia (41%; 6%), hypertension (33%; 22%), and mucositis (19%; 5%). RNA was isolated from archived tumor specimens and gene expression analyses revealed no association between angiogenic biomarkers and clinical outcomes.ConclusionThe combination of capecitabine and ziv-aflibercept at the RPTD demonstrated acceptable safety and tolerability. PFS at 2 months in patients with chemotherapy refractory metastatic CRC was significantly greater than that in historical controls, indicating that this combination warrants further study.Trial registrationThis clinical trial was registered in the www.clinicaltrials.gov system as NCT01661972 on July 31, 2012.

CD44/CD133-Positive Colorectal Cancer Stem Cells are Sensitive to Trifluridine Exposure

Cancer stem cells (CSCs) are involved in metastatic colorectal cancer recurrence, but no effective therapy targeting these cells is currently available. Because trifluridine (FTD)/tipiracil therapy is used for refractory colorectal cancer, we sought to determine whether FTD is effective against CSC-like cells. CD44+CD133+ high-expressing and other populations of human DLD-1 colon cancer cells were separately isolated through fluorescence-activated cell sorting. The sphere-forming activity of each population and the anti-sphere-forming effects of FTD and fluorouracil (5-FU) on CD44+CD133+ cells were then measured. CD44+CD133+ DLD-1 cells formed substantially more spheres than other cells. Moreover, treating CD44+CD133+ DLD-1 cells with subtoxic concentrations of FTD (1 µM) inhibited sphere formation, and this was superior to the effect of subtoxic concentrations (1 µM) of 5-FU. The associated inhibition rates for FTD and 5-FU were 58.2% and 26.1%, respectively. Further, CD44+CD133+ DLD-1 cells expressed higher levels of thymidine kinase 1, which is responsible for FTD phosphorylation, than DLD-1 cells, and FTD was incorporated into the DNA of CD44+CD133+ DLD-1 cells. Thus, our data show that FTD treatment is effective against CSC-like cells and might be applied as CSC-targeting chemotherapy for tumor subtypes with high CD44 and CD133 expression.

P-052 - Is there an optimal choice in refractory colorectal cancer? A network meta-analysis

P-052 - Is there an optimal choice in refractory colorectal cancer? A network meta-analysis

Trifluridine/Tipiracil (TAS-102) for refractory metastatic colorectal cancer in clinical practice: a feasible alternative for patients with good performance status.

Our aim was to assess efficacy and safety and prognostic factors associated with TAS-102 in clinical practice. Retrospective, multicenter, and observational study including patients with advanced refractory colorectal cancer who started TAS-102 between March 2016 and August 2018. The primary end point was overall survival (OS). Secondary end points included progression-free survival, toxicity and analyze prognostic factors present at the beginning of TAS-102. 84 patients were evaluable. The median OS was 8.30 (95% CI 6.23-9.87) months and PFS was 2.62 (95% CI 2.36-3.05) months. In multivariate analysis, ECOG0 and reduced dose combined with more cycles were associated with better prognosis. Patients with an ECOG > 0 had worse prognosis (HR 3.34, 95% CI 1.09-10.27, p = 0.035). 95.2% experienced some type of adverse effect and 45.2% had grade ≥ 3 toxicities. Results suggest reconsidering TAS-102 in patients with ECOG >0, something that should be investigated in prospective randomized clinical trials.

Meat consumption and BRAF mutation status in colorectal cancer.

e15135 Background: Consumption of red and processed meat has been associated with increased risk of developing colorectal cancers, but less is known about the association of meat consumption with tumor molecular features. In this study, we tested the association of total meat consumption with molecular features of colorectal cancer and overall survival in a local cohort of patients. Methods: Data on meat consumption were collected using self-directed environmental surveys from patients with stage IV/locally advanced, treatment refractory colorectal cancer who were enrolled on the Assessment of Targeted Therapies Against Colorectal Cancer clinical protocol. Data on tumor molecular features were collected through medical record review. Patients were categorized into low, medium or high meat consumption groups based on servings per day tertile. Associations between tumor molecular features and meat intake were evaluated by Chi-square and logistic regression. Potential effects of meat consumption on overall survival were assessed using Cox Proportional Hazards models. Analyses were conducted with IBM SPSS v25. Results: Patients consumed an average of 0.74, 1.57 and 3.32 servings of meat per day in the low, medium and high categories, respectively. Out of 593 patients with evaluable data, 27 were found to have a BRAF V600E mutation. Total meat consumption differed significantly by BRAF V600E mutation status (p value 0.02) and by sex (p value &lt; .01), but did not differ by tumor location, microsatellite instability, or RAS mutation status. Using logistic regression, we found that compared to patients with the highest level of meat consumption, those in the medium consumption group may be less likely to have a BRAF V600E mutation (OR 0.24; p value 0.08). Although meat consumption may be associated with BRAF mutation status, it was not predictive of overall survival in our analyses. Conclusions: Among patients in our study, meat consumption may be associated with tumor BRAF V600E mutation status but is not directly associated with survival. Additional work is needed to test this association in cohorts including more BRAF mutant cases. If confirmed, this finding may add further insight into the etiology and biology of these tumors.

A phase IIb study of ramucirumab in combination with TAS102 versus TAS102 monotherapy in metastatic, chemotherapy refractory colorectal cancer patients: The RAMTAS trial of the German AIO (KRK-0316).

TPS3617 Background: Patients with metastatic colorectal cancer (mCRC) with progressive disease on/after or who are intolerant to fluoropyrimidines, oxaliplatin, irinotecan, anti-angiogenic and anti-EGFR therapies have limited therapeutic options and a dismal prognosis, with a median survival below 6 months. Recently, Trifluridin/Tipiracil (TAS102) significantly improved survival in patients with refractory mCRC and ramucirumab has been approved in combination with FOLFIRI for the treatment of patients with mCRC after prior FOLFOX/bevacizumab first line therapy. Previous studies on both components provide a strong rationale to conduct a randomized study evaluating the efficacy and safety of ramucirumab in combination with TAS102 in patients with refractory mCRC to improve efficacy and prevent resistance. Methods: This is an interventional, randomized, open label, multicenter, phase IIb study in patients with advanced mCRC. Eligible patients will be randomized 1:1 and receive either ramucirumab and TAS102 (ramucirumab 8 mg/kg on d1+15, q4w and TAS102 35 mg/m² on d1-5 and d8-12, q4w) or TAS102 alone. Primary endpoint is overall survival as assessed by the Kaplan-Meier method, assuming a 6 months survival probability of 70% with ramucirumab in combination with TAS102 and 58% with TAS102 alone. Treatment groups are compared using the log-rank test. A total of 144 patients will be enrolled at 30 sites (1-sided alpha 0.10, power 0.80). Main secondary endpoints are overall response rate, disease control rate, progression free survival and quality of life. In addition, a large comprehensive translational research program will be conducted to identify novel predictive and prognostic biomarkers. The study started in December 2018. By February 2019, a total of 3 patients have been enrolled. Clinical trial information: NCT03520946.

A phase I/II study of pexa-vec oncolytic virus in combination with immune checkpoint inhibition in refractory colorectal cancer: Safety report.

646 Background: The efficacy of immune checkpoint inhibitor has been limited to small portion of colorectal cancer (CRC) patients whose tumors with mismatch repair (MMR) gene abnormalities. There is an urgent need for patients with MMR proficient (pMMR) tumors. Oncolytic immunotherapy represents a novel therapeutic platform for the treatment of cancer with unique activity compared to conventional chemotherapy. The trial is to evaluate if the combination of Pexa-Vec oncolytic virus (PV) with immune checkpoint inhibition enhance antitumor immunity. Methods: Patients with microsatellite-stable and MSI-H mCRC refractory to PD-1 monotherapy were enrolled. Patients received either Arm A treated with PV + Durvalumab or Arm B with PV + Durvalumab and Tremelimumab. Each arm had two dose levels (DL) of PV, 3 x 108 pfu in DL1 and at 109 pfu in DL2, every 2 weeks for total 4 doses. The first dose of PV was administered on Day -12, followed by three more dose administration on Days 2, 16 and 30 in combination with the immune checkpoint inhibition. The primary endpoint is response rate, safety, tolerability and feasibility of these combination therapy in refractory metastatic CRC. Results: Here we report the safety data of Arm A.A total of 9 patients was enrolled so far. The longest follow-up time is 8 months. Four patients received DL1 PV and subsequent five patients received DL2 PV. No DLT was observed at the time of this abstract. No grade 4-5 adverse event (AE) were observed. All patients experienced lymphopenia. All patients with DL2 developed fever, hypotension and papulopastular rashes and were successfully managed with antipyretics, fluid support and skin protection, respectively. The most frequent treatment-related AEs were lymphopenia (8 [100%], fever (7 [87.5%]), chills (6 [75.0%]), hypotension (5 [62.5%]), papulopastular rashes (5 [62.5%], flu-like symptoms (2 [12.5%]), Nausea/vomiting (2 [12.5%]). Conclusions: Pexa-Vec in combination with Durvalumab showed a favorable safety profile. Clinical trial information: NCT03206073.

The toxicity profile of TAS-102. Practical considerations about neutropenia.

TAS-102 represents an important therapeutic resource for patients with metastatic refractory colorectal cancer. Albeit generally well tolerated, clinically relevant neutropenia may interfere with the regular delivery of full-dose cycles with a possible detrimental effect on the dose-intensity. Judicious and personalized use of colony-stimulating growth factors as well as alterative schedules of drug delivery could mitigate neutropenia, so contributing to an even better therapeutic index of the drug.

Efficacy of Regorafenib in Metastatic Colorectal Cancer: A Multi-institutional Retrospective Study

Background:Regorafenib is a multi-kinase inhibitor approved for treatment of refractory advanced colorectal cancer. It was found in the clinical trials to have a modest benefit and significant toxicity. Our aim was to assess the outcome in our local clinic practice.Patients and methods:Records of patients with confirmed colorectal cancer treated with regorafenib were reviewed. Clinical, pathological, and molecular data were collected. Efficacy and factors of possible prognostic significance were analyzed.Results:A total of 78 patients with metastatic colorectal cancer were treated with regorafenib from February 2014 to February 2016 in 4 different institutions (median age: 50.5 years; male: 40 [51.3%]; KRAS mutant: 41 [52%]; right colonic primary: 18 [23%]). A total of 52 patients (66.7%) had Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 1, whereas in 25 patients (32.1%) it was >1. In total, 58 patients (74%) had dose reduction. No patient achieved objective response, 15 patients (19%) achieved stable disease, and 56 patients (72%) had progressive disease. With a median follow-up of 6.5 months, the median progression-free survival was 2.8 months (95% confidence interval [CI], 2.5-3.3) and overall survival was 8.0 months (95% CI, 6.2-9.7). Only performance status of ⩽1 had a statistically significant impact on progression-free survival and overall survival in both univariate and multivariate analyses.Conclusions:Regorafenib in our clinical practice has equal efficacy to reported data from pivotal registration trials. Our data suggest that performance status is the most important prognostic factor in patients treated with regorafenib, suggesting a careful selection of patients.

Oligomeric proanthocyanidins (OPCs) from grape seed extract suppress the activity of ABC transporters in overcoming chemoresistance in colorectal cancer cells.

Multidrug resistance is a major hindrance in managing cancer. By performing a series of experiments in chemoresistant colorectal cancer cell lines, we demonstrate that oligomeric proanthocyanidins (OPCs) from grape seed extracts can sensitize both acquired (HCT116-FOr cells) and innately chemoresistant (H716 cells) cancer cells to chemotherapeutic drugs, 5-fluorouracil (5FU) and oxaliplatin, by inhibiting adenosine triphosphate-binding cassette (ABC) transporter proteins. When combined with chemotherapeutic drugs, OPCs significantly inhibited growth of the chemoresistant cells (P < 0.05 to < 0.001) and decreased the expression of several key ABC transporters. Moreover, the activity of the ABC transporters was also significantly decreased by OPCs in the cell lines (P < 0.05). We further confirmed that co-treatment with OPCs sensitized the chemoresistant cells to 5FU and oxaliplatin, as observed by improvement in cell cycle arrest, double-strand breaks and p53 accumulation in these cells. In addition, we confirmed that co-administration of OPCs with chemotherapeutic drugs significantly decreased chemoresistant xenograft tumor growth in mice (P < 0.05). Together, our study illuminates the downregulation of multiple ABC transporters as a mechanism by which OPCs overcome chemoresistance in cancer cells and may serve as adjunctive treatments in patients with refractory colorectal cancer.

Irinotecan-Eluting 75–150-μm Embolics Lobar Chemoembolization in Patients with Colorectal Cancer Liver Metastases: A Prospective Single-Center Phase I Study

PurposeThe primary end point of this trial was to determine the feasibility and safety of transarterial chemoembolization with the use of 75–150-μm drug-eluting embolics loaded with irinotecan (DEE-IRI) for the treatment of metastatic colorectal cancer (CRC) refractory to systemic chemotherapy. Materials and MethodsFourteen patients (mean age 57.9 years) with liver-dominant metastatic disease (14.3% unilobar, 85.7% bilobar), who had failed at least 1 line of chemotherapy, were enrolled and received up to 4 (mean 2.3) cycles of DEE-IRI lobar transarterial chemoembolization. Technical complications and adverse events were recorded, and response was assessed by means of imaging-based criteria. Levels of irinotecan and angiogenesis biomarkers in the serum were measured at multiple time points. ResultsThirty-two DEE-IRI transarterial chemoembolizations were successfully performed, and the full dose (100 mg) was delivered in all cases. The only grade 3–4 toxicity was abdominal pain (29%). One patient had objective response according to the Response Evaluation Criteria in Solid Tumors and World Health Organization, and 3 patients had objective response according to the European Association for the Study of the Liver. The median overall survival was 18.14 months, and the 1-year survival was 65%. The average plasma Cmax of the active metabolite was 41.5 ± 26.1 ng/mL, with average Tmax of 1.3 ± 0.5 hours. The treatment significantly reduced levels of vascular endothelial growth factor receptor 1 (VEGFR1) at 24 hours. ConclusionsLobar transarterial chemoembolization with the use of DEE-IRI is a technically feasible and well tolerated palliative treatment for patients with refractory liver-predominant CRC metastatic disease and has acceptable pharmacokinetics. VEGFR1 is a potential biomarker for predicting treatment efficacy and risk of adverse events.

Nintedanib for the treatment of patients with refractory metastatic colorectal cancer (LUME-Colon 1): a phase III, international, randomized, placebo-controlled study

BackgroundAngiogenesis is critical to colorectal cancer (CRC) growth and metastasis. Phase I/II studies have demonstrated the efficacy of nintedanib, a triple angiokinase inhibitor, in patients with metastatic CRC. This global, randomized, phase III study investigated the efficacy and safety of nintedanib in patients with refractory CRC after failure of standard therapies. Patients and methodsEligible patients (Eastern Cooperative Oncology Group performance status 0–1, with histologically/cytologically confirmed metastatic/locally advanced CRC adenocarcinoma unamenable to surgery and/or radiotherapy) were randomized 1 : 1 to receive nintedanib (200mg twice daily) or placebo (twice daily), until disease progression or undue toxicity. Patients were stratified by previous regorafenib, time from onset of metastatic disease to randomization, and region. Co-primary end points were overall survival (OS) and progression-free survival (PFS) by central review. Secondary end points included objective tumor response and disease control by central review. ResultsFrom October 2014 to January 2016, 768 patients were randomized; 765 were treated (nintedanib n=384; placebo n=381). Median follow-up was 13.4months (interquartile range 11.1–15.7). OS was not improved [median OS 6.4months with nintedanib versus 6.0months with placebo; hazard ratio (HR), 1.01; 95% confidence interval (CI), 0.86–1.19; P=0.8659]. There was a significant but modest increase in PFS with nintedanib versus placebo (median PFS 1.5 versus 1.4months, respectively; HR 0.58; 95% CI 0.49–0.69; P<0.0001). There were no complete or partial responses. Adverse events (AEs) occurred in 97% of 384 nintedanib-treated patients and 93% of 381 placebo-treated patients. The most frequent grade ≥3 AEs were liver-related AEs (nintedanib 16%; placebo 8%) and fatigue (nintedanib 9%; placebo 6%). ConclusionsThe study failed to meet both co-primary end points. Nintedanib did not improve OS and was associated with a significant but modest increase in PFS versus placebo. Nintedanib was well tolerated. ClinicalTrials.gov numberNCT02149108 (LUME-Colon 1).