Pretreated Metastatic Colorectal Cancer Patients Research Articles

Abstract 1899: Novel combinations of aplitabart, a DR5 agonist IgM antibody, with ADCs or chemotherapeutic agents lead to robust anti-tumor responses in solid tumor models

Abstract Agonism of death receptor 5 (DR5), a tumor necrosis factor receptor superfamily member, induces the killing of tumor cells via the extrinsic apoptotic pathway upon receptor multimerization. We have engineered a multivalent IgM DR5 agonist antibody, aplitabart (IGM-8444), that induces robust anti-tumor activity in both in vitro and in vivo preclinical models. We also demonstrated potent synergistic in vitro activity of aplitabart with different classes of chemotherapeutic agents including microtubule inhibitors, nucleoside analogs and topoisomerase inhibitors in a range of solid cancer cell lines. Preliminary results from an ongoing phase 1a/ab clinical study show that aplitabart has an encouraging safety profile and promising activity in combination with FOLFIRI ± bevacizumab in heavily pretreated metastatic colorectal cancer patients. To further explore the combination therapies for aplitabart in lung and breast cancers, we evaluated standard of care chemotherapies, such as paclitaxel, carboplatin, and antibody drug conjugates (ADCs) in vitro on a range of human lung and breast cancer cell lines. We observed dose-dependent synergistic cytotoxic effects of aplitabart on tumor cells when combined with these agents. Additionally, these agents increased the expression of DR5 on tumor cells and could explain their synergistic combinatorial activity with aplitabart. Representative cancer cell lines were selected to evaluate these combinations in vivo using xenograft mouse models where robust anti-tumor responses were demonstrated in the xenograft lung and breast cancer models, resulting in enhanced tumor growth inhibition and extended survival. Our findings demonstrate potent in vitro synergistic cytotoxicity and enhanced anti-tumor response in preclinical models in vivo by combining aplitabart with ADCs, or carboplatin and paclitaxel. These results support the combination of DR5 agonist IgM antibodies with agents known to upregulate DR5 expression on solid tumors. Aplitabart is currently under evaluation in a randomized clinical study in combination with FOLFIRI + bevacizumab in comparison with FOLFIRI + bevacizumab in patients with colorectal cancer (NCT04553692). Citation Format: Mélanie Desbois, Susan E. Calhoun, Kevin C. Hart, Carolyn R. Denson, Poonam Yakkundi, Thomas J. Matthew, Maya K. Leabman, Sanela Bilic, Genevive Hernandez, Eric W. Humke, Albert F. Candia, Bruce Keyt, Angus M. Sinclair, Maya F. Kotturi, Beatrice T. Wang. Novel combinations of aplitabart, a DR5 agonist IgM antibody, with ADCs or chemotherapeutic agents lead to robust anti-tumor responses in solid tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1899.

Quality of Life and Survival of Metastatic Colorectal Cancer Patients Treated With Trifluridine-Tipiracil (QUALITAS)

IntroductionThe RECOURSE trial demonstrated a modest benefit in overall survival (OS) for trifluridine/tipiracil (FTD/TPI) versus placebo in pretreated metastatic colorectal cancer (mCRC) patients. Unfortunately, quality of life (QoL) was not assessed. We evaluated QoL and survival of patients treated with FTD/TPI in daily practice. Patients and MethodsQUALITAS is a substudy of the Prospective Dutch CRC cohort (PLCRC). From 150 mCRC patients treated with FTD/TPI, QoL (EORTC QLQ-C30 and QLQ-CR29) was assessed monthly from study entry, and linked to clinical data of the Netherlands Cancer Registry. Joint models were constructed combining mixed effects models with Cox PH models. Primary endpoint was difference in QoL over time (which was deemed clinically relevant if ≥10 points). Secondary endpoints were progression-free survival (PFS), time to treatment failure (TTF), and OS. We analyzed the association between QLQ-C30 Summary Score (QoL-SS) at FTD/TPI initiation (baseline) and survival. ResultsThere was no clinically relevant change in QoL-SS from baseline to 10 months post-baseline (i.e. the cut-off point after which 90% of patients had discontinued FTD/TPI treatment): -5.3 [95% CI -8.7;-1.5]. Patients who were treated with FTD/TPI for ≥ 3 months (n = 85) reported 6.3 [1.6;11.1] points higher baseline QoL, compared to patients treated < 3 months (n = 65, “poor responders”). In the latter, time to a clinically relevant QoL deterioration was < 2 months. Median PFS, TTF and OS were 2.9 [2.7;3.1], 3.1 [2.9;3.2] and 7.7 [6.6;8.8] months, respectively. Worse baseline QoL-SS was independently associated with shorter OS (HR 0.45 [0.32;0.63]), PFS (0.63 [0.48;0.83]), and TTF (0.64 [0.47;0.86]). ConclusionThe maintenance of QoL during FTD/TPI treatment in daily practice supports its use. The QoL deterioration in “poor responders” is likely due to disease progression. The strong association between worse baseline QoL and shorter survival suggests that clinicians should take QoL into account when determining prognosis and treatment strategy for individual patients.

Percutaneous liver venous deprivation: outcomes in heavily pretreated metastatic colorectal cancer patients.

To evaluate liver venous deprivation (LVD) outcomes in patients with colorectal liver metastasis (CRLM) heavily pretreated with systemic and hepatic arterial infusion pump (HAIP) chemotherapies that had an anticipated insufficient future liver remnant (FLR) hypertrophy after portal vein embolization (PVE). PVE was performed with liquid embolics using a transsplenic or ipsilateral transhepatic approach. Simultaneously and via a trans-jugular approach, the right hepatic vein was embolized with vascular plugs. Liver volumetry was assessed on computed tomography before and 3-6 weeks after LVD. Twelve consecutive CRLM patients that underwent LVD before right hepatectomy or trisectionectomy were included, all previously treated with systemic chemotherapy for a mean of 11.9 months. Six patients had additional HAIP. After embolization, FLR ratio increased from 28.7%±5.9 to 42.2%±9.0 (P<0.01). Mean kinetic growth rate (KGR) was 3.56%/week±2.3, with a degree of hypertrophy (DH) of 13.8%±7.1. In the HAIP subgroup, mean KGR and DH were respectively 3.58%/week±2.8 and 14.3%±8.7. No severe complications occurred. Ten patients reached surgery after 39 days±7.5. In heavily pretreated patients, LVD safely stimulated a rapid and effective FLR hypertrophy, with a resultant high rate of resection.

Precision Medicine for the Management of Therapy Refractory Colorectal Cancer.

In this analysis, we examined the efficacy, feasibility, and limitations of molecular-based targeted therapies in heavily pretreated metastatic colorectal cancer (mCRC) patients after failure of all standard treatments. In this single-center, real-world retrospective analysis of our platform for precision medicine, we mapped the molecular profiles of 60 mCRC patients. Tumor samples of the patients were analyzed using next-generation sequencing panels of mutation hotspots, microsatellite instability testing, and immunohistochemistry. All profiles were reviewed by a multidisciplinary team to provide a targeted treatment recommendation after consensus discussion. In total, we detected 166 mutations in 53 patients. The five most frequently found mutations were TP53, KRAS, APC, PIK3CA, and PTEN. In 28 cases (47% of all patients), a molecularly targeted therapy could be recommended. Eventually, 12 patients (20%) received the recommended therapy. Six patients (10%) had a clinical benefit. The median time to treatment failure was 3.1 months. Our study demonstrates the feasibility and applicability of using targeted therapies in daily clinical practice for heavily pretreated mCRC patients. This could be used as a targeted treatment option in half of the patients.

P-27 Retrospective observational analysis of p53 mutational status as a prognostic factor in TAS-102 treated metastatic colorectal cancer patients

Tipiracil-trifluridine combination (TAS-102) has recently been introduced as a treatment option in pretreated metastatic colorectal cancer (MCRC) patients. Owing to the favourable safety profile of the drug, the number of patients that are currently been treated is increasing. Based on the results of the registration trials, about 40% patients achieve disease control (either stable disease or partial response) at their first radiological evaluation. In previous preclinical models it has been shown that p53 mutational status might affect tumor cells' sensitivity to the drug: p53 wild-type cells seem to have increased sensitivity to trifluridine compared with p53 mutated cells.

Evaluation of long term survival in pretreated metastatic colorectal cancer patients undergoing GOLFIG chemoimmunotherapy regimen.

e15057 Background: In the last few years, there has been a renewed interest on the potential use of immunotherapy alone or combined to chemotherapy (CHT) for mCRC patients. GOLFIG regimen (biweekly Gemcitabine+FOLFOX and IL2 and GM-CSF) was designed to enhance immunomodulating effects of selected cytotoxic drugs by combining them with cytokines able to promote priming and effector phases of the immune-response. This regimen has been tested in two different phase II and III clinical trials in mCRC patients, whose successful results have been published. Here we present the results a retrospective analyses including all the patients treated in a period of 16 years. Methods: This is a multi-institutional retrospective study including 179 mCRC patients (106 men, 73 women). They received a median of 12 courses of GOLFIG regimen (treated between June 2002 and November 2018). K-RAS mutational status has also been evaluated in 74 pts (41 wild type and 33 mutated); as for sidedness 112 pts had a left disease and 67 pts right disease; 71 pts received only one previous CHT line and 100 more than two lines. PFS and OS were evaluated by Kaplan-Meier curves and Cox-regression analyses in different subgroups (RAS mutational status, sidedness, previous CHT lines) to estimate their effect on survival endpoints. Results: We recorded a mean PFS and OS of 15,28 [95%CI:10,36-20,20] and 24,61 [95%CI:19,07-30,14] months, respectively, with no difference in efficacy outcomes observed among the different subgroups (one vs. more than one previous CHT lines; left vs. right primary side; k-ras status mutated vs. wt). Finally, we recorded a 2, 5 and 10 year OS-rate, in 42, 17 and 14 percent of the patients, respectively. The occurrence of self-limiting autoimmunity was confirmed as highly predictive of longer survival. Conclusions: These results confirm that GOLFIG regimen has strong efficacy in mCRC pts and may represent a reliable option in pretreated setting without evident effect of known prognostic variants. Such data offer a strong basis for future clinical trials in mCRC patients, where GOLFIG may represent a scaffold for combinatory immunotherapy approaches with immune-checkpoint blocking drugs.

The use of regorafenib for patients with refractory metastatic colorectal cancer in clinical practice.

AimPatients in clinical practice are relatively vulnerable compared to those enrolled in clinical trials. We focused on analyzing the pattern of regorafenib use in routine clinical practice, which included initial starting dose and follow-up schedule. We also evaluated the efficacy and safety according to clinical regimen.MethodsWe retrospectively reviewed the medical records of 134 Korean heavily pretreated metastatic colorectal cancer (mCRC) patients who had received regorafenib monotherapy as salvage treatment in routine clinical practice between January 2014 and January 2018.ResultsAmong the 134 mCRC patients, the median age was 55 years (range, 22–80 years), and 51% had previously received four or more chemotherapy treatments. Thirty-eight (28.3%) patients had more than three metastatic lesions. As an initial starting dose, 120 mg regorafenib was mostly frequently used (n=65, 48.5%), followed by 80 mg (32.8%) and 160 mg (18.7%). The first follow-up after regorafenib initiation was most frequently at 28 days (45.5%), followed by 14 days (29.9%), 7 days (13.4%), and 21 days (11.2%). There was no significant difference in response rate according to initial dose of regorafenib (80 mg vs 120 mg vs 160 mg, 4.5% vs 1.5% vs 4.0%, P=0.596) or disease control rate (80 mg vs 120 mg vs 160 mg, 38.6% vs 29.2% vs 31.6%, P=0.299). Progression-free survival did not differ according to initial dose (80 mg vs 120 mg vs 160 mg, 2.8 months [95% CI 2.1–3.5] vs 2.2 months [95% CI 1.7–2.8] vs 1.9 months [95% CI 1.3–2.4], P=0.076). Grade 3/4 adverse events occurred in 17 (12.7%) patients and were not related to initial dose of regorafenib (P=0.126).ConclusionHere, we present efficacy and safety data according to different initial doses of regorafenib in clinical practice. These data may provide useful information when using regorafenib for refractory mCRC in clinical practice.

Effect of primary tumor side on survival outcomes in metastatic colorectal cancer patients after hepatic arterial infusion chemotherapy.

AIMTo analyze the survival data between patients diagnosed with right-sided primary (RSP) tumors and patients diagnosed with left-sided primary (LSP) tumors after hepatic arterial infusion chemotherapy (HAIC) at our center.METHODSA retrospective analysis of pretreated metastatic colorectal cancer patients who received HAIC from May 2006 to August 2015 was conducted. A Cox proportional hazard regression analysis was used to assess the long-term survival outcomes. The mean and median age of patients was 61 years (range 27-85 years). There were 115 males and 53 females in our study.RESULTSOne hundred sixty-eight patients were enrolled in this study. The overall response rate was 28.9% in LSP patients and 27.3% in RSP patients. The disease control rate was 76.3% in LSP patients and 69.7% in RSP patients. The median overall survival in response to HAIC was 16.3 mo in the LSP arm and 9.3 mo in the RSP arm (P = 0.164). The median progression-free survival was 5.7 mo in the LSP arm and 4.2 mo in the RSP arm (P = 0.851).CONCLUSIONThere was no significant difference in survival between LSP patients and RSP patients after HAIC. Further prospective studies are needed to confirm these findings.

Temozolomide and irinotecan (TEMIRI regimen) as salvage treatment of irinotecan-sensitive advanced colorectal cancer patients bearing MGMT methylation

BackgroundNon-randomized studies showed that temozolomide (TMZ) achieves an average 10% response rate in heavily pretreated metastatic colorectal cancer (mCRC) patients with promoter methylation of the DNA repair gene O6-methylguanine-DNA methyltransferase (MGMT). In this phase II trial, irinotecan and temozolomide (TEMIRI) combination regimen was assessed in irinotecan-sensitive, MGMT methylated/microsatellite stable (MSS) pretreated mCRC patients. Patients and methodsKey inclusion criteria were centrally confirmed MGMT methylation by methylation-specific PCR, MSS mCRC, progression after at least two prior chemotherapy regimens for advanced disease and irinotecan-free interval >3months. TEMIRI (TMZ 150mg/m2 on days 1–5 plus irinotecan 100mg/m2 on days 1, 15 q28 days) was administered for six cycles, followed by maintenance with TMZ. The primary end point was overall response rate (ORR). Exploratory translational analyses included MGMT immunohistochemistry (IHC) and methyl-BEAMing (MB). ResultsBetween December 2014 and June 2017, 25 patients were enrolled. The primary end point was met, since six patients achieved a partial response [ORR 24%, 95% confidence interval (CI) 11% to 43%]. At a median follow-up of 15.6months, median progression-free survival (mPFS) and overall survival (mOS) were 4.4 and 13.8months, respectively. Only four (16%) patients had ≥ grade 3 (CTCAE 4.0) adverse events. All patients whose cancer was MGMT-positive IHC were non-responders. Consistently, patients with MGMT-negative/low tumors had a significantly longer mPFS than others (6.9 versus 2.0months; hazard ratio=0.29, 95% CI 0.02–0.41; P=0.003) and a non-significant trend for longer mOS. MB testing showed similar accuracy. ConclusionsTEMIRI regimen is a safe and active option in pre-treated, irinotecan-sensitive mCRC patients with MGMT methylation.

A retrospective study of trifluridine/tipiracil in pretreated metastatic colorectal cancer patients in clinical practice

Aim: RECOURSE trial has shown a benefit for trifluridine/tipiracil (also known as TAS-102) over placebo in chemorefractory metastatic colorectal cancer (mCRC) patients. We evaluated efficacy and safety of patients treated with trifluridine/tipiracil in compassionate use. Patients &amp; methods: RETROTAS is a retrospective study designed to evaluate efficacy and safety of trifluridine/tipiracil in mCRC patients previously exposed or not a candidate to all available drugs. Results: A total of 85 mCRC patients were included. Our data showed that 37.6% of patients achieved disease control. Median progression-free survival was 2.3 months; at 16 months follow-up, median overall survival was 9.2 months. Conclusion: This real-life experience confirms the safety and efficacy of trifluridine/tipiracil, resulting as a valid option in chemorefractory mCRC treatment scenario.

Off-target effects and clinical outcome in metastatic colorectal cancer patients receiving regorafenib: The TRIBUTE analysis

Regorafenib is an orally administered multikinase inhibitor indicated for the treatment of heavily pretreated metastatic colorectal cancer patients with good performance status, albeit less than 50% treated patients achieve disease stabilisation or better at the first radiological evaluation. In addition to that a particularly broad spectrum of toxicities (experienced as G3 or more NCI CTCAE graded by 50% of patients treated) have led to reconsider its widespread use in the majority of patients. We retrospectively collected data about the magnitude of off-target effects experienced during the first 8-weeks of regorafenib monotherapy and analysed their correlation with overall survival, progression free survival and disease control rate. Our findings suggest that skin rash (Exp (B): 0.52, p = 0.0133) or hypothyroidism (Exp (B): 0.11, p = 0.0349) were significantly correlated with improved overall survival at multivariate regression analysis. It was also demonstrated a statistically significant role of diarrhea as predictor of improved survival but its independent prognostic role was lost at multivariate analysis (Exp (B): 0.63, p = 0.162). This is the first analysis showing a potential correlation between the onset of these forms of side effects and regorafenib efficacy, however sample size limitations and the retrospective nature of our analysis prevent us from drawing definitive conclusions.

Regorafenib induced severe toxic hepatitis: characterization and discussion.

Regorafenib is the first small-molecule multikinase inhibitor which showed survival benefits in pretreated metastatic colorectal cancer (mCRC) patients. Besides classical adverse events of this drug class, hepatotoxicity has been described as a frequent side effect. Patients with refractory mCRC treated with regorafenib in our institution were reviewed. Severe treatment-related liver toxicity was investigated. Clinical history, liver histology and genetic assessment (sequence analysis) of cytochrome P3A4 (CYP3A4) and uridine diphosphate-glucuronosyltransferase 1A9 (UGT1A9) involved in regorafenib metabolization were here reported for patients with severe hepatotoxicity. Among the 93 reviewed patients, 3 presented severe and icteric toxic hepatitis which was fatal for 1 patient. Histopathological liver lesions were different depending on the onset of hepatotoxicity (acute or subacute): acinar zone 3 necrosis in case of acute symptoms, and portal tract inflammation with porto-central bridging and fibrosis in the delayed presentation. None of the patients had CYP3A4 gene mutations. Similar polymorphisms in UGT1A9 gene promoter region (UGT1A9 variant -118T9>10 [rs3832043]) were found in both patients who presented acute hepatitis. Moreover, it appears retrospectively that both of them already experienced significant toxicity under irinotecan-based chemotherapy. This is the first report of severe hepatotoxicity with available liver histology and genetic assessment of enzymes involved in regorafenib metabolization. This report also reminds the importance of close liver tests monitoring during regorafenib treatment.

Mitomycin-C+fluoropyrimidines in heavily pretreated metastatic colorectal cancer: a systematic review and evidence synthesis.

Mitomycin-C (MMC) combined with fluoropyrimidines has historically been used for pretreated patients with some activity in this setting, in particular, as third-line chemotherapy (CT) or beyond. We have evaluated the efficacy and safety of MMC-based therapy as a further line of CT in advanced colorectal cancer. Prospective or retrospective studies of MMC-based CT were included in the pooled analysis. PubMed, EMBASE, SCOPUS, Web of Science, the Cochrane Library database and CINAHL were searched systematically. The outcomes were progression-free survival, overall survival, overall response rate and grades 3-4 drug-related adverse events. Seventeen trials involving 681 patients were included in the analysis. Overall, the pooled average weighted progression-free survival and overall survival were 2.84 [95% confidence interval (CI) 2.5-3.1] and 7.47 (95% CI 6-8.9) months, respectively. The corresponding pooled overall response rate was 7.2% (95% CI 5.2-9.9%) and the pooled disease control rate was 38.7% (95% CI 31.7-46.3%). The G3-4 neutropenia and anaemia were the most frequent haematological toxicities (range 0-20%). Nonhaematological G3-4 toxicities were compatible with the associated agent. MMC with fluoropyrimidines represents a viable and active combination for pretreated metastatic colorectal cancer patients. It is thus an option when other agents have failed, or are unavailable or not indicated.

P-154 Combined oxaliplatin, irinotecan and fluorouracil as a rescue regimen for heavily pretreated metastatic colorectal cancer patients

P-154 Combined oxaliplatin, irinotecan and fluorouracil as a rescue regimen for heavily pretreated metastatic colorectal cancer patients

A phase I study of MEK162 and FOLFOX in chemotherapy-resistant metastatic colorectal cancer.

679 Background: Pre-clinical studies have shown that the combination of MEK inhibitors and 5-FU improves antitumor activity and that MEK inhibition overcomes both 5FU and platinum resistance. This phase I study was conducted to determine the maximum tolerated dose (MTD) of the combination MEK162 and FOLFOX. Methods: Patients (pts) with metastatic colon or rectal cancer who progressed or failed prior 5FU, irinotecan, oxaliplatin and anti-EGFR therapy (in cases of RAS wild type tumors) received twice daily MEK162 in combination with every-2-week FOLFOX. Two dose levels of MEK162 (30mg and 45mg) were investigated in a standard 3 + 3 escalation design in combination with standard doses of FOLFOX without bolus 5-FU. Dose limiting toxicity (DLT) was defined as any treatment-related grade (G) 3 or 4 non-hematological toxicity (with the exception of G3 diarrhea or vomiting &lt; 48 hrs) or G 4 neutropenia or thrombocytopenia within the first 2 cycles (4 weeks) of the treatment. Limited pharmacokinetic (PK) analysis of 5FU, oxaliplatin and MEK162 was performed at the MTD level. Results: 16 pts were enrolled (median age (range) 53 yrs (49-78); 11 men; ECOG 0/1 in 9/7 patients). No DLT was noted on the study. The MTD of MEK162 was 45 mg PO BID. An additional 6 pts (for a total of 12) were enrolled at the MTD for PK analysis and none of them developed DLT defining toxicities. A median of 8 cycles (range 1-19) was administered. Treatment-related ≥ grade 3 toxicities included anaphylaxis due to oxaliplatin (n = 1), CPK elevation (n = 2), neutropenia (n = 1), peripheral neuropathy (n = 3), thrombocytopenia (n = 1), retinal vascular disorder (n = 1), and acneiform rash (n = 1). 10 pts had SD at 2 months (m) by radiographic assessment, 5 of whom with stabilizations of &gt; 5 months (5-10 months). There were no significant differences in the PKs of 5FU or oxaliplatin when administered with or without MEK162. Conclusions: The combination of MEK162 and FOLFOX has a manageable toxicity profile and promising antitumor activity in heavily pretreated metastatic colorectal cancer patients. Clinical trial information: NCT02041481.

Prognostic clinical factors in pretreated colorectal cancer patients receiving regorafenib: Implications for clinical management.

591 Background: Most of the patients receiving regorafenib do not seem to benefit from this treatment approach and are therefore exposed to unnecessary toxicity. Angiogenesis and inflammation-related factors may have a relevant role in modulating the activity of anti-angiogenetic drugs such as regorafenib. In our study, we investigated LDH serum levels, platelet, neutrophil, and lymphocyte counts, and neutrophil-to-lymphocyte ratio (NLR) in predicting clinical outcomes for colorectal cancer patients receiving regorafenib. The final aim was to individuate an easy to use and reliable selection tool for these patients in the clinical practice. Methods: We collected LDH serum levels, neutrophil, lymphocyte, and platelet counts within one month before the start of regorafenib in 208 pretreated metastatic colorectal cancer patients. Cut-off values were calculated by ROC curve analysis. Survival analysis was performed by Kaplan-Meier method, and multivariate analysis by Cox method. Results: At multivariate analysis: high platelet count (p=0.0439), low lymphocyte count (p=0.0013), and high NLR (p=0.0237) were related to worse overall survival (OS); high neutrophil count and high NLR (p=0.0058) were related to worse progression free survival (PFS). Among 52 (25%) patients who were negative for all risk factors, a significant correlation was found with improved OS and PFS if compared with the group of patients with at least one risk factor. In particular, median OS was respectively 15.9 vs. 3.1 months (HR: 3.81, 95% CI: 2.32-4.82, p&lt;0.0001) whereas median PFS was 5.9 vs. 2.1 months (HR: 2.62, 95% CI: 2.06-3.86, p&lt;0.0001). Conclusions: We can speculate that colorectal cancer patients showing high neutrophil, high platelet, low lymphocyte count or high NLR may not be optimal candidates for regorafenib treatment. After confirmation in further prospective series, these clinical factors could play a role in the treatment strategy process.

531P - Neutrophil/Lymphocyte Ratio and Piastrinosis Correlate with Clinical Outcome in Metastatic Colorectal Cancer Patients Receiving Regorafenib

ABSTRACT Aim: A non-negligible proportion of colorectal cancer patients receiving regorafenib does not seem to benefit from such a treatment approach and are then exposed to unnecessary toxicity. Neutrophil/lymphocyte ratio and piastrinosis (platelet number increase) may represent indirect indicator of tumour induced inflammation and angiogenesis and have been suggested to influence patients’ outcome. Our analysis investigated the role of neutrophil/lymphocyte ratio and piastrinosis in pretreated metastatic colorectal cancer patients receiving regorafenib. Methods: We collected neutrophil, lymphocyte and platelet count at the start of treatment. Cut-off values for neutrophil/lymphocyte ratio and platelets were calculated by ROC curve analysis. Other tested variables were: age, sex, performance status, k-ras status, number of metastatic sites, previous adjuvant chemotherapy, number of previous systemic anticancer therapies, Overall survival (OS) and progression free survival (PFS) were calculated by Kaplan-Meier method, multivariate analysis was performed by Cox method. Results: 208 patients were eligible. In the global population median OS was 4.2 months whereas median PFS was 2.4 months. Ten (5%) achieved a partial response, 58 (29%) disease stabilization and the remaining 134 (66%) progressed under treatment. The cut off value for piastrinosis and neutrophil/lymphocyte ratio was determined at 0.545 ULN and 0.381 respectively. At univariate analysis neutrophil/lymphocyte ratio and piastrinosis both correlated with clinical outcome. At multivariate analysis a high platelet count and high neutrophil/lymphocyte ratio were related to a worse OS (Exp(b):1.49, 95%CI:1.0130-2.2103, p = 0.0439 and Exp(b):1.6963, 95%CI: 1.0757-2.6751, p = 0.0237 respectively) and PFS (Exp(b):1.4985, 95% CI: 1.0925-2.0556, p = 0.0126 and Exp(b): 1.9277, 95% CI: 1.3226-2.8097, p = 0,0007 respectively). Interestingly in 52 (25%) patients negative for these factors, median overall survival was 15.9 months vs. 3.1 months for patients harbouring at least one of the factors examined (HR:3.81, 95% CI:2.3260-4.8274, p Conclusions: Our analysis suggests that a high platelet count and a high neutrophil/lymphocyte ratio are predictive factors for clinical outcome in patients treated with regorafenib. Disclosure: All authors have declared no conflicts of interest.

Oral multikinase inhibitor regorafenib for the treatment of patients with metastatic colorectal cancer

SUMMARY Regorafenib is an oral small molecule inhibitor of multiple kinases involved in pathogenic processes, such as oncogenesis, tumor angiogenesis and maintenance of the tumor microenvironment, whose efficacy has been recently demonstrated in the treatment of pretreated metastatic colorectal cancer patients. The introduction of regorafenib into clinical practice allows medical oncologists to offer a new line of therapy to patients who have already received all of the other available drugs. Nevertheless, some issues deserve to be further examined in order to improve our knowledge of this drug’s potentialities and to better integrate its use in the daily routine, including the evaluation of response beyond convential size-based response evaluation criteria in solid tumors, the identification of molecular predictors of benefit, and the investigation of the potential role of regorafenib in different settings and in combination with other agents.

Critical appraisal of the use of regorafenib in the management of colorectal cancer

The lack of valid clinical management options for patients affected by metastatic colorectal cancer, which has progressed after all approved standard treatments, has lead to research into new active molecules. Regorafenib is an oral small-molecule multi kinase inhibitor, binding to several intracellular kinases, with powerful inhibitory activity against vascular endothelial growth factor receptors (VEGFR-1,VEGFR-2, and VEGFR-3), platelet-derived growth factor receptor, fibroblast growth factor receptor 1, Raf, TIE-2, and the kinases KIT, RET, and BRAF. The antitumor activity of regorafenib has been tested in vitro and in vivo, and inhibition of tumor growth has been observed in several cancer models, particularly colorectal cancer and gastrointestinal stromal tumors. The most frequent adverse events of grade 3 or higher related to regorafenib were hand-foot skin reaction, fatigue, diarrhea, hypertension, and rash or desquamation. Only a few Phase I–II trials, and most recently a Phase III trial in pretreated colorectal cancer, have been carried out to date. Several ongoing trials are testing the efficacy of regorafenib in combination with chemotherapy. At this point in time, regorafenib is the first small-molecule tyrosine kinase inhibitor to gain approval by the US Food and Drug Administration for pretreated metastatic colorectal cancer patients.

Cost-effectiveness of regorafenib for pretreated metastatic colorectal cancer patients in the United States.

578 Background: There is an unmet need for treatments that provide a survival benefit for patients with heavily pretreated metastatic colorectal cancer (mCRC). In a randomized, double-blind, placebo-controlled trial, patients treated with regorafenib plus best supportive care (BSC) had significant improvement in overall survival (OS) versus patients in the placebo arm receiving BSC alone. The aim of this study was to estimate the cost-effectiveness of regorafenib for the treatment of patients with mCRC after failure or intolerance to irinotecan-, oxaliplatin-, and fluorouracil-based regimens, from the perspective of a U.S. health care payer. Methods: A cohort-partition model was developed to simulate treatment costs and survival for patients treated with regorafenib or BSC alone. Survival was projected by fitting Weibull distributions to trial data. Mean duration of treatment (3.0 months regorafenib, 2.1 months BSC), utilities (0.71 on treatment, 0.59 post-treatment) and serious adverse event rates were also based on trial data. Monthly drug monitoring and physician fee costs were based on Medicare fee schedules. Routine mCRC care and adverse event unit costs were obtained from an analysis of administrative claims in two large managed care databases. Costs were estimated in 2012 USD. Results: Patients treated with regorafenib had prolonged survival versus BSC alone (0.75 versus 0.60 years) and also had higher lifetime costs ($97,700 versus $59,494). The improvement in quality-adjusted life years (0.47 versus 0.37) was small due to the heavily pretreated nature of the patient population. The increase in costs was attributable to increases in costs for drug acquisition, adverse events , and routine care from increased survival. Conclusions: Regorafenib increases life expectancy for patients with pretreated metastatic colorectal cancer. The cost of this benefit could be considered high; however, it could be justifiable given high unmet need for these patients. The increase in cost is primarily due to drug acquisition costs, similar to other recent treatments for metastatic cancers.