Pretreated Metastatic Colorectal Cancer Research Articles

93P Trifluridine-tipiracil (FTD/TPI) plus bevacizumab (BV) in patients (pts) with pretreated metastatic colorectal cancer (mCRC): A real-life Italian multicenter experience

93P Trifluridine-tipiracil (FTD/TPI) plus bevacizumab (BV) in patients (pts) with pretreated metastatic colorectal cancer (mCRC): A real-life Italian multicenter experience

31P Effect of fruquintinib in patients with heavily pretreated metastatic colorectal cancer according to prognostic factors at baseline: Exploratory analysis of FRESCO-2

31P Effect of fruquintinib in patients with heavily pretreated metastatic colorectal cancer according to prognostic factors at baseline: Exploratory analysis of FRESCO-2

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.

RAS mutation specific survival in patients with metastatic colorectal cancer treated with trifluridine/tipiracil.

197 Background: Trifluridine/tipiracil (T/T) is effective in patients with pretreated metastatic colorectal cancer (mCRC). RAS mutational status could predict magnitude of T/T effect (van de Haar et al, Nat Med. 2023), but the data are conflicting. Methods: We retrospectively reviewed the clinical data of 402 patients consecutively treated with T/T in two institutions in the Czech Republic and analysed the potential predictive value of different RAS mutations. Results: Baseline characteristics: median age 65 (range 28-84), female 32.8%, ECOG PS 0 in 32.8% and 1 in 64.9%, primary tumor location left colon in 76.3%. The median line in which T/T was administered was 3 (range 2-8). Median number of T/T cycles administered was 3 (range 2-27). Median follow-up was 32.4 months, 358 patients died (89.1%). Overall survival (OS) was 9.3 months (95% CI 8.7 to 10.3) and progression-free survival (PFS) 3.5 months (3.2 to 3.6). RAS mutation was detected in 54.2% patients. KRAS G12 mutation was found in 117 patients (29.1%), KRAS G13 in 19 (4.7%), other RAS mutation in 25 (6.2%), non-specified RAS mutation in 57 (14.2%), and BRAF mutation in 14 (4.8%). No difference in OS in RAS wildtype (wt) vs mutated group (P=.50) was observed. OS in the defined groups was found: wtRAS group (9.1 months), KRAS G12 (9.1 m), KRAS G13 (5.6 m), and other RAS mutations (10.6 m, P=.180). Patients with KRAS G13 had worse OS vs all other patients (P=.029; HR 1.97), vs wt (P=.02; HR 2.08), vs other mutated (P=0.067; HR 1.75), vs KRAS G12 mutated patients (P=.069; HR 1.75). Patients with KRAS G12 had no OS difference vs other groups of patients. In KRAS G12 group we found that specific gene variants have different OS (for G12C, 7 patients, OS was 6.0 months; for G12D, 41 patients, 9.0 m; for G12V, 45 patients, 10.5 m; for G12S, 7 patients, 16.1 m; for G12A, 11 patients, 7.6; other G12 variants, 5 patients, 10.0 months, P=.028). BRAF mutation was associated with worse OS (6.6 vs 9.1 months, P=.02, HR 2.46). Conclusions: We did not confirm the negative predictive value of KRAS G12 mutation in patients treated with T/T, however, OS depends on the specific G12 mutation. In contrast, patients with KRAS G13 mutation had worse survival.

Predictive Impact of RNF43 Mutations in Patients With Proficient Mismatch Repair/Microsatellite Stable BRAFV600E-Mutated Metastatic Colorectal Cancer Treated With Target Therapy or Chemotherapy.

Target therapy (TT) with encorafenib plus cetuximab is a standard option in patients with BRAFV600E-mutated (mut) pretreated metastatic colorectal cancer (mCRC). Recently, mutations in RNF43, encoding a negative regulator of the WNT pathway, were associated with longer progression-free survival (PFS) and overall survival (OS) in patients with proficient mismatch repair/microsatellite stable (pMMR/MSS) BRAFV600E-mut mCRC treated with TT. Here, we explored the effect of RNF43 mutations on the efficacy of second-line TT versus standard chemotherapy (CT). A retrospective cohort of patients with pMMR/MSS BRAFV600E-mut tumors, available RNF43 mutational status, and treated with second-line TT or oxaliplatin- and/or irinotecan-based CT was analyzed. One hundred thirty-two patients with pMMR/MSS BRAFV600E-mut mCRC were included. RNF43 was found mut in 34 (26%) cases. Among RNF43 mutants, TT was associated with longer PFS (7.7 v 3.0 months; P = .002) and higher overall response rate (ORR; 45% v 0%; P = .009) compared with CT. Conversely, among RNF43 wild-type (wt) patients, only a trend for longer PFS (4.5 v 3.7 months; P = .064) favoring TT, with no differences in ORR (P = .14), was observed. After excluding 36 patients receiving TT in third line or beyond, a longer OS (19.4 v 10.1 months; P = .022) and a numerically OS advantage (10.6 v 6.6 months; P = .068) were reported for TT both in the RNF43-mut and in the RNF43 wt groups. However, no interaction effect was reported between RNF43 mutational status and treatment in ORR (Pinteraction = .96), PFS (Pinteraction = .13), and OS (Pinteraction = .44). Patients with pMMR/MSS BRAFV600E-mut mCRC achieve benefit from TT versus CT independently of RNF43 mutational status, although a higher magnitude of benefit from TT is observed in RNF43-mut tumors. These findings deserve confirmation in concluded and ongoing randomized trials.

Phase II biomarker identification study of anti-VEGF agents withFOLFIRI for pretreated metastatic colorectal cancer.

Chemotherapy plus antiangiogenic agents, including bevacizumab, ramucirumab and aflibercept, is a standard second-line treatment for patients with metastatic colorectal cancer, but which specific agents should be selected is ambiguous due to a lack of clear evidence from prospective studies. Previous reports have suggested ramucirumab and aflibercept could be more effective than bevacizumab in patients with high VEGF-D and high VEGF-A, respectively. JCOG2004 is a three-arm, randomized, phase II study to identify predictive biomarkers for these agents in patients who have failed first-line treatment. The study will enroll 345 patients from 52 institutions for 2years, with progression-free survival in high VEGF-D (bevacizumab vs ramucirumab) and high VEGF-A (bevacizumab vs aflibercept) serving as the primary end point. Clinical Trial Registration: jRCTs031220058 (www.jrct.niph.go.jp).

Fruquintinib versus placebo in patients with refractory metastatic colorectal cancer (FRESCO-2): an international, multicentre, randomised, double-blind, phase 3 study

There is a paucity of effective systemic therapy options for patients with advanced, chemotherapy-refractory colorectal cancer. We aimed to evaluate the efficacy and safety of fruquintinib, a highly selective and potent oral inhibitor of vascular endothelial growth factor receptors (VEGFRs) 1, 2, and 3, in patients with heavily pretreated metastatic colorectal cancer. We conducted an international, randomised, double-blind, placebo-controlled, phase 3 study (FRESCO-2) at 124 hospitals and cancer centres across 14 countries. We included patients aged 18 years or older (≥20 years in Japan) with histologically or cytologically documented metastatic colorectal adenocarcinoma who had received all current standard approved cytotoxic and targeted therapies and progressed on or were intolerant to trifluridine-tipiracil or regorafenib, or both. Eligible patients were randomly assigned (2:1) to receive fruquintinib (5 mg capsule) or matched placebo orally once daily on days 1-21 in 28-day cycles, plus best supportive care. Stratification factors were previous trifluridine-tipiracil or regorafenib, or both, RAS mutation status, and duration of metastatic disease. Patients, investigators, study site personnel, and sponsors, except for selected sponsor pharmacovigilance personnel, were masked to study group assignments. The primary endpoint was overall survival, defined as the time from randomisation to death from any cause. A non-binding futility analysis was done when approximately one-third of the expected overall survival events had occurred. Final analysis occurred after 480 overall survival events. This study is registered with ClinicalTrials.gov, NCT04322539, and EudraCT, 2020-000158-88, and is ongoing but not recruiting. Between Aug 12, 2020, and Dec 2, 2021, 934 patients were assessed for eligibility and 691 were enrolled and randomly assigned to receive fruquintinib (n=461) or placebo (n=230). Patients had received a median of 4 lines (IQR 3-6) of previous systemic therapy for metastatic disease, and 502 (73%) of 691 patients had received more than 3 lines. Median overall survival was 7·4 months (95% CI 6·7-8·2) in the fruquintinib group versus 4·8 months (4·0-5·8) in the placebo group (hazard ratio 0·66, 95% CI 0·55-0·80; p<0·0001). Grade 3 or worse adverse events occurred in 286 (63%) of 456 patients who received fruquintinib and 116 (50%) of 230 who received placebo; the most common grade 3 or worse adverse events in the fruquintinib group included hypertension (n=62 [14%]), asthenia (n=35 [8%]), and hand-foot syndrome (n=29 [6%]). There was one treatment-related death in each group (intestinal perforation in the fruquintinib group and cardiac arrest in the placebo group). Fruquintinib treatment resulted in a significant and clinically meaningful benefit in overall survival compared with placebo in patients with refractory metastatic colorectal cancer. These data support the use of fruquintinib as a global treatment option for patients with refractory metastatic colorectal cancer. Ongoing analysis of the quality of life data will further establish the clinical benefit of fruquintinib in this patient population. HUTCHMED.

Suvemcitug as second-line treatment of advanced or metastatic solid tumors and with FOLFIRI for pretreated metastatic colorectal cancer: phase Ia/Ib open label, dose-escalation trials

Suvemcitug (BD0801), a novel humanized rabbit monoclonal antibody against vascular endothelial growth factor, has demonstrated promising antitumor activities in preclinical studies. The phase Ia/b trials investigated the safety and tolerability and antitumor activities of suvemcitug for pretreated advanced solid tumors and in combination with FOLFIRI (leucovorin and fluorouracil plus irinotecan) in second-line treatment of metastatic colorectal cancer using a 3+ 3 dose-escalation design. Patients received escalating doses of suvemcitug (phase Ia: 2, 4, 5, 6, and 7.5 mg/kg; phase Ib: 1, 2, 3, 4, and 5 mg/kg plus FOLFIRI). The primary endpoint was safety and tolerability in both trials. All patients in the phase Ia trial had at least one adverse event (AE). Dose-limiting toxicities included grade 3 hyperbilirubinemia (one patient), hypertension and proteinuria (one patient), and proteinuria (one patient). The maximum tolerated dose was 5 mg/kg. The most common grade 3 and above AEs were proteinuria (9/25, 36%) and hypertension (8/25, 32%). Forty-eight patients (85.7%) in phase Ib had grade 3 and above AEs, including neutropenia (25/56, 44.6%), reduced leucocyte count (12/56, 21.4%), proteinuria (10/56, 17.9%), and elevated blood pressure (9/56, 16.1%). Only 1 patient in the phase Ia trial showed partial response, [objective response rate 4.0%, 95% confidence interval (CI) 0.1% to 20.4%] whereas 18/53 patients in the phase Ib trial exhibited partial response (objective response rate 34.0%, 95% CI 21.5% to 48.3%). The median progression-free survival was 7.2 months (95% CI 5.1-8.7 months). Suvemcitug has an acceptable toxicity profile and exhibits antitumor activities in pretreated patients with advanced solid tumors or metastatic colorectal cancer.

Real-World Results of Raltitrexed Combined with S-1 and Bevacizumab in Heavily Pretreated Metastatic Colorectal Cancer.

Treatment options for refractory metastatic colorectal cancer (CRC) are scarce. This retrospective study aimed to evaluate the efficacy and safety of raltitrexed combined with S-1 and bevacizumab in patients with heavily pretreated metastatic CRC in a clinical real-world setting. Records of patients with metastatic CRC refractory to standard therapies who initiated raltitrexed plus S-1 and bevacizumab from October 2017 to December 2021 were retrospectively reviewed at our institution. The study endpoints included median overall survival (OS), overall response rate (ORR), progression-free survival (PFS), disease control rate (DCR), and adverse events (AEs). Forty-four patients with metastatic CRC, who had previously undergone standard chemotherapy received the regimen comprising raltitrexed plus S-1 and bevacizumab. As of March 2022, the median follow-up was 23.2 months (95% confidence interval 15.8-30.6). The median OS and median PFS were 13.5 (95% CI 9.9-17.1) and 4.7 months (95% CI 3.6-5.8), respectively, with a 16-week PFS rate of 60.9%. Among 43 patients with measurable lesions, the ORR and DCR were 7.0% (3/43) and 65.1% (28/43), respectively. Patients without peritoneal metastases (P = 0.003, hazard ratio 0.160, 95% CI 0.048-0.531), lower carcinoembryonic antigen level (≤42.8 ng/mL) (P = 0.039, HR 0.382, 95% CI 0.153-0.952), and no previous treatment with both vascular endothelial growth factor inhibitors (VEGF) and S-1 (P = 0.020, HR 0.215, 95% CI 0.059-0.785) had better OS. The incidence of any grade of treatment-related AEs was 88.6%, most of which were mild to moderate, and no treatment-related deaths occurred. Raltitrexed combined with S-1 and bevacizumab shows promising antitumor activity and safety and could be an alternative for patients with metastatic CRC who are refractory or intolerant to standard therapy.

Multicenter retrospective study of trifluridine/tipiracil (FTD/TPI) plus bevacizumab (BEV) for vulnerable patients with pretreated metastatic colorectal cancer (mCRC): WJOG14520G (TWILIGHT).

121 Background: In the phase III SOLSTICE study, FTD/TPI plus BEV showed similar efficacy to capecitabine plus BEV as first-line treatment for patients with mCRC ineligible for full-dose combination chemotherapy with oxaliplatin [OX] or irinotecan [IRI] (intensive therapy). We evaluated clinical outcomes of FTD/TPI plus BEV as second- or later lines treatment for vulnerable patients, who were defined to be intolerant to intensive therapy. Methods: This was a multicenter retrospective study of vulnerable patients with unresectable mCRC who received FTD/TPI plus BEV as second- or later lines treatment between May 2014 and October 2020. Main eligibility criteria were histologically proven adenocarcinoma, ECOG PS 0-2, prior chemotherapy for unresectable disease, considered intolerant to intensive therapy, and underwent FTD/TPI plus BEV without prior exposure to at least one key cytotoxic agent (fluoropyrimidines [FP], OX, or IRI). Results: Of 96 patients enrolled from 26 Japanese hospitals, 93 patients were evaluable. Patient characteristics were as follows: median age, 79 years (range 21-90); male, 53%; ECOG PS 0-1, 89%; right-sided primary tumor, 30%; primary tumor resection, 86%; RAS mutant, 63%; BRAF mutant, 1%; second-line treatment, 80%; prior exposure to FP 100%, OX 50%, and IRI 15%. Main reasons for intolerance to intensive therapy were older age (65%), poor PS (20%), and renal failure (5%). Initial dose of FTD/TPI was reduced in 30 (32%) patients. The response rate was 5% and disease control rate was 68%. With median follow-up of 21.6 months, the median progression-free survival, time to treatment failure, and overall survival were 6.3, 4.5, and 18.6 months, respectively. Major grade &gt;3 adverse events were neutropenia (54%), anemia (20%), thrombocytopenia (9%), hypertension (7%), and febrile neutropenia (2%). No treatment-related deaths were observed. The treatment was discontinued in 89 patients due to disease progression (n = 72), patient’s refusal (n = 10), and adverse events (n = 6). After FTD/TPI plus BEV, chemotherapies such as regimens including IRI or OX (n = 20), regorafenib (n = 16), and anti-EGFR antibody monotherapy (n = 7) were performed in 42 patients. Conclusions: FTD/TPI plus BEV as second- or later lines treatment for vulnerable patients with mCRC showed promising clinical activity and acceptable safety profile. This study suggested that FTD/TPI plus BEV could be a treatment option for vulnerable patients with pretreated mCRC. Clinical trial information: UMIN000044136 .

Response prediction by mutation- or methylation-specific detection of ctDNA dynamics in pretreated metastatic colorectal cancer.

Serial analysis of circulating tumor DNA (ctDNA) levels is a promising tool for both relapse prediction in the curative setting, as well as predicting clinical benefit from systemic treatment in metastasic colorectal cancer (mCRC). Most data in this context are derived from treatment naive patients. To predict progressive disease (PD) as early as possible through monitoring of changes in ctDNA levels during systemic treatment in pretreated patients with mCRC. A prospective, single-center, observational study. Patients treated beyond first-line were prospectively included between February 2020 and September 2021. Blood for ctDNA detection was taken before every treatment cycle from start of treatment until first restaging by CT-scan. ctDNA was detected by mutation- (mut-ctDNA) and methylation-specific ddPCR. Receiver Operating Characteristic (ROC)-analysis was used to describe sensitivity and specificity for prediction of PD at restaging for all time points. A total of 42 patients were included who all carried a mutation in tumor tissue. Detection rate of mut-ctDNA was 88.1% and 74.4% for meth-ctDNA. Absolute ctDNA levels before treatment were prognostic in terms of overall survival. Levels of ctDNA were significantly higher in patients with PD at restaging. Median time from start of treatment to restaging was 93 days (95% CI 88.8-96). After a median of 19 days of treatment (95% CI 16.1-20.2), a decline of either mutation- or methylation-specific ctDNA levels of ⩽58% predicted PD at restaging with a sensitivity/specificity of 92.9/85.7% and 85.7/100%, respectively. Median time to restaging was 66 days (95% CI 56.8-75.2). There was no significant increase of sensitivity/specificity at later time points of ctDNA measurements. Monitoring early changes of ctDNA levels either by mut- or meth-ctDNA allows for early prediction of PD in pretreated patients with mCRC. This has the potential to complement RECIST-based treatment assessment with the aim to switch potentially insufficient treatments as early as possible, which is of particular interest in higher treatment lines.

Effect of KRAS codon 12 or 13 mutations on survival with trifluridine/tipiracil in pretreated metastatic colorectal cancer: a meta-analysis

BackgroundKRAS gene mutations can predict prognosis and treatment response in patients with metastatic colorectal cancer (mCRC).MethodsWe undertook a meta-analysis of three randomized, placebo-controlled trials (RECOURSE, TERRA and J003) to investigate the impact of KRAS mutations in codons 12 or 13 on overall survival (OS) and progression-free survival in patients receiving trifluridine/tipiracil (FTD/TPI) for refractory mCRC.ResultsA total of 1375 patients were included, of whom 478 had a KRAS codon 12 mutation and 130 had a KRAS codon 13 mutation. In univariate analyses, the absence of a KRAS codon 12 mutation was found to significantly increase the OS benefit of FTD/TPI relative to placebo compared with the presence of the mutation {hazard ratio (HR), 0.62 [95% confidence interval (CI): 0.53-0.72] versus 0.86 (0.70-1.05), respectively; interaction P = 0.0206}. Multivariate analyses showed that taking confounding factors into account reduced the difference in treatment effect between the presence and the absence of KRAS codon 12 mutations, confirming that treatment benefit was maintained in patients with [HR, 0.73 (95% CI: 0.59-0.89)] and without [HR, 0.63 (95% CI: 0.54-0.74)] codon 12 mutations (interaction P = 0.2939). KRAS mutations in codon 13 did not reduce the OS benefit of FTD/TPI relative to placebo, and, furthermore, KRAS mutations at either codon 12 or codon 13 did not affect the progression-free survival benefit.ConclusionsTreatment with FTD/TPI produced a survival benefit, relative to placebo, regardless of KRAS codon 12 or 13 mutation status in patients with previously treated mCRC.

P-95 Bevacizumab, irinotecan and biweekly trifluridine/tipiracil for pretreated metastatic colorectal cancer: MODURATE, a phase Ib study

Treatment of refractory metastatic colorectal cancer (mCRC) with trifluridine/tipiracil yields some survival benefits. Trifluridine/tipiracil combined with bevacizumab or irinotecan suggested enhanced therapeutic effects in preclinical models. A phase Ib study combining standard trifluridine/tipiracil regimens with irinotecan resulted in better antitumor activity, accompanied by a high degree of febrile neutropenia. This phase Ib study of trifluridine/tipiracil, irinotecan, and bevacizumab in previously treated mCRC was conducted at two centers, Shizuoka Cancer Center and Aichi Cancer Center in Japan, and consisted of dose escalation (3+3 design) and expansion cohorts. Key eligibility criteria included histologically confirmed colorectal adenocarcinoma, failure or intolerant to fluoropyrimidine and oxaliplatin, no prior therapy with trifluridine/tipiracil and irinotecan, age of 20–75 years, and ECOG PS of 0–1. Patients received trifluridine/tipiracil (25–35 mg/m2 twice daily on days 1–5), irinotecan (150–180 mg/m2; day 1), and bevacizumab (5 mg/kg; day 1) every 2 weeks. The recommended phase II dose (RPTD) in the dose escalation cohort was administered to at least 15 patients in both cohorts. A total of 28 patients from two centers were enrolled between August 2016 and January 2020, comprising 18 in dose escalation cohort and 10 additional patients in expansion cohort. Five dose-limiting toxicities were observed in dose escalation cohort. RPTD was defined as trifluridine/tipiracil 35 mg/m2, irinotecan 150 mg/m2, and bevacizumab 5 mg/kg. Of the 16 patients who received RPTD, patients characteristics were as follows; median age (range), 64 (38-73) years; male/female, 11/5; PS 0/1, 13/3; right-/left-sided tumor, 1/15; median number of metastatic site (range), 2 (1-5); RAS mutant/wild-type, 9/7; uridine diphosphate glucuronosyltransferase 1A1 genotype wild/single hetero/double hetero or homo, 7/8/1; prior history of bevacizumab/anti-EGFR antibody, 6/4. The most common grade 3/4 adverse events were neutropenia (86%) and leukopenia (63%) without febrile neutropenia. No treatment-related death was observed. Dose reduction, delay, and discontinuation occurred in 94%, 94%, and 6% of patients, respectively. At a median follow-up time (range) of 417 (346–611) days, the overall response rate was 19%, with 3 patients achieving a partial response. The disease control rate was 75%, with an additional 9 patients exhibiting stable disease for >4 months duration in 5 patients. The median progression-free survival and overall survival were 7.1 (95% confidence interval [CI], 3.7–not reached [NR]) months and 21.7 (95% CI, 11.3–NR) months, respectively. Biweekly administration of trifluridine/tipiracil, irinotecan, plus bevacizumab may decrease febrile neutropenia with moderate antitumor activity in previously treated mCRC patients. Further investigation of this combination therapy is required.

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.

Combined inhibition of CXCL12 and PD-1 in MSS colorectal and pancreatic cancer: modulation of the microenvironment and clinical effects

BackgroundImmunotherapy in microsatellite stable colorectal or pancreatic cancer has not shown promising results. It has been hypothesized that targeting immunosuppressive molecules like SDF1-alpha/CXCL12 could contribute to immunotherapy and animal models...

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.

TAS-102 in metastatic colorectal cancer (mCRC): efficacy, tolerability, and quality of life in heavily pretreated elderly patients: a real-life study.

BackgroundTAS-102 is an oral monotherapy, combining trifluridine and tipiracil hydrochloride, indicated for the treatment of pretreated metastatic colorectal cancer (mCRC). The aim of this real-life study is to evaluate the efficacy and safety of TAS-102 in heavily pretreated elderly patients with mCRC whose disease has progressed with standard therapies.MethodsIn this retrospective observational study, we enrolled 50 elderly patients >70 years of age (median age 78 years) with a diagnosis of mCRC who were previously treated or were not considered candidates for treatment with other available therapies. Patients aged >70 years with advanced colorectal cancer and with an ECOG performance status of grade 0 (n=18) or grade 1 (n=32) were included. Overall survival and progression-free survival were the primary endpoints, whereas objective response rate, tolerability, and quality of life were the secondary endpoints.ResultsTreatment with TAS-102 appeared to be well tolerated and side effects were generally mild, achieving disease control and a benefit on quality of life. The median overall survival was 6.7 (95% CI 5.7–11.3) and the median progression-free survival was 2.1 months (95% CI 1.2–3.2), estimated using the Kaplan–Meier method.ConclusionTAS-102 represents a manageable and effective therapeutic opportunity and appeared to be well tolerated with generally mild side effects in elderly patients with mCRC who were heavily pretreated with standard therapies.

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.

P-179 The screening and consensus based on practices and evidence (SCOPE) survey: Results of a real-world survey on metastatic colorectal cancer practice patterns

The SCOPE project was undertaken to gather insights on current clinical practices for patients with pretreated metastatic colorectal cancer (mCRC) across different countries. The aim was to better understand medical and social factors influencing practice patterns, identify drivers for treatment choices, and describe any geographic disparities.