Treatment Of Metastatic Colorectal Cancer Research Articles

Improving sustainability of a patient decision aid for systemic treatment of metastatic colorectal cancer: A qualitative study

ObjectiveTo improve sustainability of a patient decision aid for systemic treatment of metastatic colorectal cancer, we evaluated real-world experiences and identified ways to optimize decision aid content and future implementation. MethodsSemi-structured interviews with patients and medical oncologists addressed two main subjects: user experience and decision aid content. Content analysis was applied. Fifteen experts discussed the results and devised improvements based on experience and literature review. ResultsThirteen users were interviewed. They confirmed the relevance of the decision aid for shared decision making. Areas for improvement of content concerned; 1) outdated and missing information, 2) an imbalance in presentation of treatment benefits and harms, and 3) medical oncologists' expressed preference for a more center-specific or patient individualized decision aid, presenting a selection of the guideline recommended treatment options. Key points for improvement of implementation were better alignment within the care pathway, and clear instruction to users. ConclusionWe identified relevant opportunities for improvement of an existing decision aid and developed an updated version and accompanying implementation strategy accordingly. InnovationThis paper outlines an approach for continued decision aid and implementation strategy development which will add to sustainability. Implementation success of the improved decision aid is currently being studied in a multi-center mixed-methods implementation study.

Trifluridine–tipiracil plus bevacizumab versus trifluridine–tipiracil monotherapy for chemorefractory metastatic colorectal cancer: a systematic review and meta-analysis

Colorectal cancer is the leading cause of cancer death worldwide. The first and second lines of treatment for metastatic colorectal cancer (mCRC) include chemotherapy based on 5-fluorouracil. However, treatment following progression on the first and second line is still unclear. We searched PubMed, Scopus, Cochrane, and Web of Science databases for studies investigating the use of trifluridine-tipiracil with bevacizumab versus trifluridine-tipiracil alone for mCRC. We used RStudio version 4.2.3; and we considered p < 0.05 significant. Seven studies and 1,182 patients were included − 602 (51%) received trifluridine-tipiracil plus bevacizumab. Compared with control, the progression-free survival (PFS) (HR 0.52; 95% CI 0.42–0.63; p < 0.001) and overall survival (OS) (HR 0.61; 95% CI 0.52–0.70; p < 0.001) were significantly higher with bevacizumab. The objective response rate (ORR) (RR 3.14; 95% CI 1.51–6.51; p = 0.002) and disease control rate (DCR) (RR 1.66; 95% CI 1.28–2.16; p = 0.0001) favored the intervention. Regarding adverse events, the intervention had a higher rate of neutropenia (RR 1.38; 95% CI 1.19–1.59; p = 0.00001), whereas the monotherapy group had a higher risk of anemia (RR 0.60; 95% CI 0.44–0.82; p = 0.001). Our results support that the addition of bevacizumab is associated with a significant benefit in PFS, OS, ORR and DCR.Graphical

Efficacy of fadraciclib (CYC065), a novel dual CDK2/9 inhibitor, on patient-derived models of colorectal cancer.

3596 Background: Colorectal cancer (CRC) is the third most common type of cancer among adults in the United States. Given the heterogeneous nature of the disease and the limited number of treatments available, there is an unmet need to identify new therapeutic vulnerabilities for advanced CRC. One promising approach is targeting of cyclin dependent kinases (CDKs). In our current study, we sought to understand the potential efficacy of fadraciclib (CYC065), a novel dual CDK 2/9 inhibitor, as a novel treatment for metastatic CRC. Methods: Eighteen CRC patient-derived organoids (PDOs) were generated from patients undergoing biopsy or resection for their primary or metastatic CRC under an IRB approved protocol at Duke University. IHC and H&amp;E staining were first performed on the established PDOs to confirm the diagnosis of CRC. PDOs were treated with standard of care chemotherapy (oxaliplatin, irinotecan (SN38) and 5-Flurouracil), CDK4/6 inhibitor palbociclib, and fadraciclib (CYC065). All drugs were used in doses ranging from 6.4nM to 100µM, and drug sensitivities were determined using Cell-Titer Glo (CTG) 72 hours after treatment. Subsequently, three matching PDXs were generated for in vivo validation and treated with fadraciclib (CYC065) via oral gavage at a dose of 25 mg/kg BID five days a week for two weeks. Target validation for CDK2/9 inhibition was performed via western blotting, cell cycle arrest was determined via flow cytometry, and killing by anaphase catastrophe was determined by immunofluorescence staining. Results: CRC PDOs were more sensitive to fadraciclib (CYC065) than chemotherapy and palbociclib, with IC50 values lower than chemotherapy or palbociclib (2.65±3.92µM for fadraciclib (CYC065) vs. 29.92±41.98µM for chemotherapy (P&lt;0.05) or palbociclib (12.33±9.87µM)). Subsequently, we validated our findings in vivo using 3 matched PDX showing significant tumor growth inhibition (TGI) with fadraciclib (CYC065) compared to control (p&lt;0.05) without serious adverse effects. We showed that fadraciclib (CYC065) induces G2/M cell cycle arrest, resulting in anaphase catastrophe as evident by the presence of multipolar mitosis in fadraciclib (CYC065)-treated cells. CDK2/9 inhibition leads to downregulation of c-Myc levels and upregulation of apoptosis induction as a second mechanism of action for this drug. Conclusions: Our data using both in vitro and in vivo patient-derived models support further exploration of fadraciclib (CYC065) has a potential therapy for advanced CRC. CDK2/9 inhibition impacts multiple critical pathways involved in transcription, mitosis and apoptosis. Further studies will be needed to reveal molecular biomarkers of sensitivity and resistance to this novel agent.

Trifluridine/tipiracil plus capecitabine and bevacizumab as upfront treatment for metastatic colorectal cancer: Results of the phase 1 TriComB study.

3558 Background: Capecitabine (cap) plus Bevacizumab (bev) is a standard option for previously untreated unresectable metastatic colorectal cancer (mCRC) patients (pts) deemed not fit for upfront chemotherapy doublets. A synergistic effect of the sequential administration of cap and Trifluridine/Tipiracil (FTD/TPI) has been shown both in vitro and in vivomodels. Here, we present safety and preliminary activity results of the phase 1 TriComB study, an open-label, multicenter, phase 1/2 trial, evaluating FTD/TPI in combination with cap and bev in mCRC pts. Methods: Patients with previously untreated mCRC, ineligible for oxaliplatin- and/or irinotecan- based regimens, were enrolled. A 3 + 3 dose escalation design was used to identify the recommended dose (RD) of FTD/TPI (days 15-19 and 22-26) in combination with cap (1000 mg/sqm/BID days 1-14) and bev (5 mg/kg day 1,15) in 28-days cycles. Adverse events (AEs) were reported according to CTCAE version 5.0 and tumor response was assessed by RECIST version 1.1. Results: 11 pts (5 men, 6 women; median age: 77, range: 47-84 years) were enrolled. For the first three patients (FTD/TPI: 25mg/sqm BID) no dose limiting toxicities (DLTs) were observed. At 30 mg/sqm BID dose level, 3/5 DLTs were reported: 2 pts experienced a dose delay of &gt;7 days from the scheduled timing and 1 patient was unable to receive ≥ 75% of study drugs’ doses during the first cycle. FTD/TPI was de-escalated and 3 additional patients were treated at 25 mg/sqm BID. Since 1/6 pts experienced a DLT (grade 4 colonic perforation) that was identified as the RD. Grade 3/4 AEs are listed in the Table. As of January 2024, Overall Response Rate is 72.7% (8/11 pts) and 66.7% (4/6 pts) in the overall population and at the RD, respectively. Conclusions: The sequential combination of cap and FTD/TPI with bev is feasible. The phase 2 of the study is ongoing to evaluate antitumor activity of this regimen in the same patients' population. Clinical trial information: NCT04564898 Safety summary Clinical trial information: NCT04564898 . [Table: see text]

Fruquintinib plus capecitabine versus capecitabine as first-line maintenance treatment of metastatic colorectal cancer (mCRC): Update results from the randomized, controlled, phase Ib/II study.

3567 Background: Capecitabine (Cap) is a standard first-line maintenance treatment option for colorectal cancer. Fuquinitinib (Fru) is a highly selective small molecule tyrosine kinase inhibitor that inhibits VEGFR1/2/3, which has been approved by the U.S. Food and Drug Administration (FDA) for adults with mCRC who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy and has recommended by NCCN guidelines as a standard treatment. Preliminary research results found that adding Fru to Cap as maintenance treatment was safe and improved progression-free survival (PFS, primary endpoint) for mCRC patients (pts). Methods: Eligible pts had been confirmed mCRC who achieved disease control (including CR/PR and SD) after at least six cycles of first-line standard chemotherapy. During phase Ib, pts received Fru (4 mg p.o. qd, 3 weeks on/1 week off, q4w]) plus Cap (850 mg/m2, p.o. bid, d1-7 and d15-21, q4w). In phase II, pts were randomized in a 1:1 ratio to receive either Fru (RP2D, 3mg, 3 weeks on/1 week off) plus Cap or Cap alone. The primary outcome was PFS 1 (defined as time from randomization to disease progression or death). Secondary were PFS 2 (defined as time from first time receiving 1L treatment to disease progression or death), ORR and DCR. Results: At data cutoff (Jan 23, 2024), 46 pts were enrolled and 38 pts who had at least one tumor assessment post treatment were randomly assigned in Fru plus Cap arm (n=20) and Cap arm (n=18). Of these pts, the median age was 59.5 (39-78) and 58.5 (32-75) years, 11 (55.0%) and 10 (55.6%) had left-sided tumors, respectively. Most pts had previously received bevacizumab therapy (65.0% /66.7%) or cetuximab (30% /22.2%). The median cycles of first-line treatment were 8 (5-12) and 8 (4-13), 8 (40.0%) and 8 (44.4%) achieved PR in the pts who had received first-line therapy, respectively. The median PFS 1 was 9.2 mo in Fru plus Cap arm and 3.1 mo in Cap arm (HR=0.385 [95% CI: 0.163 - 0.906], p=0.024). And PFS 2 was also significantly prolonged in Fru plus Cap vs Cap (16.8 vs 8.5 mo, HR=0.314 [95% CI: 0.125 - 0.788], p=0.0098). Consistently, ORR (15.0% vs 5.6%) and DCR (80% vs 55.6%) were improved in Fru plus Cap arm. The safety was similar to the previous results without new safety signals appearing. Conclusions: PFS was significantly prolonged and ORR was improved in mCRC pts treated with Fru plus Cap as first-line maintenance treatment. This trial is ongoing and updated data will be presented in the future. Clinical trial information: NCT05451719 .

60P Comparison of the efficacy of third-line treatments for metastatic colorectal cancer: A network meta-analysis

60P Comparison of the efficacy of third-line treatments for metastatic colorectal cancer: A network meta-analysis

A phase II trial of alternating mXELOX/mXELIRI plus bevacizumab (BEV) as first-line treatment for metastatic colorectal cancer (mCRC).

A phase II trial of alternating mXELOX/mXELIRI plus bevacizumab (BEV) as first-line treatment for metastatic colorectal cancer (mCRC).

Single-center retrospective analysis of second-line treatment with regorafenib in patients with advanced colorectal cancer among the COVID-19 pandemic.

e15552 Background: Regorafenib targets multiple tyrosine kinases that has been approved for the third-line treatment in metastatic colorectal cancer (mCRC) patients in China. Here, We retrospectively analyzed the efficacy and safety of regorafenib alone or combined with chemotherapy/immunotherapy in the second-line treatment for those who cannot visit hospital for their chemotherapies because of the COVID-19 pandemic. Methods: Individual patient data from Peking University Third Hospital were analyzed retrospectively from January 2020 to September 2023. The primary endpoint was progression-free survival (PFS), and secondary endpoints were overall survival (OS) and safety. Results: The median age of 31 patients was 65 years, the median PFS was 6 months (1–21 months), and the median OS was 20 months (3–38 months). PFS tended to be prolonged with regorafenib plus capecitabine or immunotherapy in 12 subjects versus regorafenib alone in 19 subjects (8 months vs. 4 months, P = 0.306), with no statistical difference, and so did OS (27 months vs. 15 months, P = 0.899).The analysis of PFS (2.5 months vs. 7 months vs. 4 months, P = 0.164) and OS (13 months vs. 28 months vs. 20 months, p = 0.417) in patients with liver, lung, or abdominal/peritoneal metastases at the initiation of treatment demonstrated poor survival prognosis in patients with liver metastasis. Multivariate analysis showed that regorafenib combined with capecitabine or immunotherapy (wald = 5.766, p = 0.016) and non-liver metastasis (wald = 4.223, p = 0.040) were independent prognostic factors for PFS in the second-line treatment. Adverse drug reactions (ADRs) mainly included hand-foot skin reactions (HFSRs), fatigue, hypertension, and proteinuria, due to which 3 subjects discontinued the treatment. The incidence of Grade 3/4 ADRs was 19.3%, 16.9%, 12.9%, and 9.6%, respectively. Conclusions: Regorafenib alone or combined with chemotherapy/immunotherapy is safe and feasible in the second-line treatment for advanced colorectal cancer, and therefore further prospective studies can be conducted to explore combination therapies.

Real-world impact of KRAS mutations on clinical outcomes in metastatic colorectal cancer treated with trifluridine-tipiracil in the USA.

e15566 Background: Defining the impact of KRAS mutation status on outcomes to standard of care treatments in metastatic colorectal cancer (mCRC) is of increasing clinical relevance. We interrogated a large real-world genomic database to further explore the association between KRAS mutations and benefit to trifluridine-tipiracil (FTD-TPI) in patients with mCRC. Methods: 19,364 patients with mCRC and known KRAS mutation status were analyzed by next-generation sequencing (NextSeq, 592 Genes; NovaSeq, whole exome sequencing (WES)) at Caris Life Sciences. Real-world overall survival (rwOS) and time on treatment (ToT) was inferred from insurance claims data and calculated from time of start of treatment with FTD-TPI to last contact and time from first to last treatment with FTD-TPI with comparison done by the Kaplan-Meier test, respectively. Chi-square test was applied where appropriate, with p-value adjusted for multiple comparisons (p &lt; 0.05). Results: 764 of 10,571 (7.2%) patients with wild-type (WT) KRAS, 768 of 6,984 (11%) with KRAS G12 mutation, and 170 of 1,809 (9.4%) with KRAS G13 mutation received FTD-TPI. Age distribution was similar among groups. Sidedness of primary site was reported in 692 (40.3%) patients; an increased proportion of right-sided tumors was observed in KRAS G12 (53.4% vs. 28.3%, p &lt; 0.0001) and G13 (56% vs 28.3%, p &lt; 0.0001) groups compared to KRAS WT. An increased proportion of TP53 mutations in KRAS WT was observed compared to KRAS G12 mutation (87% vs. 70%, p &lt; 0.0001) and KRAS G13 mutation groups (87% vs. 75%, p &lt; 0.0001). KRAS G12 mutation was associated with shorter median rwOS compared to KRAS WT (7.33 vs. 8.43 months (mo), HR 1.13 (95% CI 1.11-1.42), p = 0.041). KRAS G13 mutation was associated with similar rwOS to KRAS WT. Median ToT was shorter in patients with KRAS G12 mutations than KRAS WT (1.8 vs. 2 mo, HR of 1.22 (95% CI 1.11-1.42), p &lt; 0.001). Median ToT was longer in patients with KRAS G13 versus KRAS G12 (2.3 vs. 1.8 mo, HR 0.82 (95% CI 0.68-0.98), p = 0.032). Conclusions: To our knowledge, this is the largest primarily US-based cohort of mCRC treated with FTD-TPI to be reported. KRAS G12 mutation, but not KRAS G13 mutation, was associated with shorter rwOS and ToT compared to KRAS WT, despite enrichment of TP53 and BRAF mutations in the KRAS WT group. This finding is consistent with previously published analyses of large randomized prospective trials of FTD-TPI in mCRC and further support KRAS mutation status as a predictive biomarker in this setting. [Table: see text]

Irinotecan plus anlotinib or further in combination with penpulimab as second-line treatment of metastatic colorectal cancer (ZL-IRIAN).

Irinotecan plus anlotinib or further in combination with penpulimab as second-line treatment of metastatic colorectal cancer (ZL-IRIAN).

First-line serplulimab plus HLX04 and XELOX versus placebo plus bevacizumab and XELOX in metastatic colorectal cancer: A phase 2/3 study.

3569 Background: This is a randomized, double-blind, multicenter phase 2/3 study comparing the efficacy and safety of serplulimab (a novel anti-PD-1 antibody) plus HLX04 (an approved bevacizumab biosimilar) and XELOX chemotherapy vs. placebo plus bevacizumab and XELOX as first-line treatment for metastatic colorectal cancer (mCRC). Interim analysis presented at the 2024 ASCO Gastrointestinal Cancers Symposium showed improvement in progression-free survival (PFS), and duration of response (DOR) for the serplulimab arm. Here we present the updated results with an extended follow-up duration of 24.2 months and the subgroup analysis results. Methods: In the phase 2 part, 114 patients with mCRC and no prior systemic therapy were randomized 1:1 (serplulimab arm, n = 57; placebo arm, n = 57) to receive intravenous (IV) serplulimab (300 mg) plus HLX04 (7.5 mg/kg) and XELOX (IV oxaliplatin [130 mg/m2] and oral capecitabine [1000 mg/m2]) (group A) or placebo plus bevacizumab and XELOX (group B) once every 3 weeks. Stratification factors were PD-L1 expression level, ECOG PS score, and primary tumor site. The primary endpoint was independent radiological review committee (IRRC)-assessed PFS per RECIST 1.1. Secondary endpoints included other efficacy endpoints, safety, pharmacokinetics, biomarker explorations, and quality-of-life assessments. Results: By the data cutoff of December 15, 2023, continuing improvements in PFS (16.8 vs. 10.7 months; stratified HR 0.62, 95% CI 0.33–1.12) and DOR (19.4 vs. 12.6 months; stratified HR 0.33, 95% CI 0.13–0.85) were observed for group A compared to group B. 55/112 (49.1%) patients in the efficacy evaluable set has died; 24/55 (43.6%) patients in group A and 31/57 (54.4%) in group B. Median overall survival (OS) was not reached (NR) in group A, and 21.2 months in group B (stratified HR 0.75, 95% CI 0.43–1.30). Subgroup analysis showed similar trends towards an improved median OS for key subgroups including microsatellite stable (MSS) (NR vs. 21.2 months; stratified HR 0.73, 95% CI 0.39–1.37), KRAS-mutant (21.9 vs. 18.2 months; unstratified HR 0.72, 95% CI 0.37–1.39), and liver metastasis (NR vs. 20.2 months; unstratified HR 0.75, 95% CI 0.40–1.41) patients. The estimated OS rate at 2 years was 53.7% (95% CI 39.1–66.2), and 43.1% (95% CI 29.5–55.9) in group A, and group B, respectively. 38 (69.1%) patients in group A and 34 (59.6%) in group B had grade ≥3 treatment-related adverse events. Serplulimab/placebo-related deaths occurred in 2 (3.6%) patients in group A and 1 (1.8%) patient in group B. Conclusions: With an extended follow-up duration, improved survival benefits demonstrated with the addition of serplulimab were maintained in the first-line treatment of mCRC, alongside a manageable safety profile. These results support serplulimab plus HLX04 and XELOX as a promising first-line treatment option for mCRC that warrants further investigation. Clinical trial information: NCT04547166 .

Cost-Effectiveness Analysis of Regorafenib versus Other Third-Line Treatments for Metastatic Colorectal Cancer

Cost-Effectiveness Analysis of Regorafenib versus Other Third-Line Treatments for Metastatic Colorectal Cancer

Stereotactic ablative radiotherapy combined with fruquintinib and tislelizumab in metastatic colorectal cancer: Updated findings from a single-arm, prospective phase II trial (RIFLE).

e15570 Background: Stereotactic ablative radiotherapy (SABR) has been shown to sensitize immunotherapy through inducing immunogenic death and remodeling the tumor immune microenvironment. In addition, anti-angiogenic therapy exhibits synergistic antitumor effects with PD-1/PD-L1 antibodies through its immunomodulatory effects for metastatic colorectal cancer (mCRC) patients. Here, we report the updated results from RIFLE trial: the efficacy and safety of the combination of fruquintinib, PD-1 inhibitor tislelizumab and SABR in mCRC patients. Methods: This is a single-center, single-arm, prospective phase II clinical trial (NCT04948034). mCRC patients with at least 2 measurable lesions (≥1 of which can be targeted with radiation and ≥1 lesion outside the radiation field) who have failed ≥ 1L standard therapy will receive SABR followed by fruquintinib (5 mg, d1-14, qd) and tislelizumab (200 mg, d1, q3w) within two weeks from completion of radiation. The percentage change from baseline in the sum of longest diameter of target lesions, consist of specified radiated and non-radiated lesions, will be assessed after at least 2 cycles’ drug treatment. Primary endpoint is best objective response rate (ORR) of target lesions. Secondary endpoints include disease control rate (DCR), duration of response (DoR), progression-free survival (PFS) rate, overall survival (OS) rate and toxicity. Results: From August 2021 to February 2024, 34 patients were included in the trial and 31 in the efficacy analysis. Median age was 62 years, 24 (77.4%) patients were male, 26 (83.9%) had ≥ 3 metastases, and 14 (45.2%) had received ≥ 3 prior lines of systemic therapy. The biological effective dose (BED) for irradiated lesions ranged from 37.5 to 105 Gy. Median study follow-up was 17.3 months (95%CI:13.841-20.759), 24 patients were alive and 13 remained on treatment. 1 patient achieved complete response (CR) for target lesions, 8 partial response (PR), 14 stable disease (SD), illustrating an ORR of 29% and a DCR of 74.2%. Median PFS was 8.8 months (95%CI:5.868-11.732). The most common treatment-related adverse events (TRAEs) were proteinuria (35.5%), hypertension (22.6%) and rash (19.4%). Grade 3-4 AEs occurred in 9 patients, including proteinuria and hypertension, and there were no treatment-related deaths. Conclusions: SABR combined with tislelizumab and fruquintinib shows promising effects and good safety in the treatment of metastatic colorectal cancer, which is expected to provide new therapeutic strategies and improve the prognosis for mCRC patients. Clinical trial information: NCT04948034 . [Table: see text]

Chemotherapy Rechallenge or Reintroduction Compared to Regorafenib or Trifluridine/Tipiracil for Pretreated Metastatic Colorectal Cancer Patients: A Propensity Score Analysis of Treatment Beyond Second Line (Proserpyna Study)

BackgroundThe optimal treatment for metastatic colorectal cancer (mCRC) beyond second line is still questioned. Besides the standard of care agents (regorafenib, REG, or trifluridine/tipiracil, FTD/TPI), chemotherapy rechallenge or reintroduction (CTr/r) are commonly considered in clinical practice, despite weak supporting evidence. The prognostic performance of CTr/r, REG and FTD/TPI in this setting are herein evaluated. Patients and methodsPROSERpYNa is a multicenter, observational, retrospective study, in which patients with refractory mCRC, progressing after at least 2 lines of CT, treated with CTr/r, REG or FTD/TPI, are considered eligible and were enrolled in 2 independent data sets (exploratory and validation). Primary endpoint was overall survival (OS); secondary endpoints were investigator-assessed progression-free survival (PFS), objective response rate (RR) and safety. A propensity score adjustment was accomplished for survival analyses. ResultsData referring to patients treated between Jan-10 and Jan-19 from 3 Italian institutions were gathered (341 and 181 treatments for exploratory and validation data sets respectively). In the exploratory cohort, median OS (18.5 vs. 6.5 months), PFS (6.1 vs. 3.5 months) and RR (28.6% vs. 1.4%) were significantly longer for CTr/r compared to REG/FTD/TPI. Survival benefits were retained at the propensity score analysis, adjusted for independent prognostic factors identified at multivariate analysis. Moreover, these results were confirmed within the validation cohort analyses. ConclusionsAlthough the retrospective fashion, CTr/r proved to be a valuable option in this setting in a real-world context, providing superior outcomes compared to standard of care agents at the price of a moderate toxicity.

Regorafenib Plus for third-line treatment in metastatic colorectal cancer: A real-world study.

e15562 Background: Regorafenib, approved as a monotherapy for refractory metastatic colorectal cancer (mCRC), is recognized for its potential immunomodulatory effects and ability to reverse chemotherapeutic resistance. In response to this, a combination regimen known as regorafenib Plus has been customized for specific patients. This study aims to evaluate the effectiveness and safety of regorafenib as a standalone treatment and in combination with other therapies (including concurrent/sequential chemotherapy, immunotherapy, transarterial chemoembolization [TACE]) in the real-world setting. The goal is to present viable treatment options for patients with mCRC. Methods: In this retrospective study, patients with chemo-refractory metastatic colorectal cancer (mCRC) who underwent regorafenib treatment at Beijing Chaoyang Hospital between January 2018 and October 2023 were stratified into two cohorts: monotherapy (Rego Mono) and concurrent/sequential combination therapy (Rego Plus). Index date was the initiation of regorafenib therapy in a sequence and median follow-up was 19.1 months. The clinical outcomes included progression-free survival (PFS), overall survival (OS), and 1/2-year OS rates. Results: A total of 67 pts were included (n = 39 Rego Mono; n = 28 Rego Plus). Baseline characteristics were comparable between cohorts. The median progression-free survival (PFS) was significantly extended in the Rego Plus group compared to Rego Mono (8.0 vs. 3.6 months, P = 0.000), and overall survival (OS) was also notably prolonged (24.4 vs. 19.1 months, P = 0.046). The 1/2-year OS rates were also improved by Rego Plus (63% vs 37.1%, 25.5% vs 11.4%). However, there were no statistical differences in PFS between concurrent and sequential combination therapies (8.4 vs 8.0 mont). Notably, under sequential therapy, after 3.7 months of PFS with regorafenib alone, an additional 4.7 months of PFS was observed when combined therapy was introduced. Regarding safety, Rego Plus was associated with an increased rate of adverse events (AEs) without an escalation in severity. Common AEs included rash, hand-foot syndrome, hypertension, and diarrhea. Conclusions: Rego Plus significantly prolonged PFS and OS in patients with chemo-refractory mCRC. Particularly when tumor stabilization is evident during monotherapy, the introduction of Rego Plus can offer a comparable or even longer PFS benefit, nearly doubling the PFS. Despite an elevated rate of AEs, the severity of these events did not increase, suggesting good tolerability. This approach has the potential to enhance the effectiveness of existing third-line therapies for mCRC, ultimately contributing to an improved prognosis for patients.

Cost-effectiveness analysis of later-line treatments for refractory metastatic colorectal cancer.

3525 Background: Recent clinical trials support regorafenib dose optimization (ReDO), a combination therapy with trifluridine/tipiracil and bevacizumab (TAS-BEV), and fruquintinib (FRUQ) for the treatment of refractory metastatic colorectal cancer (mCRC). This study evaluated relative cost-effectiveness of ReDO, TAS-BEV, and FRUQ for mCRC from a payer perspective in the United States. Methods: A Markov model was constructed to estimate total costs and quality-adjusted life years (QALY) for each treatment. In the base case, clinical parameters were obtained from the ReDOS study for ReDO, the SUNLIGHT study for TAS-BEV, and the FRESCO study for FRUQ. Economic parameters were obtained from IBM Micromedex RED BOOK for treatment costs and from the Centers for Medicare &amp; Medicaid Services and the Agency for Healthcare Research and Quality for health care resource use. Incremental cost-effectiveness ratio (ICER) was used to evaluate relative cost-effectiveness of treatments. Model robustness was checked with deterministic (DSA) and probabilistic sensitivity analysis (PSA). A subgroup analysis was performed in patients with and without previous use of anti-VEGF therapy, but using the FRESCO-2 study for FRUQ because OS and PFS for this subgroup was unavailable in the FRESCO study. Results: In the base case, ReDO provided a higher QALY at a lower cost than TAS-BEV and FRUQ. During the first two months following treatment initiation, TAS-BEV had a higher total cost ($67,862) than ReDO ($44,695) and FRUQ ($48,688), partly due to the cost of managing neutropenia and using concomitant granulocyte colony stimulating factors (GCSF). The base case results were robust in DSA and PSA. Most influential parameters determining relative cost-effectiveness were related to treatment cost and effectiveness. In patients with previous anti-VEGF therapy, ReDO provided a higher QALY at a lower cost (0.571 QALY; $86,694) than TAS-BEV (0.490 QALY; $148,784) and FRUQ (0.411 QALY; $101,236). In patients without previous anti-VEGF therapy, TAS-BEV had a higher QALY (0.755 vs 0.571) and a higher cost ($232,701 vs $86,694) than ReDO, resulting in an ICER of $790,988 per QALY. Conclusions: ReDO was cost-effective compared with TAS-BEV and FRUQ, regardless of previous use of anti-VEGF therapy. In the base case, ReDO had a lower treatment cost than TAS-BEV and FRUQ, especially during the first month of dose optimization. TAS-BEV had the highest total cost, partly due to the cost of managing neutropenia and GCSF use. [Table: see text]

110P Circulating tumor DNA (ctDNA) to detect acquired resistance to first-line (1L) treatment of RASWT metastatic colorectal cancer (mCRC): Insights from the PLATFORM-B study

110P Circulating tumor DNA (ctDNA) to detect acquired resistance to first-line (1L) treatment of RASWT metastatic colorectal cancer (mCRC): Insights from the PLATFORM-B study

Simultaneous operations in patients with colorectal cancer with liver metastases.

e15586 Background: Metastatic colorectal cancer (CRC) treatment is a complex process involving surgical oncologists, chemotherapy specialists, and radiation oncologists. Objective: To assess the long-term outcomes of treating patients with metastatic CRC who has gone through simultaneous liver operations. Methods: Data and medical records of 61 patients with primary metastatic CRC treated at the Republican Specialized Scientific-Practical Center of Oncology and Radiology of the Republic of Uzbekistan between 2016 and 2020 were reviewed. Disease diagnosis and treatment were conducted following the current recommendations of the Ministry of Health of the Republic of Uzbekistan. The median follow-up period was 35 months. Results: The mean age of the patients included in the study was 59.1 years (ranging from 36 to 81 years). Of them, 32 male and 29 female patients. Metastatic cancer of the rectum was diagnosed in 18 patients (29.5%), rectosigmoid junction in 9 (14.8%), and colon in 34 (55.7%). Among the patients, 3 had low-grade tumor differentiation, 24 had medium-grade, and 34 had high-grade. According to the "T" criterion, 65.6% of the tumors were categorized as T3, 29.5% as T4, and 4.9% as T2. Different types of surgeries were performed for primary tumor localization, including abdominoperineal resection of the rectum (2 patients), right hemicolectomy (10 patients), rectal resection (5 patients), rectosigmoid junction resection (4 patients), colon resection (6 patients), left hemicolectomy (5 patients), and transabdominal rectal resection (4 patients). Postoperative complications were observed in 16 patients (bile leakage from drainage, wound suppuration, pneumonia, bladder atony). Anastomotic complications were detected in 2 patients. There were no deaths in the early postoperative period. The median overall survival was 36 months. The one-year overall survival rate in the overall group was 91.7% ± 3.7%, two-year - 76.2% ± 5.6%, three-year - 51.9% ± 7.5%. For colon cancer, the three-year overall survival was 62.7% ± 9.3%, rectosigmoid junction - 43.2% ± 20.8%, rectal cancer - 36.8% ± 13.7 (p = 0.974). Conclusions: Simultaneous operations for CRC and liver metastases combined with combination therapy contribute to stabilizing the tumor process and increasing overall survival rates.

Metabolomics analysis reveals characteristic metabolites in different levels of oxaliplatin-induced neurotoxicity.

Oxaliplatin (L-OHP), a third-generation platinum-based anti-tumor drug, finds widespread application in the first-line treatment of metastatic colorectal cancer. Despite its efficacy, the drug's usage is curtailed by a litany of side effects, with L-OHP-induced peripheral neuropathy (OIPN) being the most debilitating. This condition can be classified into varying degrees of severity. Employing serum metabolomics, a high-sensitivity, high-throughput technique, holds promise as a method to identify biomarkers for clinical assessment and monitoring of OIPN patients across different severity levels. In our study, we analyzed serum metabolites in patients with different OIPN levels using ultra-performance liquid chromatography-high resolution mass spectrometry. By employing statistical analyses and pathway enrichment studies, we aimed to identify potential biomarkers and metabolic pathways. Our findings characterized the serum metabolic profiles of patients with varying OIPN levels. Notably, pathway analysis revealed a significant correlation with lipid metabolism, amino acid metabolism, and energy metabolism. Multivariate statistical analysis and receiver operator characteristic curve evaluation pointed to anhalamine and glycochenodeoxycholic acid as potential biomarkers for OIPN C and A, which suggest that serum metabolomics may serve as a potent tool for exploring the metabolic status of patients suffering from diverse diseases and for discovering novel biomarkers.

FDA Approval Summary: Fruquintinib for the Treatment of Refractory Metastatic Colorectal Cancer.

On November 8, 2023, the FDA approved fruquintinib, an inhibitor of vascular endothelial growth factor receptor (VEGFR)-1, -2, and -3, for the treatment of patients with metastatic colorectal cancer (mCRC) who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF therapy, and if RAS wild-type and medically appropriate, an anti-EGFR therapy. Approval was based on Study FRESCO-2, a globally conducted, double-blind, placebo-controlled randomized trial. The primary endpoint was overall survival (OS). The key secondary endpoint was progression-free survival. A total of 691 patients were randomly assigned (461 and 230 into the fruquintinib and placebo arms, respectively). Fruquintinib provided a statistically significant improvement in OS with a hazard ratio (HR) of 0.66 [95% confidence interval (CI), 0.55, 0.80; P < 0.001]. The median OS was 7.4 months (95% CI, 6.7, 8.2) in the fruquintinib arm and 4.8 months (95% CI, 4.0, 5.8) for the placebo arm. Adverse events observed were generally consistent with the known safety profile associated with the inhibition of VEGFR. The results of FRESCO-2 were supported by the FRESCO study, a double-blind, single-country, placebo-controlled, randomized trial in patients with refractory mCRC who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy. In FRESCO, the OS HR was 0.65 (95% CI, 0.51, 0.83; P < 0.001). FDA concluded that the totality of the evidence from FRESCO-2 and FRESCO supported an indication for patients with mCRC with prior treatment with fluoropyrimidine, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and if RAS wild-type and medically appropriate, an anti-EGFR therapy.