Treatment Of Metastatic Colorectal Cancer Research Articles

Sequencing considerations in the third-line treatment of metastatic colorectal cancer.

Numerous advances in the standard of care for metastatic colorectal cancer (mCRC), including the approval of several new treatments indicated for treatment in the third line or later (3L+), have been made, yet data and appropriate guidance on the optimal sequencing and treatment strategies for these lines of therapy are lacking. Four treatments-regorafenib, trifluridine/tipiracil alone or with bevacizumab, and fruquintinib-are FDA-approved and recommended by the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for the treatment of mCRC in the 3L+. When considering sequencing of treatment options for patients in the 3L+, the goal of treatment is to improve survival, but also maintain quality of life, a goal that requires consideration of relative efficacy and cumulative toxicity such as persistent myelosuppression.

A decade of progress: advances in the third-line treatment of patients with metastatic colorectal cancer.

The treatment of metastatic colorectal cancer (mCRC) remains challenging. There has been substantial progress in understanding the molecular pathology of the disease that has led to meaningful advancements in treatment options with varying mechanisms of action, although treatment remains costly. Cytotoxic therapies, which are typically combined with targeted therapies, remain the mainstay of first- and second-line treatment for mCRC. While also relevant in earlier lines of therapy, molecular testing has become increasingly important to guide therapy across lines of therapy, for which treatment options are limited. A paucity of data exists in establishing clinical criteria for optimizing the sequencing of therapies in the third line and beyond. A customized approach should consider the efficacy of the therapy balanced with the patient's goals. Sequencing criteria should include a consideration for exposing patients to as many different modes of therapy as possible while preserving quality of life, avoiding serious toxicities, and accounting for the potential impact of cumulative toxicities from prior therapies.

[Organ preservation in locally advanced colorectal cancer with microsatellite instability-high after immunotherapy].

Neoadjuvant immunotherapy has achieved exciting efficacy with high clinical complete response (cCR) and pathologic complete response (pCR) rates and durable long-term effects. PD-1 checkpoint blockade-based immunotherapy has been highly successful in microsatellite instability high (MSI-H)/mismatch repair deficiency (dMMR) colorectal cancer and has been recommended as the first-line treatment for metastatic colorectal cancer by domestic and international guidelines. Several studies have shown that immunotherapy can be a potentially curable treatment for MSI-H rectal cancer and has even shown promise in organ preservation in colon cancer. In this study, we first clarified the feasibility of the watch-and-wait strategy after PD-1 checkpoint blockade treatment by indirect and direct evidence. Then from the assessment tools (including digital rectal examination, endoscopy, radiology, and lymph node assessment), the viable assessment methods of cCR for immunotherapy and related difficulties are proposed. Finally, the medication choices of immunotherapy, the treatment regimen, and the follow-up strategy are further discussed. We hope that neoadjuvant immunotherapy could be appropriately applied in MSI-H/dMMR colorectal cancer so that more patients can achieve organ preservation.

Monitoring ctDNA RAS Mutational Status in Metastatic Colorectal Cancer: A Trial Protocol of RAS-trace and RAS-trace-2 Studies.

Spatial and temporal heterogeneities of RAS and other molecular genes should be considered in the treatment of metastatic colorectal cancer (mCRC) treated with anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs); acquired RAS mutation is sometimes observed at disease progression of treatment with the anti-EGFR mAb. At the same time, discrepancy of RAS status from tissues and circulating tumor DNA (ctDNA) in the same patient is sometimes observed. Based on this, we commenced two observational studies to clarify these heterogeneities of RAS and BRAF in mCRC, using next generation sequencing from liquid biopsy. RAS-trace study is an observational study to monitor ctDNA RAS/BRAF/PIK3CA status every 4-12 weeks using the Plasma-SeqSensei™ CRC RUO Kit (Sysmex Inostics GmbH) in mCRC with RAS/BRAF wild-type (wt) on tumor tissue. The primary endpoint was the time to the acquired RAS mutations. A total of 42 patients has been accrued. RAS-trace-2 study is also an observational study aimed at comparing the efficacy of the anti-EGFR mAb in ctDNA RAS/BRAF wt with ctDNA RAS or BRAF mutant mCRC patients, whose RAS/BRAF are wt in tumor tissue. The primary endpoint was progression-free survival in patients with ctDNA RAS/BRAF wt and RAS or BRAF mutant. A total of 240 patients will be accrued over 2 years. These trials will help us understanding the clinical significance of spatial and temporal heterogeneities of RAS, BRAF and other genes, while optimizing the anti-EGFR mAb treatment strategies in mCRC.

First-line oxaliplatin-based chemotherapy and nivolumab for metastatic microsatellite-stable colorectal cancer-the randomised METIMMOX trial.

We evaluated first-line treatment of metastatic microsatellite-stable colorectal cancer with short-course oxaliplatin-based chemotherapy alternating with immune checkpoint blockade. Patients were randomly assigned to chemotherapy (the FLOX regimen; control group) or alternating two cycles each of FLOX and nivolumab (experimental group). Radiographic response assessment was done every eight weeks with progression-free survival (PFS) as the primary endpoint. Cox proportional-hazards regression models estimated associations between PFS and relevant variables. A post hoc analysis explored C-reactive protein as signal of responsiveness to immune checkpoint blockade. Eighty patients were randomised and 38 in each group received treatment. PFS was comparable-control group: median 9.2 months (95% confidence interval (CI), 6.3-12.7); experimental group: median 9.2 months (95% CI, 4.5-15.0). The adjusted Cox model revealed that experimental-group subjects aged ≥60 had significantly lowered progression risk (p = 0.021) with hazard ratio 0.17 (95% CI, 0.04-0.76). Experimental-group patients with C-reactive protein <5.0 mg/L when starting nivolumab (n = 17) reached median PFS 15.8 months (95% CI, 7.8-23.7). One-sixth of experimental-group cases (all KRAS/BRAF-mutant) achieved complete response. The investigational regimen did not improve the primary outcome for the intention-to-treat population but might benefit small subgroups of patients with previously untreated, metastatic microsatellite-stable colorectal cancer. ClinicalTrials.gov number, NCT03388190 (02/01/2018).

Sequential RAS mutations evaluation in cell-free DNA of patients with tissue RAS wild-type metastatic colorectal cancer: the PERSEIDA (Cohort 2) study.

RAS (KRAS/NRAS) mutational status on a tumor biopsy is mandatory to guide the best treatment in metastatic colorectal cancer (mCRC). Determining the RAS mutational status by tumor-tissue biopsy is essential in guiding the optimal treatment decision for mCRC. RAS mutations are negative predictive factors for the use of EGFR monoclonal antibodies. Cell-free DNA (cfDNA) analysis enables minimally invasive monitoring of tumor evolution. PERSEIDA was an observational, prospective study assessing cfDNA RAS, BRAF and EGFR mutations (using Idylla™) in first-line mCRC, RAS wild-type (baseline tumor-tissue biopsy) patients (cohort 2). Plasma samples were collected before first-line treatment, after 20 ± 2weeks, and at disease progression. 117 patients were included (103 received panitumumab + chemotherapy as first-line treatment). At baseline, 7 (6.8%) patients had RAS mutations, 4 (3.9%) BRAF mutations and no EGFR mutations were detected (cfDNA, panitumumab + chemotherapy subpopulation [panitumumab + Ch]). The baseline RAS mutational status concordance between tissue and liquid biopsies was 94.0% (93.2%, panitumumab + Ch). At 20weeks, only one patient in the study (included in the panitumumab + Ch) had an emerging cfDNA RAS mutation. No emerging BRAF or EGFR mutations were reported. At disease progression, 6 patients had emergent mutations not present at baseline (RAS conversion rate: 13.3% [6/45]; 15.0% [6/40], panitumumab + Ch). The concordance rate between liquid and solid biopsies at baseline was very high, as previously reported, while our results suggest a considerable emergence of RAS mutations during disease progression. Thus, the dynamics of the genomic landscape in ctDNA may provide relevant information for the management of mCRC patients.

Cancer therapy related cardiac dysfunction as a result of Panitumumab

Panitumumab is a human immunoglobulin monoclonal antibody designed to target the epidermal growth factor receptor (EGFR) which is used in the treatment of metastatic colorectal cancer alone or in combination with chemotherapy. In this report, we present a case of new onset heart failure with reduced ejection fraction in a patient following panitumumab therapy. A 73-year-old gentleman with metastatic rectal adenocarcinoma presented to his local hospital with increased shortness of breath, two months after his first and only dose of panitumumab. A transthoracic echocardiogram demonstrated dilated left ventricle with global hypokinesis and an estimated left ventricular ejection fraction of 25%. Our patient underwent a comprehensive diagnostic assessment at his presentation, including ECG, transthoracic echocardiogram, cardiac magnetic resonance, computed tomography coronary angiography (CTCA), invasive coronary angiogram and 18F-FDG PET-CT. These investigations revealed no evidence of ischemic events or inflammatory processes that could account for the severe left ventricular dysfunction. To our knowledge, this is the first reported case of heart failure with reduced ejection fraction linked to panitumumab with subsequent deep phenotyping. The current guidelines do not recommend specific cardiovascular monitoring protocols for patients receiving anti-EGFR monoclonal antibodies. Until more data are available, it would be prudent to implement the same cardiovascular surveillance measures outlined for individuals receiving osimertinib, which is an EGFR tyrosine kinase inhibitor.

Abstract CT275: A phase 2, randomized, open-label study of onvansertib in combination with standard-of-care (SoC) versus SoC alone for first-line treatment of RAS-mutant metastatic colorectal cancer (mCRC)

Abstract Background: Chemotherapy in combination with bevacizumab (Bev) has been a standard first-line treatment for RAS-mutated mCRC patients for the last 2 decades. The prognosis of these patients remains poor. Onvansertib is an orally available, highly potent, and selective inhibitor of Polo-like kinase 1 (PLK1), currently in clinical development. In a Phase 1b/2 study, onvansertib in combination with FOLFIRI + Bev demonstrated safety and promising efficacy in the second-line treatment of KRAS-mutated mCRC patients (NCT03829410). A subgroup analysis showed that patients not exposed to Bev (Bev-naïve) in the first-line setting had superior clinical benefit compared to Bev-exposed patients. Based on this data, we propose to investigate the combination of onvansertib with SoC (chemo + Bev) in the first-line treatment of RAS-mutated, Bev-naïve mCRC patients. Methods: This exploratory Phase 2, open-label, randomized study is designed to assess the safety, efficacy, pharmacokinetics, and pharmacodynamics of 2 doses of onvansertib (20 mg and 30 mg) in combination with SoC (FOLFIRI + Bev or FOLFOX + Bev) versus SoC alone in patients with RAS-mutated metastatic and unresectable CRC in the first-line setting. Eligible participants must have histologically confirmed mCRC, KRAS or NRAS mutation, no previous systemic therapy in the metastatic setting, ECOG performance status of 0 or 1, measurable disease as defined per RECIST v1.1. Exclusion criteria include patients with BRAF-V600 mutations or microsatellite instability high/deficient mismatch repair, prior treatment with a VEGF inhibitor, previous oxaliplatin treatment within 12 months prior to randomization. The primary endpoint is objective response as determined according to RECIST v1.1 by an independent central review. Key secondary endpoints include progression-free survival and duration of response per independent central review. The study will enroll approximately 90 patients. Each patient will be randomized to be treated with onvansertib (20 mg or 30 mg) + SoC or SoC alone. The enrollment period for this study is approximately 12 months. Patients will be followed for overall survival for up to 1 year after the end of treatment. Trial is open and recruiting as of November 2023. This trial is registered as NCT06106308. Citation Format: Heinz-Josef Lenz, Benjamin Kuritzky, Anu Thummala, Stephan Kendall, Ravindranath Patel, Sreenivasa R. Chandana, Alisha H. Bent, Nancy Sherman, Ramanand Arun Subramanian, Fairooz Kabbinavar, Joel Randolph Hecht. A phase 2, randomized, open-label study of onvansertib in combination with standard-of-care (SoC) versus SoC alone for first-line treatment of RAS-mutant metastatic colorectal cancer (mCRC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT275.

Imaging Considerations before and after Liver-Directed Locoregional Treatments for Metastatic Colorectal Cancer.

Colorectal cancer is a leading cause of cancer-related death. Liver metastases will develop in over one-third of patients with colorectal cancer and are a major cause of morbidity and mortality. Even though surgical resection has been considered the mainstay of treatment, only approximately 20% of the patients are surgical candidates. Liver-directed locoregional therapies such as thermal ablation, Yttrium-90 transarterial radioembolization, and stereotactic body radiation therapy are pivotal in managing colorectal liver metastatic disease. Comprehensive pre- and post-intervention imaging, encompassing both anatomic and metabolic assessments, is invaluable for precise treatment planning, staging, treatment response assessment, and the prompt identification of local or distant tumor progression. This review outlines the value of imaging for colorectal liver metastatic disease and offers insights into imaging follow-up after locoregional liver-directed therapy.

XELOX (capecitabine plus oxaliplatin) plus bevacizumab (anti-VEGF-A antibody) with or without adoptive cell immunotherapy in the treatment of patients with previously untreated metastatic colorectal cancer: a multicenter, open-label, randomized, controlled, phase 3 trial

Fluoropyrimidine-based combination chemotherapy plus targeted therapy is the standard initial treatment for unresectable metastatic colorectal cancer (mCRC), but the prognosis remains poor. This phase 3 trial (ClinicalTrials.gov: NCT03950154) assessed the efficacy and adverse events (AEs) of the combination of PD-1 blockade-activated DC-CIK (PD1-T) cells with XELOX plus bevacizumab as a first-line therapy in patients with mCRC. A total of 202 participants were enrolled and randomly assigned in a 1:1 ratio to receive either first-line XELOX plus bevacizumab (the control group, n = 102) or the same regimen plus autologous PD1-T cell immunotherapy (the immunotherapy group, n = 100) every 21 days for up to 6 cycles, followed by maintenance treatment with capecitabine and bevacizumab. The main endpoint of the trial was progression-free survival (PFS). The median follow-up was 19.5 months. Median PFS was 14.8 months (95% CI, 11.6–18.0) for the immunotherapy group compared with 9.9 months (8.0–11.8) for the control group (hazard ratio [HR], 0.60 [95% CI, 0.40–0.88]; p = 0.009). Median overall survival (OS) was not reached for the immunotherapy group and 25.6 months (95% CI, 18.3–32.8) for the control group (HR, 0.57 [95% CI, 0.33–0.98]; p = 0.043). Grade 3 or higher AEs occurred in 20.0% of patients in the immunotherapy group and 23.5% in the control groups, with no toxicity-associated deaths reported. The addition of PD1-T cells to first-line XELOX plus bevacizumab demonstrates significant clinical improvement of PFS and OS with well tolerability in patients with previously untreated mCRC.

Transient TCR-based T cell therapy in a patient with advanced treatment-resistant MSI-high colorectal cancer

We previously demonstrated the anti-tumor effectiveness of transiently TCR redirected T cells recognizing a frameshift mutation in TGFβRII. We here describe a clinical protocol using mRNA TCR modified T cells to treat a patient with progressive, treatment-resistant metastatic MSI-H colorectal cancer. Following 12 escalating doses of autologous T cells electroporated with in vitro transcribed Radium-1 TCR mRNA we assessed T cell cytotoxicity, phenotype and cytokine production. Tumor markers and growth on CT scans were evaluated and immune cell tumor infiltrate at diagnosis assessed. At diagnosis tumor infiltrating CD8+ T cells had minimal expression of exhaustion markers, except for PD-1. Injected Radium-1 T cells were mainly naïve and effector memory T cells with low expression of exhaustion markers, except for TIGIT. We confirmed cytotoxicity of transfected Radium-1 T cells against target cells and found key cytokines involved in tumor metastasis, growth, and angiogenesis to fluctuate during treatment. The treatment was well tolerated, and despite his advanced cancer, the patient obtained a stable disease with 6 months' survival post treatment. We conclude that treatment of metastatic MSI-H colorectal cancer with autologous T cells electroporated with Radium-1 TCR mRNA is feasible, safe, well tolerated and warrants further investigation in a Phase I/II study.

MFOLFIRINOX versus mFOLFOX 6 as adjuvant treatment for high-risk stage III colon cancer - the FROST trial: study protocol for a multicenter, randomized controlled, phase II trial

BackgroundHigh-risk stage III colon cancer has a considerably poorer prognosis than stage II and low-risk stage III colon cancers. Nevertheless, most guidelines recommend similar adjuvant treatment approaches for all these stages despite the dearth of research focusing on high-risk stage III colon cancer and the potential for improved prognosis with intensive adjuvant treatment. Given the the proven efficacy of triplet chemotherapy in metastatic colorectal cancer treatment, the goal of this study is to evaluate the oncologic efficacy and safety of mFOLFIRINOX in comparison to those of the current standard of care, mFOLFOX 6, as an adjuvant treatment for patients diagnosed with high-risk stage III colon cancer after radical resection.MethodsThis multicenter, randomized (1:1), open-label, phase II trial will assess and compare the effectiveness and toxicity of mFOLFIRINOX and mFOLFOX 6 in patients with high-risk stage III colon cancer after radical resection. The goal of the trial is to enroll 312 eligible patients, from 11 institutes, aged between 20 and 70 years, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2, or between 70 and 75 with an ECOG performance status of 0. Patients will be randomized into two arms - Arm A, the experimental arm, and Arm B, the reference arm - and will receive 12 cycles of mFOLFIRINOX and mFOLFOX 6 every 2 weeks, respectively. The primary endpoint of this study is the 3-year disease-free survival, and secondary endpoints include the 3-year overall survival and treatment toxicity.DiscussionThe Frost trial would help determine the oncologic efficacy and safety of adjuvant triplet chemotherapy for high-risk stage III colon cancers and ultimately improve prognoses.Trial registrationClinicalTrials.gov NCT05179889, registered on 17 December 2021.

Abstract 900: Development and validation of an artificial-intelligence-based pathomics biomarker to predict resistance to first-line treatment in metastatic colorectal cancer

Abstract Background: The backbone chemotherapy of first-line standard of care (SOC) for microsatellite stable (MSS) metastatic colorectal cancer (mCRC) combines 5-Fluorouracil to oxaliplatin and/or irinotecan. There are no biomarkers to predict response, which is complete or long-lasting (CR/LLR) in 20-25% of patients, while 10-15% are primary refractory. The aim of this work is to develop a predictive biomarker, based on digital pathology images, that can help stratify patients according to their risk of resistance. Methods: We trained a supervised bag-of-words artificial intelligence (AI)-based model on a cohort of response outliers mCRC patients classified as “really sensitive” (RS) if they achieved CR or LLR &amp;gt;10 months to any SOC, or “really resistant” (RR) if progression occurred at first disease reassessment. Whole-slide Imaging (WSI) of the resected primary tumors were tiled into patches of 224 × 224 pixel (0.5μm/pixel). First-order and texture features were subsequently extracted from all tumoral tiles and grouped into homogenous clusters through a k-means algorithm (k=6). For each patient, the percentage of tiles belonging to each tiles’ cluster was computed to represent new features (called bag of words) with whom different machine learning classifiers were trained. Main clinicopathological features were matched to treatment response by Fisher’s exact test. Results: To date, we analyzed 82 response outlier patients, of whom 35 were classified as RS and 46 RR. Of them, patients identified at Italian centers were used as construction cohort (N=47; 27 RR and 20 RS) and those identified at Spanish centers were used a validation cohort (N=35; 19 RR and 16 RS). The best result was obtained using a stepwise logistic regression, reaching a negative predictive value (NPV) of 90% (18/20; 95% CI=70-97%) and 71% (10/14; 95% CI=49-87%), in the construction and validation sets. No standard clinicopathological features (including stage, RAS/BRAF status, histology and sidedness) was associated with the chance of being RR. Conclusions: We demonstrated that a pathomics signature has the potential to predict resistance to SOC in MSS mCRC. Further validation of these preliminary findings on a larger cohort of response outlier patients is ongoing. Citation Format: Luca Lazzari, Gianluca Mauri, Valentina Giannini, Debora Cafaro, Giulia Nicoletti, Caterina Marchiò, Andrea Sartore-Bianchi, Federica Marmorino, Maria Nieva Munoz, Nadia Saoudi Gonzalez, Alberto Puccini, Chiara Cremolini, Clara Montagut, Elena Elez, Stefania Sciallero, Enrico Berrino, Martina Carullo, Pietro Paolo Vitiello, Maria Costanza Aquilano, Martina Di Como, Emanuela Bonoldi, Salvatore Siena, Alberto Bardelli, Daniele Regge, Silvia Marsoni. Development and validation of an artificial-intelligence-based pathomics biomarker to predict resistance to first-line treatment in metastatic colorectal cancer [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 900.

Abstract 2200: Plant-based diet and survival among patients with metastatic colorectal cancer: Findings from CALGB/SWOG 80405 (Alliance)

Abstract Background: Plant-based diet is recommended by multiple cancer survivorship guidelines and was reported to be associated with better survival among patients with non-metastatic colorectal cancer. However, the association between plant-based diet and survival in metastatic colorectal cancer is unknown. Methods: Using an NCI-sponsored systemic therapy trial conducted from 2005 to 2015 (CALGB/SWOG 80405), we included 1,279 patients who completed validated food frequency questionnaires at the initiation of treatment for metastatic colorectal cancer. To emphasize different impact of healthful plant foods, less healthful plant foods, and animal foods, we used 18 food groups to calculate three plant-based indexes (ranges: 18-90 points): overall plant-based diet index (PDI), healthful plant-based diet index (hPDI), and unhealthful plant-based diet index (uPDI). The primary outcome was overall survival, and the secondary outcome was progression-free survival. We estimated the associations of three indexes (quintiles) with survival using multivariable Cox proportional hazards regression. Results: Of 1,279 patients (median follow-up: 6.1 years), mean (SD) age at diagnosis was 58.8 (11.7) years, 57.4% were men, 85.6% were White, and 1,096 deaths and 1,201 events of progression occurred. The mean (SD) points of three indexes were 51.2 (6.3) for PDI, 51.1 (6.7) for hPDI, and 51.2 (8.1) for uPDI. Compared to the lowest quintile (Q1), the highest quintile (Q5) of PDI was significantly associated with better overall survival (HR: 0.80 [0.65-0.99]) and progression-free survival (HR: 0.80 [0.65-0.98]). Similar findings were observed for hPDI, but uPDI was not significantly associated with worse survival. Conclusions: Our findings suggest that plant-based diet is associated with better survival among patients with metastatic colorectal cancer, and plant-based dietary interventions should be considered for future trials in metastatic colorectal cancer. Table. Adjusted Associations of Plant-Based Diet with Survival in Metastatic Colorectal Cancer Q1 Q2 Q3 Q4 Q5 P for trend Overall Survival PDI 1.00 0.96 (0.80-1.16) 0.93 (0.77-1.14) 0.82 (0.67-0.99) 0.80 (0.65-0.99) 0.01 hPDI 1.00 0.95 (0.78-1.14) 0.94 (0.77-1.15) 0.86 (0.70-1.04) 0.84 (0.68-1.03) 0.07 uPDI 1.00 1.14 (0.95-1.39) 1.07 (0.87-1.31) 1.18 (0.97-1.45) 1.17 (0.95-1.45) 0.15 Progression-free Survival PDI 1.00 0.84 (0.70-1.01) 0.94 (0.78-1.14) 0.93 (0.77-1.12) 0.80 (0.65-0.98) 0.10 hPDI 1.00 0.86 (0.72-1.03) 0.83 (0.69-1.01) 0.80 (0.67-0.97) 0.80 (0.66-0.97) 0.03 uPDI 1.00 1.12 (0.94-1.34) 1.11 (0.91-1.34) 1.10 (0.91-1.34) 1.15 (0.94-1.41) 0.23 Citation Format: En Cheng, Fang-Shu Ou, Chao Ma, Alan P. Venook, Heinz-Josef Lenz, Eileen M. O’Reilly, Peter T. Campbell, Chaoyuan Kuang, Bette J. Caan, Kimmie Ng, Jeffrey A. Meyerhardt. Plant-based diet and survival among patients with metastatic colorectal cancer: Findings from CALGB/SWOG 80405 (Alliance) [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 2200.

Abstract 1102: Amentoflavone enhances regorafenib-induced apoptosis and -inhibited invasion via inactivating STAT3/NF-ΚB signaling pathway in Hepatocellular carcinoma

Abstract Hepatocellular carcinoma (HCC) is an aggressive tumor and ranks as the third leading cause of cancer-related deaths worldwide. Amentoflavone, a biflavonoid compound, possesses antiviral, angiogenesis-inhibitory, and anticancer properties. Prior studies have illustrated that amentoflavone effectively restrains tumor growth and promotes apoptosis in various cancers, including brain cancer and osteosarcoma. Regorafenib, a small molecule inhibitor of multi-kinases, can inhibit angiogenesis, tumor growth, and anti-tumor metastasis. While regorafenib is a targeted drug approved for the treatment of metastatic colorectal cancer and has also been approved for use in HCC, its effectiveness in HCC is limited. Consequently, our goal is to investigate whether amentoflavone may enhance the sensitivity of regorafenib in treating HCC and explore the underlying mechanisms. In our study, through the combined treatment and combination index analysis, we proved that the combination of regorafenib and amentoflavone may induce cytotoxicity more effectively compared to monotherapy, as assessed by the MTT assay in Huh7 and HepG2 cells. The invasion and migration assays also demonstrated a superior inhibitory effect in the combination group. Additionally, apoptosis markers such as "cleaved caspase-3, -8, -9, Fas and FasL" assayed by flow cytometry, confirm that the combination treatment may induce the extrinsic/intrinsic apoptosis pathway in HCC. In our Western blotting analysis, we observed that the phosphorylation of STAT3 and NF-κB proteins was effectively suppressed by the combination of regorafenib and amentoflavone in Huh7 and HepG2 cells, respectively. Furthermore, our in vivo study confirmed a superior tumor inhibition rate and control rate with the combination of regorafenib and amentoflavone. Importantly, no signs of general toxicity were observed in any of the treatment groups, as evidenced by body weight monitoring and Hematoxylin and Eosin stain (H&amp;E) pathology evaluation. We believe that the combined treatment of these two drugs effectively triggers cell death and suppresses metastatic patterns through the inactivation of the STAT3/NF-κB signaling pathway. These results suggest that amentoflavone has the potential to serve as an adjuvant that sensitizes regorafenib for the treatment of HCC without causing any side effects. Citation Format: Yan ting Tsai, Ying-Tzu Chen, Fei-Ting Hsu, Jai-Jen Tsai, Yu-Chiang Liu. Amentoflavone enhances regorafenib-induced apoptosis and -inhibited invasion via inactivating STAT3/NF-ΚB signaling pathway in Hepatocellular carcinoma [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 1102.

Abstract 3827: Optimizing the treatment schedule of radiotherapy combined with VEGFR-TKIs and PD-(L) 1 inhibitors in metastatic colorectal cancer

Abstract Background: The oral vascular endothelial growth factor receptor (VEGFR) inhibitor fruquintinib, an innovative Chinese drug, has recently been approved by the U.S. Food and Drug Administration (FDA) for third-line treatment of metastatic colorectal cancer (mCRC) in adults. This study aims to investigate the efficacy and safety of radiotherapy (RT) combined with VEGFR-TKIs (such as fruquintinib) and PD-(L) 1 inhibitors in mCRC, and explore optimal sequence of RT with the systemic regimen. Methods: This retrospective study enrolled eligible patients with MSS/pMMR mCRC who had received RT in combination with anti-angiogenic drugs (Fruquintinib or Regorafenib) and immunotherapy (IT) between April 2018 and September 2023. Data on treatment response, progression-free survival (PFS), overall survival (OS), and adverse events were collected. Results: A total of 42 pts were analyzed. For Fru + IT + RT (n = 33) and Reg + IT + RT (n = 9), ORR were 21.2% (7/33) and 11.1% (1/9); DCR were 81.8% (27/33) and 88.9% (8/9), respectively. Median PFS were 6.4 mo and 5.0 mo (P=0.856) while median OS were 17.2 mo and 7.2 mo (P=0.578), respectively. In-depth analysis of Fru + IT + RT treated population, the PFS and OS of 3rd-line treatment were superior to later (≥ 4th) -line treatment (median: 6.7 vs 4.2 mo, P=0.02) and (median: 17.5 vs 8.9 mo, P=0.27), seemingly. Additionally, RT before initiation of Fru + IT demonstrated superior PFS compared to simultaneous/sequential RT with Fru + IT (median 7.1 vs 6.1 vs. 3.2 mo, p&amp;lt;0.001). Simultaneously, pts with interval time ≤1 month, received numerically benefit compared to interval time &amp;gt;1 month between RT and FRU+IT (mPFS: 6.2 vs. 3.8 mo, P=0.16; mOS: not reached vs. 7.65 mo, P=0.08). Further subgroup analysis revealed that men, age ≤56 years, ECOG PS score of 1, primary focal resection, recurrent metastatic disease, liver/pulmonary metastases, and metastatic involvement of organs ≥2, were more favorably treated with Fru for prolonged OS. Intriguingly, the 3rd-line treatment of Fru exhibited a tendency to prolong OS compared to Reg. Cox multivariate regression analysis suggested that the cycle of Fru/Reg combined with PD-1 inhibitor treatment was a common independent influencing factor for PFS and OS. Safety was consistent with previous reports, and the incidence of AE appeared to be lower in Fru + IT + RT than in Reg + IT + RT. Conclusion: In pts receiving RT of localized lesions, the addition of Fru combined with PD-1 inhibitor could prolong the pts' OS more than Reg plus PD-1 inhibitor. And radiotherapy sequential Fru + IT (interval time ≤1 mo) treatment is expected to be the optimal strategy for MSS/pMMR mCRC. Citation Format: Zhenyu Lin, Menglan Zhai, Tao Zhang. Optimizing the treatment schedule of radiotherapy combined with VEGFR-TKIs and PD-(L) 1 inhibitors in metastatic colorectal cancer [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 3827.

Abstract 2000: Role of O-GlcNAc conjugation and TS translational repression in 5-FU/LV resistance in CRC and CF10 response

Abstract Rationale: Fluoropyrimidine drugs (FPs; e.g., 5-FU) are widely used to treat colorectal cancer (CRC), the 3rd leading cause of cancer-related mortality. However, acquired resistance to 5-FU is a principal cause of treatment failure in the metastatic setting. Further, previous studies selected for cells resistant to single agent 5-FU however 5-FU is invariably used clinically in combination with the reduced folate leucovorin (LV). Our studies focus on resistance mechanisms upon treatment with 5-FU+LV in folate-restricted media and test if CF10, a novel polymeric FP being developed in our laboratory displays activity in CRC cells resistant to 5-FU+LV. Experimental: We selected CRC cells (HCT-116, LS174T, HCT15, MC38) resistant to 5-FU+LV by selecting for survival upon culture in folate-restricted media with stepwise increased concentrations of 5-FU+LV over 5 months. Since elevated thymidylate synthase (TS) levels were observed in multiple studies selecting CRC cells for 5-FU resistance, we performed Western blot on cell lysates from parental and (5-FU+LV)-R cells. Since Myc and p53 expression are regulated in part via translational inhibition by TS binding to these mRNAs we also compared Myc and p53 levels in parental and (5-FU+LV)-R cells by Western blot. Further, since TS, Myc, and p53 protein stability are all regulated in part via O-GlcNAc conjugation we tested if OGT levels were changed in (5-FU+LV)-R cells. Resistance factors for CF10 were also determined in (5-FU+LV)-R cells. Results: A surprising result was that basal TS levels were reduced in (5-FU+LV)-R cells relative to the parental cells. We also observed that TS levels were increased in both parental and (5-FU+LV)-R cells by 5-FU+LV treatment however the effect was much greater in (5-FU+LV)-R cells. We observed strongly decreased p53 and Myc levels in the (5-FU+LV)-R cells. CF10 treatment further decreased p53 and Myc levels in parental cells, but increased p53 and further decreased Myc in (5-FU+LV)-R cells. In contrast, 5-FU alone treatment in (5-FU+LV)-R cells increased Myc and decreased p53 levels and further decreased in combination with LV. CF10 retained strong activity in (5-FU+LV)-R cells. Conclusions: Overall, we have validated that cancer cells can be cultured under conditions with human-like folate levels and selected for resistance to 5-FU+LV under folate-restricted conditions. The causes of 5-FU+LV resistance are multi-factorial and include TS overexpression induced by 5-FU+LV treatment that may be mediated by O-GlcNAc conjugation. We demonstrated that CF10 is more potent than 5-FU, and importantly its potency advantage is enhanced in cells selected for 5-FU+LV resistance. Our studies support CF10 translation for treatment of metastatic CRC in patients with progressive disease following treatment with combination therapy that includes 5-FU+LV. Citation Format: Charles C. Okechukwu, Xue Ma, William H. Gmeiner. Role of O-GlcNAc conjugation and TS translational repression in 5-FU/LV resistance in CRC and CF10 response [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 2000.

The Safety and Effectiveness of Bevacizumab in Metastatic Colorectal Cancer With Unresectable Metastases: A Real-Life Study From the South of Morocco.

Background Colorectal cancer constitutes a significant public health challenge, despite remarkable strides made in the last two decades, particularly in the medical management of metastatic stages. Notable progress has been achieved through targeted therapies such as anti-epidermal growth factor receptors or anti-angiogenic antibodies, as well as advancements in surgical approaches for hepatic metastases. This study seeks to assess the efficacy and safety of bevacizumab plus chemotherapy in individuals with metastatic colorectal cancer. Methodology This is an observational, cross-sectional, retrospective study of all patients who were followed up for metastatic colorectal cancer with unresectable metastases and were treated with bevacizumab in combination with standard chemotherapy from January 2010 until December 2019 in the medical oncology department of the Centre Hospitalier Universitaire (CHU) Souss-Massa of Agadir. Results Of the total 162 cases, 117 (72%) had metastatic disease, and 45 (28%) progressed to metastatic disease after initial treatment. The median age of the patients was 55 years (range = 23-79 years) with a sex ratio of 1.1 (M/F). The tumor was located in the left colon in 135 (83.3%)patients. The results represented adenocarcinoma in 137 (84.6)cases and mucinous subtype in 23 (14.19) cases. The three most common sites of metastasis were the liver (99, 61.1), peritoneum (67, 41.3), and lung (33, 20.3). In the first line, allpatients received bi-chemotherapy plus bevacizumab, i.e., fluorouracil, oxaliplatin, and leucovorin in 34 (20.9%) patients; capecitabine plus oxaliplatin in 88 (54.3%) patients; leucovorin, fluorouracil, and irinotecan in 17 (10.4%) patients; andcapecitabine plusirinotecan in 23 (14.1%) patients. Response after first-line treatment was progression in 74 (45.7) cases, stability in 42 (25.9) cases, partial response in 35(21.6) cases, and complete response in 11 (6.8) cases. Nine (6%) patients were able to benefit from surgical resection of metastatic lesions. Overall, 77 (47%)patients received second-line chemotherapy, i.e., 5-FU with irinotecan in 40 (51.8%)cases or with oxaliplatin in 30(38.8%) cases. Two patients developed undesirable side effects under bevacizumab (hypertension). The median progression-free survival and median overall survival of the study cohort were 9 months and 14 months, respectively. Nevertheless, patients who underwent primary tumor resection (p = 0.048), those with right‑sided tumors (p = 0.022), those who received a higher number of treatment cycles (p = 0.020), and those who received maintenance treatment (p = 0.001) had a longer median overall survival. Conclusions Chemotherapy combination with bevacizumab is considered as the cornerstone of metastatic colorectal cancer treatment in our region. With the new healthcare and social security systems, easier access to expensive treatments and molecular pathology tests is currently available. It is important to highlight that real-world data can offer valuable insights into the daily clinical practice of medical oncology.

Trifluridine-Tipiracil (Lonsurf)

&#x0D; CADTH recommends that Lonsurf be reimbursed by public drug plans in combination with bevacizumab for the treatment of metastatic colorectal cancer (mCRC) in adults who have been previously treated with or are not candidates for available therapies, including fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapies; anti–vascular endothelial growth factor (anti-VEGF) biological agents; and, if positive for RAS wild-type disease, anti-epidermal growth factor receptor (anti-EGFR) agents, if certain conditions are met.&#x0D; Lonsurf should be covered for use in adults with histologically confirmed adenocarcinoma that cannot be surgically removed or has spread to other parts of the body and if the patient’s disease progressed or the patient was intolerant to a maximum of 2 prior chemotherapy regimens. Eligible patients should have good overall health (performance status) and no unstable neurologic issues related to the central nervous system (CNS) or need increasing doses of steroids to control CNS disease.&#x0D; Lonsurf should be reimbursed in combination with bevacizumab. It should be prescribed by doctors who specialize in diagnosing and treating patients with mCRC. Lonsurf plus bevacizumab should be stopped if the disease worsens or the patient has severe side effects. The cost of Lonsurf should be reduced.&#x0D;

Late-Line Antitumor Treatment for Metastatic Colorectal Cancer

Введение. Колоректальный рак (КРР) занимает одно из ведущих мест в структуре онкологической заболеваемости. Лечение метастатического колоректального рака (мКРР) в 1-й и 2-й линиях достоверно улучшает общую выживаемость (ОВ). Проблема выбора терапии в поздних линиях заключается прежде всего в том, что предлеченным больным необходимо подобрать терапию, которая при управляемой токсичности сможет быть эффективной и улучшить показатели выживаемости. Цель — анализ данных литературы о современных методах лекарственного лечения мКРР в поздних линиях с учетом персонификации лечения в зависимости от молекулярно-генетических характеристик опухоли и факторов, влияющих на отдаленные результаты лечения. Результаты. В обзоре систематизированы данные литературы о вариантах терапии мКРР в 3-й и последующих линиях, сделан акцент на персонификацию лечения в зависимости от различных факторов. Выводы. Большинству больных мКРР в 3-й линии показана терапия трифлуридин/тирирацилом в сочетании с бевацизумабом, вне зависимости от статуса мутации KRAS. Монотерапия регорафенибом или трифлуридином типирацилом обладает меньшей эффективностью, в особенности при наличии неблагоприятных факторов, таких как время от диагноза метастатической болезни менее 18 месяцев, большая опухолевая масса и наличие метастазов в печени. При наличии мутации BRAF или гиперэкспрессии HER2 целесообразен более прецизионный подход с использованием таргетной терапии — анти BRAF и MEK ингибиторов в сочетании с EGFR терапией, а также комбинация трастузумаба с пертузумабом соответсвенно. Иммунотерапия также может быть использована у больных, ранее ее не получавших с опухолями, ассоциированными с микросаттелитной нестабильностью.