Chemotherapy For mCRC Research Articles

Correlation of circulating tumor DNA and recurrence in patients with metastatic colorectal cancer with no evidence of disease: An open-label, prospective, phase II study.

3549 Background: Patients with metastatic colorectal cancer (mCRC) can achieve no evidence of disease (NED) after curative treatment. However, how to precisely guide the treatment after NED remained to be explored. Minimal residual disease (MRD) detection using circulating tumor DNA (ctDNA) analysis has shown to help identify patients’ risk of relapse in early-stage CRC. Thus we aimed to explore the feasibility of ctDNA by a tumor-informed personalized approach to predict recurrence and guide chemotherapy in mCRC with NED. Methods: We enrolled mCRC patients who achieved NED after local curative treatment from June 2022 to December 2023. Surgical or puncture tissues were collected. Blood samples were collected prior to curative treatment, at 1 month after curative treatment, and subsequently every 2–3 months until disease progression or completion of a 2-year follow-up period. Tumor-derived variants were identified by whole-exon sequencing of the tissue samples. Up to 50 highly ranked variants were selected for the personalized panel design, which was used to assess the MRD status of blood samples. Patients with negative MRD post curative treatment were followed, while those with positive MRD were subjected to investigator-determined adjuvant chemotherapy (ACT). Results: A total of 106 mCRC patients with NED after curative treatment were enrolled. The ctDNA was detected in 62 patients (92.5%, 62/67) pre curative treatment and in 55 patients (51.9%, 55/106) post curative treatment. At a median follow-up period of 252 days, 42 patients experienced recurrence and 33 patients (78.6%) had positive ctDNA post curative treatment. Patients with positive ctDNA post curative treatment demonstrated an inferior recurrence-free survival (RFS) than those with negative ctDNA (HR: 4.58, 95% CI: 2.18–9.64; P<0.001), which was not observed by CEA (HR: 1.87, 95% CI: 0.84–4.15; P=0.12). In patients with negative ctDNA after curative treatment, there was no difference in RFS between those treated with ACT or not (HR: 2.51, 95% CI: 0.48–13.04; P=0.25). During the dynamic longitudinal monitoring of ctDNA, the median RFS was 5.6 months, 15.5 months, 10.2 months and unreached in patients with persistently positive ctDNA, converted negative ctDNA, converted positive ctDNA, and persistently negative ctDNA, respectively (log-rank P for trend <0.001). All recurrent patients had at least one positive ctDNA detection before imaging confirmed recurrence, and the median lead time interval of ctDNA positivity to radiographic recurrence was 112 days (range, 3–441 days). Conclusions: Our results demonstrated that patients with ctDNA negative post curative treatment had superior RFS compared with those with positive ctDNA. Post curative treatment and dynamic ctDNA had the potential to guide ACT in mCRC patients with NED. The follow-up is still on-going. Clinical trial information: NCT05635630 .

Recent Advances in Therapeutic Strategies to Improve Colorectal Cancer Treatment.

Colorectal cancer (CRC) is the second-leading cause of cancer-related mortality worldwide. CRC mortality results almost exclusively from metastatic disease (mCRC) for which systemic chemotherapy is often a preferred therapeutic option. Biomarker-based stratification of mCRC enables the use of precision therapy based on individual tumor mutational profiles. Activating mutations in the RAS/RAF/MAPK pathway downstream of EGFR signaling have, until recently, limited the use of EGFR-targeted therapies for mCRC; however, the development of anti-RAS and anti-RAF therapies together with improved strategies to limit compensatory signaling pathways is resulting in improved survival rates in several highly lethal mCRC sub-types (e.g., BRAF-mutant). The use of fluoropyrimidine (FP)-based chemotherapy regimens to treat mCRC continues to evolve contributing to improved long-term survival. Future advances in chemotherapy for mCRC will need to position development relative to the advances made in precision oncology.

Raltitrexed Chemotherapy Regimen Plus Bevacizumab as Second-Line Treatment for Metastatic Colorectal Cancer: A Prospective Multicenter Phase II Trial.

Clinical studies have shown that bevacizumab plus chemotherapy significantly improves efficacy in metastatic colorectal cancer (mCRC). This prospective study aims to investigate the efficacy and safety of changing second-line treatment to raltitrexed-based chemotherapy regimens plus bevacizumab in mCRC patients who have failed the first-line fluorouracil-based chemotherapy regimen with or without bevacizumab/cetuximab. This is a prospective, open-label, multicenter, phase II clinical study. A total of 100 patients with mCRC after failure of the first-line fluorouracil-based chemotherapy regimen with or without bevacizumab/cetuximab were enrolled from November 2016 to October 2021, and received second-line raltitrexed-based chemotherapy regimen plus bevacizumab. Patients were treated for 6 cycles, and efficacy evaluation over stable disease were followed by maintenance treatment of bevacizumab and raltitrexed until disease progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), safety, and toxicity. Ninety-four patients were treated with SALIRI (raltitrexed + irinotecan) plus bevacizumab, and six patients with SALOX (raltitrexed + oxaliplatin) plus bevacizumab. Median PFS was 8.4 (95% CI: 6.2-11.0) months, including 8.2 (95% CI 6.2, 11.0) months in the SALIRI group and 11.6 (95% CI 3.1, NA) months in the SALOX group. Median OS was 17.6 (95% CI 15.2, 22.0) months in the SALIRI group and 17.1 (95% CI 4.1, NA) months in the SALOX group. ORR and DCR were 25.5% and 87.2% in the SALIRI group, and 33.3% and 83.3% in the SALOX group, respectively. A low incidence of grade 3-4 adverse events was observed. Raltitrexed-based chemotherapy regimens plus bevacizumab improved survival duration in mCRC patients with failed first-line therapy. Therefore, treatment with raltitrexed-based chemotherapy regimens plus bevacizumab could be a superior therapeutic option for second-line chemotherapy in mCRC (ClinicalTrials.gov registration number: NCT03126071).

Cetuximab as first-line treatment for metastatic colorectal cancer (mCRC): a model-based economic evaluation in Indonesia setting

ObjectivesTo assess the cost-effectiveness of cetuximab in combination with chemotherapy fluorouracil, oxaliplatin, and leucovorin (FOLFOX) or fluorouracil, irinotecan and leucovorin (FOLFIRI) compared to standard chemotherapy alone as a first-line treatment for metastatic colorectal cancer (mCRC) with positive KRAS wild type patients in Indonesia.MethodsA cost-utility analysis applying Markov model was constructed, with a societal perspective. Clinical evidence was derived from published clinical trials. Direct medical costs were gathered from hospital billings. Meanwhile, direct non-medical costs, indirect costs, and utility data were collected by directly interviewing patients. We applied 3% discount rate for both costs and outcomes. Probabilistic sensitivity analysis was performed to explore the model’s uncertainty. Additionally, using payer perspective, budget impact analysis was estimated to project the financial impact of treatment coverage.ResultsThere was no significant difference in life years gained (LYG) between cetuximab plus FOLFOX/FOLFIRI and chemotherapy alone. The incremental QALY was only one month, and the incremental cost-effectiveness ratio (ICER) was approximately IDR 3 billion/QALY for cetuximab plus chemotherapy. Using 1–3 GDP per capita (IDR 215 million or USD 14,350) as the current threshold, the cetuximab plus chemotherapy was not cost-effective. The budget impact analysis resulted that if cetuximab plus chemotherapy remain included in the benefits package under the Indonesian national health insurance (NHI) system, the payer would need more than IDR 1 trillion for five years.ConclusionsThe combination of cetuximab and chemotherapy for mCRC is unlikely cost-effective and has a substantial financial impact on the system.

Patient-reported outcomes (PROs) and biomarker assessments in daNIS-3, a phase II platform study of NIS793 (anti–TGF-β monoclonal antibody) and other investigational drug combinations with standard of care (SOC) vs SOC alone in patients (pts) with second-line metastatic colorectal cancer (mCRC).

TPS272 Background: Despite the utilization of systemic targeted agents with chemotherapy for mCRC, long-term survival remains poor. Disease progression in mCRC is common, and SOC options are associated with reduced quality of life (QoL) that has been negatively associated with survival. Here, we present daNIS-3, a Phase II, randomized, open-label platform study (NCT04952753) of NIS793 and other investigational drug combinations in pts with second-line mCRC, with an emphasis on the exploratory PROs and biomarker assessments. Methods: Eligible pts are adults with microsatellite-stable mCRC who have progressed on or within 6 months of one prior line of systemic therapy for mCRC and are not amenable to potentially curative surgery. Pts are treated with NIS793 (Day [D]1 ± D15; 2100 mg) + SOC (D1 + D15; bevacizumab [5 mg/kg] + FOLFIRI/mFOLFOX6) +/- tislelizumab (D1; 300 mg), or SOC alone. All drugs are administered intravenously on 28-day cycles. Each investigational arm begins with a safety run-in involving ≥6 eligible pts; safety run-in of the tislelizumab arm follows completion of the NIS793 + SOC safety run-in. Following confirmation of the recommended dose, pts are randomized (2:1) in the expansion part to receive investigational drug(s) + SOC (n≈75) or SOC alone (n≈38). Exploratory objectives include PROs (expansion part only) and biomarker assessments. PRO measures (EORTC-QLQ-C30, QLQ-CR29, PRO-CTCAE, and FACT-GP5) will be collected electronically throughout the study and used to explore pt-reported disease symptoms, health-related QoL, functioning, and treatment-related side effects. Potential biomarkers of response and mechanisms of resistance will be assessed in tumor and blood samples. Baseline archival/tumor biopsies will be collected to assess the correlations between clinical response and molecular subtype, tumor mutational burden, TGF-β gene signatures, and immune-related biomarkers. Optional biopsies during Cycle 3 and at the end of treatment will be used to assess pharmacodynamic effects of NIS793 on the tumor microenvironment and resistance mechanisms, respectively. Circulating tumor DNA and cytokine and TGF-β levels will be continuously monitored through serial blood samples to evaluate treatment benefit, correlate alterations with response, and assess the effect(s) of NIS793. An additional blood sample for nucleic acid analysis will evaluate the effect(s) of TGF-β blockade. The daNIS-3 study started on November 15, 2021, and plans to recruit approximately 266 pts from 77 sites across 19 countries. Clinical trial information: NCT04952753 .

Evaluating sex as a predictive marker for response to bevacizumab in metastatic colorectal carcinoma: Pooled analysis of 3,369 patients in the ARCAD database

BackgroundPrevious studies suggest a possible sex-specific response to bevacizumab in metastatic colorectal carcinoma (mCRC), showing a benefit in males, while the effect in females is less significant. MethodsData from 3369 patients with mCRC enrolled on four first-line randomised trials testing chemotherapy with or without bevacizumab (2000–2007) were pooled. Association between sex and progression-free survival and overall survival (OS) was evaluated by stratified Cox regression model, adjusted for potential confounders. Predictive value was evaluated by interaction effect between sex and treatment. In a pre-planned secondary analysis, analyses were stratified using an age cut point of 60 years to evaluate the possible role of menopausal-related effects. ResultsBevacizumab was associated with an improved median OS in males and females, with a 2.3- and 0.6-months benefit, respectively. Stratified by age, bevacizumab resulted in improved OS in males at both age categories. In females at or above the age of 60 (n = 731), bevacizumab resulted in improved OS. However, in females below the age of 60 (n = 634), OS benefit did not reach statistical significance (adjusted hazard ratio = 0.94, 95% confidence interval 0.74–1.20). ConclusionsOur results confirmed the OS benefit from the addition of bevacizumab to first-line chemotherapy in mCRC in both sexes. Among females, the benefit was less than 1 month. For females under the age of 60, there was no survival benefit. These findings could be used to relieve financial toxicity or be redistributed within healthcare systems for other health-related purposes.

388P Early tumor shrinkage (ETS) and depth of response (DpR) analyses in metastatic colorectal cancer (mCRC) treated with first-line mFOLFOX6 plus panitumumab (PAN) or bevacizumab (BEV): Results from the phase III PARADIGM trial

The PARADIGM primary analysis demonstrated that PAN significantly improved OS vs BEV combined with mFOLFOX6 in RAS WT and left-sided mCRC. ETS and DpR are on-treatment prognostic factors related to favorable OS and PFS in mCRC chemotherapy. We report ETS and DpR and the correlation with OS and PFS in patients (pts) with RAS WT mCRC from PARADIGM. Relative change in maximum tumor diameter was analyzed between baseline and 8 wks of treatment. ETS was defined as a ≥30% decrease in tumor size by investigator assessment. OS and PFS were compared in pts with/without ETS stratified by treatment arm and primary tumor location (left-sided, overall, right-sided). DpR was the maximum post-baseline percent decrease in the sum diameter of target lesions. No hypothesis was formally tested; P-values were based on a 2-sided stratified log-rank test and were descriptive. Cutoff date: Jan 14, 2022. A greater proportion of pts had ETS with PAN (left: 64.4%; overall: 58.5%) vs BEV (left: 38.0%; overall: 38.8%). Left-sided PAN pts with ETS showed longer OS (median: 42.6 vs 27.1 mo; HR: 0.56 [95% CI: 0.42–0.75]; P<0.001) and PFS (15.7 vs 9.6 mo; 0.62 [0.48–0.81]; P<0.001) than pts without ETS. Similarly, left-sided BEV pts with ETS had longer OS (median: 41.3 vs 32.4 mo; HR: 0.69 [95% CI: 0.52–0.91]; P=0.01) and PFS (14.5 vs 11.5 mo; 0.81 [0.62–1.06]; P=0.094). Right-sided PAN pts with ETS had longer OS, but not BEV (Table). Left-sided and overall PAN groups had greater median DpR than BEV (left, -59.4 vs -43.6; overall, -57.3 vs -43.6), with no difference between right-sided arms. Although ETS was associated with favorable survival outcomes in both arms, PAN achieved more ETS and greater DpR than BEV in left-sided pts. In right-sided pts, ETS was only predictive with PAN, warranting further biomarker analysis to predict PAN benefit.Table: 388POSPAN + mFOLFOX6BEV + mFOLFOX6ETS ≥30%ETS <30%ETS ≥30%ETS <30%Leftn=201n=111n=111n=181Median (95% CI), mo42.6 (37.5–49.7)27.1 (21.8–36.3)41.3 (31.6–46.5)32.4 (27.9–36.8)HR 95% CI P value0.56 0.42–0.75 <0.0010.69 0.52–0.91 0.010Overalln=234n=166n=156n=246Median (95% CI), mo42.1 (37.5–48.4)23.1 (17.7–31.0)33.8 (29.3–41.3)30.5 (26.9–34.0)HR 95% CI P value0.50 0.39–0.64 <0.0010.78 0.62–0.99 0.036Rightn=30n=54n=42n=61Median (95% CI), mo34.1 (21.0–42.2)15.2 (11.3–20.2)22.3 (17.4–30.9)25.5 (16.9–31.6)HR 95% CI P value0.47 0.28–0.79 0.0050.94 0.60–1.45 0.746 Open table in a new tab

Germline Polymorphisms in Genes Involved in the Antioxidant System Predict the Efficacy of Cetuximab in Metastatic Colorectal Cancer Patients Enrolled in FIRE-3 Trial

BackgroundReactive oxygen species activate EGFR/RAS/MAPK signaling either through the inactivation of phosphatases or by direct oxidation of kinases. We hypothesized that functional single-nucleotide polymorphisms (SNPs) in antioxidant genes link to the efficacy of cetuximab in patients with metastatic colorectal cancer (mCRC). Patients and MethodsWe analyzed genomic and clinical data from FIRE-3, a phase III trial comparing cetuximab and bevacizumab along with FOLFIRI in untreated mCRC patients. Genomic DNA extracted from blood samples was genotyped. Thirteen functional SNPs in antioxidant genes were tested for associations with clinical outcomes. ResultsIn total, 236 patients were included (FOLFIRI/cetuximab arm, n = 129; FOLFIRI/bevacizumab arm, n = 107). In univariate analysis, two SNPs (TXN2 rs4821494 and GPX4 rs4807542) were significantly associated with overall survival (OS) in the FOLFIRI/cetuximab arm. Multivariate analysis confirmed the significant association of TXN2 rs4821494 (T/T vs. any G allele, hazard ratio = 2.47, 95% confidence interval = 1.06–5.72, P = .03). In the FOLFIRI/bevacizumab arm, no SNPs were significantly associated with clinical outcomes. Treatment-by-SNP interaction test confirmed the predictive value of TXN2 rs4821494 (OS: P = .03). ConclusionTXN2 rs4821494 involved in the antioxidant system may predict the efficacy of cetuximab-based first-line chemotherapy in mCRC, warranting further validation studies.

A Long-Term and Large-Scale Real-World Study in Taiwan: Efficacy of Target Therapy in Stage IV Colorectal Cancer.

This study expands the understanding of the role of target therapy in improving survival of patients with mCRC based on real-world study results. These data represent potential survival outcomes of Taiwanese patients with mCRC in clinical practice. CRC is the most commonly diagnosed cancer and the third leading cause of cancer-related death in Taiwan. The aim of this study was to evaluate the efficacy of target therapy in combination with chemotherapy for mCRC in Taiwan. This was a real-world, retrospective, observational study in patients diagnosed with mCRC (N=1583). A total of 792 patients received chemotherapy plus target therapy (anti-EGFR therapy, n=180; anti-VEGF therapy, n=612) and 791 patients who received chemotherapy alone. Overall survival (OS) and progression-free survival (PFS) were examined. For RAS wild-type patients, the median OS (mOS) was 34.3 months in the EGFR L (left-sided colon) group, 27.3 months in the VEGF L group, 18.4 months in VEGF R (right-sided colon) group, and 13.8 months in EGFR R group (P<0.001). Median PFS (mPFS) was 9.8 months in the EGFR L group, 8.9 months in the VEGF L group, 6.8 months in VEGF R group, and 5.8 months in EGFR R group. In patients with a RAS mutation, mOS was 25.4 months in the VEGF L group and 19.4 months in the VEGF R group (P=0.167). Judicious treatment allocation in Taiwanese patients with mCRC can result in an mOS of 34.3 months using cetuximab plus chemotherapy for left-sided tumors. An mOS of 48.5 months can be achieved using cetuximab plus chemotherapy in the neoadjuvant setting in mCRC patients with left-sided tumors. This study expands our understanding of the role of target therapy in improving survival of mCRC patients based on real-world study results.

Efficacy and safety of aflibercept plus chemotherapy in metastatic colorectal cancer: A systematic review and PRISMA-Compliant single-arm Meta-Analysis of noncomparative clinical studies and randomized controlled trials.

Aflibercept, a recombinant protein designed to suppress the vascular endothelial growth factor (VEGF) signalling pathway, has been used in patients with metastatic colorectal cancer (mCRC). We conducted the first meta-analysis to systematically review the efficacy and safety ofaflibercept in mCRC. PubMed Central/Medline, Embase and cochrane library were systematically searched for randomized controlled trials and single-arm clinical trials on aflibercept plus chemotherapy for the treatment of mCRC through 9 September 2021. Ten studies comprising 2049 patients met the inclusion criteria. The pooled estimate rates were 16.0% for 12mPFS, 64.4% for 12mOS, 32.5% for ORR, 83.5% for DCR, while the rates of III/IV AEs rate were 80.2% respectively. The pooled estimate rates were 16.8% for III/IV diarrhoea, 22.3% for III/IV hypertension, 29.5% for III/IV neutropenia, 7.3% for III/IV proteinuria and 8.6% for III/IV oral mucositis. Analysis of data from randomized controlled trials(RCT) and single-arm clinical trials confirmed the good efficacy of aflibercept plus chemotherapy in mCRC, while the safety of the treatment is concerning.

Comparison of safety and efficacy of fluorouracil + oxaliplatin + irinotecan (FOLFOXIRI) and modified FOLFOXIRI with bevacizumab for metastatic colorectal cancer: data from clinical practice.

The efficacy of fluorouracil + oxaliplatin + irinotecan with bevacizumab (FOLFOXIRI + BV) has been verified for metastatic colorectal cancer (mCRC). In clinical practice, the original (O-FOLFOXIRI + BV) and modified dose settings (M-FOLFOXIRI + BV) are adopted for Asian patients. We aimed to compare the real-world efficacy and safety of these two regimens. This retrospective cohort study reviewed clinical data of all consecutive mCRC patients treated with FOLFOXIRI + BV at a cancer centre in Japan. One hundred patients were divided into two groups: one that received O-FOLFOXIRI + BV (group O, n = 30) and another that received M-FOLFOXIRI + BV (group M, n = 70). Progression-free survival (PFS) was set as the primary endpoint, with overall survival (OS), overall response rate (ORR), and safety as secondary endpoints. PFS was superior in group M (median PFS; 8.7 vs. 11.5months, P = 0.098). The use of O-FOLFOXIRI + BV emerged as an independent risk factor of poor PFS (hazard ratio = 2.155, P = 0.012). Both ORR (43.3 vs. 65.7%, P = 0.047) and OS (median OS; 17.9 vs. 27.0months, P = 0.127) were more favourable in group M. Grade ≥ 3 adverse events were more frequently observed in group O (90 vs. 74.3%, P = 0.108), whereas dose intensity was higher in group M because a shorter duration was required for cytotoxic drug administration (2.9 vs. 2.6weeks/course, P = 0.051) in the induction term. We found that M-FOLFOXIRI + BV had more favourable efficacy and safety than O-FOLFOXIRI + BV, which may be a better fit for Asian patients and can be potentially used as an alternative for upfront chemotherapy for mCRC.

Comparative effectiveness of weekly versus every-2-weeks cetuximab in metastatic colorectal cancer in a US-insured population.

Aim: To test the noninferiority of cetuximab administered every 2weeks (Q2W) versus once weekly (Q1W) in treating metastatic colorectal cancer (mCRC) with regard to overall survival (OS). Patients: Patients receiving cetuximab plus chemotherapy for mCRC in a line-agnostic setting. Methods: This cohort study in IBM MarketScan followed patients from initiationof cetuximab for mCRC until the end of the data availability period, proxy-based death or loss of insurance coverage for >30days. Results: The hazard ratio for OS was 0.94 (0.85-1.03), and the inferiority hypothesis was rejected at p < 0.001. No significant differences were noted in rates of safety events between Q2W and Q1W. Conclusion: Our real-world study confirmed the noninferiority of cetuximab administered Q2W versus Q1W for OS.

Determinants of choice in offering drug holidays during first-line therapy for metastatic colorectal cancer.

Background: 'Drug holidays' (DH) for metastatic colorectal cancer (mCRC) were introduced to preserve quality of life. We studied factors associated to a DH offer in first line. Materials & methods: We retrospectively analyzed 754 consecutive patientstreated with chemotherapy for mCRC in two Italian institutions between 2005 and 2017. Associations between baseline clinical-pathological factors and DH (56 or more days of treatment interruption) were investigated. Results:In754 patients, previous metastasectomy, previous thermoablation and previous surgery of primary tumor were independently associated with DH. Excluding procedures or clinical trials: primary rectal cancer and resection of primary tumor were significantly associated to DH. Conclusions: DH was offered to patients with lower burden of disease, but further investigations are needed to safely guide a holiday strategy.

Analysis of early tumor shrinkage (ETS) and depth of response (DpR) in metastatic colorectal cancer (mCRC) patients (pts) treated with second-line FOLFIRI plus panitumumab (Pani) or bevacizumab (Bev): Results from a randomized phase II WJOG6210G trial.

201 Background: The WJOG 6210G trial demonstrated a similar efficacy between Pani and Bev arms at 2nd-line setting in pts with KRAS exon2 wild-type mCRC (Shitara K, et al, Cancer Sci 2016). The exploratory analyses of clinical trials evaluating 1st-line chemotherapy for mCRC have shown significant associations of ETS and DpR with prognosis; however, there is few data in 2nd-line treatment. We investigated whether ETS and DpR are associated with clinical outcomes in mCRC pts treated with 2nd-line treatment using the data of WJOG 6210G trial. Methods: ETS was defined as tumor reduction of 20% at week 8 compared to baseline in the sum of longest diameters of target lesions according to the RECIST criteria. DpR was defined as the percentage of maximum tumor shrinkage of target lesions. Fisher’s exact test and t-test were used to compare ETS and DpR between Pani and Bev arms. A Cox regression model was used to evaluate associations between ETS and progression-free survival (PFS), and overall survival (OS). The association of DpR with PFS and OS was analyzed using Spearman’s rank correlation coefficient. Results: Eighty-seven pts were evaluable for ETS and DpR (Pani, n = 41; Bev, n = 46) among 121 pts enrolled in the WJOG6210G. Pts in the Pani arm had a higher ETS rate (39.0 % vs. 8.7 %, p &lt; 0.001) and greater DpR [median: 23.7 % (range: -49.0 to 100) vs. 0 % (range: -40.7 to 61.5), p &lt; 0.001] than pts in the Bev arm. Pts with ETS achieved longer PFS [median: 10.5 vs. 5.4 m, HR: 0.40 (95% CI: 0.20-0.80), p = 0.009] and OS [median: 22.3 vs. 14.5 m, HR: 0.49 (95% CI: 0.23-0.98), p = 0.044] than pts without ETS in the Pani arm. Similarly, the Bev arm pts with ETS had longer PFS [median: 17.1 vs. 5.6 m, HR: 0.078 (95% CI: 0.004-0.38), p = 0.0002] and OS [median: 30.9 vs. 13.2 m, HR: 0.35 (95% CI: 0.083-0.99), p = 0.048]. There were moderately linear correlations of DpR with PFS and OS in both Pani (PFS: r = 0.75, p &lt; 0.001; OS: r = 0.60, p &lt; 0.001) and Bev arms (PFS: r = 0.68, p &lt; 0.001; OS: r = 0.44, p = 0.002). Conclusions: ETS and DpR were significantly associated with PFS and OS in mCRC pts treated with 2nd-line FOLFIRI in combination with Pani or Bev. Clinical trial information: UMIN000031621.

Survival impact on regorafenib (REG) and trifluridine/tipiracil hydrochloride (FTD/TPI) for patients with metastatic colorectal cancer: Single institutional experience.

43 Background: Regorafenib (REG) and trifluridine/tipiracil hydrochloride (FTD/TPI) demonstrated overall survival (OS) benefit in patients (pts) with metastatic colorectal cancer (mCRC) in the CORRECT and RECOURSE phase III trials. In Japan, REG and FTD/TPI have been approved in 2013 and 2014, respectively. However, little is known about survival impact on these agents in the real-world setting. Therefore, the aim of this retrospective study was to evaluate the effects of REG and FTD/TPI in pts with mCRC. Methods: We collected medical records from consecutive 1142 pts who had been initiated with first-line chemotherapy for mCRC from 2008 to 2016 at National Cancer Center Hospital East. The survival outcomes were compared between pts from 2008 to 2011 (cohort A) and those from 2012 to 2016 (cohort B). This study excluded pts who have not been refractory or intolerant to standard chemotherapy including fluoropyrimidine, oxaliplatin, irinotecan, and anti-EGFR antibody if KRAS exon 2/ RAS wild-type tumors. Results: A total of 590 pts were analyzed (cohort A; N = 236 and cohort B; N = 354). More patients received at least one of REG or FTD/TPI in cohort B (16.1% vs. 59.9%, p &lt; 0.001). The time from initiation to end of standard chemotherapy was comparable between the two cohort (20.0 vs. 17.5 months, p = 0.266). With a median follow-up period of 34.9 months, salvage-line OS (sOS) after standard chemotherapy was significantly longer in cohort B (4.8 vs. 6.6 months, p = 0.001), while there was only a favorable trend in cohort B in terms of OS from start of first-line treatment (27.3 vs. 28.5 months, p = 0.516). In cohort B, pts who sequentially received both of REG and FTD/TPI showed longest sOS (median, both of REG and FTD/TPI; 11.3 months, either REG or FTD/TPI; 7.0 months, neither REG nor FTD/TPI; 3.1 months). Conclusions: Our study showed that REG and FTD/TPI led to prolongation of sOS in the real-world setting, indicating the importance of strategies which make all active agents available to pts with mCRC.

114P - Efficacy and safety of the combination of bevacizumab with raltitrexed-based chemotherapy as second-line therapy in patients with metastatic colorectal cancer (mCRC): An interim analysis of a multicenter phase II trial

BackgroundThere are limited treatment options after failure of first-line fluoropyrimidine-based chemotherapy in mCRC. We studied the efficacy and safety of bevacizumab plus raltitrexed-based (Saiweijian®) chemotherapy as second-line therapy in Chinese patients with mCRC. MethodsTrial design: Open-label, single-arm, multicenter, phase II trial (NCT03126071).100 patients were required. Enrolled patients were treated with BEV+SALIRI(bevacizumab 7.5mg/kg d1, raltitrexed 3mg/m2 d1, irinotecan 250mg/m2 d1,q3w) or BEV+SALOX(bevacizumab 7.5mg/kg d1,raltitrexed 3mg/m2 d1, oxaliplatin 130mg/m2 d1,q3w)(depending on first-line regimen). Patients treated for 6 cycles with efficacy evaluation SD or above were followed by maintenance therapy(bevacizumab7.5 mg/kg d1, raltitrexed 3 mg/m2 d1,q3w) until disease progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were objective response rate (ORR), disease control rate (DCR), overall survival (OS), quality of life (QOL) and safety. ResultsBetween 12/2016 and 5/2019, 63 patients were enrolled. [The median age was 58 years(range:27-74 years), ECOG PS 1 scored 95.2%. ] A total of 376 cycles were completed and 21 patients recieved maintenance therapy. 56 patients were evaluable and ORR was 26.8%, DCR was 78.6%. 52 patients reached the primary endpoint,the median PFS (mPFS) was 5.7 months (95% CI: 1.5-16.7), the median OS (mOS) was not observed. Adverse events (AE) were mostly grade 1/2, and ≧grade 3 treatment-related AEs were mainly neutropenia (7.9%), leukopenia (6.3%), thrombocytopenia (6.3%), alanine aminotransferase increased (4.8%), aspartate aminotransferase increased (6.3%), nausea (3.2%), diarrhea (4.8%) and fatigue (3.2%). ConclusionsOur interim results suggest that the combination of bevacizumab with raltitrexed-based chemotherapy could be an efficient and safe second-line treatment option for patients with mCRC. This trial will progress as planned. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

An observational study of vascular endothelial growth factor inhibitors as second-line treatment for metastatic colorectal cancer treated with bevacizumab plus FOLFIRI beyond progression: the association with RAS mutation and tumor sidedness

Background: The BRiTE and ARIES studies suggested that the continued use of bevacizumab beyond progression (BBP) was beneficial. This study investigated the efficacy and safety of the vascular endothelial growth factor inhibitors (VEGFis) bevacizumab and aflibercept as second-line treatments for patients with metastatic colorectal cancer (mCRC) that progressed following the application of bevacizumab-containing chemotherapy as a first-line treatment. Methods: This observational cohort study (OCS) analyzed the medical records of 73 patients with mCRC divided into a no-VEGFi group (n=48) and a VEGFi group (n=25). Progression-free survival (PFS) was the primary endpoint, and the overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety were secondary endpoints. Results: The results revealed that the PFS, ORR, and DCR of the VEGFi group were significantly superior to those of the no-VEGFi group, even in those with wild-type and mutant-type RAS or left-sided mCRC (all P 0.05). Patients with primary left-sided lesions and continued use of VEGFi exhibited the most marked effect on PFS (P=0.001). No significant differences were observed in the incidence of grade 3 or 4 adverse events (AEs) between the two groups (P=0.133). Conclusions: These results support the use of VEGFi as a second-line treatment after bevacizumab beyond the initial progression in this OCS. Bevacizumab or aflibercept combined with second-line chemotherapy in mCRC has an acceptable safety profile and is relatively active. Regardless of the RAS gene type, VEGFi plus FOLOFX6 exhibited superior PFS to that of FLFOX6 as a second-line treatment, and a greater improvement in PFS was obtained for the left-sided lesions than for the right-sided lesions.

An observational study of vascular endothelial growth factor inhibitors as second-line treatment for metastatic colorectal cancer treated with bevacizumab plus FOLFIRI beyond progression: the association with RAS mutation and tumor sidedness.

BackgroundThe BRiTE and ARIES studies suggested that the continued use of bevacizumab beyond progression (BBP) was beneficial. This study investigated the efficacy and safety of the vascular endothelial growth factor inhibitors (VEGFis) bevacizumab and aflibercept as second-line treatments for patients with metastatic colorectal cancer (mCRC) that progressed following the application of bevacizumab-containing chemotherapy as a first-line treatment.MethodsThis observational cohort study (OCS) analyzed the medical records of 73 patients with mCRC divided into a no-VEGFi group (n=48) and a VEGFi group (n=25). Progression-free survival (PFS) was the primary endpoint, and the overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety were secondary endpoints.ResultsThe results revealed that the PFS, ORR, and DCR of the VEGFi group were significantly superior to those of the no-VEGFi group, even in those with wild-type and mutant-type RAS or left-sided mCRC (all P<0.05); however, OS did not differ significantly between the two groups (all P>0.05). Patients with primary left-sided lesions and continued use of VEGFi exhibited the most marked effect on PFS (P=0.001). No significant differences were observed in the incidence of grade 3 or 4 adverse events (AEs) between the two groups (P=0.133).ConclusionsThese results support the use of VEGFi as a second-line treatment after bevacizumab beyond the initial progression in this OCS. Bevacizumab or aflibercept combined with second-line chemotherapy in mCRC has an acceptable safety profile and is relatively active. Regardless of the RAS gene type, VEGFi plus FOLOFX6 exhibited superior PFS to that of FLFOX6 as a second-line treatment, and a greater improvement in PFS was obtained for the left-sided lesions than for the right-sided lesions.

Multicenter phase II study of biweekly CAPIRI plus bevacizumab as second-line therapy in patients with metastatic colorectal cancer (JSWOG-C3 study)

BackgroundTriweekly capecitabine plus irinotecan (CAPIRI) was not a replacement for fluorouracil, leucovorin, and irinotecan (FOLFIRI) in the treatment of metastatic colorectal cancer (mCRC) because of the potential for greater toxicity. Recently, it has reported that mCAPIRI is well tolerated and non-inferior to FOLFIRI. In this study, we conducted a multicenter phase II trial to assess the efficacy and safety of biweekly CAPIRI plus bevacizumab as second-line chemotherapy for mCRC with reduced toxicity and preserved efficacy.MethodsPatients with mCRC who had received prior chemotherapy, including oxaliplatin-based regimens, were eligible for this study. The treatment protocol administered capecitabine at 1000 mg/m2 twice daily from the evening of day 1 to the morning of day 8, intravenous irinotecan at 150 mg/m2 on day 1, and bevacizumab at 10 mg/kg on day 1 every 2 weeks. Primary endpoints for this study were progression-free survival (PFS) and safety. Secondary endpoints were overall survival (OS), time to treatment failure, response rate (RR), and disease control rate (DCR).ResultsFifty-one patients were enrolled in this study. Median PFS was 5.5 months [95% confidence interval (CI) 4.23–7.40 months], and median OS was 13.5 months (95% CI 11.57–20.23 months). The RR was 14.6% (95% CI 6.5–28.4%), and the DCR was 66.7% (95% CI 51.5–79.2%). Hypertension was the most common Grade 3 adverse event (27.5%), followed by neutropenia (17.6%). Only two patients suffered from grade 3 hand–foot syndrome.ConclusionsIn mCRC patients, biweekly CAPIRI + bevacizumab appears effective and feasible as a second-line chemotherapy with relatively low toxicities, and has potential as a useful substitute for FOLFIRI + bevacizumab.

Evaluating gender as a predictive marker for response to bevacizuamb (Bev) in metastatic colorectal carcinoma (mCRC): Pooled analysis of 3369 patients (pts) in the ARCAD database.

3539 Background: Previous studies suggest a possible gender-specific response to Bev in mCRC, showing a benefit in males, while the effect in females is less significant. Therefore, we evaluated response to Bev according to gender. Methods: Data from 3369 mCRC patients enrolled on 4 first-line randomized trials testing Bev (2000-2007) were pooled. Association between gender and progression-free survival (PFS)/overall survival (OS) was evaluated by stratified Cox regression model, adjusted for potential confounders. Predictive value was evaluated by interaction (inter.) effect between gender and treatment. In a pre-planned secondary analysis, analyses were stratified using an age cut-point of 60 years (commonly used in breast cancer trials) to evaluate the possible role of menopausal-related effects. Results: OS was not statistically different between males and females (median OS [mOS], 18.8 vs. 17.6 months [mo], adjusted hazard ratio [HRadj], 0.93, 95% confidence interval [CI], 0.84-1.03, p, 0.15) in the overall population. Bev was associated with an improved mOS in males and females, with a 2.3 and 0.6 mo benefit, respectively, as well as an improved PFS. There was no statistically significant interaction effect between gender and treatment (see table). Further stratified by age (&lt; vs. ≥ 60 years), Bev resulted in improved PFS and OS in both genders, at all ages, except for the effect in young females which did not reach statistical significance (see table). Conclusions: Our results confirmed the mOS benefit from addition of Bev to first-line chemotherapy in mCRC in both genders, although the benefit in females was &lt; 1 month. For females under the age of 60, there are uncertainties for mOS benefit from addition of Bev and further evaluation is needed. [Table: see text]