Treatment Of mCRC Patients Research Articles

Profile of Fruquintinib in the Management of Advanced Refractory Metastatic Colorectal Cancer: Design, Development and Potential Place in Therapy.

Colorectal cancer (CRC) is a prevalent and deadly cancer, with metastatic CRC (mCRC) often leading to poor outcomes despite advancements in screening and chemotherapy. Anti-angiogenic agents targeting vascular endothelial growth factor (VEGF) pathways have become essential in mCRC treatment. Bevacizumab, a VEGF inhibitor, was the first agent used in this context. However, drug resistance prompted the development of more selective inhibitors, such as fruquintinib, a tyrosine kinase inhibitor (TKI) that targets VEGFR-1, -2, and -3. Fruquintinib has shown promise in clinical trials, particularly for third-line mCRC treatment. The Phase III FRESCO trial in China demonstrated its efficacy, significantly improving overall survival (OS) and progression-free survival (PFS) compared to placebo, with manageable safety concerns like hypertension and hand-foot skin reactions. The FRESCO-2 trial extended these findings to European and North American populations, leading to a recent FDA approval for previously treated mCRC patients. The pharmacodynamic profile of fruquintinib includes potent inhibition of VEGFR, angiogenesis, and lymphangiogenesis. It has shown synergistic effects when combined with other treatments like chemotherapy and immune checkpoint inhibitors (ICIs). Current research focuses on exploring fruquintinib's combination with ICIs, such as PD-1 inhibitors, to enhance treatment efficacy, especially in microsatellite stable (MSS) CRC. Ongoing trials are investigating Fruquintinib's potential in combination with other therapies and its use in earlier lines of treatment. While promising, further studies are required to optimize its place in therapy and identify predictive biomarkers for better patient selection.

Real-world treatment patterns and unmet need in patients with previously treated metastatic colorectal cancer that is not MSI-H or dMMR.

53 Background: Regorafenib and trifluridine/tipiracil (TAS-102) are standard of care (SoC) systemic anticancer treatments (SACT) for metastatic colorectal cancer (mCRC) patients perviously treated with fluoropyrimidine (5-FU), irinotecan, & oxaliplatin-based chemotherapy. However, evidence is limited on post-chemotherapy & later SACT for patients with mCRC that is not microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR). This study assessed real-world patient characteristics and treatment patterns in community oncology practices among previously treated, not MSI-H/dMMR mCRC patients. Methods: This retrospective cohort study utilized The US Oncology Network (iKnowMed) electronic health record database, supplemented by chart review. The study cohort comprised adult, not MSI-H/dMMR mCRC patients treated with chemotherapy (5-FU/capecitabine, irinotecan, and oxaliplatin) who initiated subsequent SACT or received best supportive care (BSC) between 1/1/2016 & 12/31/2021. Index date for SACT users was the regimen start date. For patients on BSC and no subsequent SACT/BSC, index date was last chemotherapy administration date. Patients were followed from index date through 8/31/2022, date of death or last contact date, whichever occurred first. Descriptive statistics were used to report patient and treatment characteristics. Results: The study consisted of 292 mCRC patients, with a median age of 57 (range: 49, 68) years. The predominant histology was adenocarcinoma (n = 237, 81.2%) with 1.7% other histology and rest missing, 198 (67.8%) patients had Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 and 206 (70.5%) had primary tumors located in the colon. Liver (n = 207, 70.9%) and lung (n = 78, 26.7%) were the most common metastasis sites. Diabetes (n = 33, 11.3%) and peripheral vascular disease (n = 18, 6.2%) were the most common comorbidities. Eighty-seven (29.8%) patients received at least one chemotherapy in the adjuvant/neo-adjuvant setting, while majority (70.2%) patients received chemotherapies in the metastatic setting. Overall, 203 (69.5%) received SACT post-chemotherapy, 84 (28.8%) received BSC and 5 (1.7%) did not receive SACT/BSC. Among the SACT post-chemotherapy users, 30 (14.8%) received regorafenib, 25 (12.3%) received TAS-102 and 148 (72.9%) received other SACT. Other SACT included irinotecan-based (n = 76, 37.4%), oxaliplatin-based (n = 30, 14.8%), irinotecan and oxaliplatin-based (n = 6, 3.0%) chemotherapy, and anti-EGFR (n = 15, 7.4%) or anti-VEGF (n = 8, 3.0%) targeted therapies. Conclusions: Overall, only 27.1% of previously treated mCRC patients with tumors that were not MSI-H or dMMR received SoC. The real-world variability in choice of treatments and the high percentage of patients rechallenged with chemotherapy in subsequent lines, highlights an unmet need in this population.

BOLD-100-001 (TRIO039): A phase 2 study of BOLD-100 in combination with FOLFOX in patients with advanced mCRC previously treated with FOLFOX/CAPOX—Efficacy and safety analysis.

143 Background: BOLD-100 is a first-in-class metallotherapeutic with a unique multimodal mechanism of action currently in phase 2 clinical development for the treatment of advanced gastrointestinal cancers. Standard treatment options for patients (pts) with metastatic colorectal cancer (mCRC) include FOLFOX or CAPOX in first or second line therapy. This study explored the benefit of BOLD-100 + FOLFOX in previously treated mCRC patients. Methods: This prospective, phase 2 study evaluates BOLD-100 + FOLFOX in pts with mCRC. All pts received prior standard treatment, including FOLFOX or CAPOX. Pts received 625 mg/m2 of BOLD-100 + FOLFOX on day 1 of each 14-day cycle and treated until progressive disease or unacceptable toxicity. The primary objective is to evaluate PFS, OS, and ORR in treated patients. Disease Control Rate (DCR) was also determined. Results: As of 31Aug2023, 36 pts with advanced mCRC were treated. Median age was 62 years (range 40-78), 56% were women, all pts were ECOG 0 (25%) or 1 (75%). Enrolled pts had a median of 4 prior systemic therapies, including FOLFOX/CAPOX. All but one patient had stage IV disease. On study, pts received a median of 6 cycles of BOLD-100 + FOLFOX [range 1-17]. Five pts remain on treatment with 19 in follow-up. Median PFS was 3.9 [2.7, 5.7] months, median OS 9.6 [6.0, 17] months, ORR 7% [1,20] and DCR 76% [58, 88] in the 29 evaluable pts. Two pts achieved a partial response, and 2 pts had target tumor lesion decreases between 20-29%. Study treatment was well tolerated. Of the 36 treated pts, 33 had 1 or more treatment-emergent adverse events (AEs), most common neutropenia (n=17, 47%), nausea (n=15, 42%), vomiting (n=8, 22%), fatigue (n=7, 19%), infusion related reaction (n=7, 19%), and pruritus (n=6, 17%). Most related AEs were grade (G) 1-2. 15 pts (42%) had G3/4 neutropenia. Despite previous oxaliplatin treatment, fewer than 6% of pts reported peripheral neuropathy or peripheral sensory neuropathy and all were G1/2. Conclusions: BOLD-100 + FOLFOX is an active and well-tolerated treatment in this heavily pre-treated Stage IV mCRC study population. There were no new safety signals. The mPFS, mOS, ORR and DCR data demonstrate significant clinical benefit and improvement over the currently available therapies, with minimal treatment emergent neuropathy or significant toxicities. This promising treatment combination should be further studied. Clinical trial information: NCT04421820 .

Abstract B048: NUC-3373 in combination with irinotecan (NUFIRI) or oxaliplatin (NUFOX) and bevacizumab for second-line treatment of patients with advanced colorectal cancer (NuTide:302)

Abstract Background: Fluoropyrimidines, such as 5-FU, exert anti-cancer activity via fluorodeoxyuridine-monophosphate (FUDR-MP). NUC-3373, a phosphoramidate transformation of FUDR-MP, generates high intracellular levels of FUDR-MP; avoiding toxic metabolite generation; and improving pharmacokinetics to enable more convenient administration. NuTide:302 is a three-part study investigating NUC-3373 in combination with chemotherapy agents used for the treatment of metatstaic CRC (mCRC). Part 1 established the safety of NUC-3373 in combination with leucovorin (LV) . Part 2 investigated NUC-3373 + LV in dose-escalation cohorts with either irinotecan (NUFIRI) or oxaliplatin (NUFOX) and determined the MTDs. Parts 1 and 2 established that LV had no effect on the safety or PK profile of NUC-3373 and the addition of oxaliplatin and irinotecan was well-tolerated. Here we present data from Part 3 (ongoing) which investigates NUFIRI and NUFOX in combination with bevacizumab (NUFIRI-bev; NUFOX-bev). Methods: Patients (pts) who had received 1 prior fluropyrimindine-containing therapy for mCRC were treated with either NUFIRI-bev (1,500 mg/m2 NUC-3373 (Q1W); 400 mg/m2 LV (Q1W); 180 mg/m2 irinotecan (Q2W); 5 mg/kg bevacizumab (Q2W)) or NUFOX-bev (1,875 mg/m2 NUC-3373 (Q1W); 400 mg/m2 LV (Q1W); 85 mg/m2 oxaliplatin (Q2W); 5 mg/kg bevacizumab (Q2W)). Results: At the time of data cut-off, 14 pts had been treated (NUFIRI-bev n=8; NUFOX-bev n=6); median age 60 (range: 37-81), 36% female, 38% ECOG 0 and 36% with liver metastases. In the NUFIRI-bev arm, there were no Grade 3 TRAEs. Seven pts (88%) achieved prolonged SD (median= 5.5 mo; range= 3.7-7.4) and 5 pts are ongoing. In the NUFOX-bev arm, Grade 3 TRAEs (occurring in 2 pts) were pancreatitis, ALT increased and hypokalaemia. Four pts (67%) achieved prolonged SD (median= 5 mo; range= 3-6.5) and 5 pts are ongoing. Updated safety and efficacy data will be presented. Conclusions:This study demonstrated safety and anti-tumour activity of NUFIRI-bev and NUFOX-bev in previously treated mCRC patients . A randomised Phase 2 study is currently investigating the safety and efficacy of NUFIRI-bev vs FOLRIFI-bev in 171 second-line pts with CRC (NuTide:323). Clinical trial information: NCT03428958 Citation Format: Khurum Khan, Uma Mukherjee, Benjamin L Schlechter, Kristen K Ciombor, Aglaia Skolariki, Andrew L Coveler, Janet S Graham, Mary Linton Peters, Stacey A Cohen, Niharika Mettu, Hélène Marijon, David Cosgrove, Fiona G McKissock, Elisabeth Oelmann, Jeffrey D Bloss, Sarah P Blagden, Aimery de Gramont, Jordan Berlin, T.R. Jeffry Evans. NUC-3373 in combination with irinotecan (NUFIRI) or oxaliplatin (NUFOX) and bevacizumab for second-line treatment of patients with advanced colorectal cancer (NuTide:302) [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B048.

Fruquintinib in combination with sintilimab or TAS-102 as third-line or above treatment in patients with metastatic colorectal cancer: a real-world study.

For metastatic colorectal cancer (mCRC), the efficacy of third-line or above treatments is not ideal. Combining targeted vascular endothelial growth factor (VEGF) or vascular endothelial growth factor receptor (VEGFR) biological agents with chemotherapy or anti-programmed death receptor 1 (PD-1) treatment can bring longer survival benefits to patients with mCRC compared with the application of a single drug. In this study, fruquintinib was used as the research drug, and the main purpose was to compare the efficacy and safety of fruquintinib in combination with sintilimab (FS) or trifluridine and tipiracil (TAS-102) (FT) in the third-line or above treatment in mCRC patients. Based on real-world clinical practice, mCRC patients who progressed after second-line or higher-line chemotherapy regimens and received FS or FT as third-line or above treatment from December 2020 to November 2022 were analyzed. Progression-free survival (PFS) was the primary endpoint. Safety, disease control rate (DCR) and objective response rate (ORR) were secondary end points. In the FS group, 47 patients received FS, and in the FT group, 45 patients received FT. The DCR values in the FS and FT groups were 80.9% (38/47) and 55.6% (25/45), respectively (P<0.05). The median PFS (mPFS) in the FS group was 6.0 months, and the mPFS in the FT group was 3.5 months (P<0.05). Most adverse events (AEs) were grade 1-2 in severity. As a third-line or above regimen in mCRC patients, compared to FT, treatment with FS provides a higher DCR and longer mPFS and is better tolerated. The combination of fruquintinib and sintilimab may become a new treatment option for mCRC patients.

The REWRITE Study – REal-WoRld effectIveness of TrifluridinE/tipiracil in Patients with Previously Treated Metastatic Colorectal Cancer

AimsIn the pivotal RECOURSE trial, trifluridine/tipiracil improved survival outcomes in refractory metastatic colorectal cancer (mCRC), while demonstrating an acceptable toxicity profile. Routine clinical practice evidence is important to support the ongoing value of recently approved medicines. Our objective was to assess the utilisation patterns and real-world effectiveness of trifluridine/tipiracil in previously treated mCRC patients. Materials and methodsThis was a retrospective observational study including consecutive patients who started trifluridine/tipiracil between 1 April 2018 and 30 September 2019 in the medical oncology departments of three major public hospitals in Portugal. The primary outcome measure was overall survival. Associations between overall survival and patient and tumour characteristics were assessed using multivariate Cox regression analyses. ResultsIn total, 111 patients were included in the study, with a mean age of 64 years. From these, 45.9% received two prior lines of treatment, 47.8% had three or more previous lines of treatment and 83.6% had Eastern Cooperative Oncology Group (ECOG) performance status 0–1 at baseline. The median duration of trifluridine/tipiracil treatment was 3.7 cycles (95% confidence interval 3.4–4.1). Most patients (80.4%) remained on their planned dose throughout the trifluridine/tipiracil treatment period, fulfilling 100% relative dose intensity. The median overall survival in the total study cohort was 7.9 months (95% confidence interval 6.4–9.8) and the median progression-free survival was 3.4 months (95% confidence interval 3.2–3.9). The median overall survival was significantly higher in patients with a normal serum lactate dehydrogenase (LDH) level (median overall survival 11.2 months for [135, 205] IU/l LDH [95% confidence interval 8.2–NR] and 13.6 months for [205, 251] IU/l LDH [95% confidence interval 8.2–NR]) and in better fitted (ECOG = 0–1) patients (median overall survival 8.0 months; 95% confidence interval 6.7–10.0). The median time to worsening performance status was 6.2 months (95% confidence interval 5.0–8.0). Treatment discontinuation due to adverse events was low (3.1%). ConclusionOur study confirms the effectiveness of trifluridine/tipiracil in real-life mCRC patients. Overall survival and progression-free survival outcomes are consistent with the efficacy profile reported in the earlier randomised RECOURSE clinical trial. Like other real-world studies, we found no additional safety concerns in the use of trifluridine/tipiracil.

Treatment modalities of regorafenib and survival in metastatic colorectal (mCRC) patients: A real-world multicenter retrospective study.

e15571 Background: Regorafenib has been widely used as the later-line treatment for mCRC. This study aimed to describe the treatment modalities, as well as the efficacy and safety of regorafenib in a real-world setting. Methods: We conducted a retrospective study of patients (Pts) with refractory mCRC receiving at least one cycle of regorafenib as the third or higher line treatment from August 2017 to June 2020 in China. Demographic characteristics, treatment modality and survival were collected. The primary endpoint was overall survival. Uni- and multivariate analysis were conducted by Kaplan-Miere analysis and Cox regression model. Results: A total of 768 Pts from 10 centers were screened and 621 Pts were finally enrolled with a median age of 61 (18-84) years. 376 Pts received regorafenib monotherapy and 245 Pts accepted combination therapy. With a median follow-up time of 28.4 months, the median progression-free survival (mPFS) was 4.3 months (95%CI: 3.8-5.2) and the median overall survival (mOS) was 11.6 months (95% CI: 10.5-12.6). The mOS of Pts received regorafenib monotherapy (R, n = 376), regorafenib plus PD-1 inhibitor (R+I, n = 161), regorafenib plus chemotherapy (R+C, n = 53) and regorafenib plus chemotherapy, PD-1 inhibitor (R+C+I, n = 31) were 10.0, 13.2, 13.5 and 19.3 months, respectively (p = 0.0017). While the median PFS were 3.8, 5.4, 4.6 and 4.8 months, respectively (p = 0.4944). In multivariate analysis, treatment with R+I (HR = 0.712, 95%CI 0.521-0.973; p = 0.0330) and ECOG PS (HR = 0.400, 95%CI 0.232-0,690; p = 0.0010) were the only significant factors for superior mOS. Univariate analysis in subgroups demonstrated longer OS as well as PFS in KRAS mutated or antiangiogenesis therapy naïve Pts in R+I group than those in R group. Moreover, there was a tendency of shorter OS in Pts received 80mg as the final tolerated dose in R+I group compared to 160mg, while Pts received 120mg presented comparable survival. The incidence of all grade treatment-related adverse events was higher in R+I (87.9%) vs R (66.3%) group. Conclusions: The combination of regorafenib and PD-1 inhibitor was commonly adopted as the later-line treatment in mCRC patients in real-world practice and seemed to have a prolonged overall survival than regorafenib alone. Further confirmatory studies are warranted. Clinical trial information: NCT04835324 .

Abstract A013: Role of EGFR in KRAS-mediated resistances in colorectal cancer. &amp;lt;/title&amp;gt;

Abstract The standard of care therapies for metastatic colorectal cancer (mCRC) patients with wild-type (WT) RAS or BRAF consists of chemotherapy combined with targeted anti-EGFR antibodies. Still, only half of the RAS WT mCRC patients are sensitive to anti-EGFR therapy1, and eventually some of them stop responding due to intrinsic and acquired resistance to anti-EGFR treatment2. Moreover, recent clinical studies have also shown that left-sided mCRC respond better to anti-EGFR treatment for reasons that are still unknown. Studies from our lab and others using genetically engineered mouse models (GEMMs) showed that EGFR expressing tumor-associated myeloid cells release inflammatory cytokines that have a pro-tumorigenic role in CRC3,4. Deletion of EGFR in tumor cells of these mice had no effect in tumor size, whereas deletion of EGFR in myeloid cells impaired CRC development3. Moreover, human CRC biopsies confirmed that presence of EGFR+ myeloid cells is associated with a worse overall survival of mCRC patients. From our results in GEMMs, it seems that the therapeutic action of EGFR inhibitors is mediated via EGFR inhibition in myeloid cells. Assuming that tumor cells are not the primary target of anti-EGFR therapies, it is puzzling that KRAS mutations in tumor cells confer resistance to anti-EGFR treatment in mCRC patients. We hypothesize that epithelial KRAS mutations alter the tumor microenvironment (TME) towards an immunosuppressive milieu. We are testing this hypothesis by comparing expression signatures derived from tumor and stroma of human mCRC biopsies that are WT or mutant for KRAS to elucidate the molecular signature driven by KRAS that explains anti-EGFR treatment resistance. In parallel, we employ CRC mouse models generated by orthotopic implantation of WT and RAS mutant mouse CRC organoids into GEMMs lacking the EGFR in different cell types to mimic right and left-sided metastatic disease. Targets identified in human mCRC patients are being mechanistically validated in organoids and derived tumors by CRISPR/Cas9-mediated genetic engineering. The results of these experiments will be presented. The expected results will provide a better understanding of how anti-EGFR antibodies work, how resistance mechanisms are developed, and possible new treatment combinations for KRAS mutated CRC.

Economic evaluation of encorafenib with cetuximab in patients with BRAF V600E-mutant metastatic colorectal cancer in France: a cost-effectiveness analysis using data from the BEACON CRC randomised controlled trial

ObjectiveThe BEACON CRC randomised controlled trial (NCT02928224) in BRAF-mutant metastatic colorectal cancer (mCRC) patients showed improved overall survival for the combination treatment of encorafenib (BRAF inhibitor) with cetuximab (EGFR inhibitor)...

LBA23 Avelumab versus standard second-line treatment chemotherapy in metastatic colorectal cancer (mCRC) patients with microsatellite instability (MSI): The SAMCO-PRODIGE 54 randomised phase II trial

Immune checkpoint inhibitors have failed in treating mCRC patients (pts) except those with MSI/dMMR tumours. However, in pts with MSI/dMMR mCRC, only one randomized trial in the first-line setting, showed the superiority of an anti-programmed death 1 (anti–PD-1) antibody over standard treatment. The SAMCO-PRODIGE 54 trial aimed to evaluate efficacy and safety of an anti-programmed death ligand-1 (anti–PD-L1) antibody compared with a standard treatment in the second-line setting in pts with MSI/dMMR mCRC.

The prognostic role of neutrophil-to-lymphocyte ratio and C-reactive protein in metastatic colorectal cancer using regorafenib: a systematic review and meta-analysis.

BackgroundThe application of regorafenib has changed the landscape of subsequent-line treatment in metastatic colorectal cancer (mCRC). Baseline neutrophil-to-lymphocyte ratio (NLR) and C-reactive protein (CRP), as two of the most common inflammatory factors, are suggested to be potential prognostic factors for mCRC patients treated with regorafenib, but the results are conflicting. In this study, we conducted a meta-analysis to evaluate the prognostic role of NLR and CRP in mCRC patients treated with regorafenib.MethodsWe searched online databases such as Embase, PubMed, and the Cochrane library up to April 2022, without language limitation, to identify clinical studies evaluating the prognostic role of NLR or CRP in regorafenib treated mCRC patients. The main endpoints were hazard ratio (HR) of overall survival (OS) and progression-free survival (PFS). The associations between NLR, CRP, and the above endpoints were extracted. Review Manager 5.4 was used to conduct the combined analysis. The Newcastle-Ottawa Scale (NOS) was applied for assessing the quality of included studies. Heterogeneity was detected by chi-square-based Q test and I2 statistic, and publication bias was evaluated by funnel plot asymmetry and Egger’s test.ResultsEight studies involving 1,287 cases were included, with 5 reporting survival outcomes based on NLR level and 4 reporting survival according to CRP level. The results of meta-analysis showed that the calculated HR of OS for subsequent-line regorafenib in mCRC patients with high versus low NLR was 2.52 [I2=52%, 95% confidence interval (CI): 1.75–3.64; P<0.00001]. The combined HR of PFS with high versus low baseline NLR was 2.11 (I2=12%, 95% CI: 1.80–2.48; P<0.00001). For patients with a high level of CRP, the OS was significantly shorter when compared with patients with a low level of CRP (I2=0%, HR =1.88; 95% CI: 1.55–2.29; P<0.00001).ConclusionsHigh level of NLR could be associated with OS in mCRC patients treated with regorafenib. It is suggested that the impact of regorafenib on OS may vary according to the baseline NLR.

Toripalimab with Fruquintinib as the third-line treatment for refractory advanced metastatic colorectal cancer: Results of a single-arm, single-center, prospective, phase II clinical study.

e15573 Background: The most effective treatment of immune checkpoint inhibitors (ICIs) is restricted in microsatellite instability (MSI-H) subsets of advanced colorectal cancer, but MSI-H only accounts for 4-5% among them. Currently, Fruquintinib/ Regorafenib is the standard third-line treatment for metastatic colorectal cancer (mCRC) with microsatellite stable (MSS), which efficacy remains limited in pre-clinical trials. According to the published literature, ICIs has little efficacy in the treatment of refractory advanced mCRC patients with MSS. However, there may be a good synergistic mechanism in the combination of ICIs and anti-VEGFR drugs, which can improve the tumor microenvironment (TME). Our study aimed to evaluate the efficacy and safety of Fruquintinib plus Toripalimab as third-line treatment for refractory advanced mCRC. Methods: This was a single-arm, single-center, phase II clinical trial with 30 patients. Pts received toripalimab (240mg, i.v., Q3W), combined with Fruquintinib (5mg, p.o., 3 weeks on/ 1 week off) until the disease progresses/unacceptable toxicity or receiving the above two drugs as maintenance treatment. The primary endpoint was objective response rate (ORR); the secondary endpoints were disease control rate (DCR), 1-year progression-free survival (PFS) rate, overall survival (OS) and safety. Results: As of Feb 5, 2022, 24 mCRC pts (female: 29.2%, median age: 52.1 years) with ECOG PS ≤ 2 who failed to at least 2 previous lines of therapy containing fluoropyrimidine, oxaliplatin or irinotecan combined with Bevacizumab or Cetuximab were enrolled. The ORR was 16.7% (95% CI：59.7%-94.8%). The DCR was 54.1%, including 4 patients with PR and 9 patients with SD, respectively. 16 patients were alive and the study treatments for 6 patients were still ongoing. Median PFS was 6.0 months (95% CI：3.511-12.489), the 1-year PFS rate was 18%; median OS was 8.0 months (95% CI：1.452-10.548). Overall, 24 pts were enrolled for safety analysis, The most frequent treatment related adverse events were fatigue (50%), hepatocyte dysfunction (36.3%), hypertension (29.1%) and abdominal pain (27.0%). 6 patients (25%) experienced grade 3/4 TRAE (including hypertension, liver enzyme elevation, and immune-associated pneumonia). No treatment-related death was reported. TRAEs leading to either Fruquintinib or Toripalimab discontinuation occurred in 3 (12.5%) pts each. Conclusions: Fruquintinib plus Toripalimab showed certain efficacy and favorable safety profile in refractory advanced mCRC with MSS. It may provide a new choice for mCRC patients who are receiving third-line treatment. The results supported ongoing combined treatment in mCRC patients with MSS and more data will being updated subsequently. Clinical trial information: ChiCTR2000028965.

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

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

Reckoning apigenin and kaempferol as a potential multi-targeted inhibitor of EGFR/HER2-MEK pathway of metastatic colorectal cancer identified using rigorous computational workflow.

In the past two decades, the treatment of metastatic colorectal cancer (mCRC) has been revolutionized as multiple cytotoxic, biological, and targeted drugs are being approved. Unfortunately, tumors treated with single targeted agents or therapeutics usually develop resistance. According to pathway-oriented screens, mCRC cells evade EGFR inhibition by HER2 amplification and/or activating Kras-MEK downstream signaling. Therefore, treating mCRC patients with dual EGFR/HER2 inhibitors, MEK inhibitors, or the combination of the two drugs envisaged to prevent the resistance development which eventually improves the overall survival rate. In the present study, we aimed to screen potential phytochemical lead compounds that could multi-target EGFR, HER2, and MEK1 (Mitogen-activated protein kinase kinase) using a computer-aided drug design approach that includes molecular docking, endpoint binding free energy calculation using MM-GBSA, ADMET, and molecular dynamics (MD) simulations. Docking studies revealed that, unlike all other ligands, apigenin and kaempferol exhibit the highest docking score against all three targets. Details of ADMET analysis, MM/GBSA, and MD simulations helped us to conclusively determine apigenin and kaempferol as potentially an inhibitor of EGFR, HER2, and MEK1 apigenin and kaempferol against mCRC at a systemic level. Additionally, both apigenin and kaempferol elicited antiangiogenic properties in a dose-dependent manner. Collectively, these findings provide the rationale for drug development aimed at preventing CRC rather than intercepting resistance.

The role of genetic variants involved with ferroptosis regulator genes in predicting outcomes in patients (pts) with RAS-mutant metastatic colorectal cancer (mCRC): Data from MAVERICC and TRIBE trials.

197 Background: Ferroptosis, an iron-dependent programmed cell death, is one of the anti-tumor mechanisms of anti-angiogenesis drugs. RAS mutation can confer ferroptosis in colorectal cancer (CRC). Previous studies suggested that polymorphisms of ferroptosis regulator genes are associated with the increased risk of CRC. Therefore, we hypothesized that genetic variants in the ferroptosis regulator genes may predict first-line treatment outcome in RAS-mutant mCRC pts treated with bevacizumab (bev)-based chemotherapy. Methods: Genomic DNA from blood samples of mCRC pts enrolled in two independent randomized trials, MAVERICC (FOLFIRI+bev arm: discovery cohort, RAS-mutant, n = 56; control-1: RAS-wildtype, n = 87) and TRIBE (FOLFOXIRI+bev arm: validation cohort, RAS-mutant, n = 57; control-2: RAS-wildtype, n = 34), was genotyped through the OncoArray, a customized array manufactured by Illumina including approximately 530K SNP markers. The impact on outcome of 13 selected SNPs in 5 main ferroptosis regulator genes (ACSL4, LPCAT3, SLC3A2, SLC7A11, ALOX15) was analyzed. Results: In the MAVERICC bev cohort, pts with RAS-mutant tumors carrying ALOX15 rs7217186 any C allele (n = 35) showed significant longer overall survival (OS) than carrier of T/T allele (n = 5) in both univariate (24.97 vs. 12.22 months, hazard ratio [HR] = 0.23; 95% confidence interval [CI]: 0.06-0.9; p = 0.02) and multivariate (HR = 0.06; 95%CI 0.007-0.5; p = 0.009) analysis. In the TRIBE bev cohort, RAS-mutant carriers of any C allele (n = 30) showed numerically longer progression-free survival (PFS), compared to carriers of T/T allele (n = 13) in both univariate (11.91 vs. 9.47 months, HR = 0.45; 95%CI 0.2-1.02; p = 0.05) and multivariate (HR = 0.42; 95%CI 0.16-1.1; p = 0.09) analysis. Conversely, RAS-wildtype carriers of any C allele (n = 17) showed significant shorter PFS than T/T carriers in the TRIBE bev cohort (8.91 vs. 15.59 months, univariate HR = 3.39, 95%CI: 1.03-11.18, p = 0.04). Conclusions: Our study demonstrated for the first time that ALOX15 polymorphisms may have different predictive values for the bev-based treatment in mCRC patients based on RAS mutational status. These findings may provide novel insights for the combination of ferroptosis inducers and anti-VEGF treatment.

Dynamics of neutrophil-to-lymphocyte ratio predict outcomes of metastatic colorectal carcinoma patients treated by FOLFOX.

Peripheral blood cell count is the most common clinical laboratory test. Neutrophil-to-lymphocyte ratio (NLR) as an economic marker has been reported in various cancer types. It is believed that NLR is associated with the prognosis and treatment outcomes of some cancers. Low baseline NLR has been reported as associated with better overall survival (OS) in advanced cancer patients. In this study, we aimed to determine whether the changes of NLR may predict the outcome of metastatic colorectal carcinoma (mCRC) patients treated with folinic acid, fluorouracil, and oxaliplatin (FOLFOX) combined with bevacizumab/cetuximab. The clinical data obtained from 128 mCRC patients between January 2014 and December 2018 were retrospectively analyzed. The NLR values of patients were calculated after 4 cycles of treatments. Kaplan-Meier analysis and Cox regression modeling were performed to assess the impact of NLR dynamics on OS and progression-free survival (PFS). Among the 128 participants, the optimum pre-treatment NLR cutoff value was 3. A total of 70 (54.7%) participants had a pre-treatment of NLR lower than 3. The median of PFS was 9.1 months for NLR <3 compared with 6.1 months for pre-treatment NLR >3. A lower pre-treatment NLR was significantly associated with better PFS (P<0.001), but not associated with OS (P=0.064). A total of 94 (73.4%) participants had a post-treatment NLR <3, which was associated with better PFS and OS (P=0.007). However, changes in NLR significantly affected PFS and OS. Decrease in post-treatment NLR was associated with longer PFS and OS. Patients with changes from low pre-treatment NLR to high post-treatment NLR had worse OS and PFS than that of NLR changes from high to low. It is not the NLR but the changes of NLR that may predict the efficacy of FOLFOX treatment in mCRC patients.

Real-world use of bevacizumab-awwb, a bevacizumab biosimilar, in US patients with metastatic colorectal cancer.

Aim: Evaluated realworld use of bevacizumab-awwb (MVASI®), a bevacizumab biosimilar, for treating metastatic colorectal cancer (mCRC). Materials & methods: Adult mCRC patients who received bevacizumab-awwb during the first year after market availability were identified from the ConcertAI oncology dataset. Results: Of 304 patients, 47% initiated bevacizumab-awwb as reference product (RP)naive patients and 53% received bevacizumab-awwb with prior exposure to RP. Overall, 78% received bevacizumab-awwb as first-line therapy; the proportion was higher (91%) in RP-naive patients. Among RP-experienced patients, 83% were transitioned from RP to bevacizumab-awwb in the same line without disease progression; of those, the majority (83%) were transitioned within 28days. Conclusion: Early evidence from US oncology practices suggests clinical adoption of bevacizumab-awwb in treating mCRC patients.

Genetic variants involved in the cGAS-STING pathway to predict outcome in patients (pts) with metastatic colorectal cancer (mCRC): Data from FIRE-3 and TRIBE trials.

3535 Background: The intracellular DNA sensor stimulator of interferon genes (STING) plays a vital role in anti-tumor immune responses by recognition of self-DNA from tumors and by-products of genomic instability. Activation of STING was reported to enhance cetuximab mediated natural killer cell activation and dendritic cell maturation. Previous reports suggested that polymorphisms of cGAS-STING can affect innate immune response. Therefore, we hypothesized that genetic variants in the cGAS-STING pathway may predict first-line treatment outcome in mCRC pts treated with bevacizumab/cetuximab-based chemotherapy. Methods: Genomic DNA from blood samples of pts enrolled in two independent randomized trials, FIRE-3 (cetuximab arm, n = 129; bevacizumab arm, n = 107) and TRIBE (bevacizumab arm, n = 215), was genotyped through the OncoArray, a customized array manufactured by Illumina including approximately 530K SNP markers. The impact on outcome of 7 selected SNPs in 3 genes involved in the STING pathway (cGAS, STING, IFNB1) was analyzed. Results: In the Cetuximab cohort, pts with STING rs1131769 any T allele (N = 29) showed significantly shorter overall survival (36.3 vs 56.07 months) compared to carriers of C/C (N = 95) in both univariate (hazard ratio [HR] = 2.08; 95% confidence interval [CI]: 1.06-4.07; p = 0.003) and multivariate (HR = 2.98; 95%CI 1.35-6.6; p = 0.00848) analysis; Pts carrying IFNB1 rs1051922 any A allele (N = 68) showed significant shorter progression-free survival (10.23 vs 14.1 months) than carriers of G/G (n = 59) in both univariate (HR = 1.87; 95%CI 1.26-2.78; p = 0.00163) and multivariate (HR = 2.03; 95%CI 1.25-3.3; p = 0.004) analysis. No association were observed in the bevacizumab cohort of TRIBE and FIRE-3. Conclusions: Our study demonstrates for the first time that STING and IFNB1 polymorphisms could predict outcomes of Cetuximab-based treatment in mCRC patients; These finding may provide insight for the combination of STING agonist and anti-EGFR treatment in mCRC patients.

The role of PP2A variants to predict outcome in patients (pts) with metastatic colorectal cancer (mCRC): Data from FIRE-3 and TRIBE trials.

3581 Background: Protein phosphatase 2A (PP2A) is a serine/threonine phosphatase with functions that counter-balance kinase-mediated phosphorylation throughout cell signaling networks. PP2A was reported to upregulate the angiogenesis, while negatively regulate the pathways downstream of receptor tyrosine kinases at multiple nodes. Previous studies showed PP2A variants were associated with the increased risk of cancer. Therefore, we hypothesized that PP2A variants may predict first-line treatment outcome in mCRC pts treated with bevacizumab (bev)/cetuximab (cet)-based chemotherapy. Methods: Genomic DNA from blood samples of pts enrolled in two independent randomized trials, TRIBE (bev arm, n=215, as discovery cohort) and FIRE-3 (bev arm, n=107, as validation cohort; cet arm, n=129, as control cohort), was genotyped through the OncoArray, a customized array manufactured by Illumina including approximately 530K SNP markers. The impact on outcome of 17 selected SNPs in 3 main PP2A core subunits (PPP2CA, PPP2R1B, PPP2R1A), one phosphatase activator (PPP2R4) and 2 endogenous inhibitors (TIPRL, CIP2A) was analyzed. Results: In the discovery cohort, pts with PPP2R4 rs2541164 A/A (N=16) showed significantly shorter overall survival (15.3 vs 27.3 months) compared to carriers of any G allele (N=198) in both univariate (hazard ratio [HR]=1.8; 95% confidence interval [CI]: 1.1-3.1; p=0.02) and multivariate (HR=2.4; 95%CI: 1.4-4.4; p=0.006) analysis. These data were validated in the FIRE-3 bev cohort in both univariate (A/A vs. Any G: 17.3 vs 39.9 months, HR=2.8, 95%CI: 1.4-5.9, p=0.004) and multivariate (HR=4.3, 95%CI: 1.5-12.2, p=0.0095) analysis. Conversely, pts carrying CIP2A rs13069780 C/C (N=24) only showed significantly longer progression-free survival (17.7 vs 12.3 months) than carriers of any T allele (n=105) in the FIRE-3 cet cohort in both univariate (HR=0.6; 95%CI 0.4-0.99; p=0.04) and multivariate (HR=0.5; 95%CI 0.3-0.94; p=0.02) analysis, but no association were observed in the bev cohort of TRIBE and FIRE-3. Conclusions: Our study demonstrated for the first time that PPP2R4 polymorphisms could predict outcomes of bev-based treatment in mCRC patients; Meanwhile CIP2A polymorphism could predict outcomes of cet-based treatment in mCRC patients. These findings support a possible role of the PP2A variants in contributing to resistance to anti-VEGF/EGFR treatment.

Management of BRAF Gene Alterations in Metastatic Colorectal Cancer: From Current Therapeutic Strategies to Future Perspectives.

BRAF mutations constitute an important poor prognostic factor in metastatic colorectal cancer (mCRC) and the development of treatments in this context is of great necessity to prolong patient survival. Although the association between BRAF mutations and microsatellite instability (MSI) has been known for several years, previous clinical trials have revealed that the former has a limited prognostic impact and that immune checkpoint inhibitors offer a significant survival benefit to mCRC patients with both characteristics. Furthermore, the genomic classification of BRAF mutations according to their molecular functions enables greater understanding of the characteristics of mCRC patients with BRAF mutations, with therapeutic strategies based on this classification made more ideal to improve poor prognosis through the delivery of targeted therapies. Recently, a phase III trial was conducted in previously treated mCRC patients with BRAF V600E–mutated tumors and revealed that the combination therapy approach of BRAF inhibition and anti–epidermal growth factor receptor antibody therapy with or without MEK inhibition was more efficacious than standard chemotherapy alone. This review discusses current treatment strategies and future perspectives in BRAF-mutated mCRC.