Chemorefractory Metastatic Colorectal Cancer Research Articles

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

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

Are survival outcomes dependent on the tumour dose threshold of 139 Gy in patients with chemorefractory metastatic colorectal cancer treated with yttrium-90 radioembolization using glass particles? A real-world single-centre study.

To compare the survival and objective response rate (ORR) of the patients receiving estimated tumour absorbed dose (ETAD) <140 Gy versus ETAD ≥140 Gy in patients with advanced chemorefractory colorectal carcinoma liver metastases (CRCLM) treated with yttrium-90 transarterial radioembolization (90Y TARE). Between August 2016 and August 2023 adult patients with unresectable, chemorefractory CRCLM treated with 90Y TARE using glass particles, were retrospectively enrolled. Primary outcomes were overall survival (OS) and hepatic progression free survival (hPFS). Secondary outcome was ORR. A total of 40 patients with a mean age of 66.2 ± 7.8 years met the inclusion criteria. Mean ETAD for group 1 (ETAD <140 Gy) and group 2 (ETAD ≥140) were 131.2 ± 17.4 Gy versus 195 ± 45.6 Gy, respectively. The mean OS and hPFS for group 1 versus group 2 were 12 ± 10.3 months and 8.1 ± 9.3 months versus 9.3 ± 3 months and 7.1 ± 8.4 months, respectively and there were no significant differences (P = .181 and P = .366, respectively). ORR did not show significant difference between the groups (P = .432). In real-world practice, no significant difference was found in OS, hPFS, and ORR between patients who received ETAD <140 Gy versus ETAD ≥140 Gy in patients with CRCLM, in this series. This study demonstrated that increased tumour absorbed doses in radioembolization may not provide additional significant advantage for OS and hPFS for patients with CRCLM.

First report of the randomized phase III study of bi-weekly trifluridine/tipiracil (FTD/TPI) plus bevacizumab (BEV) vs. FTD/TPI monotherapy for chemorefractory metastatic colorectal cancer (mCRC): JCOG2014 (ROBiTS).

118 Background: FTD/TPI has been widely used as one of the standard therapies in the late-line treatment for patients with mCRC, and the efficacy of FTD/TPI plus BEV combination was also recently reported in the SUNLIGHT trial. However, the combination of FTD/TPI plus BEV increased the frequency of hematologic toxicity. On the other hand, several phase II studies suggested that modifying the FTD/TPI schedule in combination with BEV from 4-week intervals (2 weeks-on, 2 weeks-off) to bi-weekly dosing (1 week-on, 1 week-off) reduced hematologic toxicities without reducing efficacy. Therefore, we commenced a phase III study to confirm the superiority of bi-weekly FTD/TPI plus BEV to 4-week intervals FTD/TPI monotherapy. Methods: This study is an open-label, multicenter, phase III trial conducted in Colorectal Cancer Study Group of Japan Clinical Oncology Group. We randomly assigned, in a 1:1 ratio, patients who were refractory or intolerant to fluoropyrimidine, oxaliplatin, irinotecan, angiogenesis inhibitor, anti-EGFR antibody (if RAS-wild type), BRAF inhibitor and anti-EGFR antibody (if BRAF V600E-mutant), and immune check point inhibitor (if dMMR/MSI-H) to the treatment of mCRC to receive 4-week intervals FTD/TPI 70mg/m2/day monotherapy (arm A) or bi-weekly FTD/TPI plus bevacizumab 5mg/kg (arm B). The primary endpoint was overall survival (OS). Secondary endpoints were progression-free survival (PFS), response rate (RR), disease control rate (DCR), and safety. Results: In consideration of the results of the SUNLIGHT trial, this study was prematurely terminated. Between January 2022 and February 2023, a total of 152 patients were randomized (75 in the arm A and 77 in the arm B). Patient backgrounds between the two arms were well balanced. At the data cut-off date, all enrolled patients discontinued protocol treatment due to disease progression (69.3% vs. 59.7%) and treatment-related adverse events (6.7% vs. 2.6%). With a median follow-up of 8.3 months for surviving patients (OS events, 45% vs. 40%), the median OS was 12.2 vs. 11.8 months (hazard ratio [HR], 0.905; 95% confidence interval [CI], 0.556 to 1.473) and the median PFS was 2.4 vs. 4.0 months (HR, 0.607; 95% CI, 0.426 to 0.865). RR was 1.3% vs. 5.3% and DCR was 45.3% vs. 53.3%. The most common Grade 3 or higher adverse events in each group were neutropenia (46.6% vs. 24.0%), anemia (15.1% vs. 4.0%), fatigue (2.7% vs. 8.0%), anorexia (5.5% vs. 5.3%), nausea (5.5% vs. 5.3%) and febrile neutropenia (4.1% vs. 0%). Conclusions: Although this study was terminated early, the bi-weekly FTD/TPI plus BEV combination in late-line chemotherapy for patients with mCRC resulted in prolonged PFS and reduced hematologic toxicity compared to 4-week intervals FTD/TPI monotherapy. Long-term results including OS are currently under follow-up. Clinical trial information: jRCTs031210544 .

A Retrospective Study of Trifluridine/Tipiracil with Fruquintinib in Patients with Chemorefractory Metastatic Colorectal Cancer.

Trifluridine/tipiracil (TAS-102) and fruquintinib are novel antitumor agents for patients with refractory metastatic colorectal cancer (mCRC). We conducted a retrospective study to explore the clinical efficacy and drug toxicities of combination therapy with TAS-102 and fruquintinib in real-life clinical practice. Between March 2021 and February 2023, patients at two different centers with mCRC who failed two or more lines of prior therapy and received TAS-102 in combination with fruquintinib were recruited. In total, 32 mCRC patients were included in the analysis. The objective response rate (ORR) and the disease control rate (DCR) were 9.4% and 75%. The median progression-free survival (PFS) and overall survival (OS) were 6.3 (95% CI: 5.3-7.3) and 13.5 (95% CI: 9.5-17.5) months, respectively. Patients without liver metastasis or peritoneal metastasis obtained better median PFS (7.1 m vs. 5.6 m, p = 0.03 and 6.3 m vs. 3.4 m, p = 0.04), and OS (15.2 m vs. 10.4 m, p = 0.01 and 13.6 m vs. 7.1 m, p = 0.03), respectively. Other clinicopathological features, including age, tumor site, KRAS status, dosage of fruquintinib, and treatment line, did not affect the clinical efficacy of TAS-102 combined with fruquintinib. The most common grade three-four toxicities were neutropenia (46.9%), anemia (21.9%), diarrhea (15.6%), nausea (12.5%), and hand-foot syndrome rash (12.5%). Our results suggest that TAS-102 combined with fruquintinib has promising clinical efficacy and manageable safety for refractory mCRC patients in a real-world clinical setting. Further prospective trials are warranted to confirm our results.

115P Sidedness and survival of chemo-refractory metastatic colorectal cancer treated with lonsurf or regorafenib: A nationwide population-based study in Taiwan

115P Sidedness and survival of chemo-refractory metastatic colorectal cancer treated with lonsurf or regorafenib: A nationwide population-based study in Taiwan

Sotorasib plus Panitumumab in Refractory Colorectal Cancer with Mutated KRAS G12C

BackgroundKRAS G12C is a mutation that occurs in approximately 3 to 4% of patients with metastatic colorectal cancer. Monotherapy with KRAS G12C inhibitors has yielded only modest efficacy. Combining the KRAS G12C inhibitor sotorasib with panitumumab, an epidermal growth factor receptor (EGFR) inhibitor, may be an effective strategy.MethodsIn this phase 3, multicenter, open-label, randomized trial, we assigned patients with chemorefractory metastatic colorectal cancer with mutated KRAS G12C who had not received previous treatment with a KRAS G12C inhibitor to receive sotorasib at a dose of 960 mg once daily plus panitumumab (53 patients), sotorasib at a dose of 240 mg once daily plus panitumumab (53 patients), or the investigator’s choice of trifluridine–tipiracil or regorafenib (standard care; 54 patients). The primary end point was progression-free survival as assessed by blinded independent central review according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Key secondary end points were overall survival and objective response.ResultsAfter a median follow-up of 7.8 months (range, 0.1 to 13.9), the median progression-free survival was 5.6 months (95% confidence interval [CI], 4.2 to 6.3) and 3.9 months (95% CI, 3.7 to 5.8) in the 960-mg sotorasib–panitumumab and 240-mg sotorasib–panitumumab groups, respectively, as compared with 2.2 months (95% CI, 1.9 to 3.9) in the standard-care group. The hazard ratio for disease progression or death in the 960-mg sotorasib–panitumumab group as compared with the standard-care group was 0.49 (95% CI, 0.30 to 0.80; P=0.006), and the hazard ratio in the 240-mg sotorasib–panitumumab group was 0.58 (95% CI, 0.36 to 0.93; P=0.03). Overall survival data are maturing. The objective response was 26.4% (95% CI, 15.3 to 40.3), 5.7% (95% CI, 1.2 to 15.7), and 0% (95% CI, 0.0 to 6.6) in the 960-mg sotorasib–panitumumab, 240-mg sotorasib–panitumumab, and standard-care groups, respectively. Treatment-related adverse events of grade 3 or higher occurred in 35.8%, 30.2%, and 43.1% of patients, respectively. Skin-related toxic effects and hypomagnesemia were the most common adverse events observed with sotorasib–panitumumab.ConclusionsIn this phase 3 trial of a KRAS G12C inhibitor plus an EGFR inhibitor in patients with chemorefractory metastatic colorectal cancer, both doses of sotorasib in combination with panitumumab resulted in longer progression-free survival than standard treatment. Toxic effects were as expected for either agent alone and resulted in few discontinuations of treatment. (Funded by Amgen; CodeBreaK 300 ClinicalTrials.gov number, NCT05198934.)

Phase II of desynchronized irinotecan plus bevacizumab, oxaliplatin, 5-fluorouracil, and folinic acid (bFOLFIRINOX-3) administration in chemorefractory metastatic colorectal cancer patients.

e15563 Background: In chemorefractory metastatic colorectal cancer (mCRC), targeted therapy such as TAS-102 and regorafenib have shown a modest survival benefit with a median progression free survival (PFS) of only about 2 months. A phase I of FOLFIRINOX3-bevacizumab (bFOLFIRINOX 3) defined the RP2D for irinotecan and showed promising activity. The aim of this phase II trial was to evaluate the safety and efficacy of bFOLFIRINOX-3 in chemorefractory mCRC. Methods: The phase I trial defined the combination of bFOLFIRINOX-3 at the irinotecan’s RP2D of 70mg/m² day 1 and day 3. In phase II, patients &gt; 18years and ECOG 0 or 1, with a pathological confirmed mCRC and experienced treatment failure after standard chemotherapies that include at least 5-fluorouracil, oxaliplatin and irinotecan were enrolled. Absence of residual neuropathy and previous grade 3 irinotecan related toxicity was manditory. Regimen tested consisted of bevacizumab (5mg/kg), folinic acid (400mg/m2), 5-fluorouracil (2400mg/m2 for 46h), oxaliplatin (85mg/m2) and irinotecan (70mg/m² administered before and after infusional 5-fluorouracil). CT scan were performed every 2 months. Primary endpoint was the 2-months PFS. Secondary endpoints included objective response rate (ORR), median PFS, overall survival (OS) and toxicity. Results: Twenty-free patients were enrolled (October 2018 to December 2022). Median age was 62 y (range: 50-70y). These patients have been treated with several previous lines of chemotherapy (median = 3, range [1-6]). Median follow up was 11 months (range [3-31.3]). The 2-months PFS was 100%. Overall response rate was 17,4%. Median PFS was 7.8 months (IC95%[5.9;9.5]) and median OS was 31.3 months (IC95% [12.4;NR]). Grade 3 adverse events occured in 43.5% with mostly diarrhea (39.1%) and neutropenia (21.7%). Grade 3 diarrhea was consistently resolving after a dose reduction of chemotherapy. The most common drug-related adverse events (all grades) were fatigue (60.9%), diarrhea (73.9%), nausea (39.1%), peripheral neuropathy (47.8%), thrombopenia (82.6%) and anemia (56.5%). Conclusions: The combination of bFOLFIRINOX-3 yielded better ORR, median PFS and OS than standard of care. The regimen was well tolerated. The study met its primary endpoint and support for future randomized phase III compared to standard of care. Clinical trial information: NCT03795311 .

Panitumumab plus trifluridine/tipiracil as third-line anti-EGFR rechallenge therapy in chemo-refractory RAS WT metastatic colorectal cancer: The VELO randomized phase II clinical trial.

129 Background: Rechallenge therapy with epidermal growth factor receptor (EGFR) inhibitors in chemo-refractory metastatic colorectal cancer (mCRC) is an emerging therapeutic approach. Trifluridine-tipiracil is approved for treatment of chemo-refractory mCRC patients. Methods: Chemo-refractory RAS WT mCRC patients, that had a major response (partial or complete response) to first-line chemotherapy plus an anti-EGFR monoclonal antibody and had an-anti-EGFR drug-free interval during second-line therapy of four or more months were randomized in a phase II trial to assess the addition of the anti-EGFR monoclonal antibody panitumumab to trifluridine-tipiracil as third-line rechallenge therapy. The primary endpoint was progression free survival (PFS). Baseline plasma was analyzed for circulating free tumor (ct) DNA by using Biocartis Idylla platform to detect mutations in KRAS, NRAS, BRAF ( V600E) and EGFRextracellular domain ( S492R). In 24 patients with baseline RAS/BRAF wild type (WT) ctDNA, Foundation One liquid CDx (324 gene profiling) was also performed before treatment and at disease progression. Results: 62 patients were treated with trifluridine-tipiracil (31 patients, arm A) or with trifluridine-tipiracil plus panitumumab (31 patients, arm B). As of September 16, 2022, 1 patient in arm A and 2 patients in arm B were on treatment. The primary endpoint was met. Median PFS (mPFS) was 4 months in arm B versus 2.5 months in arm A [hazard ratio (HR): 0.48; 95% CI 0.28-0.82; P = 0.007]. Baseline plasma RAS/BRAF WT ctDNA was found in 23/31 patients in Arm A and in 26/31 patients in Arm B. In this group, mPFS was 4.5 months in Arm B versus 2.6 months in Arm A (HR: 0.48; 95% CI 0.26-0.89; P = 0.019). Disease control (major responses plus stable disease) was higher for patients in Arm B compared to Arm A (81% versus 48%), whereas disease progression was the best response in 19% versus 52% patients, respectively. PFS rates at 6 and 12 months were 38.5% and 15.4% in arm B versus 13% and 0% in arm A. At disease progression, Foundation One liquid CDx detected several mutations within the EGFR pathway, which could correlate with cancer cell resistance to panitumumab. Conclusions: This is the first prospective randomized trial which evaluated anti-EGFR monoclonal antibody (panitumumab) in addition to standard of care (trifluridine-tipiracil) as third-line rechallenge therapy in chemo-refractory RASWT mCRC patients. Baseline liquid biopsy allows selection of RAS/BRAF WT ctDNA patients who could have a relevant clinical benefit. Clinical trial information: NCT05468892 .

437TiP Trial in progress: A phase III global study of sotorasib, a specific KRAS G12C inhibitor, in combination with panitumumab versus investigator’s choice in chemorefractory metastatic colorectal cancer (CodeBreaK 300)

Sotorasib selectively and irreversibly inhibits the Kirsten rat sarcoma (KRAS) G12C mutant protein. This inhibition can result in accumulation of activated epidermal growth factor receptor (EGFR), which may drive resistance to sotorasib. Therefore, the combination of sotorasib with an EGFR inhibitor, such as panitumumab, might lead to more complete inhibition of tumor cell growth and survival. Early data for the combination of sotorasib and panitumumab from CodeBreaK 101 subprotocol H showed promising antitumor activity in chemorefractory metastatic colorectal cancer (mCRC). The objective of the current study is to evaluate whether the combination of sotorasib and panitumumab is superior to standard of care trifluridine/tipiracil or regorafenib in the setting of chemorefractory mCRC. CodeBreaK 300 (NCT05198934) is a global phase III randomized, open-label, active-controlled study of the efficacy and safety of oral sotorasib combined with intravenous panitumumab in patients with mCRC. Key eligibility criteria include mCRC with KRAS G12C mutation confirmed by central molecular testing of tumor biopsy, and at least 1 prior line of therapy. Patients must have received and progressed or experienced disease recurrence on or after fluoropyrimidine, irinotecan, and oxaliplatin given for metastatic disease unless ineligible in the opinion of the investigator. Approximately 153 patients will be enrolled and randomized 1:1:1 to receive either sotorasib 960 mg daily and panitumumab or sotorasib 240 mg daily and panitumumab or investigator’s choice (trifluridine and tipiracil, or regorafenib). The primary endpoint is progression-free survival using Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) by Blinded Independent Central Review (BICR). Key secondary endpoints include overall survival and objective response. Global enrollment is ongoing. NCT05198934. Medical writing support was provided by Tim Harrison, PharmD (Amgen Inc.). Amgen Inc.

446TiP Randomized phase III study of bi-weekly trifluridine/tipiracil (FTD/TPI) plus bevacizumab (BEV) vs. FTD/TPI for chemorefractory metastatic colorectal cancer (mCRC): ROBiTS/JCOG2014

FTD/TPI is widely used as a late-line treatment for patients with mCRC who are refractory or intolerant to standard chemotherapy based on the results of phase III studies RECOURSE (Mayer RJ, N Engl J Med 2015.) and TERRA (Xu J, J Clin Oncol 2018.). More recently, the efficacy of the combination of FTD/TPI and BEV has also been reported, albeit in phase II studies (Kuboki Y, Lancet Oncol 2017. Pfeiffer P. Lancet Oncol 2020.). However, the combination of FTD/TPI and BEV increased the frequency of neutropenia, a dose-limiting toxicity of FTD/TPI, with Grade 3 or higher reported as 44%-72%.

O-4 Trifluridine/tipiracil (TAS-102) with or without bevacizumab in patients with pretreated metastatic esophago-gastric adenocarcinoma (mEGA): A Danish randomized trial (LonGas)

Trifluridine/tipiracil (FTD/TPI, also known as TAS-102) prolongs survival in patients with heavily pretreated metastatic gastric cancer (Shitara, Lancet Oncol 2018). The randomized Danish Lonsurf trial showed that a combination of FTD/TPI and bevacizumab prolonged PFS and OS in patients with chemo-refractory metastatic colorectal cancer (Pfeiffer, Lancet Oncol 2020). Inspired by these results, we designed the present investigator-initiated randomized trial testing FTD/TPI and bevacizumab in patients with pretreated mEGA. The main inclusion criteria were histologically confirmed mEGA, previous therapy with a fluoropyrimidine and platinum, PS 0-1. In arm A, FTD/TPI was administered orally at the dose of 35 mg/m2/dose bid from days 1-5 and 8-12 and in arm B the same dose of FTD/TPI was combined with bevacizumab at a dose of 5 mg/kg on day 1 and on day 15 of a 28-day treatment cycle. A total of 96 patients were needed to show an increase in progression-free survival (PFS – primary endpoint) from 2.0 months to 4.0 months. To ensure at least 96 evaluable patients we included 103 patients. Here we report efficacy and safety data of all randomized patients (intention-to-treat population). 103 pretreated patients with mEGA were randomized from October 2019 to September 2021 at 4 Danish University Hospitals. Baseline characteristics were (arm A/arm B): median age 66/64 years, females 19%/22%; PS 0 47%/44%, median number of metastatic sites 2/2, at least 2 prior lines of therapy 42%/42%. Baseline characteristics including blood tests were well balanced. There was no significant difference in PFS (6 months PFS 28% vs 40%, 12 months PFS 6% vs18%, median PFS 3.7 vs 3.9 months; HR 0.71, p=0.11), median OS (9.0 vs 9.9 months; HR 0.86, p=0.53), response rate (2% vs 6%; p=0.35) or disease control rate (47% vs 56%; p=0.43)b. Therapies were well tolerated with adverse events as expected and with no significant difference in severe toxicity. Neutropenia ≥ grade 3 was observed in 49%/46% of patients, but only febrile neutropenia in 8%/10%. Other severe adverse events were fatigue 4%/10% and nausea 6%/6%. In patients with pretreated mEGA, FTD/TPI + bevacizumab did not improve efficacy compared with FTD/TPI monotherapy in patients previously treated with fluoropyrimidine and platinum. Both regimens produced encouraging PFS and OS and both regimens were well tolerated with adverse events as expected. Compared to the heavily pretreated patients in TAGS, only 42% of patients in LonGas had received at least 2 lines of therapy. This may account for the unexpected long PFS in patients receiving FTD/TPI monotherapy.

P-50 RETRO-TAS, a retrospective observational study of rifluridine/tipiracil in chemorefractory metastatic colorectal cancer

Trifluridine/tipiracil (TAS-102) is an oral combination of an antineoplastic thymidine-based nucleoside analogue, trifluridine, and the thymidine phosphorylase (TPase) inhibitor, tipiracil hydrochloride, indicated for patients (pts) with metastatic colorectal cancer (mCRC) as third line therapy. The approved dose of TAS-102 in adults is 35 mg/m2/dose administered orally twice daily on Days 1 to 5 and Days 8 to 12 of each 28-day cycle as long as benefit is observed or until unacceptable toxicity occurs.

Impact of trough concentrations of regorafenib and its major metabolites M-2 and M-5 on overall survival of chemorefractory metastatic colorectal cancer patients: Results from a multicentre GERCOR TEXCAN phase II study

PurposeThis prospective pharmacokinetic (PK) ancillary study of the TEXCAN phase II GERCOR trial of patients with chemorefractory metastatic colorectal cancer and treated with regorafenib (REGO) investigated correlations between overall survival (OS) and concentrations (C) of REGO and its active metabolites, M-2 and M-5. Methods55 patients received REGO 160 mg/day for 21 days of a 28-day cycle (NCT02699073). REGO, M-2, M-5 were measured by liquid chromatography-mass spectrometry assay on day 15 of cycle 1 (C1) and 2 (C2). We studied the association between OS and Cmin of REGO, M-2 and M-5 at C1 and their accumulations between C1 and C2. ResultsMedians of C2/C1 M-2 and M-5 ratios were 0.82 (interquartile range 0.50–1.78) and 0.75 (interquartile range 0.41–1.93), respectively. Patients with C2/C1 M-2 ratio ≥ median had improved survival compared to those < median (12.6 versus 4.0 months, P = 0.023), corresponding to a 66% mortality risk reduction in multivariate analysis.The C2/C1 M-2 ratio correlated with C1 REGO+M-2+M-5 (Csum; P = 0.006). Restricted cubic spline analysis showed an increased OS benefit as the C2/C1 M-2 ratio raises and when C1 Csum ranged between 2.5 and 5.5 mg/L. Patients within the Csum range had a reduced incidence of serious adverse events and improved OS. ConclusionsWe identified PK parameters associated with a survival benefit in patients with metastatic colorectal cancer treated by REGO. OS and safety were favourable when C1 REGO+M-2+M-5 Csum ranged between 2.5 and 5.5 mg/L. These results pave the way for individual REGO dose modification strategies based on PK monitoring. Clinical trial referenceNCT02699073

Early modulation of Angiopoietin-2 plasma levels predicts benefit from regorafenib in patients with metastatic colorectal cancer

BackgroundNo biomarkers are currently available to predict the efficacy of trifluridine/tipiracil (FTD/TPI) in chemorefractory metastatic colorectal cancer. The multicohort REGOLAND study aims at exploring and validating circulating markers potentially able to predict benefit from regorafenib in this setting. Material and methodsIn the retrospective ‘regorafenib exploratory cohort’, including 105 patients treated with regorafenib, baseline (d1) plasma levels of angiogenesis-related biomarkers and their early modulation after 15 days (d15) of treatment were investigated for correlation with clinical outcome. Based on a pre-specified statistical hypothesis, main retrospective findings were prospectively challenged in the ‘regorafenib validation cohort’, including 100 patients treated with regorafenib. Prospectively validated putative biomarkers were then assessed in the control ‘FTD/TPI cohort’, including 93 patients treated with FTD/TPI. ResultsIn the ‘regorafenib exploratory cohort’, the early (d15) increase of Angiopoietin-2 (Ang-2) was associated with longer progression-free survival (HR:0.57 [95%CI:0.38–0.88], P = 0.004) and a trend towards longer OS (HR:0.74 [95%CI:0.48–1.14], P = 0.165), than the early decrease. Similar results were prospectively confirmed in the ‘regorafenib validation cohort’ (HR for progression-free survival:0.72 [95%CI:0.48–1.08], P = 0.095; HR for OS:0.77 [95%CI:0.51–1.16], P = 0.204). No predictive impact was shown for the early modulation of Ang-2 in the ‘FTD/TPI cohort’. High baseline Ang-2 levels predict poor prognosis in all the investigated cohorts, independently of other clinical prognostic variables. ConclusionsThe early modulation of circulating Ang-2 predicts the efficacy of regorafenib. Baseline Ang-2 plasma levels are an independent prognostic biomarker in chemorefractory metastatic colorectal cancer.

Treatment patterns and outcomes of patients with metastatic colorectal cancer in third-line and beyond systemic therapy: Real-world data from a setting with limited resources.

58 Background: Regorafenib and trifluridine/tipiracil (TAS-102) are the only therapeutic options for patients with chemorefractory metastatic colorectal cancer (mCRC) with demonstrated benefit in overall survival (OS). However, they are not accessible worldwide. In Brazil, they have been recently approved, but they have not yet been provided by public health system or private health insurances. We aimed to describe the treatment patterns and clinical outcomes of that population in a setting with limited access to those drugs. Methods: Retrospective study evaluating 510 patients with mCRC who were treated at five Oncoclinicas centers in Brazil from January 2011 to December 2019. Demographic and clinical data were retrieved from electronic medical records. The median OS was calculated by Kaplan-Meier method and prognostic factors were evaluated via multivariable Cox Regression, calculating the Hazard Ratio (HR) and the confidence interval (CI95%). Results: A total of 163 patients (33% of the overall population) received third-line and 73 (15%) fourth-line systemic therapy. Median age was 62 years, 59% were male. Tumors were right-sided in 19%, RAS mutated 44%, BRAF mutated 3%, and high-frequency microsatellite instability 3%. Metastasectomy prior to third-line was performed in 62% of the patients. From the start of third-line therapy, median follow-up was 9.0 months, with 67% of deaths, and median OS was 13.7 months (CI95% 11.8m–20.0m). Most adopted regimens in third-and fourth-line were (1) rechallenge with oxaliplatin-based therapy (39% and 26%, respectively); (2) rechallenge with irinotecan-based therapy (32% and 34%); (3) rechallenge with anti-EGFR monoclonal antibodies (20% and 29%); (4) regorafenib (13% and 25%); and (5) TAS-102 (2% and 4%). In multivariable model including clinical and molecular variables, prior metastasectomy was the only significant prognostic factor for OS (HR 0.51, CI95% 0.31–0.83, p=0.007). Conclusions: In real-world, a meaningful proportion of patients with mCRC are eligible for third and later lines of therapy. Rechallenge with chemotherapy and anti-EGFR agents is overused in a setting of limited access to therapies with demonstrated OS benefit, such as regorafenib and TAS-102. Barriers to drug access impair the adoption of the best evidence-based continuum of care and strategies to overcome them are urgently needed. Refractory patients in later lines of therapy derive survival benefit from prior metastasectomy.

Phase I Dose-Escalation Trial of an Innovative Chemotherapy Regimen Combining a Fractionated Dose of Irinotecan Plus Bevacizumab, Oxaliplatin, 5-Fluorouracil, and Folinic Acid (bFOLFIRINOX-3) in Chemorefractory Metastatic Colorectal Cancer.

Simple SummaryTreatment of non-resectable metastatic colorectal cancer (mCRC) involves chemotherapy based on 5-fluorouracil, oxaliplatin and irinotecan and monoclonal antibodies targeting VEGF or EGFR. After an initial progression, it is usual to change the chemotherapy regimen and targeted therapy, with rather moderate results. Several studies have focused on the interest of using again already used molecules and rechallenge with oxaliplatin and irinotecan bi fractionation (FOLFIRI3) have previously shown efficacy in chemorefractory patients, but desynchronized triplet chemotherapy was never tested. The aim of this study was to evaluate the safety and efficacy of a new regimen so-called: FOLFIRINOX-3 bevacizumab in chemorefractory metastatic colorectal cancer. The care of metastatic colorectal cancers is based on combination chemotherapies including 5-fluorouracil, oxaliplatin, irinotecan, and monoclonal antibodies targeting the epidermal growth factor receptor or vascular endothelial growth factor. The regimen is determined based on the patient’s molecular biology and general condition. Irinotecan bifractionation showed efficacy in chemorefractory patients in a previous study, FOLFIRI-3, but a desynchronized triplet has never been tested. The aim of bFOLFIRINOX-3 is to determine the safety, tolerance, and efficacy of a new regimen (FOLFIRINOX-3 bevacizumab) in chemorefractory patients. The aim of this study was to evaluate the safety and efficacy of FOLFIRINOX-3 bevacizumab in chemorefractory metastatic colorectal cancer (mCRC). A standard phase I, “3 + 3” design study was performed. The standard protocol comprised simplified FOLFOX 4 (folinic acid 400 mg/m2), 5-fluorouracil (a 400 mg/m2 bolus followed by 2400 mg/m2 for 46 h), oxaliplatin (85 mg/m2) and irinotecan (administered before and after 5-fluorouracil infusion), plus bevacizumab (5 mg/kg). In a “3 + 3” design, three different doses of irinotecan were tested: 60, 70 and 90 mg/m2. The primary endpoint was the maximum tolerable dose (MTD) of irinotecan. The secondary endpoints included the objective response (at 8 and 16 weeks) according to the RECIST 1.1 criteria and progression free survival. Thirteen patients were enrolled, and twelve patients were finally evaluated for dose-limiting toxicity (DLT). The dose level defined was 70 mg/m2 irinotecan. A total of three DLTs were observed (grade 3 diarrhea): two DLTs at the 90 mg/m2 dose level and one at the 70 mg/m2 dose level. The most frequently described adverse events were asthenia (93%), diarrhea (77%), nausea (62%) and peripheral sensory neuropathy (46%). The most frequent biological event was thrombopenia (54%). Regarding efficacy, among the 11 evaluable patients, no progression was observed at 8 weeks, and the partial response rate was 18.2%. At 16 weeks, a partial response rate of 27.3% was observed, and five patients had a stable disease. The new regimen of bFOLFIRINOX-3 with irinotecan at 70 mg/m2 was well tolerated. In chemorefractory patients, this protocol shows a high response rate.

Initial experience of TAS-102 chemotherapy in Australian patients with Chemo-refractory metastatic colorectal cancer

For patients with refractory metastatic colorectal cancer (mCRC) treatment with Trifluridine/Tipiracil, also known as TAS-102, improves overall survival. This study aims to investigate the efficacy and safety of TAS-102 in a real-world population from Victoria, Australia. A retrospective analysis of prospectively collected data from the Treatment of Recurrent and Advanced Colorectal Cancer (TRACC) registry was undertaken. The characteristics and outcomes of patients receiving TAS-102 were assessed and compared to those enrolled in the registration study (RECOURSE).Across 13 sites, 107 patients were treated with TAS-102. The median age was 60 years (range: 31-83), compared to 63 for RECOURSE. Comparing registry TAS-102-treated and RECOURSE patients, 75% vs 100% were ECOG performance status 0-1, 74% vs 79% had initiated treatment more than 18 months from diagnosis of metastatic disease and 36% vs 49% were RAS wild-type. Median time on treatment was 10.4 weeks (range: 1.7-32). Median progression-free survival (PFS) was 3.3 months compared to 2 months in RECOURSE, while median overall survival was the same at 7.1 months. Two patients (2.3%) had febrile neutropenia and there were no treatment-related deaths, where TAS-102 dose at treatment initiation was at clinician discretion.TRACC registry patients treated with TAS-102 were younger than those from the RECOURSE trial, with similar overall survival observed. Less strict application of RECIST criteria and less frequent imaging may have contributed to an apparently longer PFS.

Yttrium-90 Hepatic Radioembolization for Advanced Chemorefractory Metastatic Colorectal Cancer: Survival Outcomes Based on Right- Versus Left-Sided Primary Tumor Location.

BACKGROUND. Primary colon cancer location affects survival of patients with metastatic colorectal cancer (mCRC). Outcomes based on primary tumor location after salvage hepatic radioembolization with 90Y resin microspheres are not well studied. OBJECTIVE. The objectives of this study are to assess the survival outcomes of patients with advanced chemorefractory mCRC treated with 90Y radioembolization, as stratified by primary tumor location, and to explore potential factors that are predictive of survival. METHODS. A total of 99 patients who had progressive mCRC liver metastases while receiving systemic therapy and who were treated with 90Y radioembolization at a single center were retrospectively analyzed. For 89 patients, tumor response on the first imaging follow-up examination (CT or MRI performed at a mean [± SD] of 1.9 ± 0.9 months after 90Y radioembolization) was evaluated using RECIST. Overall survival (OS), OS after 90Y radioembolization, and hepatic progression-free survival (PFS) were calculated using the Kaplan-Meier method. Outcomes and associations of outcomes with tumor response were compared between patients with left- and right-sided tumors. RESULTS. A total of 74 patients had left-sided colon cancer, and 25 patients had right-sided colon cancer. Median OS from the time of mCRC diagnosis was 37.2 months, median OS after 90Y radioembolization was 5.8 months, and median hepatic PFS was 3.3 months. Based on RECIST, progressive disease on first imaging follow-up was observed in 38 patients (43%) after 90Y radioembolization and was associated with shorter OS after 90Y radioembolization compared with observation of disease control on first imaging follow-up (4.0 vs 10.5 months; p < .001). Patients with right-sided primary tumors showed decreased median OS after 90Y radioembolization compared with patients with left-sided primary tumors (5.4 vs 6.2 months; p = .03). Right- and left-sided primary tumors showed no significant difference in RECIST tumor response, hepatic PFS, or extrahepatic disease progression (p > .05). Median survival after 90Y radioembolization was significantly lower among patients with progressive disease than among those with disease control in the group with left-sided primary tumors (4.2 vs 13.9 months; p < .001); however, this finding was not observed in the group with right-sided primary tumors (3.3 vs 7.2 months; p = .05). CONCLUSION. Right-sided primary tumors were independently associated with decreased survival among patients with chemorefractory mCRC after 90Y radioembolization, despite these patients having a similar RECIST tumor response, hepatic PFS, and extrahepatic disease progression compared with patients with left-sided primary tumors. CLINICAL IMPACT. Primary colon cancer location impacts outcomes after salvage 90Y radioembolization and may help guide patient selection.

Rationale and Study Design of the PARERE Trial: Randomized phase II Study of Panitumumab Re-Treatment Followed by Regorafenib Versus the Reverse Sequence in RAS and BRAF Wild-Type Chemo-Refractory Metastatic Colorectal Cancer Patients

BackgroundA recent phase II randomized Japanese study reported better survival with regorafenib followed at progression by cetuximab ± irinotecan compared with the reverse standard sequence in chemo-refractory and anti-EGFR-naïve, RAS wild-type (wt) mCRC patients. Nowadays the use of anti-EGFR antibodies is more frequently anticipated to the first-line of therapy especially in patients with left-sided RAS/BRAF wt tumours. However, retrospective analyses and phase II single-arm trials showed promising activity of re-using anti-EGFRs in metastatic colorectal cancer (mCRC) patients who previously achieved benefit from a first-line anti-EGFR-based treatment. Post-hoc analyses of these trials revealed that the detection of RAS mutations in circulating tumour DNA (ct-DNA) at the time of re-treatment may be useful to identify resistant patients. Patients and MethodsPARERE (NCT04787341) is a prospective, open label, multicentre phase II study in which 214 RAS/BRAF wt chemo-refractory mCRC patients with previous benefit from first-line anti-EGFR-based treatment and RAS/BRAF wt ct-DNA in the liquid biopsy collected at the time of inclusion will be randomized in a 1:1 ratio to receive panitumumab followed after progression by regorafenib versus the reverse sequence. Primary endpoint is overall survival. Secondary endpoints are 1st-progression free-survival (PFS), 2nd-PFS, time to failure strategy, objective response rate, and safety. Aim of the studyThe aim of this study is to validate the role of anti-EGFR retreatment and its proper placement in the therapeutic route of mCRC patients selected according to the analysis of ct-DNA in liquid biopsy. Results are expected at the end of 2023.

Phase I dose-escalation study of desynchronized irinotecan plus bevacizumab, oxaliplatin, 5-fluorouracil, and folinic acid (bFOLFIRINOX-3) administration in chemorefractory metastatic colorectal cancer patients.

e15573 Background: Treatment of non-resectable metastatic colorectal cancer (mCRC) involves chemotherapy based on 5-fluorouracil, oxaliplatin and irinotecan and monoclonal antibodies targeting VEGF or EGFR. Rechallenge with oxaliplatin and irinotecan bi fractionation (FOLFIRI3) have previously shown efficacy in chemorefractory patients but desynchronized triplet chemotherapy was never tested. The aim of this study was to evaluate the safety and efficacy of a new regimen so-called: FOLFIRINOX-3 bevacizumab in chemorefractory mCRC. Methods: A phase I study to test bFOLFIRINOX 3 regimen was designed using Standard “3 + 3” design for dose escalation. Patients enrolled, &gt;18years and ECOG 0 or 1, have a pathologically confirmed mCRC and experienced treatment failure after standard chemotherapy that include 5-fluorouracil, oxaliplatin and irinotecan. Absence of residual neuropathy and previous grade 3 irinotecan related toxicity was manditory. Regimen tested consisted of bevacizumab (5mg/kg) plus simplified FOLFOX4 (folinic acid (400mg/m2), 5-fluorouracil (400mg/m2 bolus followed by 2400mg/m2 for 46h), oxaliplatin (85mg/m2) and irinotecan (administered before and after infusional 5-fluorouracil). Three irinotecan levels were planned at 60, 70 and 90 mg/m² (day 1 and day 3). Dose limiting toxicities (DLT) were identified during the first 2 cycles. Primary endpoint was assessment of maximum tolerable dose trough evaluation of acute toxicities (CTCAE v4.03). Secondary endpoints included objective response (RECIST 1.1), progression free survival, overall survival and late toxicity. Results: Thirteen patients received experimental treatment on this study. The RP2D was irinotecan 70mg/m² day 1 and day 3. Two patients experienced DLTs (G3 diarhea ) at dose level 90mg/m² and one DLT occured (G3 diarrhea) at 70mg/m² level. The most common drug-related adverse events (all grades) were fatigue (92.3%), diarrhea (76.9%), nausea (61.5%), peripheral neuropathy (61.5%), thrombopenia (46.1%) and anemia (15.3%). Among 11 response-evaluable patients, we noticed 4 partial responses, 7 stable disease and no progression as best response. Conclusions: The combination of bFOLFIRINOX-3 at the RP2D of 70mg/m² day 1 and day 3. was well tolerated and feseably. The regimen resulted in high response rate in chemorefractory metastatic colorectal cancer. Phase II is ongoing. Clinical trial information: NCT03795311.