FOLFIRI Regimen Research Articles

Effectiveness and Cost-Utility Analysis of Different Doses of Irinotecan Plus Bevacizumab in Patients With Metastatic Colorectal Cancer: A Long-Term and Prospective Cohort Study.

ObjectivePatients with metastatic colorectal cancer (mCRC) had oncological benefits with irinotecan dose escalation of FOLFIRI regimen combined with bevacizumab according to UGT1A1 genotypes in our previous study. In the current study, we performed a quality of life (QOL) outcome evaluation and cost-utility analysis of different irinotecan dose regimens in patients with mCRC.Materials and MethodsWith inverse probability-of-treatment weighting (IPTW) matching on all covariates, 75 patients with dose escalation of irinotecan (study group) and 121 patients with the recommended dose of irinotecan (control group) were recruited between October 2015 and December 2019. The QOL outcome measures were Functional Assessment of Cancer Therapy-Colorectal, Beck Anxiety Inventory, Beck Depression Inventory, and SF-36; cost-utility outcome measures were medical direct costs, quality-adjusted life-years (QALYs), and incremental cost-utility ratios (ICURs).ResultsAll mCRC patients exhibited a significant decrease in both emotional wellbeing and depression from pretherapeutic period to posttherapeutic 6th month (P < 0.05); however, from the posttherapeutic 1st year to the 2nd year, improvement in most QOL measures was significantly better in the study group than in the control group (P < 0.05). Over a 2-year time period, the study group had higher total medical direct costs than the control group (US$ 54,742 ± 14,013 vs. US$ 54,608 ± 9,673) and higher average QALYs gained (1.88 vs. 1.65), with an ICUR of US$ 583 per QALY gained.ConclusionFor patients with mCRC, irinotecan dose escalation appeared cost-effective with considerable QOL improvements during the study period. Further randomized, multi-institutional controlled trials are warranted to corroborate these results.

Lobaplatin hyperthermic intraperitoneal chemotherapy plus cytoreduction and rechallenge using cetuximab for wild-type RAS peritoneal metastatic colon cancer: a case report and literature review

BackgroundSynchronous peritoneal metastasis of colorectal cancer usually predicts a bleak prognosis. Hyperthermic intraperitoneal chemotherapy (HIPEC) and cytoreductive surgery (CRS) have brought a glimmer of hope to the treatment of peritoneal cancer. Few cases treated with lobaplatin have been reported in the literature and the regimen is controversial. In this case, the comprehensive treatment scheme of lobaplatin-based HIPEC plus CRS and rechallenge using cetuximab plus systemic chemotherapy is effective, especially for the patients with left colon cancer (wild-type RAS).Case presentationA 49 year-old man with signet ring cell carcinoma of sigmoid colon with extensive abdominal metastasis (wild-type RAS) was hospitalized with prolonged abdominal pain, distention and abdominal mass. After receiving HIPEC with lobaplatin and XELOX regimen combined with cetuximab for eight cycles, the patient had been treated with the FOLFIRI regimen and cetuximab for 24 cycles, which discontinued due to myelosuppression. Because the disease recurred unfortunately 4 months later, the FOLFIRI + cetuximab regimen was initiated again and stopped after two cycles. Intestinal obstruction occurred 1 month later, so open total colectomy, CRS + HIPEC and ileorectal anastomosis were performed. Capecitabine adjuvant chemotherapy was administered, followed by the maintenance therapy with FOLFIRI + cetuximab regimen. After that, the patient has been in relatively stable condition. By August 2021, the overall survival is more than 45 months, which displays significant curative effect.ConclusionFor peritoneal metastasis from left colon cancer, the management with CRS + lobaplatin HIPEC and rechallenge of systemic chemotherapy plus targeted medicine based on gene detection can dramatically improve prognosis and extend the overall survival.

Evaluation of SN-38 PK profile in patients with RAS wild-type metastatic colorectal cancer treated with a combination of SCO-101 and FOLFIRI.

185 Background: The FOLFIRI regimen (5-fluorouracil, leucovorin and irinotecan) is a predominant treatment regimen for metastatic colorectal cancer. To optimize the benefit for the patients, it would be desirable to increase the efficacy of irinotecan by increasing the exposure of SN-38 (the active metabolite of irinotecan) to the cancer cells, while maintaining a good safety profile. The oral drug SCO-101, that is currently being developed by Scandion Oncology A/S, was tested in an early clinical trial (CORIST-trial, ClinicalTrials.gov identifier: NCT04247256). SCO-101 is an inhibitor of ABCG2, UGT1A1 and SRPK1. The CORIST trial was set up to address the safety, tolerability, and efficacy of SCO-101 given orally for 6 days followed by FOLFIRI at varying doses from day 5 to 7, in a biweekly schedule, in patients with metastatic colorectal cancer who have formerly been treated with FOLFIRI and afterwards progressed. The first part of the study was a dose-finding study, where the impact of SCO-101 on the pharmacokinetics (PK) of SN-38 was studied. Methods: 12 patients from the dose-finding part of the CORIST study received 150 mg SCO-101 for 6 days and 45 – 80% of the recommended dose of FOLFIRI. 6 of the patients had RAS wild-type tumors and these patients are the subject of the current analysis. Blood for PK analysis was sampled from the patients at 1, 2, 4, 8, 24, 48, and 96 hours after treatment with FOLFIRI and SCO-101. The blood samples were analyzed for Cmax, T½ and AUC (0-24h) of SCO-101, irinotecan and SN-38. Results: The PK of SN-38 from the patients in the study, normalized to a dose of irinotecan of 90 mg/m2 showed a T½ day 5 of 19 hours (SD 5,7) a Cmax of 60 ng/ml (SD 20,6) and an AUC_0-24h of 1415 hxng/ml (SD: 670). The results were compared to SN-38 data from treatment with irinotecan at 180 mg/m2, which is used in standard doses of FOLFIRI and the data is presented in the table. The data analysis showed an increased T½, increased Cmax and increased AUC of SN-38 when combining SCO-101 with 90 mg/m2 irinotecan, compared to SN-38 PK data from standard irinotecan treatment of 180 mg/m2. The toxicity profile of the patients treated with 90 mg irinotecan/m2 (50% FOLFIRI) showed only grade 1 and 2 adverse events. Conclusions: SCO-101 in combination with FOLFIRI has demonstrated the ability to modulate the PK profile of SN-38 in mCRC patients with RAS wild-type tumors, by significantly increasing the half-life, the peak plasma concentration, and area under the curve of SN-38. The combined treatment was well tolerated, and the drug is now being tested for efficacy in the CORIST trial.[Table: see text]

Cetuximab and vemurafenib plus FOLFIRI (5-fluorouracil/leucovorin/irinotecan) for BRAF V600E-mutated advanced colorectal cancer (IMPROVEMENT): An open-label, single-arm, phase II trial

BackgroundCurrent therapeutic regimens for patients with v-raf murine sarcoma viral oncogene homolog B1 (BRAF) V600E-mutated colorectal cancer show unsatisfactory efficacy. To improve outcomes in this area, we assessed the safety and efficacy of a new protocol using vemurafenib and cetuximab combined with FOLFIRI (5-fluorouracil/leucovorin/irinotecan) in patients with BRAF V600E-mutated colorectal cancer. Methods and materialsThis was an investigator-initiated, open-label, single-arm, phase II trial conducted in patients with BRAF V600E-mutated advanced colorectal cancer. Patients were eligible to receive FOLFIRI combined with vemurafenib and cetuximab. The primary end-point was the objective response rate, and the secondary end-points included disease control rate, progression-free survival, overall survival and safety. This trial is registered with ClinicalTrials.gov, NCT03727763. ResultsBetween 12th January 2018, and 18th June 2021, we screened 27 patients, 21 of which were enrolled in this study. Efficacy analysis showed that objective response rates were 81.0% (17/21; 95% confidence interval [CI] 57.4–93.7) in the intention-to-treat population and 85.0% (17/20, 95%CI 61.0–96.0) in the per-protocol population; two patients achieved complete response, and 15 patients achieved a partial response. In the entire cohort, the median progression-free survival was 9.7 months (95%CI 6.3–10.9), and the median overall survival for all patients was 15.4 months (95%CI 8.5–15.4). The most common adverse events (grade 3 to 4) were neutropenia (8/21), anaemia (3/21) and skin rash (3/21). ConclusionVemurafenib and cetuximab can be safely combined with the FOLFIRI regimen, showing promising antitumour activity and tolerable toxicity in patients with BRAF V600E-mutated advanced colorectal cancer. This regimen warrants a further randomised study in phase III clinical trials.

European-Australasian consensus on the management of advanced gastric and gastro-oesophageal junction cancer: current practice and new directions.

Gastric carcinoma and gastro-oesophageal junction (GC/GEJ) carcinoma remain a significant global problem, with patients presenting with symptoms often found to have advanced or metastatic disease. Treatment options for these patients have broadened in recent years with new chemotherapy agents, agents targeting angiogenic pathways and the development of immune checkpoint inhibitors (ICIs). Most initial advances have occurred in the refractory setting, where it is important to balance treatment benefits versus toxicity and patient quality of life. In the first-line treatment of advanced/metastatic GC/GEJ, platinum- and fluoropyrimidine-based chemotherapy protocols remain the backbone of therapy (with or without HER2-targeted therapy), with the FOLFIRI regimen offering an alternative in patients deemed unsuitable for a platinum agent. Microsatellite instability-high or mismatch repair-deficient cancers have been shown to benefit most from ICIs. In unselected patients previously treated with doublet or triplet platinum- and fluoropyrimidine-based chemotherapy and second-line chemotherapy with irinotecan or taxanes have formed the backbone of therapy with or without the addition of the vascular endothelial growth factor receptor-2 inhibitor ramucirumab in addition to paclitaxel. Beyond this, efficacy has been demonstrated with oral trifluridine/tipiracil and with single-agent nivolumab, in selected refractory patients. In this review, we highlight the positive evidence from key trials that have led to our current practice algorithm, with particular focus on the refractory advanced disease setting, discussing the areas of active research and highlighting the factors, including biomarkers and the influence of ethnicity, that contribute to therapeutic decision-making.

Evaluation of febrile neutropenia and myelosuppression in patients receiving FOLFOX/FOLFIRI in gastrointestinal cancer treated with same-day (SD) pegfilgrastim/pegfilgrastim-CBQV (PFG).

311 Background: The National Comprehensive Cancer Network (NCCN) guidelines and the manufacturers of PFG recommend administration at least 24 hours after chemotherapy (CTX). Administering SD PFG carries the potential risk for exacerbation of neutropenia based on analyses in lymphoma and breast cancer regimens; however, little data exists on infusional fluorouracil and SD PFG administration. The availability of biosimilar PFG and increased utilization of growth factors during the COVID-19 pandemic has led to changes in practice for SD PFG administration. This study explored the incidence of febrile neutropenia (FN) and myelosuppression with FOLFOX and FOLFIRI regimens in Gastrointestinal malignancies (GI) to address the safety of SD utilization of PFG. Methods: Patient data was extracted through electronic health records search of ICD-9 and ICD-10 codes for GI malignancies and treated with FOLFOX or FOLFIRI-based regimens from November 2013 to May 2021. SD administration was defined as administration of PFG within 15 minutes after fluorouracil pump disconnect. The primary endpoint of our study was to evaluate the incidence of FN across all CTX cycles for up to four cycles, in SD PFG administration. Secondary outcomes included chemotherapy induced neutropenia (CIN), hospitalizations, and CTX dose reduction or delay. Results: Three hundred and thirty-nine patient charts were reviewed with 55 patients meeting the inclusion criteria. In our study cohort, 72.7% received FOLFOX and 27.2% received FOLFIRI-based regimens. Out of all 194 CTX cycles, 136 (70.1%) cycles received pegfilgrastim and 58 cycles received pegfilgrastim-cbqv (29.9%). Two patients had grade 3/4 CIN (1%), with both cases resulting in FN (1%). Both FN cases resulted in hospitalizations, and dose delays or reductions. Investigation of FN incidences revealed that both patients received CTX with active infections, one case with a urinary tract infection and the other with a chronic gangrene infection. Conclusions: Our study results suggest that SD administration of PFG can be as a safe and effective alternative to 24-hour post-chemotherapy administration in patients receiving FOLFOX or FOLFIRI-based regimens. The incidence of FN was noted to be minimal in our study. Furthermore, no noted increase in myelosuppression was seen in our analysis, as compared to previous studies in breast cancer and lymphoma-based regimens. SD administration not only minimizes travel burdens on long-distance patients but also has allowed for reduction in infusion appointments and therefore possible exposure to the SARS-COV2 virus during the 2020-2021 pandemic. Future prospective studies are warranted in order to elucidate the risk of FN and myelosuppression in patients undergoing chemotherapy for GI malignancies with SD PFG administration.

1108P Folfirinox in the treatment of advanced gastroenteropancreatic neuroendocrine carsinomas

Neuroendocrine neoplasms most commonly arise from the gastroenteropancreatic (GEP) system. The WHO classification of digestive system tumors describes four main types: Neuroendocrine tumor (NET) grades 1-3 and neuroendocrine carcinoma (NEC). NECs have an aggressive biology and are often diagnosed in an advanced stage associated with poor prognosis. First-line palliative chemotherapy is commonly carboplatin or cisplatin in combination with etoposide, while in second-line capecitabine-temozolomide, FOLFIRI or FOLFOX regimens are used.

Recent Updates on Mechanisms of Resistance to 5-Fluorouracil and Reversal Strategies in Colon Cancer Treatment.

Simple SummaryAcquired resistance to chemotherapy by cancer cells is the predominant factor in chemotherapy failure, which ultimately leads to disease progression and death. Recent studies have presented compelling evidence of the various mechanisms and pathways through which cancer cells have developed resistance to drugs. This review summarises the mechanisms pertaining to 5-FU resistance and discusses ongoing efforts to prevent chemotherapy resistance in cancer cells and to re-sensitise them to cancer drugs.5-Fluorouracil (5-FU) plus leucovorin (LV) remain as the mainstay standard adjuvant chemotherapy treatment for early stage colon cancer, and the preferred first-line option for metastatic colon cancer patients in combination with oxaliplatin in FOLFOX, or irinotecan in FOLFIRI regimens. Despite treatment success to a certain extent, the incidence of chemotherapy failure attributed to chemotherapy resistance is still reported in many patients. This resistance, which can be defined by tumor tolerance against chemotherapy, either intrinsic or acquired, is primarily driven by the dysregulation of various components in distinct pathways. In recent years, it has been established that the incidence of 5-FU resistance, akin to multidrug resistance, can be attributed to the alterations in drug transport, evasion of apoptosis, changes in the cell cycle and DNA-damage repair machinery, regulation of autophagy, epithelial-to-mesenchymal transition, cancer stem cell involvement, tumor microenvironment interactions, miRNA dysregulations, epigenetic alterations, as well as redox imbalances. Certain resistance mechanisms that are 5-FU-specific have also been ascertained to include the upregulation of thymidylate synthase, dihydropyrimidine dehydrogenase, methylenetetrahydrofolate reductase, and the downregulation of thymidine phosphorylase. Indeed, the successful modulation of these mechanisms have been the game plan of numerous studies that had employed small molecule inhibitors, plant-based small molecules, and non-coding RNA regulators to effectively reverse 5-FU resistance in colon cancer cells. It is hoped that these studies would provide fundamental knowledge to further our understanding prior developing novel drugs in the near future that would synergistically work with 5-FU to potentiate its antitumor effects and improve the patient’s overall survival.

Case report of partial response on second line with Ramucirumab and FOLFIRI in treatment of 74 year old male with metastatic HER2-negative gastric adenocarcinoma

According to the data of the world statistics, gastric cancer (GC) occupies the 5th place by morbidity and the 3rd one by mortality among malignant neoplasms. A significant proportion of patients are elderly patients, the proportion of which in real clinical practice can reach up to 60%. Ramucirumab is among the standards of second-line drug therapy both in monotherapy and in combination with paclitaxel. The feasibility of prescribing ramucirumab to patients with disseminated cancer of the elderly and its satisfactory tolerability is shown in a subgroup analysis of the REGARD and RAINBOW studies. The use of paclitaxel, included in the standard first-line regimens, may be limited by persistent neurotoxicity, a side effect of platinum derivatives. In this regard, the effectiveness of the combination of ramucirumab with the FOLFIRI regimen as a second-line therapy began to be studied. The article presents a clinical case of achieving a partial effect on the second-line therapy with ramucirumab with FOLFIRI regimen in a 74-year-old patient with HER2-negative gastric adenocarcinoma while registering rapid progression after 4 courses of first-line chemotherapy in XELOX regimen. Tolerability of the second line was acceptable: asthenia grade 1, stomatitis grade 1-2, neutropenia grade 3 were observed, so the irinotecan dose was reduced to 165 mg/m2. By June 2021, there were 10 28-day cycles of treatment, which is ongoing. The duration of disease control in the second line therapy was 11+ months, of which 9+ months – on the background of FOLFIRI regimen drug therapy with ramucirumab.

Prospective Observational Study Comparing Calcium and Sodium Levofolinate in Combination with 5-Fluorouracil in the FOLFIRI Regimen

The use of sodium levofolinate (Na-Lev) is safe in combination with continuous infusion 5-fluorouracil in patients with gastrointestinal tumors treated with the FOLFIRI regimen. A comparison with calcium levofolinate (Ca-Lev) showed a similar toxicity profile. The advantages of Na-Lev over Ca-Lev might be the faster drug preparation and the shorter time of drug administration. The objectives of this study were to compare the safety profiles of sodium levofolinate (Na-Lev) and calcium levofolinate (Ca-Lev) in combination with 5-fluorouracil (5-FU) in the FOLFIRI regimen and to measure the organizational impact of the introduction of Na-Lev on drug production and administration. The study opened in November 2015 and closed in August 2019. Patients with gastrointestinal cancers who were candidates for treatment with the FOLFIRI regimen were included in this nonrandomized study. Age ≥18 years, life expectancy >3 months, adequate bone marrow reserve, adequate hepatic and renal function, and an ECOG performance status of 0-2 were required. Patients in the Ca-Lev arm received a 2-hour infusion of Ca-Lev followed by 5-FU, whereas those in the Na-Lev arm received Na-Lev and 5-FU administered in a single 48-hour pump. Sixty patients were enrolled, 30 in each arm. Patient characteristics were balanced. Grade (G)1-2 adverse events occurred in 18 (60.0%) and 19 (63.4%) patients of Na-Lev and Ca-Lev cohorts, respectively, whereas G3-4 adverse events occurred in 12 (40.0%) and 11 (36.6%) patients, respectively. The use of Na-Lev enabled us to save approximately 13 minutes for drug preparation and 2 hours for treatment administration, per patient per cycle. Na-Lev showed a reassuring toxicity profile and a favorable impact on drug preparation and administration.

The Correlation Between UGT1A1 Gene Phenotypes and the Clinical Prognosis of Advanced Colorectal Cancer After FOLFIRI Therapy

Objective: This study investigated the correlations between the different phenotypes of the uridine diphosphate glucuronyl transferase (UGT) 1A1 gene and the treatment of advanced colorectal cancer after the FOLFIRI regimen. Materials and Methods: A total of 240 advanced colorectal cancer patients with stage IV colon cancer or recurrence after radical surgery between January 2014 and December 2018 were included in a retrospective study. All participants were treated with the FOLFIRI regimen until the disease progressed or an intolerable level of toxicity occurred. Results: In this study, three phenotypes of the UGT1A1 gene promoter were found: the homozygous wild type (TA6/6 type, 78.3%), the heterozygous mutant type (TA6/7 type, 19.6%), and the homozygous mutant type (TA7/7 type, 2.1%). Compared with TA6/7 and TA6/6, the risk of nonresponse to FOLFIRI chemotherapy increased by 16%, but the difference was not significant. The risk of death increased by 24%, and there was no significant difference. There was a risk of hematologic and nonhematologic adverse reactions occurring in TA6/7 and TA6/6, and the total risk of adverse reactions increased by 9.3773 times among patients with more than two metastatic organs. Compared with patients with TA6/6, the risk of toxic side-effects increased by 42.8066 times (p = 0.0259) for patients with TA6/7. Among patients who received FOLFIRI chemotherapy for more than four cycles, the proportion with TA6/7 was greater than that with TA6/6. Compared with those with TA6/6, patients with TA6/7 showed a higher risk of hematologic toxicity (22.3246 times, p = 0.0035). Conclusion: The TA6/7 in patients with advanced colorectal cancer had more than two metastatic organs, and received FOLFIRI chemotherapy for more than four cycles compared with TA6/6 patients. Furthermore, the risk of hematologic and nonhematologic adverse reactions significantly increased, and the risk of digestive-tract and hematologic toxicity was more significant.

Effect of Aprepitant for the Prevention of Chemotherapy-Induced Nausea and Vomiting in Women

The prevention of chemotherapy-induced nausea and vomiting has an important role in the overall management of cancer treatment. To evaluate whether adding aprepitant to palonosetron and dexamethasone can further prevent the incidence and severity of nausea and vomiting caused by FOLFIRI (fluorouracil, leucovorin, and irinotecan) or FOLFOX (fluorouracil, leucovorin, and oxaliplatin) chemotherapy regimens among women with gastrointestinal cancer at higher risk. This phase 3, double-blind, placebo-controlled randomized clinical trial recruited young women (age ≤50 years) who drank little or no alcohol and had gastrointestinal cancer for which they received FOLFOX or FOLFIRI chemotherapy. A total of 248 women were enrolled and assigned in the ratio 1:1 to intervention and control groups from August 4, 2015, to March 31, 2020. Intention-to-treat analysis was used to evaluate patient baseline characteristics and efficacy. The analysis was conducted on October 30, 2020. Patients were randomly assigned to the aprepitant group (aprepitant, 125 mg, orally 60 minutes before initiation of chemotherapy on day 1 and 80 mg orally each morning of days 2 and 3; palonosetron, 0.25 mg, intravenously; and dexamethasone, 6 mg, orally 30 minutes before chemotherapy initiation on day 1) or the placebo group (placebo, 125 mg, orally 60 minutes before initiation of chemotherapy on day 1 and 80 mg orally on each morning of days 2 and 3; palonosetron, 0.25 mg, intravenously; and dexamethasone, 12 mg, orally 30 minutes before chemotherapy initiation on day 1). The primary end point was the complete response (CR) rate, defined as the proportion of patients without emesis episodes or rescue medication use during the overall phase of the first cycle. Other efficacy indicators, such as no vomiting and no nausea, were measured as the secondary and exploratory end points. A total of 248 women from 4 clinical centers in China entered this study, and 243 patients (aprepitant regimen, 125 patients [51.4%]; placebo regimen, 118 patients [48.5%]) were evaluable for efficacy and safety; mean (SD) age of the total population was 40.1 (7.3) years. The CR rate was significantly higher in the aprepitant group vs the control group overall (107 [87.0%] vs 80 [66.7%]; P < .001) and in the acute (114 [92.7%] vs 91 [75.8%]; P = .001) and delayed (109 [88.6%] vs 84 [70.0%]; P = .001) phases of the trial. The incidence of adverse events was similar between the 2 groups (100 [80.0%] vs 96 [81.3%]; P = .79), and no grade 3 or 4 aprepitant treatment-related adverse events were observed. Multivariable analysis revealed that aprepitant use was the only independent factor associated with CR during the overall phase. The combination of aprepitant with palonosetron and dexamethasone provided increased antiemetic efficacy in the FOLFOX or FOLFIRI chemotherapy regimen and was well tolerated by younger women with gastrointestinal cancer who have a history of little or no alcohol consumption. ClinicalTrials.gov Identifier: NCT03674294.

Effects of Chemotherapy for Metastatic Colorectal Cancer on the TGF-β Signaling and Related miRNAs hsa-miR-17-5p, hsa-miR-21-5p and hsa-miR-93-5p.

Metastatic colorectal cancer (mCRC) patients are treated with standard chemotherapeutic drugs in the form of FOLFOX and FOLFIRI regimens. There are no reliable markers that could predict response to chemotherapy for mCRC. TGF-β signaling which interacts with microRNA (miRNA) network has important roles in tumor progression and chemotherapy resistance, thus the interplay between TGF-β signaling and miRNAs could be crucial for treatment response. The aim of this study was to analyze the effect of chemotherapy for mCRC on TGF-β signaling and related miRNAs. Hsa-miR-17-5p, hsa-miR-21-5p and hsa-miR-93-5p were selected out of 316 miRNAs with multiple targets within the TGF-β signaling by in silico analysis. SW620 cells were treated with chemotherapeutic drugs for mCRC for 1, 3 and 6 days and expression of selected miRNAs, PAI-1, CDH1 and VIM was measured. Expression of TGF-β signaling-related hsa-miR-17-5p, hsa-miR-21-5p and hsa-miR-93-5p was time-dependently altered in SW620 cells treated with chemotherapeutics for mCRC. The expression of hsa-miR-93-5p remained downregulated after 6 days under combined treatments FOX and FIRI as well as the hsa-miR-17-5p expression under FIRI. Chemotherapy regimens for mCRC increased expression of a major TGF-β signaling target gene PAI-1, independently of the selected miRNAs expression. These treatments also increased the expression of epithelial-mesenchymal transition (EMT) markers CDH1 and VIM on day 3 resulting in decrease of mesenchymal-like characteristics. However, their expression returned close to basal level on day 6. In conclusion, after initial response to chemotherapeutic drugs SW620 cells start to return close to the basal mesenchymal state while the long-term downregulated expression pattern of hsa-miR-93-5p and hsa-miR-17-5p makes them candidates worth testing as biomarkers for monitoring combined chemotherapeutic treatments therapy response in mCRC patients.

CHEMOTHERAPY IN RECTAL CANCER

The aim: To evaluate and analyze early and late results of treatment of patients with rectal cancer after chemotherapy. Materials and methods: The study is based on the results of observation of 779 patients with stage II, III and IV rectal cancer (RC) who were divided into groups according to the chemotherapy treatment. Results: In the course of chemotherapy treatment of RC patients, most of them received the FOLFOX regimen treatment – 87 patients (43.5%). 40 people (20%) received Mayo regimen. 36 patients (18%) underwent FOLFIRI regimen. Another 33 patients received the XELOX regimen chemotherapy (16.5%). In four cases, patients underwent Tegafur monotherapy (2%). Conclusions: The obtained data for patients with stage III RC showed that at all studied time intervals, the highest percentage of surviving patients was recorded in those who received chemotherapeutic treatment according to the FOLFOX regimen. In patients with stage II RC, the most effective was Mejo regimen – 30.7% (survived patients for the 5 year observation).

The effectiveness of cetuximab and panitumumab when combined with FOLFIRI in second-line treatment of KRAS wild type metastatic colorectal cancers. Single centre experience

Panitumumab and cetuximab are monoclonal antibodies known to be effective in metastatic colorectal cancer (mCRC). Although the survival benefits when combined with chemotherapy have been determined, there are no studies comparing the two agents with chemotherapy in the second-line treatment. In this study, we aimed to compare the efficacy of cetuximab vs panitumumab in patients who previously received chemotherapy. Who progressed after first-line treatment for K-ras wild type mCRC were analyzed. The efficacy of cetuximab vs panitumumab on overall survival (OS) and progression-free survival (PFS) when combined with FOLFIRI regimen was compared retrospectively. Median PFS was 6.9 months in the cetuximab group and 4.7 months in the panitumumab group. Median OS cetuximab and panitumumab groups were 18.4 and 12.2 months, respectively. In the second-line treatment of K-ras wild type mCRC, both PFS and OS were found to be longer in patients receiving cetuximab than in patients receiving panitumumab, but no statistically significant difference was found.

Safety and efficacy of aflibercept in FOLFIRI regime in treatment of metastatic colorectal cancer in real clinical practice: results of Russian prospective multicentre observational study SAFETRAP

Aim. The main objective of the prospective multicentre observational study is to describe adverse events occurred during treatment with aflibercept plus FOLFIRI therapy in real life practice. In despite of broad use of aflibercept in Federal oncological centers, this regimen is still perceived by healthcare professionals (HCPs) as having worse safety profile in comparison with other antiangiogenic agents. Taking into account limited experience of using aflibercept in Russia it s critically important to evaluate and document adverse events occurred with treatment in aflibercept plus FOLFIRI regimen in patients with metastatic colorectal cancer (mCRC) in real-life practice. Methods. The physician selection was performed as a random process. Twenty sites with experience in treatment of mCRC patients were selected. The investigators were encouraged to enroll all patients meeting eligibility criteria in consecutive manner. Total number of included patients into the study patient was 101. Data were evaluable for 91 patients. 14 of 91 (15.4 %) patients didn ’t meet inclusion criteria and were excluded from the per protocol analysis: 10 patients didn ’t receive oxaliplatin within the last line of therapy preceding inclusion into the study and in 4 patients progression occurred more than 6 months after the end of adjuvant therapy. Results. Overall, 265 treatment emergent adverse events (TEAEs) occurred in the 77 patients analysed per protocol. In total, 23 grade 3 and 5 grade 4 TEAEs were reported by 16 and 4 patients, respectively. The most common TEAEs were nausea (68 events in 31 [40.3 %j patients), diarrhea (43 events in 25 [32.5 %j patients), hypertension (36 in 20 [26.0 %] patients), neutropenia (29 events in J5 [J9.5 %] patients), asthenia (28 events in 12 [15.6 %]patients). Three cases of grade 1-2 stomatitis were reported in 2 (2.6 %) patients. And one patient reported grade 1 epistaxis during the study. There was no case of gastrointestinal perforation, fistula development, ulceration, arterial or venous thromboembolism. During this study seven serious adverse events were documented in 5 (6.5 %) patients of 77. The reason for treatment discontinuation in 5 (11.1 %) of 45 cases was adverse event. No death, classified as related to any component of therapy, was reported in this study. Conclusion. This national (Russian) prospective multicentre non-interventional study conducted in patients with mCRC in daily practice suggests that aflibercept plus FOLFIRI has a manageable safety profile in line with VELOUR phase III study.

FOLFOX vs FOLFIRI as Second-line of Therapy After Progression to Gemcitabine/Nab-paclitaxel in Patients with Metastatic Pancreatic Cancer.

BackgroundSeveral progresses have been achieved for first-line chemotherapy in metastatic pancreatic ductal adenocarcinoma (PDAC) with Gem-NabP and FOLFIRINOX extensively used as standard first line regimens. However, the best second-line chemotherapy choice after progression is still not completely defined. The aim of this study is to compare effectiveness and safety of two possible second-line therapeutic options, FOLFOX and FOLFIRI, after progression to Gem-NabP.MethodsFrom January 2015 to December 2018, patients with metastatic PDAC, progressed to the first-line treatment with Gem-NabP, and treated with a fluoropyrimidine-based second-line chemotherapy were considered eligible for our retrospective analysis. Overall survival (OS) and progression free survival (PFS) were set as primary endpoints whereas, disease control rate (DCR) and the rate and severity of treatment-related AEs were secondary endpoints.ResultsOverall, 31 patients were treated with Gem-NabP in first-line regimen, 11 received second-line with FOLFOX and 20 with FOLFIRI after progression. Baseline demographic and clinic features were similar in the two groups excluding median age of 55.5 years (range: 50–73) and 68 years (range: 59–72) in FOLFIRI and FOLFOX groups, respectively (p=0.002). Median PFS was three months (95%CI: 3–4), with no significative difference between the two groups. Median OS was eight months (95%CI: 5–10) and was significantly higher in the FOLFIRI group compared with the FOLFOX group, nine months (95%CI: 7–17) vs five months (95%CI: 2–10; p<0.01). The most commonly reported adverse events were grade 1 or 2 with anemia most frequent in the FOLFOX group (36.4% vs 10.0%) and diarrhea in the FOLFIRI group (40.0% vs 9.1%). Grade 3–4 adverse events as neutropenia, diarrhea and nausea/vomiting, occurred in 10 patients (32.2%) without differences between the two groups.ConclusionOur results seem to support the use of fluoropyrimidine-based second-line therapy for patients with metastatic pancreatic cancer, confirming the effectiveness and safety, to a greater extent with FOLFIRI regimen, after progression to the Gem-NabP.

Salvage Chemotherapy by FOLFIRI Regimen for Poorly Differentiated Gastrointestinal Neuroendocrine Carcinoma.

Chemotherapy is the mainstay treatment for advanced poorly differentiated gastrointestinal neuroendocrine carcinoma (GI-NEC), with platinum-containing regimens being the optimal first-line regimen. However, the role and efficacy of second-line chemotherapy for GI-NEC are unclear. This study aimed to evaluate the feasibility and efficacy of fluorouracil, leucovorin, and irinotecan (FOLFIRI) as second-line therapy in patients with relapsed or recurrent GI-NEC after first-line platinum plus etoposide therapy. We retrospectively evaluated eight consecutive patients with unresectable GI-NEC treated between 2017 and 2020. The inclusion criteria were pre-treatment with platinum doublet therapy, performance status (PS) 0-2, having measurable lesions, and treatment with FOLFIRI as second-line therapy. The overall response rate, progression-free survival (PFS), overall survival (OS), safety, and relative dose intensity were evaluated. Five patients met the inclusion criteria. Overall, 37 cycles of FOLFIRI were administered. The relative dose intensities for irinotecan, continuous infusion of 5-FU, and a bolus injection of 5-FU were 76%, 72%, and 54%, respectively. Overall, 2 of the 5 patients achieved partial response (40%), and the duration of response (DOR) was 4.0 months. The PFS and OS rates were 5.8 (95% CI, 1.5-NA) and 11 (95% CI, 6.3-NA) months, respectively. Overall, 4 of the 5 patients (80%) proceeded with further chemotherapy. Grade ≥ 3 adverse events except hematological toxicity included febrile neutropenia (n = 2), anorexia (n = 2), and fatigue (n = 1). Treatment discontinuation due to treatment-related adverse events was not observed. FOLFIRI showed modest efficacy and feasibility for GI-NEC patients and has thus potential for patients who fail the first-line treatment.

Abstract 561: Preclinical efficacy data for the anti-CEACAM5-DM4 ADC SAR408701 supports further development in lung and gastro-intestinal cancers

Abstract Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) is a cell-surface glycoprotein highly expressed in several tumor types including non-small cell lung cancer (NSCLC), colorectal cancer (CRC) and gastric cancer (GC). SAR408701 is an antibody-drug conjugate (ADC) which consists of anti-CEACAM5 antibody conjugated to the maytansinoid DM4 cytotoxic agent, a highly potent tubulin inhibitor. SAR408701 was investigated in a First in Human trial (FIH) in patients with advanced solid tumors. During the early dose escalation phase, preliminary anti-tumor activity was observed with objective response reported in 3 patients with CRC and 1 patient with GC. In an interim analysis of an ongoing expansion cohort of patients with non-squamous NSCLC and with CEACAM5 expression in ≥ 50% of tumor cells, 25% overall response rate (ORR) (8/32 evaluable patients) and 37.5% (12 patients) stable disease were observed. In parallel to FIH trial, several preclinical studies were performed to support the clinical development of SAR408701 in NSCLC, CRC and GC. A single mouse trial (SMT) was carried out on a panel of 28 patent-derived xenografts (PDX) covering the top 3 indications. The SMT format employs a single mouse per PDX model and treatment arm and uses RECIST criteria as readout. Results showed an efficacy profile in the preclinical trial close to that obtained in clinic with an ORR of 10% in CRC, of 50% in lung cancers and of 37.5% in GC. The efficacy of SAR408701 is correlated with CEACAM5 expression in lung and gastric indications. To further assess the potential of SAR408701 in NSCLC, preclinical investigations have been done to determine if an ADC-DM4 could be beneficially combined with immune checkpoint inhibitors (ICIs). The capacity of DM4-treated tumor cells to immunize immune competent mice to the tumor was evaluated, indicating that DM4 can induce immunogenic cell death. This result supports the development of SAR408701 in combination with ICIs in NSCLC. The combination of SAR408701 with 4 different standard of care (SoC) therapies were tested in 2 CRC PDX models, one sensitive and one resistant to SAR408701 alone. Combinations of SAR408701 were evaluated with either FOLFOX regimen, FOLFIRI regimen, TAS-102 or cetuximab. All combinations resulted in significantly better antitumor activity than single agent arms in both resistant and sensitive PDXs without an increase in toxicity and showed a therapeutic synergy. These results suggest that SAR408701 can be advantageously combined with SoC in gastro-intestinal (GI) cancers. In summary, preclinical data show that SAR408701 displays a strong antitumor activity as a single agent in NSCLC and in combination with SOC in GI cancers, supporting further development in these indications. Furthermore, SAR408701 could be a potential good candidate to be combined with ICIs in NSCLC. Citation Format: Stephanie Decary, Olivier Lemaitre, Anne-Marie Lefebvre, Alexandra Ferrier, Marielle Chiron, Dmitri Wiederschain, Anne-Sophie Lacoste-Bourgeacq, Nathalie Le Bail, Sukhvinder Sidhu, Cecile Combeau, Mustapha Chadjaa, Celine Nicolazzi. Preclinical efficacy data for the anti-CEACAM5-DM4 ADC SAR408701 supports further development in lung and gastro-intestinal cancers [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 561.

Gemcitabine plus nab-paclitaxel until progression or alternating with FOLFIRI.3, as first-line treatment for patients with metastatic pancreatic adenocarcinoma: The Federation Francophone de Cancérologie Digestive-PRODIGE 37 randomised phase II study (FIRGEMAX)

BackgroundChemotherapy is effective in metastatic pancreatic adenocarcinoma (mPA), but new approaches are still needed to improve patients' survival and quality of life. We have previously published good efficacy and tolerability results on a sequential treatment strategy of gemcitabine followed by an intensified FOLFIRI (5FU+irinotecan) regimen. In the present study, we evaluated the same sequence but replaced gemcitabine by the new gemcitabine + nab-paclitaxel standard first-line combination. Patients and methodsWe randomised chemotherapy-naive patients with proven mPA, bilirubin levels ≤1.5 upper limit of normal values and performance status 0–2 to alternately receive gemcitabine + nab-paclitaxel for 2 months then FOLFIRI.3 for 2 months in arm A, or gemcitabine + nab-paclitaxel alone until progression in arm B. The primary objective was to increase the 6-month progression-free survival (PFS) rate from 40% (H0) to 60% (H1); using the binomial exact method, 124 patients were required. Analyses were carried out in preplanned modified intention-to-treat (mITT) and per-protocol (PP) populations. ResultsBetween November 2015 and November 2016, 127 patients were enrolled. Main grade III–IV toxicities (% in arm A/B) were: diarrhoea (12.5/1.7), neutropenia (46.9/31, including febrile neutropenia: 1.6/0), skin toxicity (6.3/13.8), and peripheral neuropathy (6.3/8.6). No toxic deaths occurred. The objective response rate was 40.3% (95% confidence interval [CI]: 28.1–53.6) in arm A and 26.7% (95% CI: 16.1–39.7) in arm B. The primary end-point (6-month PFS rate) was 45.2% [one-sided 95% CI: 34.3–56.4] in arm A and 23.3% in arm B [one-sided 95% CI: 14.3–32.3] in the mITT population. In the PP population, median PFS and OS were 7.6 months and 6 months and 14.5 months and 12.2 months in arm A and B, respectively. ConclusionsThe FIRGEMAX strategy with gemcitabine + nab-paclitaxel alternating with FOLFIRI.3 every 2 months, appears feasible and effective, with manageable toxicities, in patients able to reach >2mo of treatment. Trial registration informationEudraCT: 2014-004449-28: NCT: 0282701.