Irinotecan-based Regimens Research Articles

Efficacy of chemotherapy for patients with gastric cancer with early recurrence during or after adjuvant chemotherapy with S-1 alone: a multicenter retrospective study

This study aimed to survey the efficacy of chemotherapy regimens in the real world setting and explore the most promising regimen for patients experiencing early recurrence for gastric cancer. We retrospectively reviewed the clinical course of 207 patients with gastric cancer, who developed early recurrence during or within 6 months after completing S-1 adjuvant therapy at 19 Japanese institutions between 2012 and 2016. The treatment regimens after recurrence were fluoropyrimidines plus platinum-based regimens (FP) in 91 (44%) patients, paclitaxel-based regimens (PTX) in 102 (49%), and irinotecan-based regimens (IRI) in 14 (7%). The overall response and disease control rates were 28.7% and 54.1%. Median progression-free survival (PFS) and overall survival (OS) were 5.1 and 12.9 months, respectively. In the FP, PTX, and IRI regimens, the median PFS and OS were 5.9, 4.1, 4.1 months and 12.8, 12.9, and 11.8 months, respectively. The combination of PTX and ramucirumab showed survival comparable to capecitabine plus platinum. Multivariate analyses for OS showed that recurrence during adjuvant chemotherapy and undifferentiated histological type were independent poor prognostic factors. Although the prognosis of patients with early recurrence even with adjuvant S-1 was poor, PTX plus ramucirumab therapy could be a potential treatment option.

Impact of DNA damage repair alterations on real-world response to therapy in metastatic colorectal cancer.

e15557 Background: Alterations in the DNA damage repair (DDR) pathway genes contribute to tumor development. These alterations can be exploited by cytotoxic chemotherapy regimens that induce DNA damage. Platinum chemotherapy agents have been shown to be particularly effective in breast and ovarian cancer patients with alterations in the DDR pathway. However, the clinical impact of DDR alterations in metastatic colorectal cancer (mCRC) is still poorly understood. In this study, we utilize a large national database to evaluate clinical outcomes in patients with mCRC and alterations in DDR pathway genes. Methods: We reviewed 5602 patients that received standard fluorouracil based first-line chemotherapy regimens for mCRC using the nationwide Flatiron Health EHR-derived de-identified database. Chemotherapy regimens were categorized as a platinum-based doublet (FOLFOX, CAPOX), irinotecan-based doublets (FOLFIRI), or triplet (FOLFOXIRI). Overall survival (OS) was summarized within groups via Kaplan-Meier survival estimates. OS was compared between groups in the context of univariable and multivariable Cox proportional hazards models controlling for age, gender, DDR status, stage at diagnosis, ECOG, RAS/RAF status, MMR status, albumin and CEA at diagnosis. OS was defined as the time in months between date of first line therapy initiation to death. Results: DDR gene alterations were indentified in 35.7% (2001) patients.The most frequent mutations were in ATM (13.3%) and BRCA2 (8.3%). There was no significant difference in OS based on DDR mutation status. Within DDR altered patients, there was no difference in OS between those who received a platinum-based doublet, irinotecan-based doublet or triplet first-line therapy. Time to next treatment or death (TTNTD) was significantly improved with an irinotecan-containing doublet regimen and triplet regimen compared to a platinum-based doublet in a multivariable model (HR 0.79, p = 0.001 and HR 0.68, p = 0.002, respectively). There was no difference in OS in DDR-mutated patients that received an irinotecan-based regimen in the first line followed by an oxaliplatin-based regimen in the second line or the reverse sequence. When evaluating the impact of commonly co-mutated genes on survival we observed a worse OS in patients with a KRAS mutation in addition to a DDR mutation (HR 1.19, p = 0.045). An APC mutation was associated with an improved OS in the entire cohort, regardless of DDR status (HR 0.76, p < 0.001). Conclusions: In this real-world population, approximately one third of patients with mCRC harbored an alteration in a DDR pathway gene. In these patients, TTNTD was greater with irinotecan-containing first line therapies (doublet or triplet). However, OS was similar regardless of which first-line chemotherapy was used.

The efficacy of chemotherapy for colorectal cancer with early recurrence after adjuvant chemotherapy.

43 Background: Adjuvant chemotherapy is the standard treatment for patients with stage III colorectal cancer (CRC) underwent surgery.However, the efficacy of chemotherapy for early recurrence after adjuvant chemotherapy remains unclear. This study aimed to assess the efficacy of chemotherapy for CRC with early recurrence during or after adjuvant chemotherapy. Methods: We retrospectively reviewed CRC patients who underwent surgery at 3 institutions between 2016 and 2021. The inclusion criteria were as follows: ECOG performance status was 0 or 1, histology was adenocarcinoma, patients who received adjuvant chemotherapy following surgical resection, early recurrence during or within 12 months after adjuvant chemotherapy and no prior treatment for CRC after early recurrence. The interval from the last administration of adjuvant chemotherapy to recurrence was defined as the recurrence-free interval (RFI). Overall survival (OS), progression-free survival (PFS), objective response rates (ORR), and disease control rate (DCR) were assessed according to the RFI. Results: Of 448 patients, 32 patients were eligible. Median age was 57 years (range 26–79), 14 patients (44%) were male and ECOG performance status 0 / 1 was 29 (91%) / 3 (9%). RAS wild-type / mutant was 12 (38%) / 20 (62%) and right / left as sidedness was 21 (66%) / 11 (34%). Regarding adjuvant chemotherapy, 4 patients (12%) received single-agent therapy, while 28 patients (88%) received combination therapy with two agents. Palliative chemotherapy after early recurrence included Oxaliplatin-based regimens in 13 patients (41%), irinotecan-based regimens in another 13 patients (41%), and other regimens in 6 patients (18%). For all patients, the median PFS and OS were 10.4 months and 43.0 months, respectively. The ORR and DCR were 34.4% and 75.0%, respectively. When patients were divided into RFI < 6 months and RFI ≥ 6 months, the ORR was superior in the RFI ≥ 6 months group to RFI < 6 months group (56 % vs. 26%). The PFS (median 10.4 months vs. 17.8 months, HR 0.92; 95% Cl 0.36-2.38, p = 0.87) and OS (median 31.3 months vs. 43.0 months, HR 0.97; 95% Cl 0.31-3.08, p = 0.97) did not differ between the RFI < 6 months group and the RFI ≥ 6 months group. Multivariate analysis for OS indicated a trend toward a poor prognosis in the RFI < 6 months group compared to the RFI ≥ 6 months group (HR 1.78; 95% CI 0.35-8.98, p = 0.48). Conclusions: In patients with CRC experienced early recurrence, the RFI < 6 months group had a trend of poor efficacy compared to the RFI of ≥ 6 months group.

Clinical characterization and therapeutic outcomes of patients (pts) with colorectal cancer (CRC) harboring somatic BRCA1/2 mutations.

134 Background: Somatic BRCA1/2 mutations in BRCA-associated cancers increase therapeutic sensitivity to platinum-based chemotherapies and PARP inhibitors, but the implications of BRCA mutations in non- BRCA-associated cancers such as CRC is unknown and hypothesized to be shaped by tumor lineage. We thus conducted a retrospective analysis of outcomes with platinum-based chemotherapy and PARP inhibition in pts with CRC, where the estimated prevalence of BRCA1/2 alterations is 3-4%. Methods: Pts with blood or tissue next generation sequencing (NGS) positive for a somatic BRCA1/2 variant and a diagnosis of CRC were identified from a single institution database. The pathogenicity of each mutation was annotated using public genomic databases (e.g. ClinVar). Pt characteristics were compared using Fisher’s exact test. Log-rank test was used for comparison of survival distribution among groups. Results: 8,258 NGS reports with a BRCA1/2 alteration from 1760 cancer pts were identified of which 189 (11%) had a diagnosis of CRC. 54/189 CRC pts (29%) had ≥1 pathogenic BRCA1/2 variant, 19 pts (10%) had ≥1 benign variant, and 134 pts (69%) had 1 ≥ variant of unknown significance (VUS); 26 pts (14%) had more than one BRCA1/2 variant. Pts with ≥1 pathogenic mutation (n=54) were more likely to have an inactivating DNA polymerase epsilon (POLE) mutation versus pts with only benign/VUS BRCA1/2 variants (n=135) (20% vs 6%, p=0.004) while prevalence of microsatellite instability (MSI-H) (19% vs 13%, p=0.37) and Ras/Raf (53% vs 53%, p=1.00) were similar between groups. Median progression free survival (PFS) among 115 CRC pts (unselected for BRCA1/2 pathogenicity) who received an oxaliplatin-based regimen for advanced disease in the 1st line (n=52) was similar to the median PFS among pts who received an irinotecan-based regimen (n=63) (7.0 mths vs 7.0 mths, p=0.48). Median PFS with an oxaliplatin-based regimen in the 1st line among 52 pts with pathogenic BRCA1/2 variants (n=13) was 5.1 mths vs 7.4 mths among pts with benign/VUS BRCA1/2 variants (n=39) (p=0.398). There were no significant differences in median PFS among pts with a pathogenic vs benign/VUS BRCA1/2 variants when the analysis was restricted to pts with BRCA1/2 variants identified in tissue (p=0.76) and to pts without co-occurring driver mutations (Ras/Raf, MSI-H, and/or POLE) (p=0.1). Overall survival in patients with advanced disease was similar between pts with a pathogenic (n=52) vs benign/VUS (n=122) BRCA variants (37.1 mths vs 45.1 mths, p=0.14). 6 pts (4 with pathogenic BRCA1/2 and 3 with VUS) received a PARP inhibitor after a median of 3 lines of treatment and the best response was disease progression in 6 pts (100%). Conclusions: In the context of CRC, somatic BRCA1/2 mutations frequently co-occur with pathogenic POLE mutations, but do not appear to confer therapeutic benefit to platinum-based chemotherapy and PARP inhibitors.

Prognostic Value of TACE With Irinotecan-loaded Drug-eluting Beads (DEBIRI) in Patients With Liver Metastases from Unresectable Colorectal Cancer.

The standard of care for patients with colorectal cancer and liver metastases, who fail to respond to systemic chemotherapy has not yet been established. Therefore, we investigated the prognostic value of transarterial chemoembolization (TACE) using irinotecan-loaded drug-eluting beads (DEBIRI) in treating liver metastases due to colorectal cancer. Forty-six patients with colorectal cancer and unresectable liver metastases, who received systemic chemotherapy beyond the third line at our hospital between July 2014 and April 2020 were analyzed. They were divided into two groups: 1) Seventeen patients who received TACE with DEBIRI, and 2) twenty-nine patients who did not receive TACE. The median age was 68 years (range=37-85 years), and the male-to-female ratio was 29:17. The primary sites were the cecum in six cases, ascending colon in seven cases, transverse colon in two cases, descending colon in three cases, sigmoid colon in 14 cases, and rectum in 14 cases. All patients had received at least two prior systemic chemotherapy regimens including oxaliplatin-based and irinotecan-based regimens, and trifluridine tipiracil hydrochloride (38 patients) or regorafenib (12 patients) as the third line or beyond (overlap). Median survival was 272 days overall, 416 days in the TACE group, and 229 days in the non-TACE group, with significantly better survival in the TACE group (p=0.0126). TACE with DEBIRI may improve the prognosis of patients with liver metastases from unresectable colorectal cancer. We suggest that TACE with DEBIRI should be highly considered, especially in patients in whom liver metastasis may be a prognostic factor.

Irinotecan- vs. Oxaliplatin-Based Doublets in KRASG12C-Mutated Metastatic Colorectal Cancer-A Multicentre Propensity-Score-Matched Retrospective Analysis.

KRASG12C-mutated metastatic colorectal cancer (mCRC) has recently been recognized as a distinct druggable molecular entity; however, there are limited data on its sensitivity to standard chemotherapy. In the near future, the combination of chemotherapy plus a KRASG12C-inhibitor might become the standard of care; however, the optimal chemotherapy backbone is unknown. A multicentre retrospective analysis was conducted including KRASG12C-mutated mCRC patients treated with first-line FOLFIRI or FOLFOX +/- bevacizumab. Both unmatched and propensity-score-matched analysis (PSMA) were conducted, with PSMA controlling for: previous adjuvant chemotherapy, ECOG PS, use of bevacizumab in first line, timing of metastasis appearance, time from diagnosis to first-line start, number of metastatic sites, presence of mucinous component, gender, and age. Subgroup analyses were also performed to investigate subgroup treatment-effect interactions. KRASG12D-mutated patients were analysed as control. One hundred and four patients treated with irinotecan-(N = 47) or oxaliplatin-based (N = 57) chemotherapy were included. In the unmatched population, objective response rate (ORR) and median (m) progression-free and overall survival (mPFS and mOS) were comparable between the treatment arms. However, a late (>12 months) PFS advantage was observed with irinotecan (HR 0.62, p = 0.02). In the PSMA-derived cohort, a significant improvement with irinotecan vs. oxaliplatin was observed for both PFS and OS: 12- and 24-month PFS rates of 55% vs. 31% and 40% vs. 0% (HR 0.40, p = 0.01) and mOS 37.9 vs. 21.7 months (HR 0.45, p = 0.045), respectively. According to the subgroup analysis, interaction effects between the presence of lung metastases and treatment groups were found in terms of PFS (p for interaction = 0.08) and OS (p for interaction = 0.03), with a higher benefit from irinotecan in patients without lung metastases. No difference between treatment groups was observed in the KRASG12D-mutated cohort (N = 153). First-line irinotecan-based regimens provided better survival results in KRASG12C-mutated mCRC patients and should be preferred over oxaliplatin. These findings should also be considered when investigating chemotherapy plus targeted agent combinations.

Risk factors for irinotecan-induced liver injury: a retrospective multicentre cross-sectional study in China

ObjectivesThe hepatotoxicity of irinotecan has been widely implicated in the treatment of multiple solid tumours. However, there are few studies on the influencing factors of irinotecan-induced hepatotoxicity. Herein, we investigated...

A phase 1/2a, multicenter, open-label study of CNA3103 (LGR5-targeted, autologous CAR-T cells) in patients with metastatic colorectal cancer (mCRC).

TPS3632 Background: Leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5) is a cancer stem cell (CSC) marker that is abundant in solid tumors, highly expressed in colorectal cancer and involved in tumor initiation, growth, and metastasis. Its expression is linked to poor survival and poor patient response to therapy in mCRC, and presents an attractive opportunity for selectively targeting a highly specific, functional CSC receptor in this disease. CNA3103 is a first-in-class cell product consisting of autologous T cells transduced to express a CAR to target LGR5. It contains the antigen-biding domain of BNC101, a humanized monoclonal LGR5 antibody previously tested in Phase 1 in mCRC subjects and demonstrated to be safe and well tolerated with no off-target binding activity. Methods: This is a first in human, multicenter, open label, Phase 1/2a dose escalation and expansion study to determine the safety of and overall best response to CNA3103 in subjects with mCRC. Up to 44 subjects (24 in Phase 1 and 20 in Phase 2a) will be enrolled. The trial follows a BOIN design with a minimum of 3 consecutively enrolled subjects per cohort, and a 28-day DLT evaluation period. Four cell dose levels (5 × 107, 1.5 × 108, 4.5 × 108, 1.5 × 109) of CNA3103 will be evaluated. A Safety Monitoring Committee (SMC) will oversee the conduct of the study. The pharmacokinetic (PK) profile of CNA3103 in blood will be assessed. Exploratory objectives include evaluation of LGR5+ cells and CNA3103 in tumor biopsies, immune cellular profile, cytokine levels and circulating tumor DNA in blood, and immunogenicity of CNA3103. Main inclusion criteria: mCRC subjects positive for LGR5 expression and failing prior treatment with 5-FU, oxaliplatin and irinotecan-based regimens for metastatic disease; >1 radiologically measurable lesion per RECISTv1.1; >1 biopsiable lesion at baseline; ECOG 0 or 1; serum albumin >3 g/dL; and normal organ and marrow function. Main exclusion criteria: BRAF-mutated disease, clinical ascites/ pleural effusions; active autoimmune/ connective tissue disease; history of inflammatory bowel disease or active peptic ulcer disease. The trial is sponsored by Carina Biotech. Phase 1 enrolment is limited to Australian sites. Phase 2a enrolment will take place in Australia and the US. For information, contact Lina Jablonskis lina@carinabiotech.com or +61 437 891 563.

Predictive Value of ABCC2 and UGT1A1 Polymorphisms on Irinotecan-Related Toxicities in Patients with Cancer.

Background: There is extensive interindividual variability in response and tolerance to anticancer drugs. This heterogeneity provides a major limitation to the "rational" use of cytotoxic drugs, and it becomes a major problem in oncology giving a narrow therapeutic window with a vital risk. Among these anticancer drugs, irinotecan can cause dose-limiting toxicities, commonly diarrhea and neutropenia. Interaction among pathways of activation/inactivation (UGT1A1) and hepatobiliary transport of irinotecan and its metabolites could, in part, explain its interindividual variability. The objective of this study was to perform an exploratory analysis to evaluate the correlation between the genetic polymorphisms of UGT1A1 and ABCC2 with the different toxicities associated with irinotecan treatment. Materials and Methods: Seventy-five patients with solid cancers were included, all were administered an irinotecan-based regimen in both Mission Bay Medical Center; and Zuckerberg San Francisco General Hospital from May 2016 to December 2016. The patients' genotyping was performed for both the UGT1A1*28 polymorphism, and the ABCC2 - 1549G>A, and ABCC2 - 1249G>A single nucleotide polymorphism. Comparisons among qualitative data were assessed using the χ2-test, and Fisher's exact test in the case of small group sizes. Results: Diarrhea was observed in 40 patients (53.3%), among them only 9 patients had high grades diarrhea (grades III and IV). Grades III/IV of nausea were more frequently associated with the ABCC2-1549 AA genotype (83.3% p = 0.004) in patients with colorectal cancer. In pancreatic cancer, a significant absence of diarrhea grades III-IV was noted in patients with the ABCC2 1249 GG genotype compared to the other ABCC2 1249 genotypes.

In brief: A second indication for tucatinib (Tukysa).

The oral kinase inhibitor tucatinib (Tukysa – Seagen) has received accelerated approval from the FDA for use in combination with trastuzumab (Herceptin) for treatment of adults with RAS wild-type human epidermal growth factor receptor 2 (HER2)-positive unresectable or metastatic colorectal cancer that has progressed following treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy regimens. Tucatinib was approved in 2020 for use in combination with trastuzumab and capecitabine (Xeloda, and generics) for treatment of adults with advanced unresectable or metastatic HER2-positive breast cancer, including those with brain metastases, who received at least one prior anti-HER2-based regimen for metastatic disease.

Real-world clinicopathological and molecular characteristics, treatment patterns, and outcomes in patients with KRAS G12C–mutated metastatic colorectal cancer in AACR Project GENIE.

41 Background: KRAS mutation accounts for ~37% of colorectal cancer (CRC), with KRAS G12C occurring in ~3% of CRC tumors. KRAS G12C mutation is associated with poorer prognosis in terms of real-world progression-free survival (rwPFS) and overall survival (OS) compared to other KRAS mutations and KRAS wild-type. As KRAS G12C mutated metastatic CRC (mCRC) is recognized as a discrete potentially druggable target, there is a need to further describe this patient population. This retrospective cohort study provides real-world clinicopathological and molecular characteristics, treatment patterns, and outcomes (OS, rwPFS) in patients with KRAS G12C mutated mCRC. Methods: Adult (≥18 years old) patients diagnosed between 01 January 2009 and 01 February 2019 with KRAS G12C mutated mCRC were assessed from three US academic centers in AACR Project GENIE: Dana-Farber Cancer Institute, Memorial Sloan Kettering Cancer Center, and Vanderbilt-Ingram Cancer Center. Patient characteristics and treatment patterns were reported, and median OS and rwPFS by line of therapy (LOT) were estimated with the Kaplan-Meier method, including exploratory analyses by co-mutation profile. Results: Among 71 mCRC patients, median age at initial diagnosis was 52.1 years, 59% were women, 83% were White, and 68% had initial stage 4 disease. Co-mutations with an oncogenic, likely oncogenic, or predicted oncogenic OncoKB annotation were assessed, and the most commonly observed were APC in 79% of patients, TP53 in 63%, and PIK3CA in 20%. Only 8% of patients had high tumor mutational burden (>10 mut/Mb), and no patients had microsatellite instability-high among those measured (n=48). Most patients (71%) had evidence of surgical resection in the metastatic setting. Nearly all (93%) patients had received systemic therapy: 15 (23%) had only one LOT, 20 (30%) had only two LOTs, and 31 (47%) had three or more. Most patients received oxaliplatin- or irinotecan-based regimens in the first two LOTs. Median OS from the start of first LOT was 33.5 months (95% CI: 26.9, 37.1), 20.7 months (95% CI: 6.4, 23.2) from start of second LOT, and 15.8 months (95% CI: 3.1, 23.4) from start of third LOT. Median rwPFS from start of first LOT was 20.9 months (95% CI: 8.4, 32.0), 4.0 months (95% CI: 2.2, 9.7) from start of second LOT, and 3.1 months (95% CI: 1.1, 7.2) from start of third LOT. Patients with FBXW7 co-mutation had shorter OS and patients with PIK3CA co-mutation had longer rwPFS, compared to those with KRAS G12C alone. Conclusions: In this select patient cohort with KRAS G12C mutated mCRC from US academic centers, outcomes, particularly rwPFS, were poor in later lines of therapy. Frontline OS and rwPFS were longer than in other similar studies, which may be attributable to the young median age and high proportion of surgical resection in the metastatic setting observed in this cohort.

Irinotecan- vs oxaliplatin-based regimens for neoadjuvant chemotherapy in colorectal liver metastasis patients: A retrospective study.

BACKGROUNDNeoadjuvant chemotherapy (NC) improves the survival outcomes of selected patients with colorectal liver metastasis (CRLM). The benefits of irinotecan-based regimens in these patients are still under debate.AIMTo compare the benefits of irinotecan- and oxaliplatin-based regimens in patients with resectable CRLM.METHODSFrom September 2003 to August 2020, 554 patients received NC and underwent hepatectomy for CRLM. Based on a 1:1 propensity score matching (PSM) model, 175 patients who received irinotecan were matched to 175 patients who received oxaliplatin to obtain two balanced groups regarding demographic, therapeutic, and prognostic characteristics.RESULTSChemotherapy was based on oxaliplatin in 353 (63.7%) patients and irinotecan in 201 (36.3%). After PSM, the 5-year progression-free survival (PFS) and overall survival (OS) rates with irinotecan were 18.0% and 49.7%, respectively, while the 5-year PFS and OS rates with oxaliplatin were 26.0% and 46.8%, respectively. Intraoperative blood loss, operating time, and postoperative complications differed significantly between the two groups. In the multivariable analysis, carbohydrate antigen 19-9, RAS mutation, response to NC, tumor size > 5 cm, and tumor number > 1 were independently associated with PFS.CONCLUSIONIn NC in patients with CRLM, irinotecan is similar to oxaliplatin in survival outcomes, but irinotecan is superior regarding operating time, intraoperative blood loss, and postoperative complications.

Outcomes of Patients with Metastatic Colorectal Cancer Treated with Trifluridine/Tipiracil beyond the Second Line: A Multicenter Retrospective Study from Saudi Arabia.

Background The outcome of patients with refractory metastatic colorectal cancer (mCRC) treated with trifluridine/tipiracil (FTD/TPI) beyond the second-line has not been studied in Saudi Arabia. Therefore, this multicenter retrospective analysis was conducted to evaluate the efficacy of FTD/TPI. Methods This multicenter retrospective analysis included five centers in Saudi Arabia. FTD/TPI was administered to all the patients beyond the oxaliplatin- and irinotecan-based chemotherapy regimens. The electronic medical records were reviewed, and progression-free survival (PFS) and overall survival (OS) were determined. Results The study included 100 patients with a mean age of 55.4 ± 11.8 years. The overall response to FTD/TPI was 4%. The median PFS was 4 months (95% confidence interval (CI) 3.487–4.513), and the median OS was 11 months (95% CI, 9.226–12.771). In a Cox regression analysis of the independent predictors for PFS, advanced stage of the disease (P = 0.037; HR, 2.614; and CI, 1.102–7.524), presence of lymph node metastasis (P = 0.018; HR, 3.664; and 95% CI, 1.187–8.650), and >2 metastatic sites (P = 0.020; HR, 1.723; and 95% CI, 1.089–2.727) were independent factors predicting disease progression. The Cox regression analysis confirmed that age ≥ 55 years (P = 0.046; HR, 1.667; and 95%, 1.097–3.100), advanced disease stage (P = 0.044; HR, 1.283; and 95% CI, 1.035–2.940), prior use of adjuvant chemotherapy (P = 0.037; HR, 0.892; and 95% CI, 0.481–0.994), liver metastasis (P = 0.025; HR, 2.015; and 95% CI, 1.091–3.720), >2 metastatic sites (P = 0.038; HR, 1.248; and 95% CI, 1.036–1.846), development of neutropenia after receiving first cycle of FTD/TPI (P = 0.042; HR, 1.505; and 95% CI, 1.064–2.167), and increased number of FTD/TPI cycles (P = 0.002; HR, 0.769; and 95% CI, 0.664–0.891) were independent variables for OS. Conclusion Treatment with FTD/TPI is feasible and effective in daily clinical practice in Saudi Arabian patients. The risk of progression increased with advanced disease stage, lymph node metastasis, bone metastasis, and metastasis to >2 sites. Age ≥ 55 years, advanced disease stage, liver metastasis, metastasis to >2 sites, neutropenia after the first cycle of FTD/TPI, and increased number of FTD/TPI cycles were independent factors predicting mortality.

Molecular evolutionary process of advanced gastric cancer during sequential chemotherapy detected by circulating tumor DNA

BackgroundEfficacy of conventional sequential chemotherapy paradigm for advanced gastric cancer (AGC) patients has largely plateaued. Dynamic molecular changes during and after sequential chemotherapy have not been fully delineated. We aimed to profile the molecular evolutionary process of AGC patients during sequential chemotherapy by next generation sequencing (NGS) of plasma circulating tumor DNA (ctDNA).MethodsA total of 30 chemo-naïve patients who were diagnosed with unresectable advanced or metastatic stomach adenocarcinoma were enrolled. All patients received sequential chemotherapy regimens following the clinical guideline. One hundred and eight serial peripheral blood samples were collected at baseline, radiographical assessment and disease progression. Plasma ctDNA was isolated and a customized NGS panel was used to detect the genomic features of ctDNA including single nucleotide variants (SNVs) and gene-level copy number variations (CNVs). KEGG pathway enrichment analysis was performed.ResultsPlatinum-based combination chemotherapy was administrated as first-line regimen. Objective response rate was 50% (15/30). Patients with higher baseline values of copy number instability (CNI), CNVs and variant allel frequency (VAF) were more sensitive to platinum-based first-line regimens. Tumor mutation burden (TMB), CNI and CNV burden at partial response and stable disease were significantly lower than those at baseline, where at progressive disease they recovered to baseline levels. Dynamic change of TMB (ΔTMB) was correlated with progression-free survival of first-line treatment. Fluctuating changes of SNVs and gene-level CNVs could be observed during sequential chemotherapy. Under the pressure of conventional chemotherapy, the number of novel gene-level CNVs were found to be higher than that of novel SNVs. Such novel molecular alterations could be enriched into multiple common oncologic signaling pathways, including EGFR tyrosine kinase inhibitor resistance and platinum drug resistance pathways, where their distributions were found to be highly heterogenous among patients. The impact of subsequent regimens, including paclitaxel-based and irinotecan-based regimens, on the molecular changes driven by first-line therapy was subtle.ConclusionBaseline and dynamic changes of genomic features of ctDNA could be biomarkers for predicting response of platinum-based first-line chemotherapy in AGC patients. After treatment with standard chemotherapy regimens, convergent oncologic pathway enrichment was identified, which is yet characterized by inter-patient heterogenous gene-level CNVs.

NSABP FC-11: A phase II study of neratinib (N) plus trastuzumab (T) or N plus cetuximab (C) in patients (pts) with "quadruple wild-type" metastatic colorectal cancer (mCRC) based on HER2 status.

3564 Background: Patients (pts) with KRAS wild-type (WT) mCRC treated with single agent anti-EGFR therapy (tx) have improved OS compared to BSC but only a 10-15% response rate. Prior EGFR tx may upregulate HER amplification. For pts with quadruple WT mCRC (KRAS, NRAS, BRAF, PIC3KA), data suggest that dual targeting of the MAPK pathway, specifically EGFR and HER2, may be more effective. The purpose of this study was to evaluate the activity of dual MAPK pathway inhibition based on HER2 status: amplified (amp), non-amplified (non-amp), or mutated (mt). Methods: This 2-arm phase II trial enrolled pts with quad WT mCRC with ECOG PS 0-2, adequate organ function, prior oxaliplatin- and irinotecan-based regimens, and known HER2 status. Arm 1: HER2 amp (confirmed as >2.14 copy number by Guardant 360) and prior anti-EGFR tx or HER2 mt (with qualifying mt) with or without prior anti-EGFR tx; Arm 2: HER2 non-amp or HER2 amp without prior anti-EGFR tx. Tx included T 4 mg/kg IV loading dose → 2 mg/kg/wk and N 240 mg po daily (Arm 1) or C 400 mg/m2 IV loading dose → 250 mg/m2/wk and N 240 mg po daily (Arm 2). Imaging was performed every 8 wks with response per RECIST 1.1. Primary end point (EP) of each arm was 6 mo PFS (PFS6). Secondary EPs: Response rate (ORR), clinical benefit rate (CBR), toxicity and exploratory assessments of N pharmacokinetics, genetic and molecular analyses, and evaluation of multiple drug combinations in PDX/PDXO models. We tested H0: PFS6 <0.13 v HA: PFS6 >0.47 (α=0.05; power=0.90 to reject HA). Treating 15 pts in each arm, if ≥5 pts are alive and progression free (PFS6 0.33), the arm is worth further testing. Results: From Jul 2018 - Mar 2021, 25 pts enrolled from 9 different centers. Arm 1 closed due to poor accrual (n=4). Those pts have been excluded from further analysis. Arm 2 enrolled 21 pts. with 15 evaluable for response by imaging. Early discontinuation occurred in 6 of 21 pts: 2 withdrew consent, 3 due to toxicity, and 1 physician withdrawal. Of the 15 evaluable pts, there were 6 PR, 5 of 13 HER2 non-amp, 1 of 2 HER2 amp, (duration 120-171 days; mean 140) and 5 SD (duration 59-231 days; mean 124). The ORR (CR/PR) in all pts who received at least one dose of tx is 33% (6/20). 8 of 15 evaluable pts (53%) were progression free at cycle 6. Common grade 3+ AEs (>5%) included diarrhea (24%), rash (8%), and abdominal pain/distension (8%), without any grade 5 AEs. Conclusions: The combination of C+N was reasonably well tolerated with expected toxicities of diarrhea and rash. The ORR, CBR, and PFS compare favorably to pts previously relapsed following oxaliplatin and irinotecan and treated with single-agent anti-EGFR tx. Upon entry, biopsies for PDX implantation had an engraftment success rate of ̃80%. We anticipate using these grafts to establish PDXO models for molecular analyses and further drug testing. Support: NSABP Foundation, Puma Biotechnology. Clinical trial information: NCT03457896.

P-69 Anal squamous cell carcinoma (ASCC) outcomes in clinical practice: From localized to metastatic setting

Anal cancer is an infrequent neoplasm, usually diagnosed at localized stages. A multidisciplinary approach involving chemoradiotherapy (CRT) and surgery is necessary. Real-world data in both locally advanced and metastatic setting is needed to support therapeutic decisions. Patients with ASCC diagnosis between 2004 and 2022 in three tertiary care centers in Spain were reviewed. Demographic, clinical, pathological, and therapeutic variables were collected. Comparative analyses have been performed by Chi-squared tests. Survival estimates have been calculated by Kaplan-Meier method and comparations have been made using Cox proportional hazards model. 111 patients were included (45.9% males, median age 61y, 9.9% metastatic at initial diagnosis). Preferred treatment in localized stage was CRT (88.1%) with 5-fluorouracil and mytomicin-C (5FU-MMC) (55%) or 5FU-Cisplatin (33%). Response in patients treated with CRT was assessed by MRI at 3 and/or 6 months after CRT in 60.4% and 53.1% respectively. 19.6% of patients needed surgical intervention due to persistent or progressive disease after CRT. There were no significant differences between 5FU-MMC or 5FU-Cisplatin in terms of complete radiological response (45,28% vs. 51,61%; p = 0.58), need of surgical rescue (18,85% vs. 19,35%; p = 0.96), distant or localized relapse (30,18% vs. 25,80%; p = 0.67), median disease-free survival (DFS) (50,00 months vs. non reached (NR); p = 0.24) or overall survival (117,26 months vs. NR; p = 0.45). OS was significantly improved in patients who achieved a complete radiological response vs. patients who not (117,26 months vs. 29,01 months p 42,57% of all patients treated with curative intent relapsed locally (44.2%) or distant (55.8%), being regional nodes most common place of recurrence. The median OS of metastatic patients at diagnosis was 14,75 months. Considering all metastatic patients (de novo or relapsed), no significant differences in OS were found between patients who received treatment with curative intent (surgery, CRT) and patients only candidate to palliative chemotherapy 15,97 months vs. 13,11 months; p = 0.072). Median progression-free survival (PFS) of Carboplatin-Paclitaxel was 4,76 months. 62,85% of metastatic patients received a 2nd line of treatment. 48,57% of metastatic patients received immunotherapy. PD-(L)1 was only determined in 11,42% of metastatic patients. PFS of immunotherapy was 2,27 months. One patient receiving immunotherapy achieved a complete response and two patients achieved a PFS > 12 months. Other regimens used in latter lines included oxaliplatin (5,71%) and irinotecan-based (14,28%) regimens. Real world data in ASCC population reveals a complex scenario with significant heterogeneity in response to treatments and outcomes. Multidisciplinary collaboration is essential. Role of immunotherapy in ASCC patients in clinical practice is still unknown. More research is needed in the refractory setting after Carboplatin-Paclitaxel to increase OS.

The bevacizumab plus oxaliplatin-based chemotherapy regimen is more suitable for metastatic colorectal cancer patients with a history of schistosomiasis: a clinical retrospective analysis

The basic platelet counts of schistosomiasis patients are low. If it does not meet the requirements for chemotherapy, the patient's treatment will not be carried out, which directly affects their prognosis. Therefore the impact of treatment on platelet counts is critically important. The effects of bevacizumab plus oxaliplatin-based chemotherapy and bevacizumab plus irinotecan-based chemotherapy regimens on platelets are different but have not been determined. In order to find a more suitable plan for metastatic colorectal cancer (mCRC) patients with a history of schistosomiasis, we conducted a retrospective analysis of mCRC patients and evaluated the impact of bevacizumab on their platelets. The medical records of all mCRC patients with a history of schistosomiasis who received oxaliplatin-based chemotherapy or irinotecan-based chemotherapy as first-line treatment for no less than 4 cycles, with or without bevacizumab from September 1, 2017, to June 30, 2019, in Kunshan Hospital were reviewed. Six-month cumulative incidence rates of splenomegaly and thrombocytopenia of chemotherapy with and without bevacizumab groups, oxaliplatin-based chemotherapy with and without bevacizumab groups, irinotecan-based chemotherapy with and without bevacizumab groups were compared from the first cycle until the completion of chemotherapy using Kaplan-Meier analysis and Log-rank test. Evaluable splenic enlargement and thrombocytopenia results were obtained from 153 mCRC patients. The 6-month cumulative incidence rates of splenomegaly (23.3% vs. 55%; P=0.01) and that of thrombocytopenia (43.8% vs. 57.5%; P=0.40) were lower in the bevacizumab group than the non-bevacizumab group, however there were no statistical differences for the rates of thrombocytopenia. For patients treated with oxaliplatin, the rates of splenomegaly (19.5% vs. 66.7%; P=0.01) and thrombocytopenia (31.7% vs. 77.2%; P=0.02) were lower in the bevacizumab-treated cohort than that in the non-bevacizumab cohort. When stratified for irinotecan, there were no statistical differences in the frequency of splenomegaly between the two groups. However, the rates of thrombocytopenia were higher in the bevacizumab-treated cohort than that in the non-bevacizumab cohort (59.4% vs. 8.7%; P=0.01). The bevacizumab plus oxaliplatin-based chemotherapy regimen is safer for mCRC patients with a history of schistosomiasis, especially for patients with a lower platelet count.

Real-world safety and supportive care use of second-line 5-fluorouracil-based regimens among patients with metastatic pancreatic ductal adenocarcinoma

Objective Chemotherapy-related adverse events (AEs) can negatively impact the care of patients. The prevention and management of AEs often require additional medications. This study evaluated the percentages of patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) undergoing second-line therapy with 5-fluorouracil (5-FU)-based regimens that experienced AEs during treatment and received medication to manage those AEs. Methods We conducted a retrospective observational analysis utilizing the Flatiron Health database of adult patients with mPDAC who started second-line therapy between January 2016 and August 2020. The occurrence of diarrhea, fatigue, nausea and vomiting, neuropathy, and hematologic AEs including G3/G4 anemia, neutropenia, and thrombocytopenia was assessed. The use of concomitant medications including atropine and granulocyte colony stimulating factor (G-CSF) was assessed. Results Of the 825 eligible patients, 29.0% (n = 239) received FOLFIRINOX, 24.0% (n = 198) received FOLFOX, 6.8% (n = 56) received FOLFIRI, and 40.2% (n = 332) received liposomal irinotecan-based regimens. FOLFIRI and FOLFIRINOX regimens were associated with the highest rates of anemia (16.1% and 15.5%), neutropenia (19.6% and 22.6%), and thrombocytopenia (14.3% and 9.6%). The liposomal irinotecan and FOLFOX regimens were associated with lower rates of anemia (11.8% and 12.1%), neutropenia (12.4% and 14.7%), and thrombocytopenia (2.4% and 8.1%). G-CSF use was observed among 63.6%, 34.9%, 33.9%, and 44.9% of patients treated with FOLFIRINOX, FOLFOX, FOLFIRI, and liposomal irinotecan-based regimens, respectively. Diarrhea was observed among 12.5%, 4.5%, 12.5%, and 10.2% of patients who were treated with FOLFIRINOX, FOLFOX, FOLFIRI, and liposomal irinotecan-based regimens, respectively. Nausea and vomiting occurred in 14.9%, 12.6%, 10.5%, and 13.1% of patients treated with FOLFIRINOX, FOLFOX, FOLFIRI, and liposomal irinotecan-based regimens, respectively. Atropine use was higher in patients treated with FOLFIRINOX and FOLFIRI (90.8% and 94.6%, respectively) than in patients treated with liposomal irinotecan-based regimens (75.6%). Conclusions In patients with mPDAC who received second-line therapy, those who received liposomal irinotecan-based regimens had the lowest rates of anemia, neutropenia, and thrombocytopenia compared to FOLFIRI, FOLFIRINOX, and FOLFOX, while requiring a similar or lower level of medication to treat and manage those adverse events. Patients treated with FOLFIRI received the highest dose of pegfilgrastim to manage neutropenia. The results of this real-world analysis are consistent with prior evaluations of patients with mPDAC and highlight the importance of managing adverse events and associated cost implications.

Understanding extended duration of therapy (DOT) among patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) treated with liposomal irinotecan-based regimens.

579 Background: Few analyses have identified characteristics associated with extended DOT (eDOT) among a large group of patients (pts) treated with liposomal irinotecan. This study examines the characteristics associated with eDOT among pts with mPDAC treated with liposomal irinotecan in a real-world setting. Methods: This retrospective observational study utilized the Flatiron Health EHR database from over 280 cancer clinics in the US. Data were analyzed for adult pts with mPDAC treated with liposomal irinotecan-based regimens between January 2016 and October 2020. eDOT was defined as a DOT > 2 standard deviations (SD) above the mean. Demographic and clinical characteristics evaluated included age, sex, stage at diagnosis, ECOG performance score (PS), and the number of prior lines of therapy at the time of treatment initiation. Dose delays and dose reductions during treatment were assessed. Additionally, changes in lymphocyte counts during treatment were described. Chi-squared test and Fisher’s exact test were used to test for significance for categorical variables and the t-test was used for continuous variables. Results: 675 pts with mPDAC treated with a liposomal irinotecan-based regimen were included. The overall mean DOT was 14.6 weeks (SD: 22.1). There were 30 pts (4.4%) that met the definition for eDOT. Patient sex and median age at treatment initiation were similar between those with eDOT and non-eDOT: male, 46.7% vs. 51.9% (p = 0.582); age, median 70 years vs 69 years (p = 0.923), respectively. A higher proportion of pts with eDOT had ECOG PS of 0-1 compared to those with non-eDOT, 73.3% vs 57.7%, respectively (p = 0.397). At treatment initiation 80.0% of pts who had eDOT had a serum albumin level of ≥ 35g/L versus 55.2% of pts with non-eDOT (p = 0.013). On average, those with eDOT experienced a 55.1% reduction in lymphocyte count (baseline to nadir) during treatment compared to a 34.7% reduction among pts with non-eDOT (p < 0.0001). Pts who experienced eDOT were more likely to be treated in earlier lines of therapy than those with non-eDOT: 33.3% vs 14.1% received 0 prior lines and 46.7% vs 47.3% received 1 prior line, respectively (p = 0.008). 53.3% of pts with eDOT experienced a dose reduction (of at least 7mg/m2) compared to 24.7% pts with non-eDOT (p = 0.0005). All pts with eDOT experienced a dose delay of > 16 days during treatment versus 45.3% of pts with non-eDOT (p < 0.0001). Conclusions: This real-world study identified pts treated earlier in their disease course with a liposomal irinotecan-based regimen and normal baseline serum albumin were more likely experience extended DOT. Treatment modifications and delays appear to have enabled longer treatment duration with liposomal irinotecan-based regimens. Further prospective studies should be considered to characterize factors that may predict extended DOT.

Real-world clinical outcomes of patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) treated with liposomal irinotecan-based regimens: Impact of prior irinotecan (IRI) exposure.

580 Background: Subgroup analyses of the NAPOLI-1 study identified that among patients who were IRI naïve prior to entering the clinical trial, a survival benefit was observed between the study arm and control arm (overall survival (OS): 6.7 months vs 4.2 months). This treatment benefit was not observed among those previously exposed to IRI (OS: 4.6 months in study arm vs 4.8 months in control arm). This study sought to understand the impact of prior exposure to IRI on clinical outcomes among patients treated with liposomal irinotecan in the real-world setting. Methods: This retrospective observational study utilized the Flatiron Health EHR database. Data were analyzed for adult patients with mPDAC treated with liposomal irinotecan -based regimens between January 2016 and October 2020. Patient characteristics, OS and progression-free survival (PFS) were assessed. Prior IRI was defined as IRI given in a prior regimen in the metastatic setting. Cox proportional hazard (PH) methods were used to calculate hazard ratios (HRs). HRs were adjusted to account for demographics and relevant clinical covariates. Patients without prior exposure to IRI were used as the reference population for the Cox PH model (an HR < 1 represents worse survival for unexposed patients relative to the exposed). Results: 675 patients with mPDAC treated with a liposomal irinotecan-based regimen were included. Median age at treatment initiation was 69 (IQR: 62 – 75) years and among patients with available ECOG performance status (PS), 77.4% had a PS of 0-1. 181 (27%) patients were previously exposed to IRI in the metastatic setting (Table). The unadjusted OS HR was 1.3 (95% CI: 1.1 – 1.6, p < 0.001) and the unadjusted PFS HR was 1.4 (95%CI: 1.2 – 1.7, p < 0.001). After adjustment for baseline characteristics the adjusted OS HR was 1.0 (95% CI: 0.8 – 1.3, p = 0.8836) and the adjusted PFS HR was 1.1 (95%: 0.8 – 1.4, p = 0.5626). Conclusions: The results of this study suggest prior exposure to IRI is not a predictor of worse clinical outcomes for patients treated with liposomal irinotecan-based treatment when accounting for key clinical characteristics in a multivariable model. The results from this real-world study can be used to support treatment sequencing decisions for patients with mPDAC following first line therapy. This is the largest real-world evidence study to date of patients with mPDAC treated with liposomal irinotecan.[Table: see text]