Irinotecan-based Regimens Research Articles

Resource utilization and total cost of care among Medicare advantage patients with metastatic pancreatic cancer receiving NCCN category 1 preferred regimens.

531 Background: Medicare Advantage accounts for almost 40% of Medicare beneficiaries in 2021. There is limited research evaluating utilization and cost for Medicare Advantage patients with metastatic pancreatic cancer (m-PANC) receiving various NCCN Category 1 preferred regimens. Methods: We used ICD-10 diagnosis codes to identify patients with m-PANC without end-stage renal disease in the 2016-2019 Milliman Consolidated Health Cost Guidelines Sources Database (CHSD) claims files. Study patients had 2+ claims with a pancreatic cancer diagnosis and Medicare Advantage coverage for 3 months pre- and 1 month post-metastasis diagnosis. Patients with stand-alone Part D plan coverage or aged<65 years were excluded. Total cost of care (TCOC) was the sum of the average paid by the insurer and patient. Study patients were treated with NCCN Category 1 preferred regimens: 1L gemcitabine/nab-paclitaxel (gem/nab), 1L gemcitabine monotherapy (gem mono), 1L FOLFIRINOX (FFX), and 2L+ liposomal irinotecan (5FU was not included in this analysis; see Limitations for further details). Results: Of the approximately 2.5 million patients covered by Medicare Advantage in CHSD, there were 946 patients that received an NCCN Category 1 chemotherapy regimen between 2016 and 2019. Among NCCN Category 1 preferred regimens, patients receiving 2L+ liposomal irinotecan had the lowest mean admissions per beneficiary and mean readmission rate (0.5 and 8%) compared to patients receiving gem/nab (0.8 and 12%), gem mono (0.6 and 8%), or FFX (0.6 and 9%). Patients receiving 2L+ liposomal irinotecan also had the shortest length of stay per inpatient admission in days (2.9) compared to patients receiving gem/nab (5.1), gem mono (3.6), or FFX (4.3). Mean claims per beneficiary for emergency department observations was lowest among patients receiving 2L+ liposomal irinotecan (0.7), compared to patients receiving gem/nab (0.9), gem mono (1.0), or FFX (0.89). Patients receiving 2L+ liposomal irinotecan had lower median TCOC ($31,885) than patients receiving gem/nab ($39,479) or FFX ($32,632). Conclusions: Patients with Medicare Advantage receiving 2L+ liposomal irinotecan-based regimens to treat m-PANC had lower healthcare resource utilization in key categories and lower median total costs than patients receiving other NCCN Category 1 preferred regimens. Limitations: Analysis of different populations or time periods may yield different results. Our study used claims data and not electronic health records (EHRs), so we could not control for clinical covariates. Patient characteristics and regimen performance might influence which regimens patients receive. We did not adjust TCOC or utilization for LOT durations. We did not study whether liposomal irinotecan-based therapy patients received concomitant 5FU or prior gemcitabine-based therapy.

All You Need to Know About UGT1A1 Genetic Testing for Patients Treated With Irinotecan: A Practitioner-Friendly Guide.

Irinotecan is an anticancer agent widely used for the treatment of solid tumors, including colorectal and pancreatic cancers. Severe neutropenia and diarrhea are common dose-limiting toxicities of irinotecan-based therapy, and UGT1A1 polymorphisms are one of the major risk factors of these toxicities. In 2005, the US Food and Drug Administration revised the drug label to indicate that patients with UGT1A1*28 homozygous genotype should receive a decreased dose of irinotecan. However, UGT1A1*28 testing is not routinely used in the clinic, and specific reasons include lack of access to concise information on this wide issue as well as mixed recommendations by regulatory and professional entities. To assist oncologists in assessing whether and when to use UGT1A1 genetic testing in patients receiving irinotecan-based therapies, this article provided (1) essential knowledge of UGT1A1 polymorphisms; (2) an update on the impact of UGT1A1 polymorphisms on efficacy and toxicity of contemporary irinotecan-based regimens; (3) dosing adjustments based upon the UGT1A1 genotypes, and (4) recommendations from currently available guidelines from the US and international scientific consortia and major oncology societies.

Abstract P05-01: A phase 1b study evaluating the safety and efficacy of sotorasib, a KRASG12C inhibitor, in combination with trametinib, a MEK inhibitor, in KRAS p.G12C-Mutated Solid Tumors

Abstract Background KRAS p.G12C is an oncogenic driver in solid tumors, including non-small cell lung cancer (NSCLC) and colorectal cancer (CRC). Sotorasib, a specific, irreversible KRASG12C inhibitor, was recently approved by the FDA for treatment of adults with KRAS p.G12C-mutated locally advanced or metastatic NSCLC who received at least one prior systemic therapy. Sotorasib combined with trametinib, a selective allosteric MEK1/MEK2 inhibitor, displayed synergist antitumor activity in tumor xenografts. Here we report the first safety and interim efficacy of sotorasib in combination with trametinib in advanced KRAS p.G12C-mutated solid tumors in this phase 1b CodeBreaK101 master study. Methods In this dose exploration/expansion study, patients (pts) with KRAS p.G12C-mutated solid tumors were treated with 960 mg QD sotorasib and trametinib (1 or 2 mg QD). For NSCLC, prior anti-PD1/PD-L1 and/or platinum-based combination chemotherapy and targeted therapy (if applicable) was required. For CRC, at least 1 prior systemic regimen including fluoropyrimidine, oxaliplatin, and irinotecan-based regimens was required. 1° endpoint was safety/tolerability. 2° endpoint was efficacy. Results Based on a July 12, 2021 snapshot, 41 pts (22 male, median age: 60.0 y [34-84]) were enrolled and treated with combination of sotorasib and trametinib (18 pts NSCLC, 18 pts CRC, 5 pts other). Thirty-three pts (80.5%) received ≥2 prior lines of therapy (range, 0–8); 11 pts (26.8%) received prior KRASG12C inhibitor. Median treatment duration of the sotorasib and trametinib combination was 84.0 days (Q1, 42.0; Q3, 140.0). No new or unexpected toxicities were identified. The most common treatment-related adverse events (TRAEs) included diarrhea (43.9% pts), rash (34.1% pts), nausea (29.3% pts), and vomiting (22.0% pts), predominantly ≤grade 2. Ten pts (24.4%) discontinued sotorasib and/or trametinib due to a TRAE (2 pts-diarrhea). One dose-limiting toxicity (grade 3 maculo-papular rash, trametinib-related) was observed out of 33 pts treated with 2 mg trametinib/960 mg sotorasib QD. For the 1 mg trametinib/960 mg sotorasib QD CRC exploration cohort (N=3); 1 confirmed partial response (PR) and 1 stable disease (SD) were reported in pts with prior KRASG12C inhibitor; 1 SD was reported in a KRASG12C inhibitor-naïve pt. For the 2 mg trametinib/960 mg sotorasib QD CRC cohort (N=15), all 4 pts with prior KRASG12C inhibitor had SD; for naïve pts, 1-confirmed PR, 7-SD, and 3-progressive disease (PD) were reported. In NSCLC pts (N=18) treated with 2 mg trametinib/960 mg sotorasib QD, of pts with prior KRASG12C inhibitor, 2-SD and 1-PD were reported; of naïve pts, 3-confirmed PR, 10-SD, 1-PD, and 1-not evaluable were reported. Conclusions Combination of sotorasib and trametinib is safe and tolerable. The maximum tolerated dose tested was 2 mg trametinib/960 mg sotorasib QD. Antitumor activity was observed including responses in pts with prior KRASG12C inhibitor. Triplet combination therapy of sotorasib with trametinib and panitumumab currently are under investigation in solid tumors. Citation Format: Suresh Ramalingam, Marwan Fakih, John Strickler, Ramaswamy Govindan, Bob T. Li, Sarah Goldberg, David Gandara, Timothy Burns, Minal Barve, Catherine Shu, Richard Frank, Davendra Sohal, Pegah Jafarinasabian, Tian Dai, Omar Mather, David Hong. A phase 1b study evaluating the safety and efficacy of sotorasib, a KRASG12C inhibitor, in combination with trametinib, a MEK inhibitor, in KRAS p.G12C-Mutated Solid Tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P05-01.

Real-world prognostic factors for survival among treated patients with metastatic pancreatic ductal adenocarcinoma.

BackgroundMany real‐world studies of patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) are restricted to single centers, limiting the generalizability of their insights. This study aimed to identify important population‐based predictors for survival in patients diagnosed with mPDAC in a broader setting.MethodsData between 1 January 2017 and 31 December 2019 were extracted from the Flatiron Health EHR database. Treatment‐specific predictive models were generated for patients treated with first‐line gemcitabine+nab­paclitaxel (GNP), FOLFIRINOX, gemcitabine monotherapy (gem‐mono), and second‐line liposomal irinotecan‐based regimens. The holdout method was used for cross‐validation. Age at diagnosis, sex, BMI, smoking status, and ECOG performance score were included in all models with additional demographic, clinical characteristics, and hematological function assessed for inclusion.ResultsOf the 3625 patients, 43% received GNP, 26% received FOLFIRINOX, 7% received gem‐mono, and 23% received other regimens; 40% (n = 1448) advanced to the second line. Among all first‐line patients, the following were included in the final model: prior surgery, white blood cell (WBC) counts, serum albumin (SA), liver function tests (LFTs), serum bilirubin, serum carbohydrate antigen 19–9, and ascites. Models for patients receiving specific therapies differed from the overall model, GNP (ascites removed), FOLFIRINOX (stage at initial diagnosis added), and gem‐mono (LFTs omitted). Alkaline phosphatase (ALP), SA, and WBC counts were important predictors of survival among patients treated with second‐line liposomal irinotecan. Across all regimens, the strongest predictors of survival were ECOG score, SA, and ALP.ConclusionsIn this real‐world study of patients with mPDAC, important population prognostic factors of survival were identified in a large cohort of patients receiving systemic treatment.

A Retrospective Analysis of the Effect of Irinotecan-Based Regimens in Patients With Metastatic Breast Cancer Previously Treated With Anthracyclines and Taxanes.

BackgroundAt present, patients with metastatic breast cancer (MBC) have few treatment options after receiving anthracyclines and taxanes. Studies have shown that irinotecan has modest systemic activity in some patients previously treated with anthracyclines and taxanes. This study aimed to evaluate the efficacy of irinotecan-based chemotherapy for breast cancer patients in a metastatic setting.MethodsWe retrospectively collected the clinical information and survival data of 51 patients with MBC who received irinotecan at West China Hospital of Sichuan University. The primary endpoints were the progression free survival (PFS) and overall survival (OS), and the secondary endpoint was the objective response rate (ORR). To minimize potential confounding factors, we matched 51 patients who received third-line chemotherapy without irinotecan through propensity score matching (PSM) based on age, hormone receptor (HR), and human epidermal growth factor receptor 2 (HER2), compared their OS and PFS rates to those treated with irinotecan.ResultsFrom July 2012 to October 2020, 51 patients were treated with an irinotecan-containing regimen. The median number of previous treatment lines was 4, and a median of two previous chemotherapy cycles (ranging from 1–14 cycles) were given in a salvage line setting. The ORR was 15.7%, and the disease control rate (DCR) was 37.3%. For the irinotecan group, the median PFS was 3.2 months (95% CI 2.7–3.7), while the median OS was 33.1 months (95% CI 27.9–38.3). Univariate analysis results suggested that irinotecan could improve PFS in patients with visceral metastasis (P=0.031), which was 0.7 months longer than patients without visceral metastasis (3.5 months vs. 2.8 months). Compared to the patients who received third-line non-irinotecan chemotherapy, the irinotecan group showed a longer trend of PFS without statistical significance (3.2 months vs 2.1 months, P = 0.052). Similarly, the OS of the irinotecan group was longer than the third-line survival without irinotecan, but it was not statistically significant (33.1 months vs 18.0 months, P = 0.072).ConclusionsFor MBC patients who were previously treated with anthracyclines and/or taxanes, an irinotecan-containing regimen achieved moderate objective response and showed a trend of survival benefit, which deserves further study.

Multi‐omic molecular profiling guide’s efficacious treatment selection in refractory metastatic breast cancer: a prospective phase II clinical trial

This prospective phase II clinical trial (Side Out 2) explored the clinical benefits of treatment selection informed by multi‐omic molecular profiling (MoMP) in refractory metastatic breast cancers (MBCs). Core needle biopsies were collected from 32 patients with MBC at trial enrollment. Patients had received an average of 3.94 previous lines of treatment in the metastatic setting before enrollment in this study. Samples underwent MoMP, including exome sequencing, RNA sequencing (RNA‐Seq), immunohistochemistry, and quantitative protein pathway activation mapping by Reverse Phase Protein Microarray (RPPA). Clinical benefit was assessed using the previously published growth modulation index (GMI) under the hypothesis that MoMP‐selected therapy would warrant further investigation for GMI ≥ 1.3 in ≥ 35% of the patients. Of the 32 patients enrolled, 29 received treatment based on their MoMP and 25 met the follow‐up criteria established by the trial protocol. Molecular information was delivered to the tumor board in a median time frame of 14 days (11–22 days), and targetable alterations for commercially available agents were found in 23/25 patients (92%). Of the 25 patients, 14 (56%) reached GMI ≥ 1.3. A high level of DNA topoisomerase I (TOPO1) led to the selection of irinotecan‐based treatments in 48% (12/25) of the patients. A pooled analysis suggested clinical benefit in patients with high TOPO1 expression receiving irinotecan‐based regimens (GMI ≥ 1.3 in 66.7% of cases). These results confirmed previous observations that MoMP increases the frequency of identifiable actionable alterations (92% of patients). The MoMP proposed allows the identification of biomarkers that are frequently expressed in MBCs and the evaluation of their role as predictors of response to commercially available agents. Lastly, this study confirmed the role of MoMP for informing treatment selection in refractory MBC patients: more than half of the enrolled patients reached a GMI ≥ 1.3 even after multiple lines of previous therapies for metastatic disease.

Irinotecan, between Journeys and Stories

Irinotecan, an anticancer prodrug, entered definitively the clinical setting around the turn of the last century, after 33 years of treatment of advanced colorectal cancer patients with fluorouracil only as mainstay. Difficult-to-treat diarrhea, an initial peculiar toxicity seen with this drug in Japan, led to its withdrawal of the clinical arena for several years. At the Institute Gustave Roussy, we found out how to identify and treat this adverse event, allowing for a satisfactory recommended phase II dose (RP2D) of the compound. During our phase I study, we described that the probable pharmacological cause of the acute cholinergic events was the di-piperidinyl moiety of Irinotecan. We also related it to a potential contribution to the pathogeny of the delayed diarrhea of this drug. The journey of this Irinotecan’s moiety is still ongoing, for nobody has measured its plasmatic and urinary levels. Nobody really knows about its pharmacokinetics. Many Clinical investigators have been involved in all its phases of development and Irinotecan-based regimens are currently the standard of care therapy of metastatic colorectal cancer patients. It has an interesting activity in glioblastomas, and its combination with modulated fluorouracil and oxaliplatin proved its worth in the elusive population of advanced pancreatic and biliary tract cancer patients. This drug could have been discarded in phase I.

1480P Real-world progression outcomes among patients (pts) with metastatic pancreatic ductal adenocarcinoma (mPDAC) treated with liposomal irinotecan-based regimens in the United States

The NAPOLI-1 study, a randomized phase III study in pts with mPDAC previously treated with gemcitabine-based therapy, demonstrated an improvement in progression-free survival (PFS) with liposomal irinotecan + 5-fluorouracil/ leucovorin (5-FU/LV) vs. 5-FU/LV. Pts treated with liposomal irinotecan + 5-FU/LV in NAPOLI-1 had a median age of 63 years at treatment (tx) initiation, 97% had performance scores (PS) equivalent to ECOG 0-1, and 34% had at least 2 prior lines of therapy. This study examines the characteristics and real-world (rw) PFS of pts with mPDAC treated with liposomal irinotecan regimens.

1513P Real-world treatment discontinuation patterns among patients (pts) with metastatic pancreatic ductal adenocarcinoma (mPDAC) treated with liposomal irinotecan-based regimens in the United States

The most common reasons for treatment discontinuation (d/c) among patients treated in the liposomal irinotecan + 5-fluorouracil/ leucovorin (5-FU/LV) arm of the NAPOLI-1 study, a randomized phase 3 study in pts with mPDAC previously treated with gemcitabine-based therapy, were disease progression (55.3%), patient decision (13.6%), and clinical deterioration (12.6%). Real-world (RW) data lack detailed information regarding reasons for d/c of systemic treatment. This study examined the characteristics and reasons for treatment d/c of pts with mPDAC treated with liposomal irinotecan.

Retreatment of Irinotecan in Later Lines of Therapy for Metastatic Colorectal Cancer: A Retrospective Study

Background: Due to few efficacious options in later lines of therapy in metastatic colorectal cancer (mCRC), there has been considerable interest in the possibility of retreatment with previously administered agents. This study investigated the efficacy and safety of irinotecan retreatment (IRI2) in patients with refractory mCRC. Methods: We performed a retrospective analysis of patients with mCRC who were retreated with irinotecan-based regimens. The retreatment regimens with anti-epidermal growth factor receptor therapies were excluded. Results: A total of 64 patients were included. Patients had a median age of 56 years and were offered mainly in the setting of third- or fourth-line therapy with IRI2. The disease control rate was 78.2% including an objective response of 23.5%. Median progression-free survival and overall survival were 5.5 and 19.3 months, respectively. The most frequent grade 3 or higher toxicities were nausea/vomiting (27.9%) and neutropenia (25%). Conclusion: IRI2 might be a reasonable option for heavily pretreated patients with mCRC who achieved disease control with prior irinotecan therapy.

TLR4 deficiency upregulates TLR9 expression and enhances irinotecan-related intestinal mucositis and late-onset diarrhoea.

Severe diarrhoea, a common gastrointestinal manifestation of anticancer treatment with irinotecan, might involve single nucleotide polymorphisms (SNPs) of toll-like receptors (TLRs), described as critical bacterial sensors in the gut. Here, colorectal cancer patients carrying missense TLR4 A896G (rs4986790) or C1,196T (rs4986791) SNPs and Tlr4 knockout (Tlr4-/-) mice were given irinotecan to investigate the severity of the induced diarrhoea. Forty-six patients treated with irinotecan-based regimens had diarrhoea severity analysed according to TLR4 genotypes. In the experimental setting, wild-type (WT) or Tlr4-/- mice were given irinotecan (45 or 75 mg·kg-1 , i.p.) or saline (3 ml·kg-1 ). Diarrhoea severity was evaluated by measuring intestinal injury and inflammatory markers expression after animals were killed. All patients with TLR4 SNPs chemotherapy-treated presented diarrhoea, whereas gastrointestinal toxicity was observed in 50% of the wild homozygous individuals. Mice injected with irinotecan presented systemic bacterial translocation and increased TLR4 immunostaining in the intestine. In line with the clinical findings, Tlr4 gene deficiency enhanced irinotecan-related diarrhoea and TLR9 expression in mice. An increased myeloperoxidase activity and Il-18 expression along with IL-10 decreased production in Tlr4-/- mice also indicated an intensified intestinal damage and inflammatory response. TLR4 deficiency upregulates TLR9 expression and enhances intestinal damage and the severity of late-onset diarrhoea during irinotecan-based treatment. Identifying patients genetically predisposed to chemotherapy-associated diarrhoea is a strategy toward precision medicine.

Benefit of intensive chemotherapy for elderly patients aged 80years or older with metastatic colorectal cancer: a state-wide multicenter cohort study.

It remains unclear whether intensive chemotherapy for Stage IV colorectal cancer (CRC) patients aged 80years or older is beneficial prognostically. This study aimed to investigate the overall survival of Stage IV CRC patients aged ≥ 80years receiving intensive chemotherapy. The study design was a population-based, multicenter, historical cohort study. The extracted participants' data were consecutive patients diagnosed as Stage IV CRC between January 2008 and May 2015 in nine hospitals in Japan. Patients were classified into two groups according to age: aged group (≥ 80years) and younger group (< 80years old). Intensive chemotherapy was defined as at least two courses of doublet chemotherapy with oxaliplatin-or irinotecan-based regimens. The primary outcome was the adjusted hazard ratio (HR) of age ≥ 80years in patients who undergoing intensive chemotherapy. During the study period, 1259 patients were treated for Stage IV CRC in the participating hospitals. In total, 231 patients (18.3%) were in the aged group, and 1028 (81.7%) were in the younger group, and 788 (62.6%) underwent intensive chemotherapy. The median overall survival for the aged and younger group patients was 21.0months (interquartile range (IQR), 10.6-34.1months) and 24.3months (IQR 12.6-39.3months), respectively. The adjusted HR of age ≥ 80years was 1.29 (confidence intervals 0.84-2.00). Stage IV CRC patients aged 80years or older receiving intensive chemotherapy had a similar prognosis to those aged < 80years. Avoiding intensive chemotherapy for mCRC patients simply because they are ≥ 80years old is not recommended.

Clinical Value of Consensus Molecular Subtypes in Colorectal Cancer: A Systematic Review and Meta-Analysis.

BackgroundThe consensus molecular subtypes (CMSs) of colorectal cancer (CRC) capture tumor heterogeneity at the gene-expression level. Currently, a restricted number of molecular features are used to guide treatment for CRC. We summarize the evidence on the clinical value of the CMSs.MethodsWe systematically identified studies in Medline and Embase that evaluated the prognostic and predictive value of CMSs in CRC patients. A random-effect meta-analysis was performed on prognostic data. Predictive data were summarized. ResultsIn local disease, CMS4 tumors were associated with worse overall survival (OS) compared with CMS1 (hazard ratio [HR] = 3.28, 95% confidence interval = 1.27 to 8.47) and CMS2 cancers (HR = 2.60, 95% confidence interval = 1.93 to 3.50). In metastatic disease, CMS1 consistently had worse survival than CMS2-4 (OS HR range = 0.33-0.55; progression-free survival HR range = 0.53-0.89). Adjuvant chemotherapy in stage II and III CRC was most beneficial for OS in CMS2 and CMS3 (HR range = 0.16-0.45) and not effective in CMS4 tumors. In metastatic CMS4 cancers, an irinotecan-based regimen improved outcome compared with oxaliplatin (HR range = 0.31-0.72). The addition of bevacizumab seemed beneficial in CMS1, and anti-epidermal growth factor receptor therapy improved outcome for KRAS wild-type CMS2 patients.ConclusionsThe CMS classification holds clear potential for clinical use in predicting both prognosis and response to systemic therapy, which seems to be independent of the classifier used. Prospective studies are warranted to support implementation of the CMS taxonomy in clinical practice.

PCN27 Real-World Characteristics and Outcomes of Patients with Metastatic Ductal Adenocarcinoma (MPDAC) Treated with Liposomal Irinotecan-Based Regimens By Race

Racial disparities persist in outcomes for patients with pancreatic cancer in the United States, with Black or African American patients having higher age-adjusted incidence and mortality than White patients. Similarly, results from the pivotal phase 3 study, NAPOLI-1, and recent literature suggest that participants of East Asian ethnic origin experience better outcomes than other ethnic groups with liposomal irinotecan+5-fluorouracil/leucovorin following gemcitabine. This study seeks to describe clinical characteristics and treatment outcomes based on race. This retrospective observational study utilized the Flatiron Health EHR-derived de-identified database from over 280 cancer clinics in the US. Data were analyzed for adult patients with mPDAC treated with liposomal irinotecan-based regimens between January 2015 and February 2020. Patients were stratified based on their self-reported race. Median overall survival (OS) from treatment initiation was derived using Kaplan-Meier analysis. Of the included 608 patients (median age 68 years (y), IQR: 61-74) with mPDAC and treated with a liposomal irinotecan-based regimen, 448 patients (73.7%) were White, 48 patients (7.9%) were Black or African American, 13 (2.1%) were Asian, and 99 (16.3%) were of other race or the data were missing. White patients had a median age at metastatic diagnosis of 69y (IQR: 61–74), Black patients, 64y (60-71), and Asian patients 65y (63-72). ECOG scores of 0-1 were reported for 61.6% of White patients, 58.3% of Black patients, and 61.5% of Asian patients. Overall, median OS was 4.7 months (95% CI: 4.2–5.4). Median OS was 4.6 months 4.1–5.6) among White patients, 3.8 months (3.1–5.6) among Black patients, and 12 months (3.4–NR) among Asian patients. This analysis found racial disparities may persist in survival outcomes among patients with mPDAC treated with liposomal irinotecan-based regimens. Further studies are needed to characterize and understand the biological and socio-economic factors contributing to these disparate outcomes.

PCN17 Real-World Impact of Prior Surgery on Outcomes of Patients with Metastatic Ductal Adenocarcinoma (mPDAC) Treated with Liposomal Irinotecan-Based Regimens

This study seeks to describe demographic and clinical characteristics and treatment outcomes based on prior surgery in a real-world setting among patients with mPDAC treated with liposomal irinotecan-based regimens.

Optimizing the program of sequential chemotherapy for advanced gastric cancer based on gene-level CNVs called from ctDNA.

e16068 Background: Tumor evolutionary trade-offs under treatment pressure can be utilized to optimize therapy. We aimed to profile the dynamic pattern of gene-level copy number variations (CNVs) for advance gastric cancer (GCA) patients who underwent sequential chemotherapy and optimized the therapy program. Methods: 27 chemo-naive advanced GCA patients with distant metastasis were enrolled. Peripheral blood samples were collected at different time points, including pre-therapy and disease progression on a specific regimen. Gene-level CNVs were called from ctDNA of blood samples and drug modified score (DMS) was defined as the ratio of CNV value between samples of pre- and post-treatment for each gene. Positive and negative DMS of a gene represented its resistance and sensitivity to a selected regimen, respectively. Then, the best initial regimen was selected and the optimal program of sequential chemotherapy was designed for each patient. Results: DMS of gene was calculated for four chemotherapy regimens, including platinum-based doublet regimen (Pt-2d), oral-fluorouracil prodrug (O-FP), paclitaxel-based regimen (PTX) and irinotecan-based regimen (CPT-11). Based on DMS distribution, resistant and sensitive genes were determined for each regimen through a heuristic method. Functional enrichment analysis showed that resistant genes mainly involved in cellular response to oxygen-containing compound and regulation of cell proliferation, while sensitive genes mainly involved in positive regulation of macromolecule biosynthetic process and regulation of apoptotic process. Then, drug resistant score (DRS, defined as DMS weighted sum of CNV values of resistant genes) was calculated and the regimen with the lowest DRS was selected as the best initial treatment for each patient. The best initial treatment of 16 patients was CPT-11, of 8 patients was O-FP, of 2 patients was Pt-2d and of 1 patient was PTX. Following that, the optimal program of sequential chemotherapy was designed according to the percentage of shared resistant genes between regimens for each patient, where two regimens with the lowest percentage were recommended to use one by one. Finally, prognostic analysis showed that differences between the optimal and practical program of sequential chemotherapy were negatively correlated to overall survival of patients. Conclusions: Based on gene-level CNVs called from ctDNA of blood samples, we determined the best initial treatment and designed the optimal program of sequential chemotherapy for advanced GCA patients, pacing a key step toward precision medicine in GCA field.

The role of site of metastatic resection (MR) in metastatic colorectal cancer (mCRC) patients (PTS): A mono-institutional cohort study.

e15558 Background: Approximately 50%-60% of CRC pts develop metastases, usually to liver and lung. When feasible, MR is the only potentially curative option in the multimodal management of mCRC pts. Few studies have compared survival outcomes based on different surgical sites with contrasting data. Hence, we retrospectively analyzed mCRC pts, underwent radical lung and/or liver resection at our Institution, investigating the impact of resection site on overall survival (OS). Methods: mCRC pts underwent radical liver (group 1), lung (group 2) or liver and lung (group 3) resection were included. The following variables were collected: age ( &gt; vs ≤ 65 years); gender (male vs female); primary tumor site (right vs left); synchronous vs metachronous; RAS/BRAF status; number (N) of MR (1, 2 or ≥3); chemotherapy treatment (No treatment vs Post-operative vs Peri-operative/pre-operative treatment) and chemotherapy regimen (5FU monotherapy, Oxaliplatin-based, Irinotecan-based regimen, FOLFOXIRI, Bevacizumab, Anti-EGFR). The association of MR site and OS was evaluated. Univariate and multivariate analyses for OS were performed. Results: A total of 191 mCRC pts underwent radical MR were included in the analysis: 112 (59%) pts in group 1, 38 pts (20 %) in group 2, 41 pts (21 %) in group 3. 145 (76%) pts had a left-sided tumor and 46 (24%) a right-sided tumor. Out of 156 evaluable pts, 73 (47%) pts harbored a RAS mutation, while out of 136 evaluable pts, 4 (3%) pts had a BRAF mutation. Regarding the N of MR, 125 pts (65%) underwent 1 radical MR, 43 (23%) pts 2 MR and 23 (12%) ≥3 MR. In the overall population, median OS was 77.2 months. According to MR site, median OS was 59.4, not reached (NR) and 99.1 months, in group 1, 2 and 3, respectively (p = 0.075). At the multivariate analysis no significant association with OS was shown for MR site, while the N of MR and RAS status were indipendently associated with OS. Median OS was 58.5, 97.7 months and NR in pts underwent 1, 2 and ≥3 MR, respectively (p = 0.02). Median OS was 58.5 and 83.1 months in RAS mutated and RAS wild-type pts, respectively (p = 0.12). Conclusions: Despite the limited number of pts and the retrospective nature of our study, these results confirmed that surgery represents the only option with curative intent for mCRC pts, independently of metastatic site (liver vs lung vs liver and lung). Based on our analysis, a higher number of MR is associated to a better outcome, and this could be explained with an accurate selection of patients that could benefit from multiple radical resections. Thus, a multidisciplinary approach is essential for the management of mCRC pts and surgery should be evaluated case by case and always performed when possible, even several times, independently of site of MR.

Effectiveness and tolerability of FOLFOXIRI regimen in the third- and subsequent lines of therapy in patients with metastatic colorectal cancer.

e15584 Background: Options of therapy are limited for patients with colorectal cancer who developed disease progression during standard 5-FU-, oxaliplatin-, and irinotecan-contained regimens. There is straight information about synergy of irinotecan (SN-38) and oxaliplatin gained from fundamental and early clinical trials. We aimed to analyze effectiveness and safety of triple drug-combination of 5-FU, oxaliplatin and irinotecan (FOLFOXIRI) in heavily pretreated patients with metastatic colorectal cancer. Methods: Patients with a metastatic colorectal cancer who received more than 2 lines of standard 5-FU-, oxaliplatin- and irinotecan-based doublet regimens with or without targeted therapy were included. Reinduction of chemotherapy in previous lines was allowed. The retrospective analysis of medical histories was done. Eligible patients had to receive number of cycles that were sufficient for response rate estimation. Disease response was evaluated according to RECIST 1.1 criteria. Survival analysis was performed using the Kaplan-Meier method. Tolerability was estimated by CTCAE v. 5.0. Results: Forty-six patients were included in retrospective per protocol analysis. The median follow-up was 19 months. The median number of previous lines of chemotherapy was 2 (2-6). Primary resistance to oxaliplatin- and irinotecan-based chemo during previous lines was noted in 20 patients (43%) and 16 patients (35%), respectively, while seven patients (15%) developed the primary resistance to both agents given in a sequential order. All patients were treated with targeted therapy during previous treatment lines. The median of FOLFOXIRI cycles was 8 (range, 2-19). Two patients (4%) were treated with FOLFOXIRI without any targeted agents. The objective response rate was 33% (n = 15). The disease stabilization was reached in 43% (n = 20). The disease control rate was 76% (n = 35). Eleven patients (24%) had the progression of disease at the first follow-up. The median progression free survival and median overall survival were 6 months and 11 months, respectively. Toxicity was evaluated in 35 patients. The most common severe adverse events (grade 3 and 4) were neutropenia (46%) and fatigue (26%). Treatment was delayed in 20 patients (57%), and 13 patients (37%) required dose reduction. One patient had to discontinue treatment due to unacceptable toxicity. Conclusions: According to our study FOLFOXIRI provides the objective response and increased life expectancy in heavily pretreated patients. The further assessment of FOLFOXIRI regimen for refractory colorectal cancer in the prospective trials is needed.

Dispersion in total cost of care for Medicare fee-for-service (FFS) patients with metastatic pancreatic cancer receiving FDA-approved/NCCN Category 1 regimens at teaching versus non-teaching institutions.

e16244 Background: Teaching institutions receive additional funding from Medicare &amp; Medicaid Services (CMS) to provide specialized, quality care. Objectives: To analyze the dispersion in total cost of care (TCOC) for Medicare FFS patients (pts) with metastatic pancreatic cancer (m-PANC) treated at teaching (teach) or non-teaching (non-teach) institutions. Methods: We identified pts with m-PANC using ICD-9/10 diagnosis codes in the 2016-18 Medicare Parts A/B/D 100% Research Identifiable Files. Study pts had 2+ claims with a pancreatic cancer diagnosis and Medicare FFS coverage for 6 months pre- and 3 months post-metastasis diagnosis. Study pts were treated with NCCN Category 1 regimens: 1L gemcitabine monotherapy (gem-mono), 1L gemcitabine/nab-paclitaxel (gem-nab), 1L FOLFIRINOX (FFX), and 2L liposomal irinotecan-based regimen (nal-IRI). Pts were attributed to teach or non-teach institutions based on plurality of chemotherapy claims. TCOC reflects insurer-paid services per line of therapy (LOT) for 3 categories: chemotherapy/supportive drugs (chemo/Rx), inpatient care (IP), and other outpatient care (OP). We grouped pts by quartile (qrt), evaluated drivers of TCOC, and mean rates of admissions (admits/pt). Results: We identified 3,908 (teach) and 2,632 (non-teach) pts taking NCCN Category 1 regimens. There was a similar mix of patients in both cohorts, with gem-mono pts making up only 3% of the sample. Gem-nab accounted for 73% and 70% of pts in teach and non-teach institutions, respectively. For gem-nab, FFX, and nal-IRI pts, median TCOC was similar in both cohorts. However, median TCOC for the two non-generic drugs in our study, gem-nab (teach: $36,332; non-teach: $40,135) and nal-IRI (teach: $31,526; non-teach: $39,360), were lower at teach institutions than non-teach institutions. The components of TCOC are similar between teach and non-teach institutions in all qrts. In both cohorts, % IP costs for all regimens increased between the first and fourth qrt (teach:14% to 23%, non-teach:14% to 26%). In the teach cohort, nal-IRI pts had the lowest admits/pt in all qrts. In the non-teach cohort, there was no discernable pattern, although nal-IRI pts had the lowest admits/pt in the second and fourth qrt. Conclusions: For non-generic regimens like nal-IRI and gem-nab, median TCOC was lower at teach institutions than non-teach institutions. There were no consistent differences in TCOC dispersion or admissions between cohorts. Across qrts, chemotherapy accounted for approximately half the TCOC. However, IP costs were proportionally higher in the fourth qrt, especially for non-teach institutions. Despite nal-IRI pts being on the second LOT, both median TCOC and admits/pt across qrts were lower than gem-nab and FFX in teach institutions. In the non-teach cohort, median TCOC were similar among nal-IRI, gem-nab, and FFX.

Dispersion in total cost of care for Medicare fee-for-service (FFS) patients with metastatic pancreatic cancer receiving FDA-approved/NCCN Category 1 regimens at 340B verus non-340B institutions.

e18843 Background: The Department of Health and Human Services (HHS) designed the 340B drug pricing program to allow institutions that service specialty populations to acquire drugs at lower prices. Objective: To analyze the dispersion in total cost of care (TCOC) for Medicare FFS patients (pts) with metastatic pancreatic cancer (m-PANC) treated at 340B or non-340B institutions, by NCCN Category 1 regimen. Methods: We identified pts with m-PANC using ICD-10 diagnosis codes in the 2016-18 Medicare Parts A/B/D 100% Research Identifiable Files. Study pts had 2+ claims with a pancreatic cancer diagnosis and Medicare FFS coverage for 6 months pre- and 3 months post-metastasis diagnosis. Study pts were treated with NCCN Category 1 regimens: 1L gemcitabine monotherapy (gem-mono), 1L gemcitabine/nab-paclitaxel (gem-nab), 1L FOLFIRINOX (FFX), and 2L liposomal irinotecan-based regimen (nal-IRI). Pts were attributed to 340B or non-340B institutions based on plurality of chemotherapy claims. TCOC reflects insurer-paid services per line of therapy (LOT) for 3 categories: chemotherapy/supportive drugs (chemo/Rx), inpatient care (IP), and other outpatient care (OP). We grouped pts by quartile (qrt) and evaluated drivers of TCOC and mean rates of admissions (admits/pt). Results: We identified 2,697 (340B) and 3,839 (non-340B) pts taking NCCN Category 1 regimens. Gem-mono represented 1% and 4% of all pts in 340B and non-340B institutions, respectively. Gem-nab accounted for 72% of pts in both cohorts. For gem-nab, FFX, and nal-IRI pts, median TCOC was similar in both cohorts, although mean TCOC by qrt was lower at 340B institutions than non-340B institutions, except for gem-nab in the 1st qrt. The components of TCOC were similar between 340B and non-340B institutions in all qrts. In both cohorts, % IP costs increased between the 1st and 4th qrt (340B:15% to 23%, non-340B:14% to 25%). From the 1st to the 4th qrt, admits/pt increased in both cohorts. In the 340B cohort, nal-IRI pts had the lowest admits/pt while gem-nab pts had the highest in all qrts. In the non-340B cohort, nal-IRI pts had the lowest admits/pt except for in the 1st qrt. Conclusions: Median TCOC was lower at 340B institutions than non-340B institutions for all regimens, and the range of TCOC dispersion was also smaller at 340B institutions. Across qrts, chemotherapy accounted for approximately half the TCOC; however, IP costs were proportionally higher in the 4th qrt. Comparing regimens, despite 2L nal-IRI pts being more heavily pretreated, median costs in each cohort were similar to 1L gem-nab and 1L FFX, while admits/pt were generally lower than 1L gem-nab and 1L FFX across qrts and cohorts.