Maithel, Shishir K

Abstract Background TOPAZ-1 demonstrated durvalumab + gemcitabine and cisplatin (GemCis) superiority over GemCis in first-line treatment of advanced biliary tract cancers. Real-world data from US patients and patients excluded from TOPAZ-1 (patients with autoimmune conditions [AICs] who did not receive immunotherapy) are lacking. We report real-world data for patients with cholangiocarcinoma treated with durvalumab + GemCis. Methods This retrospective, observational study enrolled adult patients diagnosed with cholangiocarcinoma in the US from the International Cholangiocarcinoma Patient Registry (ICPR) treated with first-line durvalumab + GemCis between 2021–2023. De-identified medical records from ICPR were obtained directly from consenting patients/caregivers. Patient demographics and tumor characteristics (primary objective; assessed at initial diagnosis), comorbidities, second-line treatment modalities, median real-world overall survival (mrwOS), and median real-world time to next treatment (mrwTTNT; initiation of first-line treatment and last activity in the database or death) are reported. Results Seventy patients received first-line durvalumab + GemCis: 13 (18.6%) had AIC(s) and 57 (81.4%) did not. Patient demographics, clinical characteristics, and comorbidities are shown (Table). Median (quartile 1–3) time from diagnosis to start of first-line treatment was 1.0 (0.7–1.7) months; median follow-up from first dose of first-line treatment was 7.0 (3.7–12.1) months. The mrwOS (95% CI) was 15.5 (15.1–not evaluable [NE]) months. mrwTTNT (95% CI) was 10.8 (10.4–15.7) months overall and was 20.8 (10.4–NE) months in patients who died without receiving subsequent treatment (censored at date of last activity). Among patients with AIC(s), <5 received second-line therapy (all received chemotherapy alone). Among patients with no AICs, 15 received second-line treatment; 11 (73.3%) received targeted therapy alone and <5 received chemotherapy alone. Conclusions This dataset demonstrates patients with AIC(s) are treated with durvalumab + GemCis in clinical practice. The mrwOS for durvalumab + GemCis in this patient population is consistent with TOPAZ-1 and global real-world studies.

Abstract Background & Objectives Based on the TOPAZ-I study, durvalumab combined with gemcitabine and cisplatin (GemCis) is now supported as a standard of care treatment for cholangiocarcinoma. Patients with extrahepatic cholangiocarcinoma (eCCA) often have underlying autoimmune conditions (AICs) which could restrict immunotherapy use. Treatment patterns in patients with eCCA with AICs and non-autoimmune conditions (NAICs) are reported. Method This retrospective observational analysis of adult patients diagnosed with eCCA in the United States enrolled in the International Cholangiocarcinoma Patient Registry between 2019 and 2023, focused on those treated with durvalumab. The registry contains de-identified data from medical records obtained directly from consenting patients and caregivers. Patients were followed from index date (date of eCCA diagnosis) until the last activity in the database or death. Demographics, clinical characteristics, biomarkers, treatment patterns, and adverse events (AEs) are reported. Results Overall, 135 patients with eCCA were enrolled: 24 (17.8%) had 2:1 AICs and 111 (82.2%) had NAICs. Baseline demographics were comparable between groups: the median (quartile [Q]l-Q3) age at diagnosis was 63.0 (55.0-70.0) years, the mean number of comorbidities in the overall population was 10.1, and 50.4% of patients were female. PD-Ll positivity was noted in 12.6% of patients and HER2 positivity in 10.4%. Of 91 patients with eCCA who received first-line therapy, 34 (37.4%) received GemCis alone, 27 (29.7%) chemotherapy alone (non-GemCis +/- nab-paclitaxel), 9 (9.9%) GemCis plus nab-paclitaxel, 7 (7.7%) durvalumab plus GemCis, 7 (7.7%) durvalumab monotherapy or in combination, and 7 (7.7%) other regimens. Treatment patterns by autoimmune comorbidity status are also reported (Table). Overall, 129 patients (95.6%) had ≥1 AE; fatigue was the most common (71.1%). Conclusion More patients with eCCA received a first-line durvalumab-based regimen post-March 2022 vs the full study period. The use of durvalumab as first-line treatment in this subgroup may suggest that AICs do not restrict its use.

4084 Background: Treatment of advanced CCA has changed dramatically over the past five years with the advent of molecularly targeted therapy, now approved in the 2nd line and beyond. However, real world utilization of molecular profiling and targeted therapy is still unknown and these data are critical to empower treatment decision-making. Methods: In 2019, the Cholangiocarcinoma Foundation (CCF) and Ciitizen (a wholly owned subsidiary of Invitae Corporation) collaboratively launched a registry platform that directly consents patients and collects comprehensive medical records. De-identified data including clinical characteristics, molecular testing, interventions, and outcomes are extracted and standardized for research use. The data is longitudinal with regularly planned updates; registry participants can be re-engaged to obtain additional data and communicate tailored insights. Results: We quantified the rate of molecular testing, the presence of targetable biomarkers, and the utilization and outcomes on matched targeted therapies for 372 individuals with CCA. 328 (88.2%) individuals had molecular testing, with the identified targetable mutations and matched therapies reported. Of 328 individuals who had molecular testing, 111 (33.8%) individuals had one or more targetable mutations (116 mutations total). Only 46% (51) of individuals with targetable mutations received targeted therapy. Of the 54% (60) individuals with targetable mutations that did not receive any matched therapy, the majority (61.7%, 37) were in early disease or first line of treatment and therefore not yet eligible for targeted therapy. These individuals will be informed that based on their molecular profile, a targeted therapy may be an option, and suggest they discuss with their treating physician. Conclusions: A novel prospectively-maintained database registry for CCA has been formed in collaboration between a patient advocacy organization (CCF) and industry (Invitae). Prevalence of actionable biomarkers was higher than historically expected and may reflect patient utilization bias of the registry platform. Molecular profiling and access to targeted therapeutics remains suboptimal at this time in CCA. Future directions for the registry include identifying and targeting disparities in care and supporting biopharmaceutical development and regulatory decisions. [Table: see text]

AbstractBackgroundCytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) is increasingly performed for peritoneal surface malignancies but remains associated with significant morbidity. Scant research is available regarding the impact of insurance status on postoperative outcomes.MethodsPatients undergoing CRS/HIPEC between 2000 and 2017 at 12 participating sites in the US HIPEC Collaborative were identified. Univariate and multivariate analyses were used to compare the baseline characteristics, operative variables, and postoperative outcomes of patients with government, private, or no insurance.ResultsAmong 2268 patients, 699 (30.8%) had government insurance, 1453 (64.0%) had private, and 116 (5.1%) were uninsured. Patients with government insurance were older, more likely to be non‐white, and comorbid (p < 0.05). Patients with government (OR: 2.25, CI: 1.50−3.36, p < 0.001) and private (OR: 1.69, CI: 1.15−2.49, p = 0.008) insurance had an increased risk of complications on univariate analysis. There was no independent relationship on multivariate analysis. An American Society of Anesthesiologists score of 3 or 4, peritoneal carcinomatosis index score >15, completeness of cytoreduction score >1, and nonhome discharge were factors independently associated with a postoperative complication.ConclusionWhile there were differences in postoperative outcomes between the three insurance groups on univariate analysis, there was no independent association between insurance status and postoperative complications after CRS/HIPEC.

4097 Background: Given a high recurrence rate, surgical resection for localized intrahepatic cholangiocarcinoma (IHCC) is curative in only 30-35% of patients. BILCAP has established a standard of care for adjuvant therapy with monotherapy capecitabine. Gemcitabine, cisplatin and nab-paclitaxel combination chemotherapy (GAP) was associated with a response rate of 45% in biliary cancer and 20% of patients who were previously inoperable underwent margin negative resection. Based on these data, we conducted a neoadjuvant study of GAP for resectable but high-risk IHCC. Methods: A multi-institutional prospective single-arm phase II trial was conducted for patients with resectable high-risk disease, as defined by tumor size > 5cm, multiple tumors, presence of radiographic major vascular invasion, and lymph node involvement. Patients were administered 4 cycles (3 months) of preoperative GAP (gemcitabine 800 mg/m2, cisplatin 25 mg/m2 and nab-paclitaxel 100 mg/m2 on days 1 and 8 of a 21-day cycle) prior to an attempt at curative-intent surgical resection. The primary endpoint was completion of all therapy, including both preoperative chemotherapy and resection. Secondary endpoints were toxicity, radiologic response according to Response Evaluation Criteria in Solid Tumor (RECIST) criteria, RFS, and OS. Thirty evaluable patients provided 73% power to reject a null therapy completion rate of 50%, with a target completion rate of 70% using a one-sided exact test with a Type I error of 0.05. Results: Thirty-seven patients were screened and 30 evaluable patients were enrolled. The trial was sequentially activated at each of the 4 sites from 09/18-02/21 and the final patient was enrolled in 09/21. Median age was 60.5 years and 40% were female. Twenty-three patients (77%, 90% CI: 60.6-88.5%; p = 0.0026) completed all preoperative chemotherapy and underwent surgical resection. Ten patients (33%) experienced grade 3-4 treatment-related adverse events, the most common being neutropenia and diarrhea; 47% required at least one dose reduction. Partial response rate was 23% and disease control rate was 90% (PD: 10%, PR: 23%, SD: 67%). Of the 23 patients who successfully underwent surgical resection, 2 (9%) had minor postoperative complications. Median size of largest tumor was 5.5cm, median number of tumors was 3, and 39% were lymph node positive. Median length of hospital stay was 4 days. There was zero treatment related mortality. Conclusions: This study met its primary endpoint and demonstrated that neoadjuvant gemcitabine/cisplatin/nab-paclitaxel is feasible and safe prior to resection of intrahepatic cholangiocarcinoma and does not adversely impact perioperative outcomes. Continued follow-up for RFS and OS with this treatment strategy is underway and larger validation studies are planned. Clinical trial information: NCT03579771.

AbstractBackgroundWhile parenchymal hepatic metastases were previously considered a contraindication to cytoreductive surgery (CRS) and heated intraperitoneal chemotherapy (HIPEC), liver resection (LR) is increasingly performed with CRS/HIPEC.MethodsPatients from the US HIPEC Collaborative (2000–2017) with invasive appendiceal or colorectal adenocarcinoma undergoing primary, curative intent CRS/HIPEC with CC0‐1 resection were included. LR was defined as a formal parenchymal resection. Primary endpoints were postoperative complications and overall survival (OS).ResultsA total of 658 patients were included. About 83 (15%) underwent LR of colorectal (58%) or invasive appendiceal (42%) metastases. LR patients had more complications (81% vs. 60%; p = .001), greater number of complications (2.3 vs. 1.5; p < .001) per patient and required more reoperations (22% vs. 11%; p = .007) and readmissions (39% vs. 25%; p = .014) than non‐LR patients. LR patients had decreased OS (2‐year OS 62% vs. 79%, p < .001), even when accounting for peritoneal carcinomatosis index and histology type. Preoperative factors associated with decreased OS on multivariable analysis in LR patients included age < 60 years (HR, 3.61; 95% CI, 1.10–11.81), colorectal histology (HR, 3.84; 95% CI, 1.69–12.65), and multiple liver tumors (HR, 3.45; 95% CI, 1.21–9.85) (all p < .05). When assigning one point for each factor, there was an incremental decrease in 2‐year survival as the risk score increased from 0 to 3 (0: 100%; 1: 91%; 2: 58%; 3: 0%).ConclusionsAs CRS/HIPEC + LR has become more common, we created a simple risk score to stratify patients considered for CRS/HIPEC + LR. These data aid in striking the balance between an increased perioperative complication profile with the potential for improvement in OS.

40 Background: Postoperative complications (POCs) are associated with worse oncologic outcomes in various cancer histologies. The impact of POCs on the survival of patients with appendiceal or colorectal cancer after cytoreductive surgery/heated intraperitoneal chemotherapy (CRS/HIPEC) is unknown. Methods: US HIPEC Collaborative (2000-17) was reviewed for patients who underwent CCR0/1 CRS/HIPEC for appendiceal/colorectal cancer. Analysis was stratified by non-invasive appendiceal neoplasm vs invasive appendiceal/colorectal adenocarcinoma. POCs were grouped into infectious, cardiopulmonary, thromboembolic and intestinal dysmotility. Primary outcomes were 3-yr overall survival (OS) and recurrence-free survival (RFS). Results: Of 1304 pts, median age was 55 yrs, 41% were male (n = 537), 33% had non-invasive appendiceal (n = 426) and 67% had invasive appendiceal/colorectal adenocarcinoma (n = 878). In the non-invasive appendiceal cohort, POCs were identified in 55% (n = 233) and OS and RFS did not differ between patients who experienced a complication and those who did not (OS 94 vs 94% p = 0.26; RFS 68 vs 60% p = 0.15). In the invasive appendiceal/colorectal adenocarcinoma cohort, however, POCs (63%; n = 555) were associated with decreased OS (59 vs 74% p < 0.001) and RFS (32 vs 42% p < 0.001). Infectious POCs were most common (35%; n = 196). On MV analysis accounting for gender, PCI and incomplete resection (CCR1), infectious POCs in particular were associated with decreased OS compared to no complication (HR 2.08 95%CI 1.48-2.93 p < 0.01) or other types of complications (HR 1.7 95%CI 1.28-2.25 p < 0.01). This association persisted for infectious POCs and reduced RFS (HR 1.61 95%CI 1.23-2.10 p < 0.01). Conclusions: Postoperative complications are associated with decreased OS and RFS after CRS/HIPEC for invasive histology, but not for an indolent disease like non-invasive appendiceal neoplasm. Of all complication types, infectious complications are the main driver for this association. The exact mechanism is not known, but may be immunologic. Efforts must target best practices and standardized prevention strategies to minimize infectious POCs.

37 Background: While parenchymal hepatic metastases were previously considered a contraindication to cytoreductive surgery(CRS) and heated intraperitoneal chemotherapy(HIPEC), liver resection(LR) is increasingly performed concomitantly with CRS/HIPEC. As this practice continues to expand, identification of preoperative factors associated with poor outcomes is paramount. Methods: Patients from the US HIPEC Collaborative(2000-2017) with invasive appendiceal or colorectal adenocarcinoma undergoing primary, curative intent CRS/HIPEC with CC0-1 resection were included. LR was defined as a formal parenchymal resection. Primary endpoints were postoperative complications and overall survival(OS). Results: 658 patients were included. Average age was 54 years and 45% were male; 83 (15%) underwent liver resection of colorectal (58%) or invasive appendiceal (42%) metastases. Liver resection patients had more complications (81 vs 60%; p = 0.001), greater number of complications (2.3 vs 1.5; p < 0.001), and required more reoperations (22 vs 11%; p = 0.007) and readmissions (39 vs 25%; p = 0.014) than non-liver resection patients. Liver resection patients had decreased OS (2-year OS 62% vs 79%, p < 0.001), which persisted on multivariable Cox regression when accounting for PCI and histology type. Preoperative factors associated with decreased OS on multivariable analysis in patients undergoing liver resection included age < 60 years (HR:3.61), colorectal histology (HR:3.84), and multiple liver tumors (HR:3.45) (all p < 0.05). When assigning one point for each factor, there was an incremental decrease in 2-yr survival as the risk score increased from 0 to 3 (0: 100%; 1: 91%; 2: 58%; 3: 0%; p < 0.001). Conclusions: As concurrent liver resection with CRS/HIPEC has become more common, we created a simple risk score to stratify patients considered for CRS/HIPEC with liver resection. These data aid in striking the balance between an increased perioperative complication profile with the potential for improvement in overall survival.

184 Background: Patient age is often a significant factor in preoperative selection for major abdominal surgery. Its association with postoperative outcomes in patients undergoing cytoreductive surgery(CRS) and hyperthermic intraperitoneal chemotherapy(HIPEC) remains ill-defined. Methods: The US HIPEC Collaborative database(2000-2017) was reviewed for patients who underwent a CCR0/1 CRS/HIPEC. Age was categorized into < 65 or >65yrs. Primary outcomes were postoperative major complications, readmission, 30-day mortality, and non-home discharge(NHD). Analysis was stratified by disease histology: non-invasive(appendiceal LAMN/HAMN), and invasive(appendiceal/colorectal adenocarcinoma). Results: Of 1090pts identified, 22% were >65yrs(n = 240), 59% were female(n = 646), 25% had non-invasive(n = 276) and 51% had invasive(n = 555) histology. Median PCI was 13(IQR7-20). Patients >65yrs had a higher rate of major complications(37vs26%, p = 0.02), readmission(28vs22%,p = 0.05), 30-day mortality(3vs1%,p = 0.02), and NHD(12vs5%,p < 0.01) compared to those < 65yrs. On multivariable analysis accounting for extent of disease as measured by PCI, for non-invasive histology, age >65yrs was an independent predictor for NHD(OR:2.54,95%CI:1.08-5.99,p = 0.03), but not major complications. For invasive histology, even when accounting for PCI, age >65yrs was an independent predictor for both NHD(OR:2.54,95%CI:1.08-5.98,p = 0.03) and major complications(OR:2.04,95%CI:1.16-3.59,p = 0.05). Age was not associated with hospital readmission or 30-day mortality for any histology. Conclusions: Regardless of histology, patients >65yrs are nearly at three-fold increased risk for non-home discharge after CRS/HIPEC. For invasive histology, age >65yrs is also associated with increased major complication rates, but the procedure seems to be better tolerated when performed for indolent biology. These data inform preoperative counseling and risk stratification. Early planning for discharge disposition in this high-risk population can potentially translate to cost savings.

PURPOSE To develop an evidence-based clinical practice guideline to assist in clinical decision making for patients with resected biliary tract cancer. METHODS ASCO convened an Expert Panel to conduct a systematic review of the literature on adjuvant therapy for resected biliary tract cancer and provide recommended care options for this patient population. RESULTS Three phase III randomized controlled trials, one phase II trial, and 16 retrospective studies met the inclusion criteria. RECOMMENDATIONS Based on evidence from a phase III randomized controlled trial, patients with resected biliary tract cancer should be offered adjuvant capecitabine chemotherapy for a duration of 6 months. The dosing used in this trial is described in the qualifying statements, while it should be noted that the dose of capecitabine may also be determined by institutional and regional practices. Patients with extrahepatic cholangiocarcinoma or gallbladder cancer and a microscopically positive surgical resection margin (R1 resection) may be offered chemoradiation therapy. A shared decision-making approach is recommended, considering the risk of harm and potential for benefit associated with radiation therapy for patients with extrahepatic cholangiocarcinoma or gallbladder cancer. Additional information is available at www.asco.org/gastrointestinal-cancer-guidelines .