Tran, Nguyen H.

559 Background: Cabozantinib, a multikanase inhibitor, is approved by the Food and Drug Administration (FDA) for treatment of advanced stage hepatocellular carcinoma (HCC) following progression on sorafenib. The CELESTIAL study which demonstrated benefit from cabozantinib following sorafenib included only patients with Child Pugh class A liver function. Recently, bevacizumab plus atezolizumab has replaced sorafenib as the first line treatment for HCC. It is unclear whether there is benefit from using Cabozantinib following progression on immunotherapy as CELESTIAL trial included very few patients who received prior immunotherapy. We describe the outcomes of individuals with advanced stage HCC treated with Cabozantinib following progression on immunotherapy. Methods: This was a multicenter, retrospective analysis of patients with advanced HCC diagnosed between 2010-2021 at Mayo Clinic Arizona, Florida, and Minnesota. Progression free survival (PFS) and median overall survival analysis were performed using Kaplan-Meier method. Results: We identified a total of 26 patients with advanced stage HCC who received cabozantinib following progression on immunotherapy. The median age of patients was 61 years (range, 39 – 81) and the majority were male (85%). Eighteen (72%) patients had Child Pugh A at initiation of cabozantinib therapy. Four (15%) patients received cabozantinib as second line therapy, the rest received it as third line or later. PFS on cabozantinib was 2.1 months (95% CI: 1.3 – 3.9) and median overall survival from time of cabozantinib initiation was 7.7 months (95% CI: 5.3 – 14.9). PFS was shorter with Child Pugh Class B, 1.3 months (95% CI: 0.9 – NE) compared to those with Child Pugh Class A, 2.1 months (95% CI: 1.5 – 4); although this difference was not significant (p=0.55). Common adverse events included fatigue (50%), anorexia (35%), aspartate aminotransferase (AST) elevation (35%), and diarrhea (31%); 7 (26%) patients experienced Grade 3 or greater adverse events including hypertension, diarrhea, anorexia, and bowel obstruction. Two patients discontinued cabozantinib due to side effects including one for uncontrolled blood pressure elevations and the other due to fatigue. Conclusions: The optimal sequencing of therapy for patients with advanced HCC following progression on immunotherapy is unknown. Treatment with cabozantinib may improve clinical outcomes following progression on immunotherapy with similar adverse event profile. This study included patients with Child Pugh class B liver disease (28%) and heavily pretreated population and demonstrated mPFS and mOS similar to other work examining outcomes of cabozantinib in real world setting after progression on sorafenib. Further studies to determine optimal treatment sequencing for this patient population are needed.

507 Background: Lenvatinib, a multikinase inhibitor, is an FDA approved treatment for advanced hepatocellular carcinoma (HCC) in the first line setting. Atezolizumab and bevacizumab are considered new standard of care as first line therapy after results of the IMBrave 150 trial. Currently, we do not have data to suggest any second-line treatment after administration of immunotherapy. We describe the clinical outcomes in patients with advanced HCC who received lenvatinib following treatment with immunotherapy. Methods: We conducted a multicentric, retrospective analysis of patients with advanced HCC diagnosed between 2010 and 2021 at Mayo Clinic in Minnesota, Arizona, and Florida. The study was reviewed and approved by the intuitional review board. The primary outcomes were overall survival (OS) and progression free survival (PFS). Results: We identified 53 patients with advanced HCC who received lenvatinib following immunotherapy. Most patients (83%) were male. Median age at start of lenvatinib was 67 years old. Forty-two (79%) patients had a Child-Pugh score of A at diagnosis while 30 (58%) patients were still Child-Pugh A at time of lenvatinib initiation. Risk factors for HCC included Hep C (43%), alcohol use (34%), NASH (15%) and hepatitis B (7%). Forty-five (85%) patients received lenvatinib in the 2nd line and 8 (15%) patients received it as third line or later. At time of data extraction, 38 (72%) patients had died. Median PFS was 4 months (95% CI: 3 – 6) and median OS from time of lenvatinib initiation was 13 months (95% CI: 6 – 24). The most common adverse events of any grade included fatigue (53%), hypertension (37%), AST elevation (30%), anorexia (28%), bilirubin elevation (25%) and diarrhea (25%). Twenty-one (40%) patients experienced grade 3 or higher adverse events including hypertension (25%), confusion (6%), acute kidney injury (2%), hyperkalemia (2%), ALT elevation (2%), proteinuria (2%), arthralgia (2%), heart failure (2%), AST elevation (2%), bilirubin elevation (2%), palmar-plantar erythrodysesthesia (2%), oral mucositis (2%), weight loss (2%), hypothyroidism (2%), anorexia (2%), fatigue (2%) and diarrhea (2%). Seven patients stopped treatment due to adverse events: 1 for hypertension, 2 for confusion, 1 for heart failure, 2 for fatigue, and 1 for elevated bilirubin. Conclusions: The optimal sequencing of therapy for patients with advanced HCC following progression on immunotherapy remains unknown. We found that median OS was 13 months in patients who received lenvatinib after immunotherapy which is comparable to survival in other studies when used as first line therapy. Our experience demonstrates that patients may benefit from treatment with lenvatinib following initial progression on immunotherapy.

(1) Background: Cabozantinib, a multikinase inhibitor, is approved by the Food and Drug Administration (FDA) for the treatment of advanced hepatocellular carcinoma (HCC) following progression on sorafenib. Recently, atezolizumab plus bevacizumab has been approved in the first line setting for advanced HCC and has become the new standard of care. Whether cabozantinib improves outcomes following progression on immunotherapy remains unknown. We describe the clinical outcomes following treatment with immunotherapy in patients with advanced HCC who received cabozantinib. (2) Methods: We conducted a multicentric, retrospective analysis of patients with advanced HCC diagnosed between 2010–2021 at Mayo Clinic in Minnesota, Arizona, and Florida who received cabozantinib. Median overall survival and progression free survival analyses were performed using the Kaplan–Meier method. Adverse events were determined using Common Terminology Criteria for Adverse Events (CTCAE). (3). Results: We identified 26 patients with advanced HCC who received cabozantinib following progression on immunotherapy. Median progression free survival on cabozantinib therapy was 2.1 months (95% CI: 1.3–3.9) and median overall survival from time of cabozantinib initiation was 7.7 months (95% CI: 5.3–14.9). (4) Conclusion: The optimal sequencing of therapy for patients with advanced HCC following progression on immunotherapy remains unknown. Our study demonstrates that patients may benefit from treatment with cabozantinib following progression on immunotherapy.

PURPOSE Patients with advanced biliary tract cancers (BTCs) have a dismal prognosis. This multisite, single-institution study analyzed the efficacy and safety of immune checkpoint inhibitors (ICIs) in patients with advanced BTC. MATERIALS AND METHODS The prospectively maintained institutional database was searched for patients with advanced BTC. Electronic medical records of the patients with advanced BTC treated with an ICI that included programmed death-1 or programmed death-ligand 1 blockers were retrospectively reviewed to obtain data on patient characteristics, tumor characteristics including molecular biomarkers, detailed treatment, response characteristics, survival, and toxicities. The analysis included overall response rate, survival, and correlation between survival and molecular biomarkers. RESULTS The institutional database query identified 47 patients with advanced BTC who received at least one dose of an ICI; 11 (24%) patients in the first-line setting and the rest of the patients had refractory disease. The median age of the cohort was 62 years, and 51% were female. The overall response rate was 10.6%, with a disease control rate of 53.2%. The median progression-free survival (PFS) and overall survival were 3.6 months and 6.9 months, respectively. Biomarker analysis revealed improved PFS in patients with tumor mutational burden > 5 mutations per megabase (median PFS: 6.4 v 2.2 months; P = .0027). No unexpected adverse events were observed. CONCLUSION ICIs are well tolerated and have modest antitumor activity in patients with advanced BTC. The study result supports the exploration of tumor mutational burden as a potential predictive biomarker for response to ICIs in patients with advanced BTC.

Abstract Hepatocellular carcinoma remains a global health challenge affecting close to 1 million cases yearly. Liver transplantation provides the best long‐term outcomes for those meeting strict criteria. Efforts have been made to expand these criteria, whereas others have attempted downstaging approaches. Although locoregional approaches to downstaging are appealing and have demonstrated efficacy, limitations and challenges exists including poor imaging modality to assess response and appropriate endpoints along the process. Recent advances in systemic treatments including immune checkpoint inhibitors alone or in combination with tyrosine kinase inhibitors have prompted the discussion regarding their role for downstaging disease prior to transplantation. Here, we provide a review of prior locoregional approaches for downstaging, new systemic agents and their role for downstaging, and finally, key and critical considerations of the assessment, endpoints, and optimal designs in clinical trials to address this key question.

TPS4170 Background: IMbrave150 is the first study demonstrating the benefit of anti-PDL1 in the frontline treatment of aHCC, and established Atezo/Bev as a new 1st line standard for aHCC. There is currently limited evidence to guide subsequent therapy for aHCC patients progressing on Atezo/Bev. ACCRU-GI-2008 is designed to determine the benefit of continuing Atezo into 2nd line and the safety of Atezo plus a MKI in patients with aHCC who previously received Atezo/Bev. The study is being conducted across 12 centers in the United States (ClincalTrials.gov#: NCT05168163). Methods: This study utilizes a 2:1 randomized phase II design where eligible patients will receive either Atezo/MKI (experimental arm) or MKI alone (control). Patients will be stratified according to the MKI choice (cabozantinib or lenvatinib, per physician’s decision), etiology of HCC (viral vs. non-viral) and alpha-fetoprotein level ( < 400 vs. > = 400 ng/mL). The major eligibility criteria are histological/cytological diagnosis or clinical diagnosis of HCC per the AASLD or WASL 2018 guidelines, has advanced disease not amendable to curative treatment, previously received and progressed on Atezo/Bev, has received only 1 previous line of systemic therapy (2nd line only), ECOG PS 0-1, Child Pugh Class A, adequate organ reserves and RECIST v1.1 measurable disease; previous MKI for advanced disease is excluded. The primary endpoints are overall survival (OS) and progression free survival (PFS). A total sample size of 122, with 89 PFS events, we will have 80% power to detect an improvement in median PFS from 4 to 7 months, assuming a one-sided significance level of 0.05. With approximately 84 deaths, we will have 80% power to detect an improvement in median OS from 10 to 18 months, assuming a one-sided significance level of 0.05. The overall one-sided significance level, for the study, is 0.1. An OS interim analysis will be conducted at 89 PFS events. Secondary endpoints include objective response, duration of response, and adverse events. Archival tumor and serial blood samples will be collected to evaluate for potential prediction biomarkers and mechanisms of sensitivity/resistance. Baseline and on-treatment tumor biopsy specimens will also be collected from the initial 10 patients of each arm. The study is approved by the ethics committee and enrollment to the study will be underway by Q2/3 2022. Clinical trial information: NCT05168163.

Background: Epidermal growth factor receptor (EGFR) inhibitors cause cutaneous toxicity in over 90% of patients. Conceivably, healthcare providers could overlook such toxicity in African American/Black patients because of a darker complexion. This qualitative study sought to learn about such cutaneous signs and symptoms and, if present, to report them in patients’ own words. Methods: Any patient who self-identified as African American/Black and who had been prescribed an EGFR inhibitor was eligible. The current report focuses on patients’ responses to the following question, “What have you noticed since starting your cancer treatment (the EGFR inhibitor), any particular symptoms or reactions, positive or negative?” All interview data were audio-recorded, transcribed, and then independently coded and analyzed by two investigators. Results: Fifteen patients are the focus of this report, and all described cutaneous toxicity. Patients appeared troubled by the cosmetic aspect of these drug-induced skin changes, including their acneiform appearance, describing “little pimples with little, little pus in it.” Notable were comments on hyperpigmentation, “I’m a black person but…. became darker.” Furthermore, patients experienced physical symptoms: “it itches;” “it’s like you stuck a pin in it;” “stinging;” and “burning;”. Conclusion: Although cutaneous toxicity from EGFR inhibitors might be more difficult to visualize among darkly complected patients, the graphic descriptions offered in this qualitative study underscore the need for clinicians to heighten their awareness of such toxicity in African American/Black patients.

192 Background: Rectal cancer treatment paradigm has been evolving over time. Historically, for locally advanced rectal cancer, standard therapy (ST) consisted of neoadjuvant chemoradiation followed by surgery and adjuvant chemotherapy. Recently, total neoadjuvant treatment (TNT) approach that delivers both neoadjuvant chemotherapy (CAPOX or FOLFOX) and chemoradiation (or radiation only) prior to surgery is increasingly being utilized. The prognostic and predictive values of mismatch repair deficient (dMMR) in rectal cancer is not well characterized. Most dMMR patients receive the same treatment as MMR proficient (pMMR) patients although there is limited data that dMMR rectal cancer patients may not have the same level of benefits from neoadjuvant treatment. This retrospective study aims to evaluate the clinicopathological/molecular characteristics, disease response, and clinical outcomes in dMMR localized rectal cancer patients. Methods: A retrospective analysis was conducted on consecutive adult patients with a diagnosis of dMMR rectal cancer who were treated at Mayo Clinic between January 2000 to September 2021. Patients who presented with concurrent primary non-colorectal malignancies were excluded. The distributions of demographics, clinicopathological features, biomarkers, and outcome data were collected. Survival was assessed using Kaplan-Meier curves and Cox models were stratified by treatment arms to determine significance of treatment strategies. Results: Forty-one patients were identified with a median age of 45.3 years. Thirty (73.2%) pts were male. The most common MMR were loss of MSH2 and MSH6 (12/42; 29.3%) followed by loss of MLH1 and PMS2 (10/42; 24.4%) and solitary loss of MSH2 (4/42; 9.8%). The treatment, pathological response, and clinical outcomes are listed in table. With a median follow up of 101 months, only 6 patients (14.3%) died and median overall survival was not reached. Conclusions: Our findings showed dMMR localized rectal cancer responded to both ST and TNT with good clinical outcomes.[Table: see text]

Purpose Clinical-pathologic features and natural history of patients with isocitrate dehydrogenase ( IDH)-mutant intrahepatic cholangiocarcinoma (CCA) are not well characterized. Here, we sought to describe the natural history, clinical phenotype, and prognostic impact of advanced, IDH-mutated CCA. METHODS We conducted a multicentric, retrospective analysis of patients with IDH-mutated (IDH1 or IDH2) CCA between 2010 and 2020. Median overall survival (OS) and progression-free survival (PFS) analyses were performed using the Kaplan-Meier method. Chi-square test was used to analyze disease control rate (DCR) and overall response rate (ORR). Matched controls were used for comparing survival between patients with and without IDH mutations (mIDH). RESULTS Sixty-five patients with IDH-mutated CCA were included. All patients had intrahepatic CCA. On first-line chemotherapy, median OS and median PFS were 21.2 months and 8.3 months, respectively. Notably, median OS (32.4 v 19.5 months, P = .12) and PFS (18.0 v 8.0 months, P = .12) were not significantly affected by disease status at presentation (locally advanced v metastatic, respectively). Median OS was significantly longer in patients with mIDH (21.2 v 10.5 months; P < .01). First-line gemcitabine-containing regimens had a significantly higher DCR and ORR than non–gemcitabine-containing regimens (DCR: 75% v 33%, P = .01; ORR: 39% v 0%, P = .02). In patients receiving IDH inhibitor therapy, median PFS was 4.6 months with a DCR of 29%. CONCLUSION CCA with m IDH confers a unique subtype resulting in a better survival compared with that of counterparts. IDH inhibitors represent a promising therapeutic option in later lines of therapy in this subgroup.