328 Background: Liver transplant (LT) remains the best curative standard for HCC within Milan criteria (Milan). Nonsurgical locoregional treatments, including TACE and ablation, offer a bridge to surgical management and attempt to downstage or maintain patients (pts) within Milan pending liver transplant and donor organ availability. We investigated clinical factors that predict successful downstaging of HCC and liver transplant. Methods: In this single-institutional retrospective analysis, pts with early-intermediate stage HCC within Milan (control) vs beyond Milan were evaluated for clinical outcome. Clinical factors including treatment and response, demographics, TACE distribution (number of treatments, timing, and response), and status of liver transplantation (timing and if received) were correlated to overall survival (OS). OS was calculated using the Kaplan-Meier method. Results: HCC pts (n = 343) considered for LT or downstage to LT were included in the study: 75% male, 13% African American, 55% Caucasian, and 14% Asian. 12% of pts had HBV, 53% had HCV, 2% had both HBV and HCV. 221 pts were diagnosed within Milan vs 122 beyond Milan, in which 36% (n = 44) were still within UCSF criteria (UCSF). 43% of those diagnosed within Milan ultimately received LT vs 16% of those diagnosed beyond Milan. 49% of pts (n = 60) initially beyond Milan were downstaged to within Milan, via TACE, wherein 27% received LT; this group accounted for 13% all LT. However, in the subset of pts beyond Milan but within UCSF, 68% were downstaged to within Milan, wherein 40% received LT. In pts initially within Milan, 21% (n = 47) progressed beyond Milan, but 40% of this subset was downstaged back to within Milan. Pts both within and beyond Milan had a median of 2 TACE procedures. Differences in the rates of LT relative to the number of TACE were significant (p = 0.022) for pts initially within Milan; for < / = 2 TACE, 54% had LT; for > 2 TACE, 26% had LT. Similar comparison was nonsignificant for pts initially beyond Milan (p = 0.95); rates of LT for < / = 2 TACE and > 2 TACE were 17% and 16% respectively. Median OS for non-LT recipients was 5 years vs not reached for LT recipients ( > 70% alive at 8 years, p < 0.001). Pts initially beyond Milan but within UCSF criteria had similar OS vs those initially within Milan (both 75% at 4 years), but OS was worse (50% at 4 years) for those beyond UCSF (p = 0.024). Conclusions: Liver transplantation significantly increased OS in early-intermediate stage HCC. Increased number of TACE procedures was associated with decreased likelihood of ultimate LT in pts initially diagnosed within Milan, particularly when they had > 2 TACE. Pts initially beyond Milan but within UCSF criteria had similar OS vs those initially within Milan; this former subset had a good chance of being downstaged to Milan and ultimately receive LT. Additional clinical factors that predict successful downstaging of HCC and LT are being investigated.
e19006 Background: Chimeric antigen receptor (CAR-T) Chimeric antigen receptor (CAR) T-cell therapy presents a promising avenue in the treatment of hematological malignancies. However, the application of CAR-T cell therapy comes with a range of adverse effects, some of which are not fully understood yet. While previous research has primarily focused on immune effector cell-associated neurotoxicity (ICANs) and cytokine release syndrome (CRS), the cardiovascular safety profile of CAR-T cell therapy remains less defined. This meta-analysis assesses the incidence of cardiovascular (CV) events associated with CAR-T therapy, thereby providing critical insights into these events and guiding clinical decision-making. Methods: We conducted a Pubmed search of clinical trials evaluating the effect of CAR-T cell therapy in cancer patients with cardiovascular adverse events. For phase III trials, a quantitative assessment of Grade 3 or higher CV events was performed using the Review Manager (Rev-Man) Version 5.4 (The Cochrane Collaboration, 2020) and the results were reported as Odd Ratio (OR) with 95% Confidence Interval (CI). A fixed effect model was used. For phase I/II trials, the event rates were calculated for all-grade as well as grade 3 and higher CV adverse events. Results: A total of four Phase III clinical trials with 1345 patients were included for the comparison analysis. Among those trials, two involved multiple myeloma patients, and two involved large B cell lymphoma patients. The age range across trials was 20-83 years with a male-to-female ratio of 1.5:1. The analysis revealed that there was no statistically significant difference in Grade 3 or higher CV events between the CAR-T cell therapy and control (standard of care) groups: OR with 95% CI was 1.44 (0.73,2.82) (p=0.29). Grade 3 and above CV adverse event rates were 3.4% for the CAR-T and 2.1% for the control groups. Notably, there were two CV deaths in the CAR-T group and one CV death in the control group. Additionally, a total of 41 single-arm, Phase I/II clinical trials with 1479 participants were analyzed. Seven studies included solid cancers such as metastatic pancreatic cancer, biliary tract cancer and melanoma. The age range was 17-86 yr and male/female ratio was 1.5:1. Total all-grade CV adverse event rate was 21.83% and total grade 3 and above CV adverse event rate was 8.82%. There were eight CV deaths. Conclusions: There were significantly more CV adverse events reported in Phase I/II trials when compared to those reported in Phase III trials. This indicates that CV adverse events are important consequences of CAR-T cell therapy but are likely underreported in the Phase III clinical trials. Increased awareness and more standardized evaluation of CV adverse events of CAR-T is needed in the future clinical trials.
Biliary tract cancers (BTCs) are a heterogeneous group of malignancies that make up ~7% of all gastrointestinal tumors. It is notably aggressive and difficult to treat; in fact, >70% of patients with BTC are diagnosed at an advanced, unresectable stage and are not amenable to curative therapy. For these patients, chemotherapy has been the mainstay treatment, providing an inadequate overall survival of less than one year. Despite the boom in targeted therapies over the past decade, only a few targeted agents have been approved in BTCs (i.e., IDH1 and FGFR inhibitors), perhaps in part due to its relatively low incidence. This review will explore current data on PARP inhibitors (PARPi) used in homologous recombination deficiency (HRD), particularly with respect to BTCs. Greater than 28% of BTC cases harbor mutations in genes involved in homologous recombination repair (HRR). We will summarize the mechanisms for PARPi and its role in synthetic lethality and describe select genes in the HRR pathway contributing to HRD. We will provide our rationale for expanding patient eligibility for PARPi use based on literature and anecdotal evidence pertaining to mutations in HRR genes, such as RAD51C, and the potential use of reliable surrogate markers of HRD.
This is a review of the current state of molecular profiling in gastrointestinal (GI) cancers and what to expect from this evolving field in the future. Individualized medicine is moving from broad panel testing of numerous genes or gene products in tumor biopsy samples, identifying biomarkers of prognosis and treatment response, to relatively noninvasive liquid biopsy assays, building on what we have learned in our tumor analysis and growing into its own evolving predictive and prognostic subspecialty. Hence, the field of GI precision oncology is exploding, and this review endeavors to summarize where we are now in preparation for the journey ahead.
4087 Background: Over 20% of biliary tract cancers (BTCs) carry mutations in homologous recombination DNA damage repair (HR-DDR) pathways. The PARP inhibitor olaparib (O) blocks tumor DNA repair and may induce response in BTCs with such mutations. Furthermore, HR-DDR mutations may engender neoantigens that improve response to immune checkpoint inhibitors. We propose that treatment with O and the anti-PD-1 monoclonal antibody pembrolizumab (P) will produce a durable anti-tumor response to BTC, especially in patients with HR-DDR mutations. Methods: Consent for participation was obtained. Eligibility criteria included age > 18 years with an ECOG score of ≤1 and a histologic diagnosis of advanced or metastatic BTC with progression of disease (PD) on prior first-line therapy. Treatment featured oral O (300 mg twice daily) plus intravenous P (200 mg every 3 weeks). Response was measured radiographically using RECIST 1.1 guidelines. The primary endpoint was overall response rate (ORR), with the alternative hypothesis that O + P would improve ORR compared to historical controls (versus the null hypothesis of no improvement). Type I and II error rates were set at 5% and 15%, respectively. Simon’s optimal two-stage design was used. Planned sample size was 13 patients in the first stage. Continuation to the second stage would only occur if ≥3 patients demonstrated response. The second stage was planned to include 20 additional patients (N = 33 total), which was based on the number needed to demonstrate an improvement in ORR from 17.5% in historical controls to at least 35.0%. Results: Of 21 eligible patients, 14 were accrued between June 2020 and March 2022, and 13 were evaluable for efficacy. Patients had a median age of 63 years, were primarily female (71%), Caucasian (50%), and with metastatic disease (93%). Patients received a mean of 6.5 cycles of therapy. Best treatment response included partial response (N = 2), stable disease (N = 5), and PD (N = 6). The ORR was 15.3% (95% CI = 0.02-0.45). Of the partial responders, 1 patient achieved a duration of response of 8 months (mos), and 1 has ongoing response at 24 mos. Median (med) time to progression was 7.7 mos (95% CI = 1.2-9.3), med progression free survival was 5.5 mos (95% CI = 1.2-7.7), and med overall survival was 11.9 mos (95% CI = 5.5-15.4). Most patients (64%) developed at least one treatment-related adverse event (trAE). Grade 3 trAEs were experienced in 5 patients (36%) and included anemia (N = 3), diarrhea (N = 1), and transaminitis (N = 1). Conclusions: While O + P has acceptable safety and toxicity, the study did not achieve significant improvement in the primary endpoint. However, the two patients who demonstrated durable treatment response were found to have HR-DDR tumor mutations (including RAD51, ATM, and BRCA2), necessitating further research into the efficacy of O + P for patients with similar tumor genomes. Clinical trial information: NCT04306367 .
555 Background: Despite advances in understanding the molecular pathways of HCC, therapeutic options are limited and patient survival is dismal. IO is a promising HCC treatment. There are currently no indicators to identify which patients (pts) will have a prolonged response. Methods: In this single-institutional retrospective analysis, pts received one of five IO containing regimens with nivolumab, pembrolizumab, atezolizumab plus bevacizumab, durvalumab or cemiplimab until disease progression (PD) or unacceptable toxicity. Relevant factors including: stage, viral etiology, vascular invasion (VI), tumor thrombus (TT), multifocal disease, toxicity grade, steroid use for IO mediated toxicities and derived Neutrophil-to Lymphocyte ratio (dNLR), were correlated to clinical outcome: progression free survival (PFS), overall survival (OS), response rate (RR), using Pearson’s chi-square test or student's t-test . Responses were assessed using RECIST v 1.1 criteria for stable disease (SD), partial response (PR) and PD were correlated with best response and PFS. OS was calculated by the Kaplan-Meier method. Results: Cohort demographics (n = 76) were: 72% male; 38% African American, 30% Caucasian and 16% Asian; 29% of pts had HBV, 41% had HCV, 1% had both HBV/HCV and 13% had no viral etiology (n = 64). The majority of pts were stage III (43%) or IV (38%). At the start of IO, 32% had VI, 32% had TT and 80% had multifocal or metastatic disease. 65% of pts experienced IO toxicity, with 24.3% at grade 3 or higher, and 34% requiring steroids. Best response to IO was SD in 65.7% of pts, PR in 25.7% and PD in 8.6%. Median OS was 13m (95% CI 7.9-18.1) from the start of IO and median PFS (n = 65) was 14m (95% CI 6.8-21.2). Median OS and PFS were significantly improved in pts with PR compared to PD (45 vs 8m, p < 0.0005, PFS 15 vs 3m p = 0.007). Both OS and PFS showed benefits for SD of ≥2 months compared to those with PD (11 vs 8m, p < .0005, PFS 5 vs 3m p = .007). VI, TT, stage, viral etiology, toxicity grade or dNLR did not correlate with OS, PFS and RR, however need of steroid treatment trended toward worse outcome. Conclusions: PR and SD are independent predictors for prolonged PFS and OS in HCC pts receiving IO therapy. Absence of steroid use for toxicity trended toward improved IO response.
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