Mahipal, Amit

Abstract Background Atezolizumab plus bevacizumab (A/B) received FDA approval as the first-line therapy for patients with advanced hepatocellular carcinoma (HCC) in 2020. However, optimal subsequent treatment options are unclear. Here, we describe clinical outcomes of advanced HCC patients following first-line treatment with A/B. Patients and Methods We conducted a multi-site analysis of patients with HCC treated with first-line A/B between January 2018 and December 2022 at Mayo Clinic. This study cohort included all patients receiving second-line systemic therapy after A/B. Median overall survival (OS) and time-to-treatment discontinuation (TTD) were estimated using the Kaplan-Meier method. Child Pugh (CP) scores are also described at diagnosis, prior to first line, and prior to second-line therapy. Results Of the 342 patients who received A/B, 107 (31.3%) received second-line treatments including anti-VEGF therapy or immune checkpoint inhibitor (ICI) and were included in the final analysis. Median OS for all patients was 11.1 months from initiation of second-line therapy. Median OS was 10.7 months (95% CI: 7.2-12.8) and 15.7 months (95%CI: 6.8-NE) for those receiving anti-VEGF inhibitors and ICI ( P = .50). Median TTD for second-line therapies was 2.4 months (95% CI: 1.7-3.3) and 2.6 months (95% CI: 1.5-5.1) for anti-VEGF inhibitors and ICI, respectively (P = .87). In multivariate analyses, CP was significantly associated with survival. Conclusion Following first-line A/B treatment, there is no statistically significant difference in survival between ICI and anti-VEGF therapy, nor in time to treatment discontinuation. CP score remains an important prognostic tool.

PURPOSE SWOG S1815 was a randomized, open label phase III trial, evaluating gemcitabine, nab-paclitaxel, and cisplatin (GAP) versus gemcitabine and cisplatin (GC) in patients with newly diagnosed advanced biliary tract cancers (BTCs). METHODS Patients with newly diagnosed locally advanced unresectable or metastatic BTC, including intrahepatic cholangiocarcinoma (ICC) and extrahepatic cholangiocarcinoma (ECC) and gallbladder carcinoma (GBC), were randomly assigned 2:1 to either GAP (gemcitabine 800 mg/m 2 , cisplatin 25 mg/m 2 , and nab-paclitaxel 100 mg/m 2 intravenously once per day on days 1 and 8 of a 21-day cycle) or GC (gemcitabine 1,000 mg/m 2 and cisplatin 25 mg/m 2 intravenously once per day on days 1 and 8 of a 21-day cycle). RESULTS Among 452 randomly assigned participants, 441 were eligible and analyzable, 67% with ICC, 16% with GBC, and 17% with ECC. There was no significant difference in overall survival (OS) between GAP versus GC. Median OS with GAP was 14.0 months (95% CI, 12.4 to 16.1) and 13.6 months with GC (95% CI, 9.7 to 16.6); hazard ratio (HR), 0.91 (95% CI, 0.72 to 1.14); P = .41. Median progression-free survival (PFS) was similar between groups with median PFS for GAP being 7.5 months (95% CI, 6.4 to 8.5) versus 6.3 months for GC (95% CI, 4.4 to 8.2); HR, 0.89 (95% CI, 0.71 to 1.12); P = .32. In exploratory subset analyses, the OS and PFS benefits of GAP versus GC treatment were greater in locally advanced disease compared with metastatic disease, although not statistically significant (interaction P = .14 for OS and P = .17 for PFS). Moreover, GAP versus GC showed greater improvement in PFS among participants with GBC than those with ICC or ECC (interaction P = .01), but not OS (interaction P = .28). CONCLUSION The addition of a taxane in the GAP regimen to the standard gemcitabine-cisplatin regimen did not improve OS in newly diagnosed BTC. More toxicity was encountered with GAP versus GC.

84 Background: Local therapies potentially offer a curative approach for patients with oligometastatic colorectal cancer (CRC). The effectiveness of systemic chemotherapy following definitive local treatment in this setting is not well-defined. Tumor-informed circulating tumor DNA (ctDNA) might guide management strategies after curative-intent local treatment. Methods: This is a single institution retrospective study of patients with CRC who underwent curative-intent local therapy to an isolated site of metastatic disease and had post-intervention tumor-informed ctDNA (Signatera) testing. The study was approved by the institutional review board. Clinical characteristics, including ctDNA results, were collected and evaluated. Kaplan-Meier method and log-rank test were used to calculate and compare disease-free survival (DFS). Factors associated with DFS were analyzed using multivariate Cox proportional hazards model. Results: 45 patients were included with median age of 59 years, 62% being male, 91% white, and 53% with stage IV disease at diagnosis. 37% of the patients had RAS mutations, no patient had BRAF mutation, and 2.2% patient had mismatch repair deficient disease. Isolated liver metastases were present in 80% of patients, lung metastases in 11% and other sites in 9%. 44 patients received chemotherapy prior to definitive treatment, with a median treatment duration of 16 weeks. ctDNA tests were done prior to local therapy in 23 patients, with 14 cases (61%) testing positive. Definitive treatment included resection (58%), ablation (13%), radiotherapy (4%), and multimodality (25%). Post-definitive treatment chemotherapy was administered to 24 (53%) patients. ctDNA positivity following definitive therapy was observed in 10 patients (22%), which was associated with a poorer prognosis, with a median DFS of 5.3 months compared to 21.3 months for the ctDNA-negative group (p<0.001). These findings were confirmed on multivariate analysis. In patients who had negative ctDNA after definitive local treatment, median DFS was 14.9 months for those who received post-intervention chemotherapy versus 21.3 months for those without post-intervention chemotherapy (p=0.835). Conclusions: Patients with negative ctDNA results following definitive local therapy for isolated metastatic CRC have better prognosis. Post-intervention chemotherapy in this group of patients was not associated with improved DFS. ctDNA guided omission of post-intervention chemotherapy following curative-intent local treatment of oligometastatic CRC warrants further study. [Table: see text]

50 Background: A+B is commonly used as first line systemic therapy in HCC patients with CP-B liver function, although in the IMbrave150 clinical trial, its efficacy was only assessed in patients with CP-A liver function. We evaluated outcomes in patients with CP-B liver function and compared to those with CP-A. Methods: We completed a multi-institution, retrospective review of patients with HCC from Mayo Clinic and University Hospitals Seidman Cancer Center, who had received A+B in the first line setting between March 2018 and November 2023. CP score was calculated at time of treatment, response was assessed, and progression free (PFS) and overall (OS) survival were determined using the Kaplan Meier method. Results: Among 322 patients with HCC, median age was 66.5 years, 78.6% were male, and 82.6% were white. Eighty-six patients (27%) had CP-B liver function, while 226 (70%) had CP-A and 10 (3%) had CP-C. Etiology of liver disease in patients with CP-B included hepatitis B in 7.0%, hepatitis C in 38.4%, alcohol use in 30.2%, and metabolic associated steatohepatitis in 20.9%. Median OS in patients with CP-B liver function was 6.4 months, while mOS was 21.6 months for those with CP-A ( p<0.0001). Further stratifying, mOS in those with CP-B7 was 9.1 months, CP-B8 was 5.5 months, and CP-B9 was 4.0 months. 12-month OS in patients with CP-B was 32.4%, compared to 69.3% in CP-A. Median PFS was 4.8 months in those with CP-B and 8.9 months in those with CP-A. Median PFS in those with CP-B7, -B8, and -B9 was 6.4 months, 2.7 months, and 2.7 months, respectively. Among those with CP-B, 1 patient had a complete response, 17 (19.8%) had a partial response, 29 (33.7%) had stable disease, and 37 (43.0%) had progressive disease. Adverse events in CP-B patients included hypertension in 14.0% (grade 3 in 1 patient), bleeding in 16.3% (grade 3 or greater in 11.6%), fatigue in 38.4%, and an immune-related adverse event in 17.4% (grade 3 in 5.8%). Conclusions: Patients with advanced HCC and CP-B7 liver function may still benefit from A+B. Importantly, no additional safety risks were identified in this subgroup. Those with CP-B8 and CP-B9 have significantly worse survival than those with CP-B7 and the likelihood of benefit from systemic therapy is minimal. It is important for providers to address the impact of baseline liver function on expected outcomes in patient with HCC.

Abstract Background Atezolizumab plus bevacizumab is the standard of care for advanced hepatocellular carcinoma (HCC) in the first-line setting, although was only evaluated in patients with Child-Pugh (CP) A liver function in the IMbrave150 trial. We sought to determine the outcomes of these patients based on CP score and ALBI grade in the US population. Methods This multicenter cohort study included patients with HCC who received atezolizumab with bevacizumab as first-line systemic therapy between March 2018 and November 2023. Overall survival (OS) was determined using the Kaplan-Meier method and multivariate analyses were performed using Cox proportional hazard regression method. Results Among 322 patients, 226, 86, and 10 patients had CP-A, CP-B, and CP-C liver function, respectively. Median age was 66.5 years, 78.6% were male, and 82.6% were White. Median OS (mOS) was 21.6 months for those with CP-A, 9.1 months for those with CP-B7, and 4.7 months for those with CP-B8-C12 (P &lt; .0001). Among patients with CP-A, those with ALBI grade 1 had an mOS of 34.9 months versus 14.2 months in those with grade 2. In multivariate analyses, CP score, ALBI grade, hepatitis B, performance status, and macrovascular invasion were significantly associated with survival. Conclusions CP score is an important prognostic tool for patients with HCC receiving atezolizumab plus bevacizumab, and this regimen remains a viable option for patients with CP-B7 with no additional safety concern, although the benefit is significantly less than those with CP-A. ALBI score has independent predictive value in patients with CP-A liver function.

(1) Background: Local therapies offer a potentially curative approach for patients with oligometastatic colorectal cancer (CRC). An evidence-based consensus recommendation for systemic therapy following definitive locoregional therapy is lacking. Tumor-informed circulating tumor DNA (ctDNA) might provide information to help guide management in this setting. (2) Methods: A multi-institutional retrospective study was conducted, including patients with CRC that underwent curative-intent locoregional therapy to an isolated site of metastatic disease, followed by tumor-informed ctDNA assessment. The Kaplan–Meier method and log-rank tests were used to compare disease-free survival based on ctDNA results. ctDNA test performance was compared to carcinoembryonic antigen (CEA) test results using McNemar’s test. (3) Results: Our study cohort consisted of 87 patients treated with locoregional interventions who underwent ctDNA testing. The initial ctDNA test post-intervention was positive in 28 patients and negative in 59 patients. The median follow-up time was 14.0 months. Detectable ctDNA post-intervention was significantly associated with early disease recurrence, with a median disease-free survival (DFS) of 6.63 months compared to 21.30 months in ctDNA-negative patients (p < 0.001). ctDNA detected a numerically higher proportion of recurrences than CEA (p < 0.097). Post-intervention systemic therapy was not associated with improved DFS (p = 0.745). (4) Conclusions: ctDNA results are prognostically important in oligometastatic CRC, and further prospective studies are urgently needed to define its role in guiding clinical decisions.

4099 Background: A+B is standard of care for advanced HCC in the first line setting, although was only evaluated in patients with CP class A liver function in IMbrave150. We sought to determine outcomes of patients in the real-world setting. Methods: We conducted a multi-institution retrospective analysis of patients with HCC who received A+B as first-line systemic therapy between March 2018 and November 2023, at Mayo Clinic and University Hospitals Seidman Cancer Center. Treatment response was evaluated, and progression free survival (PFS) and overall survival (OS) were determined using the Kaplan Meier method. Multivariate analyses were performed using Cox proportional hazard regression method. Results: Among patients with HCC (n=322), 226, 86, and 10 had CP-A, -B, and -C liver function, while 120, 177, and 25 had ALBI grade 1, 2, and 3 liver function. Median age was 66.5 years, 78.6% were male, and 82.6% were white. Liver disease causes included hepatitis B (5.3%) and C (34.8%), ethanol use (26.1%), and non-alcoholic steatohepatitis (15.5%). Macrovascular invasion was seen in 42.9%, and 30.4% had extrahepatic metastatic disease. Median OS for patients with CP-A5/6 was 21.6 months, B7 (n=49) was 9.1 months, and B8-C12 was 4.7 months ( p<0.0001). Median OS by ALBI grade was 34.9, 11.7, and 4.7 months for grades 1, 2, and 3. Median PFS was 8.9, 6.4, and 2.7 months for CP-A5/6, B7, and B8-C12 ( p<0.0001). Median PFS by ALBI grade was 11.0, 6.4, and 3.7 months for grades 1, 2, and 3 ( p=0.0001). Among patients with CP-A, those with ALBI grade 1 had mOS of 34.9 months versus 14.2 months for those with grade 2. Partial response was seen in 29.2%, 19.8% and 10.0% of patients with CP-A, -B, and -C, while 32.7%, 33.7%, and 40.0% had stable disease. In a univariate analysis, factors predictive of shorter OS included CP-B7 or CP-B8-C12, ALBI grade 2 or 3, hepatitis B, poorer ECOG performance status (PS), macrovascular invasion, non-white race, and lack of prior surgery or embolization. In multivariate analyses, CP score, ALBI grade, hepatitis B, ECOG PS, and macrovascular invasion were significantly associated with survival. There was significant interaction between CP and ALBI grade (Table). Conclusions: A+B remains a viable option in patients with CP-B7 liver function, although benefit is significantly less than those with CP-A. ALBI score has predictive value and can identify two prognostic groups among those with CP-A liver function. [Table: see text]

Purpose: To investigate the molecular characteristics of and potential for precision medicine in KRAS wildtype pancreatic ductal adenocarcinoma (PDAC). Patients and Methods: We investigated 27 patients with KRASWT PDAC at our institution. Clinical data were obtained via chart review. Tumor specimens for each subject were interrogated for somatic single nucleotide variants, insertion and deletions, and copy number variants by DNA sequencing. Gene fusions were detected from RNA-seq. A patient-derived organoid (PDO) was developed from a patient with a MET translocation and expanded ex vivo to predict therapeutic sensitivity prior to enrollment in a phase 2 clinical trial. Results: Transcriptomic analysis showed our cohort may be stratified by the relative gene expression of the KRAS signaling cascade. The PDO derived from our patient harboring a TFG-MET rearrangement was found to have in vitro sensitivity to the multi-tyrosine kinase inhibitor crizotinib. The patient was enrolled in the phase 2 SPARTA clinical trial and received monotherapy with vebrelitinib, a c-MET inhibitor, and achieved a partial and durable response. Conclusions: KRASWT PDAC is molecularly distinct from KRASMUT and enriched with potentially actionable genetic variants. In our study, transcriptomic profiling revealed that the KRAS signaling cascade may play a key role in KRASWT PDAC. Our report of a KRASWT PDAC patient with TFG-MET rearrangement who responded to a cMET inhibitor further supports the pursuit of precision oncology in this sub-population. Identification of targetable mutations, perhaps through approaches like RNA-seq, can help enable precision-driven approaches to select optimal treatment based on tumor characteristics.