Tran, Nguyen

PURPOSE Recurrence after curative-intent treatment occurs in 20%-50% of patients with stage II-IV colorectal cancer (CRC), underscoring the need for early detection of minimal residual disease (MRD) using circulating tumor DNA (ctDNA). Here, we examined the pattern of use of a tumor-informed ctDNA assay in CRC MRD monitoring in routine clinical practice at Mayo Clinic, Rochester. METHODS We conducted a retrospective analysis of health records of patients with CRC who had at least one tumor-informed ctDNA assay from May 2019 through July 1, 2022. Recurrence was defined as radiographic evidence of disease. Descriptive characteristics of the cohort, ctDNA results, and subsequent interventions were recorded. RESULTS Of the 120 patients included, the median age at diagnosis was 67 years, 46% were female, and 94% were White. At diagnosis, 10 patients had stage I, 23 stage II, 60 stage III, and 25 stage IV disease. Of 476 ctDNA assays performed, 70% were performed in patients who had recurrent disease most commonly to monitor the effectiveness of therapeutic interventions and 16% resulted in a change in clinical decision making. There were 110 recurrences identified in 62 patients, as some patients experienced more than one recurrence over time. Compared with serum carcinoembryonic antigen levels, ctDNA results correlated better with radiologic imaging. CONCLUSION Routine ctDNA monitoring for MRD detection has been adopted in clinical practice; however, 84% of ctDNA assays performed did not result in a change in clinical management. This suggests the need for further clinical research data to guide routine clinical use of ctDNA MRD testing in CRC.

(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.

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.

Abstract Background: Sorafenib (Sor) remains a first-line option for hepatocellular carcinoma (HCC) or refractory renal cell carcinomas (RCC). PLC/PRF/5 HCC model showed upregulation of hypoxia with enhanced efficacy when Sor is combined with hypoxia-activated prodrug evofosfamide (Evo). Methods: This phase IB 3 + 3 design investigated 3 Evo dose levels (240, 340, 480 mg/m2 on days 8, 15, 22), combined with Sor 200 mg orally twice daily (po bid) on days 1-28 of a 28-day cycle. Primary objectives included determining maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of Sor + Evo. Results: Eighteen patients were enrolled (median age 62.5 years; 17 male /1 female; 12 HCC/6 RCC) across three dose levels (DL0: Sor 200 mg bid/Evo 240 mg/m2 [n=6], DL1:Sor 200 mg bid/Evo 480 mg/m2 [n=5], DL1a: Sor 200 mg bid/Evo 340 mg/m2 [n=7]). Two dose-limiting toxicities (DLTs) were reported with Evo 480 mg/m2 (grade 3 mucositis, grade 4 hepatic failure). Grade 3 rash DLT was observed in one patient at Evo 240 mg/m2. No DLTs were observed at Evo 340 mg/m2. MTD and RP2D were established as Sor 200 mg/Evo 340 mg/m2 and Sor 200/Evo 240 mg/m2, respectively. The most common treatment-related adverse events included fatigue, hand-foot syndrome, hypertension, and nausea/vomiting. Two partial responses were observed, one each at DL0 and DL1a.; disease control rate was 55%.Conclusions: RP2D was established as sorafenib 200 mg bid + Evo 240 mg/m2. While preliminary anti-tumor activity was observed, future development must account for advances in immunotherapy in HCC/RCC. NCT01497444Date of registration December 20, 2011