Phase 1 trial of navitoclax and sorafenib in patients with relapsed or refractory solid tumors with hepatocellular carcinoma expansion cohort.

Navitoclax (ABT-263) is an oral BCL2 homology-3 mimetic that binds with high affinity to pro-survival BCL2 proteins, resulting in apoptosis. Sorafenib, an oral multi kinase inhibitor also promotes apoptosis and inhibits tumor angiogenesis. The efficacy of either agent alone is limited; however, preclinical studies demonstrate synergy with the combination of navitoclax and sorafenib. In this phase 1 study, we evaluated the combination of navitoclax and sorafenib in a dose escalation cohort of patients with refractory solid tumors, with an expansion cohort in hepatocellular carcinoma (HCC). Maximum tolerated dose (MTD) was determined using the continual reassessment method. Navitoclax and sorafenib were administered continuously on days 1 through 21 of 21-day cycles. Ten patients were enrolled in the dose escalation cohort and 15 HCC patients were enrolled in the expansion cohort. Two dose levels were tested, and the MTD was navitoclax 150 mg daily plus sorafenib 400 mg twice daily. Among all patients, the most common grade 3 toxicity was thrombocytopenia (5 patients, 20%): there were no grade 4 or 5 toxicities. Patients received a median of 2 cycles (range 1-36 cycles) and all patients were off study treatment at data cut off. Six patients in the expansion cohort had stable disease, and there were no partial or complete responses. Drug-drug interaction between navitoclax and sorafenib was not observed. The combination of navitoclax and sorafenib did not increase induction of apoptosis compared with navitoclax alone. Navitoclax plus sorafenib is tolerable but showed limited efficacy in the HCC expansion cohort. These findings do not support further development of this combination for the treatment of advanced HCC. This phase I trial was conducted under ClinicalTrials.gov registry number NCT01364051.

Tumor-Informed Circulating Tumor DNA for Minimal Residual Disease Detection in the Management of Colorectal Cancer.

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.

Selecting Optimal First-Line Treatment for Microsatellite Stable and Non-Mutated RAS/BRAF Metastatic Colorectal Cancer.

OPINION STATEMENT: Standard frontline treatment of metastatic colorectal cancer (CRC) is cytotoxic chemotherapy plus a biologic agent such as an anti-EGFR monoclonal antibody (cetuximab or panitumumab) or anti-VEGF antibody (bevacizumab). Predictive biomarkers include mismatch repair (MMR) status, and RAS and BRAF mutation status; and important factors in treatment selection include primary tumor location, intent of therapy, and potential toxicity, as well as patient age, comorbidities, and patient preference. To date, single-, double-, or triple-agent cytotoxic chemotherapy all have important roles in appropriately selected patients, with the addition of anti-VEGF or anti-EGFR antibody therapy based on the relevant predictive biomarker. Data indicate that patients with proficient MMR, RAS/BRAF wt mCRC are candidates for an anti-EGFR antibody plus doublet chemotherapy if they have a left-sided primary tumor, or for anti-VEGF (bevacizumab) plus doublet or triplet chemotherapy if they have a right-sided primary tumor. Future studies may provide more predictive biomarkers to further personalize therapy for this heterogeneous disease.

Neoadjuvant Immune Checkpoint Inhibitor Therapy for Localized Deficient Mismatch Repair Colorectal Cancer: A Review.

Importance: Colorectal cancers (CRCs) with deficient DNA mismatch repair (dMMR) account for 15% of all CRCs. Deficient MMR is a predictive biomarker associated with responsiveness to immune checkpoint inhibitors (ICIs) in solid tumors, including CRC. The remarkable effectiveness of ICIs in metastatic CRC has led to their evaluation in the neoadjuvant and adjuvant treatment of localized disease. Observations: Multiple prospective phase 2 studies in limited numbers of patients with localized dMMR CRC demonstrate high complete clinical and pathological response rates (60%-100%) to neoadjuvant ICIs, with low rates of grade 3 or higher ICI-related toxic effects. Given the median follow-up of 12 to 25 months in these studies, longer-term monitoring is needed to determine the durability of response and to ensure that oncologic outcomes are not compromised in patients undergoing nonoperative management. Neoadjuvant ICI therapy is especially attractive for patients with rectal cancer given the significant morbidity that accompanies pelvic irradiation and total mesorectal excision. Ongoing and planned prospective phase 2 trials will provide further data on important issues, including optimal neoadjuvant treatment duration, ICI monotherapy vs combination, and the need for adjuvant ICI therapy. Conclusions and Relevance: While this review found that early results of neoadjuvant immunotherapy for localized dMMR CRC show high rates of major and complete pathological response, longer-term follow-up data are needed to ensure that oncologic outcomes are not compromised and are ideally improved. Neoadjuvant ICI therapy in localized dMMR CRC represents a potential paradigm shift with implications for organ preservation.

Synchronous Neoplasia Rates at Colonoscopic Diagnosis of Early-Onset vs Average-Onset Colorectal Cancer.

Importance: The incidence of early-onset colorectal cancer (CRC) (age, <50 years) continues to increase globally within high-income countries. Objective: To examine and compare rates of synchronous neoplasia found in patients at colonoscopic diagnosis of early-onset CRC with rates found at diagnosis of average-onset CRC. Design, Setting, and Participants: In this multisite retrospective and cross-sectional study conducted at Mayo Clinic sites and in the Mayo Clinic Health System from January 1, 2012, to December 31, 2022, 150 randomly selected patients with early-onset CRC were identified from the electronic health record and matched with 150 patients with average-onset CRC based on sex and colonoscopic indication. Patients with known hereditary syndromes, past history of CRC, or inflammatory bowel disease were excluded. Main Outcomes and Measures: Colonoscopic findings (polyp size, number, site) and related histopathologic findings (adenoma, advanced adenoma, sessile serrated polyp) were analyzed in association with cancer clinicopathologic features and molecular data (mismatch repair status, KRAS, and BRAFV600E). Results: Among 300 patients (156 men [52%]), the median age at diagnosis was 43 years (IQR, 39-47 years) for those with early-onset CRC and 67 years (IQR, 57-76) for those with average-onset CRC. Overall, 85% of patients were symptomatic at CRC diagnosis. Cancer stage, grade, molecular features, body mass index, and family history did not differ significantly between these groups. Among patients with colon cancer, the overall prevalence of synchronous neoplasia was similar, yet advanced adenomas were 3 times more frequent in those with early-onset vs average-onset cancers (31 of 75 [41%] vs 10 of 75 [13%]; P < .001). This difference was not associated with cancer stage or primary location. Among patients with rectal cancer, nonadvanced adenomas were less frequent among the early-onset group than the average-onset group (21 of 75 [28%] vs 36 of 75 [48%]), and although the prevalence of advanced adenomas was similar (11 of 75 [15%] vs 14 of 75 [19%]), they were more commonly located in the rectum (early onset, 5 of 11 [45%] vs average onset, 1 of 14 [7%]). Patients with early-onset cancer of the colon were significantly more likely than those with early-onset cancer of the rectum to have a synchronous advanced adenoma (31 of 75 [41%] vs 11 of 75 [15%]; P < .001). Conclusions and Relevance: In this cross-sectional study, synchronous advanced adenomas were more commonly found in patients with early-onset colon cancer compared with average-onset colon cancer, and they were distributed throughout the colon. In contrast, advanced adenomas were not increased in patients with rectal cancer and, when detected, were predominantly located in the rectum.

Association Between the Timing of Goals-of-Care Discussion and Hospitalization Outcomes in Patients With Metastatic Cancer.

BACKGROUND: Patients with cancer often require acute hospitalizations, many of which are unplanned. These hospitalizations have been shown to increase in frequency near the end of life. The American College of Physicians recommends that goals-of-care (GOC) discussions be initiated early for metastatic cancers. We hypothesized that discussing GOC during hospitalization could help reduce readmissions. Our aim was to examine the association between the timing of GOC discussion, length of hospital stay, and the time to readmission. METHODS: We conducted a retrospective review of medical records of patients with stage IV cancers hospitalized between August 2017 and July 2018. We recorded timing of GOC discussion, use of palliative care services, and hospital readmissions within 90 days. χ2 tests were used to identify independent associations with GOC discussion, and logistic regression was used to examine association with readmission within 90 days. RESULTS: Of all study patients (N = 241), 40.6% were female, 46% (n = 112) had a GOC discussion, and 34% (n = 82) had a palliative care consultation. Having a palliative care consult and being admitted to critical care were independently associated with having a GOC discussion. Early timing of GOC discussion was inversely associated with admission to critical care units (P < .05). Thirty-eight percent (n = 92) had unplanned hospital readmission within 90 days. Having a GOC discussion was independently associated with a reduction in the odds of an unplanned hospital readmission within 90 days by 79% (odds ratio = 0.21, 95% confidence interval: 0.12-0.37). CONCLUSION: Among hospitalized patients with stage IV cancer, performing an early GOC discussion has an important association with lower hospital readmission rates and increased rates of goal-congruent patient care.

Clinical Advancement and Challenges of ex vivo Expansion of Human Cord Blood Cells.

Apart from peripheral blood stem cell (PBSC), umbilical cord blood (UCB) is now a recognized source of stem cells for transplantation. UCB is an especially important source of stem cells for minority populations, which would otherwise be unable to find appropriately matched adult donors. UCB has fewer mature T lymphocytes compared with peripheral blood, thus making a UCB transplantation (UCBT) with a greater degree of HLA mismatch possible. The limited cell dose per UCB sample is however associated with delayed engraftment and a higher risk of graft failure, especially in adult recipients. This lower cell dose can be optimized by performing double unit UCBT, ex vivo UCB expansion prior to transplant and enhancement of the capabilities of the stem cells to home to the bone marrow. UCB contains naïve and immature T cells, thus posing significant challenges with increased risk of infections, graft versus host diseases (GVHD) and relapse following UCBT. Cell engineering techniques have been developed to circumnavigate the immaturity of the T cells, and include virus-specific cytotoxic T cells (VSTs), T cells transduced with disease-specific chimeric antigen receptor (CAR T cells) and regulatory T cell (Tregs) engineering. In this article, we review the advances in UCB ex vivo expansion and engineering to improve engraftment and reduce complications. As further research continues to find ways to overcome the current challenges, outcomes from UCBT will likely improve.

Hemophagocytic Lymphohistiocytosis in an AIDS Patient with Kaposi Sarcoma: A Treatment Dilemma.

Hemophagocytic lymphohistiocytosis (HLH) is a result of an abnormal activation of immune cells (T lymphocytes, natural killer cells, and macrophages) resulting in cytokine overproduction and immune destruction of cells, eventually resulting in multiorgan failure. Genetic causes are responsible for primary hemophagocytosis, but malignancies, infections, and autoimmunity underlie most of the secondary cases. We present an unusual case of a patient with AIDS and disseminated Kaposi sarcoma who was commenced on highly active antiretroviral therapy (HAART) but developed HLH secondary to immune reconstitution inflammatory syndrome (IRIS). We report this case to highlight the difficulty in managing this patient given the complex interplay of immunosuppression due to AIDS, immune reconstitution following initiation of HAART, and immune overdrive manifesting as HLH.