January 2024

This is a prospective multicenter, multinational, double-blind clinical trial looking at the effect of Olaparib as adjuvant therapy after neoadjuvant or adjuvant chemotherapy in patients with BRCA1 or BRCA2 mutations. They found that patients in the Olaparib group had significantly better 3-year disease free survival compared to the placebo group, suggesting that Olaparib provides benefit for this patient population.

Summary: This randomized controlled trial included 1,836 patients (median age 43 years) from 420 centers across 23 countries from 2014 to 2019 with HER2-negative primary breast cancer who were at least 2 weeks post definitive local treatment and either completion of neoadjuvant or adjuvant chemotherapy. Patients were randomized to 52 weeks olaparib (N=92) vs placebo (n=915) and stratified according to hormone receptor status, chemotherapy sequence, and use of platinum chemotherapy agents. Olaparib is a poly (adenosine diphosphate–ribose) polymerase inhibitors (PARP inhibitor) designed to target cancers with defects in homologous recombination repair found in BRCA 1 and BRCA2 mutations. Patients were followed closely with annual mammography vs MRI annually. The primary end point of invasive disease–free survival was defined as the time from randomization until the date of first occurrence of invasive breast tumor, locoregional invasive disease, distant recurrence/contralateral invasive breast cancer, second primary invasive cancer, or death from any cause. At 3-years, the difference in invasive disease–free survival was statistically significant with 85.9% in the olaparib group and 77.1% in the placebo group. The difference in 3-year distant disease–free survival was also statistically significant with 87.5% in the olaparib group and 80.4% in the placebo group (95% CI: 3.0 to 11.1). Fewer deaths were reported in the olaparib group although this was not statistically significant with a hazard ratio of 0.68 (99% CI: 0.44 to 1.05; P=0.02). The benefit of adjuvant olaparib relative to placebo was observed irrespective of the germline BRCA mutation (BRCA1 vs. BRCA2), the hormone-receptor status, or the timing of previous chemotherapy (neoadjuvant vs. adjuvant). Limitations of this study include only 3 years follow up which is not adequate to fully assess the spectrum and severity of potential adverse events. Adverse events leading to death included cardiac arrest in 1 patient in the olaparib group and AML and ovarian cancer in 1 patient in the placebo group. Additional adverse events of special interest included pneumonitis, myelodysplastic syndrome (MDS) or AML, and a new primary cancer. Although none of the reported adverse events occurred at a higher frequency in the olaparib group, additional follow up is needed to further characterize extent. Fewer deaths occurred among patients who received olaparib than among those who received placebo, although more long term follow up is recommended to fully evaluate.

Bottom line: Among patients with HER2 negative breast cancer and germline BRCA1 or BRCA2 mutations, 1 year of adjuvant olaparib after the completion of standard adjuvant or neoadjuvant chemotherapy and local therapy can meaningfully reduce recurrence risk and prevent progression to metastatic disease.

This Phase 1 clinical trial investigated the use of an individualized neoantigen mRNA vaccine for patients with pancreatic ductal adenocarcinoma (PDAC) in the adjuvant setting. The authors found that treating patients with this vaccine induced de novo high-magnitude neoantigen-specific T cells in half of the 16 patients enrolled in the trial. Furthermore, the patients with vaccine-expanded T cells had a longer median recurrence-free survival compared to patients without vaccine-expanded T cells (P=0.003). Thus, the authors concluded that use of an mRNA tumor vaccine in PDAC could induce a robust T cell response which correlated with a delayed PDAC recurrence. 

Summary:
PDAC is a deadly disease with a dismal 5-year overall survival rate of 12% that has not significantly changed in 60 years. While immunotherapy has become an important treatment strategy for other solid tumor types, PDAC has shown a near complete resistance. The observed failure of immunotherapy has been attributed to the heterogeneous and immunosuppressive tumor microenvironment that is characteristic of PDAC. Despite this restrictive microenvironment, increased T cell infiltration and neoantigen quality are predictors of long-term survival, suggesting the potential of the immune system to be harnessed for therapeutic benefit.

In this Phase 1 study, the investigators enrolled 34 patients with resectable PDAC to receive adjuvant PD-1 blockade, mFOLFIRINOX and autogene cevumeran (a personalized neoantigen mRNA vaccine). To create the personalized vaccine, portions of the resected tumor and normal tissue were sequenced. Mutations were identified and neoantigens were bioinformatically predicted and ranked by immunogenicity. The mRNA vaccines were then created to include up to 10 predicted neoantigens. After surgery, the patients then received one dose of Atexolizumab (anti-PD1 therapy) at week 6, eight priming doses of the neoantigen vaccines from weeks 9-17, twelve cycles of mFOLFIRINOX from weeks 21-43, and finally one booster vaccine at week 46. Of the 34 patients, 16 received atexolizumab and autogene cevumeran while 15 of those 16 received Atexolizumab, autogene cevumeran, and mFOLFIRINOX. Only one patient out of the 16 who received autogene cevumeran had a grade 3 adverse event which included fever and hypertension. Ex-vivo IFNγ ELISpot counts for vaccine neoantigens confirmed that 8 out of the 16 patients who received vaccine had a T cell response.

To further investigate the T cell response to autogene cevumeran, the authors developed CloneTrack which is a mathematical method that uses T cell receptor sequencing of peripheral blood samples to identify treatment expanded T cell clones. Using this method, it was observed that autogene cevumeran expanded multiple T cell clones (median 7.5) in responders from undetectable levels pre-treatment to as much as 10% of T cell clones in the peripheral blood post-treatment. Single cell RNA sequencing of these clones showed high expression of GZMB, PRF1 and IFNG, all markers of effector T cells. Ex-vivo challenging of these T cells with neoantigens showed increased degranulation as assessed by CD107a (P=0.03) and production of cytokines TNF and IFNg (P=0.03). 

While this study was not powered for efficacy, the authors did investigate the clinical effectiveness of autogene cevumeran. The median follow-up time for this study was 18 months. The median overall survival (OS) and recurrence free survival (RFS) was not met during this time frame. However, when stratified by response to autogene cevumeran, the median RFS in responders was not met (all 8 had not had recurrence) compared to 13.4 months in non-responders (HR 0.08, P=0.03). 

Bottom Line:
PDAC is considered an immune cold tumor, however, this recent study showed that a personalized mRNA tumor vaccine could induce a robust T cell response in a subset of patients which correlated with a delayed recurrence after surgery.

This secondary analysis of the UK VITALL clinical trial data looks at the long-term outcomes five years after transplant of livers perfused using ex-vivo normothermic machine perfusion (NMP) technology. They found that both patient and graft survival remained high even five years after transplant. 

Summary: The demand for liver transplant far surpasses the donor supply both in the USA and abroad, with high waitlist mortality. Between high transplant center outcomes scrutiny and declining donor quality, many livers are declined for transplant. Various types of machine perfusion technologies have been designed and studied to enhance organ preservation, re-condition organs after ischemia, and assess the viability prior to transplant. The UK VITALL study (2017), was a prospective, open-label phase 2 adaptive single-arm trial that perfused 31 livers declined for transplant at all UK centers using the OrganOx Metra device for a period of NMP to select transplantable organs. Ultimately, 22/31 (71%) of livers in the study were transplanted. The initial results of this trial found that, using a definition of viability as perfusate lactate levels ≤ 2.5 mmol/L within 4 hours, 71% of viable organs deemed unsuitable for transplantation by all the UK transplant centers could be transplanted with 100% 90-day patient and graft survival. 

In this secondary analysis, the goal was to assess long term outcomes using matched controls. Graft survival at 1, 3, and 5 years was 91%, 82% and 82% in the treatment group and 98%, 98%, and 95% in the matched controls. Patient survival was 100%, 91% and 82% in the treatment group compared to 95%, 91% and 86% in the matched controls. Graft and patient survival were not significantly different between contemporary matched controls and patients.   

There were 4 graft loses due to non-anastomotic biliary strictures, all within 6 months. Four patients died with functioning grafts, 3 with cancer recurrence and 1 from chronic rejection related to non-compliance with treatment, two of these had been re-transplanted previously. In post-hoc analysis, lactate clearance was felt to be a sufficient to guide the decision to transplant; however, they noted that bile parameters such as alkalotic pH and bicarbonate levels may aid in determination of development of non-anastomotic biliary strictures in livers from donors after circulatory death.

Notably, the goal of the study was to evaluate high-risk liver utilization and 25 discarded livers deemed “too good” were not included in the study. Additionally, in comparison to other studies, the period of static cold storage of 7.5 hours is significantly longer, likely contributing to worse outcomes. One criticism of the study has been the exclusion of high-risk recipients. Additionally, small sample size limits the power of this study and thus, results should be interpreted with caution. 

Bottom line: NMP technologies may be a feasible option for viability testing of high-risk organs for transplant and thus may be able to help increase the pool of transplantable organs.

This retrospective study looked at 3,700 patients who underwent radical cystectomy and pelvic lymph node dissection at a single institution. The authors found that patients who receive an intraoperative blood transfusion during radical cystectomy had a 70% increase in the odds of experiencing a venous thromboembolism (VTE) within 90 days of surgery, and that each unit of blood transfused corresponds to a 7% increase in odds of VTE. 

Summary: 
The rates of venous thromboembolism (VTE) after radical cystectomy range from 2%-11% and pose a significant source of morbidity, mortality, and financial burden to both the patient and the health system. Therefore, the goal of this retrospective cohort study was to assess the risk of perioperative blood transfusions on the development of VTE following radical cystectomy. 

3,755 patients who received radical cystectomy for bladder cancer at the Mayo Clinic between 1980-2020 were included and identified using the Mayo Clinic cystectomy registry. The primary exposure was perioperative blood transfusion, which was defined as transfusion of allogenic red blood cells either intraoperatively or during the initial post-operative hospitalization. The primary outcome was VTE (which include either DVT or PE) within 90 days of surgery, which was assessed based on symptomatic presentation and confirmatory diagnosis with conventional imaging standard at time. 

A multivariate logistic regression was used to assess the relationship between blood transfusion and VTE events, adjusting for covariables such as age, sex, Eastern Cooperative Oncology Group (ECOG) performance status, cystectomy year, body mass index (BMI), surgical approach, receipt of neoadjuvant chemotherapy, diversion type, length of stay, pathological tumor stage, and nodal stage. Due to the high number of patients missing data for operative time and lymph node yield, these variables are included as covariates in a separate, sensitivity analysis. To control for the impact of time, an interaction term between cystectomy year and intraoperative transfusion is included.

Overall, 4.3% of the patients in the cohort experienced a VTE within 90 days while 56% (2,112) of patients received a blood transfusion at any point, 41% (1,540) of which received an intraoperative transfusion. Patients who received intraoperative transfusion were older, had higher ECOG scores and were more likely to have received neoadjuvant chemotherapy, have pathologic tumor stage 3 or 4 disease, be pathologically node positive, and have longer operative times and lengths of stay. However, even after controlling for these factors, the receipt of intraoperative transfusion was still associated with higher odds of 90-day VTE (OR 1.73, 95% CI 1.17-2.56, P = 0.02). In the sensitivity analysis including operative time and nodal yield, this association remained significant (OR 1.90, 95% CI 1.16-1.32, P = 0.002). While descriptive analysis revealed decreasing use of intraoperative transfusion over time (84% of patients treated between 1980-1990 received transfusion as compared to 39% of patients treated from 2011-2020) and increasing rates of VTE over time, the interaction term between year and transfusion was not significant in the model, indicating that the association between transfusion and VTE can be applied to the entire timeframe under study. When intraoperative transfusion was used as a continuous variable, each unit of blood was significantly associated with increased odds of 90-day VTE as well (OR 1.07, 95% CI 1.01-1.13, P = 0.03). Similarly, BMI and later year of cystectomy were associated with higher risk of VTE. 

This study is limited by its retrospective nature and its use of such a large time span which includes significant changes in the diagnosis of and prophylaxis for VTE after radical cystectomy. Though the authors are able to include cystectomy year in the model, there is still the possibility that changing practices regarding VTE prophylaxis or other unmeasured confounders remain unadjusted in this analysis.

Bottom line: Intraoperative blood transfusion is associated with higher risk of VTE after radical cystectomy. In light of these findings, increasing efforts to diagnose and treat anemia preoperatively and to minimize blood loss intraoperatively in order to avoid intraoperative transfusion during radical cystectomy and thus lower VTE risk are of increasing importance.