Singapore Health Services (SingHealth) is Singapore's largest group of healthcare institutions. The group was formed in 2000 and consists of four public hospitals, three community hospitals, five national specialty centres and a network of eight polyclinics. The Singapore General Hospital is the largest hospital in the group and serves as the flagship hospital for the cluster.
Epidermal growth factor receptor (EGFR) exon 20 insertions are the third most common EGFR mutation subtype in non-small cell lung cancer, occurring in up to 4
Prior event rate ratio (PERR) is a method shown to perform well in mitigating confounding and is gaining popularity in real-world evidence research. However, it depends on several model assumptions. We propose an analytic strategy to correct biases arising from violation of two model assumptions, namely, population homogeneity and event-independent treatment. We propose a reformulation of PERR estimation by embedding a treatment-by-period interaction term in the Andersen-Gill model for recurrent event data, which is robust to bias arising from unobserved heterogeneity. Based on this model, we propose a set of methods to examine the presence of event-dependent treatment and to correct the resultant bias. We evaluate the proposed methods by simulation and apply it to a de-identified dataset on palliative care and emergency department visits in patients with advanced cancer. Simulation results showed that the proposed method could mitigate the two sources of bias in PERR. In the palliative care study, analysis by the Cox model showed that patients who had started receiving palliative care had higher incidence of emergency department visits than their match controls (hazard ratio 3.31; 95% confidence interval 2.78-3.94). Using PERR without the proposed bias control strategy indicated a 19% reduction of the incidence (0.81; 0.64-1.02). However, there was evidence of event-dependent treatment. The proposed correction method showed no effect of palliative care on ED visits (1.00; 0.79-1.26). In conclusion, the proposed analytic strategy can control two sources of biases in the PERR approach. It enriches the armamentarium for real-world evidence research.
BACKGROUND:In DESTINY-Breast06, trastuzumab deruxtecan (T-DXd) improved progression-free survival (PFS) versus physician's choice of chemotherapy (TPC) for patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-low/-ultralow metastatic breast cancer (mBC), without new safety signals. We report additional analyses exploring outcomes for patients with characteristics that affect prognosis. PATIENTS AND METHODS:Patients were randomly assigned 1 : 1 to receive T-DXd (5.4 mg/kg) once every 3 weeks or TPC. Subgroups were specified post hoc from the intent-to-treat population (N = 866). Outcomes were PFS, objective response rate (ORR), and duration of response (DOR) by blinded independent central review via RECIST 1.1. Time from randomization until second progression or death (PFS2) by investigator and safety were also assessed. RESULTS:Within subgroups, baseline disease characteristics and prior therapies were balanced across treatments. Median PFS (95% confidence interval) favored T-DXd versus TPC regardless of time to progression (TTP) on prior first-line endocrine therapy (ET) + cyclin-dependent kinase 4 and 6 inhibitor (CDK4/6i): <6 months: 14.0 (11.2-15.9) versus 6.5 (4.2-8.4) months for T-DXd versus TPC; 6-12 months: 13.2 (8.6-16.4) versus 6.9 (4.3-10.4) months; >12 months: 12.9 (9.8-17.1) versus 8.2 (6.9-10.9) months. A consistent PFS benefit with T-DXd over TPC was observed for patients with primary or secondary endocrine resistance, and across indicators of high or low disease burden (defined as visceral/non-visceral disease, presence/absence of liver metastases, three or more/less than three disease sites, and >median/≤median baseline tumor size). In all subgroups, confirmed ORR favored T-DXd (36.7% to 67.7%) versus TPC (16.7% to 37.5%), and median DOR (confirmed response) was longer with T-DXd. T-DXd also prolonged PFS2 versus TPC across subgroups. Safety profiles of T-DXd and TPC in subgroups were consistent with the overall safety population. CONCLUSIONS:These data support T-DXd as a broadly efficacious treatment for patients with HR-positive, HER2-low/-ultralow mBC after one or more ETs, regardless of TTP on prior first-line ET + CDK4/6i, endocrine resistance, or disease burden.
BACKGROUND/AIMS:Immune checkpoint inhibitors (ICIs) have transformed advanced HCC treatment. The benefit of sequential immunotherapy after prior ICI failure remains unclear. Given the expanded use of atezolizumab plus bevacizumab (Ate/Bev) over the past 5 years, we explored the real-world outcomes of nivolumab plus ipilimumab (Nivo/Ipi) in patients with advanced HCC, with more focus on those previously exposed to Ate/Bev. METHODS:Patients treated with Nivo/Ipi for advanced HCC from six referral hospitals in Korea, Hong Kong, Taiwan and Singapore were included. Patients with prior non-Ate/Bev ICI or Child-Pugh B-C were excluded. Outcomes were compared between the ICI-naïve and Ate/Bev-experienced groups. RESULTS:Among 116 patients with advanced HCC treated with Nivo/Ipi, 57 were ICI-naïve and 59 had prior Ate/Bev exposure. Overall objective response rate was 31.2%, higher in the ICI-naïve group (42.6% vs. 20.0%, p = 0.01). However, the median duration of response was comparable between groups (24.8 vs. 23.7 months; p = 0.71), suggesting durable benefits regardless of prior Ate/Bev therapy. Median progression-free survival (PFS) and overall survival (OS) were 2.5 and 11.3 months, respectively, with longer PFS (5.3 vs. 1.6 months; p < 0.01) and OS (16.2 vs. 7.8 months; p = 0.06) in the ICI-naïve. Immune-related adverse events (irAEs), especially thyroid dysfunction, were associated with longer PFS and OS. Notably, most Nivo/Ipi responders post-Ate/Bev (8/11) had irAEs during Nivo/Ipi treatment, whereas no irAEs occurred during prior Ate/Bev. Nivo/Ipi responders post-Ate/Bev revealed a high tumour mutational burden (5.71-12.75 mutations/Mb). CONCLUSION:Nivo/Ipi demonstrated meaningful clinical activity in patients with advanced HCC, even after Ate/Bev failure.
