Plain language summary of the HIMALAYA study: tremelimumab and durvalumab for unresectable hepatocellular carcinoma (liver cancer).

WHAT IS THIS SUMMARY ABOUT?: This is a summary of results from a phase 3 clinical study called HIMALAYA. HIMALAYA looked at treatment with one dose of a medication called tremelimumab combined with multiple doses of a medication called durvalumab (the STRIDE regimen) or multiple doses of durvalumab alone. These treatments were compared with a medication called sorafenib in participants with unresectable hepatocellular carcinoma (HCC). HCC is a type of liver cancer that is difficult to treat because it is often diagnosed when it is unresectable, meaning it can no longer be removed with surgery. Sorafenib has been the main treatment for unresectable HCC since 2007. However, people who take sorafenib may experience side effects that can reduce their quality of life, so alternative medicines are being trialed. Tremelimumab and durvalumab are types of drugs called immunotherapies, and they both work in different ways to help the body's immune system fight cancer. WHAT WERE THE RESULTS OF THE STUDY?: Participants who took STRIDE lived longer than participants who took sorafenib, whilst participants who took durvalumab alone lived a similar length of time as participants who took sorafenib. Participants who took STRIDE or durvalumab had a lower relative risk of experiencing worsening in their quality of life than participants who took sorafenib. The side effects that participants who received STRIDE or durvalumab experienced were expected for these types of treatments and could mostly be managed. WHAT DO THE RESULTS OF THE STUDY MEAN?: Overall, STRIDE is more effective than sorafenib for people with unresectable HCC.

Synergistic activity of IDH1 inhibitor BAY1436032 with azacitidine in IDH1 mutant acute myeloid leukemia.

Mutant IDH1 (mIDH1) inhibitors have shown single-agent activity in relapsed/refractory AML, though most patients eventually relapse. We evaluated the efficacy and molecular mechanism of the combination treatment with azacitidine, which is currently the standard of care in older AML patients, and mIDH1 inhibitor BAY1436032. Both compounds were evaluated in vivo as single agents and in combination with sequential (azacitidine, followed by BAY1436032) or simultaneous application in two human IDH1 mutated AML xenograft models. Combination treatment significantly prolonged survival compared to single agent or control treatment (P<.005). The sequential combination treatment depleted leukemia stem cells (LSC) by 470-fold. Interestingly, the simultaneous combination treatment depleted LSCs by 33,150-fold compared to control mice. This strong synergy is mediated through inhibition of MAPK/ERK and RB/E2F signaling. Our data strongly argues for the concurrent application of mIDH1 inhibitors and azacitidine and predicts improved outcome of this regimen in IDH1 mutated AML patients.

PERIPHERAL EXUDATIVE HEMORRHAGIC CHORIORETINOPATHY-A NEW ADDITION TO THE SPECTRUM OF PACHYCHOROID DISEASE?

PURPOSE: To demonstrate choroidal vascular changes and report a novel choroidal thickness contour in eyes with peripheral exudative hemorrhagic chorioretinopathy (PEHCR). METHODS: Retrospective, observational, comparative case series. Fourteen eyes of nine patients with PEHCR and 14 eyes of 14 age-matched and sex-matched controls underwent swept-source optical coherence tomography. Choroidal thickness was measured from posterior edge of the retinal pigment epithelium-Bruch membrane to choroidoscleral interface at 11 points 1,000 µm apart. Large choroidal vessel thickness was also measured. RESULTS: In PEHCR group, the choroid was thinnest at 3 mm nasal to fovea (mean 95.3 ± 33.5 µm) and thickest at 7 mm temporal to fovea (mean 272.7 ± 80.2 µm), with gradual increase in choroidal thickness from nasal to temporal periphery. The choroid was thickest subfoveally (259.7 ± 63.8 µm) in the control group. The choroid was significantly thicker in temporal periphery in PEHCR eyes as compared to controls (P = 0.0002). The mean large choroidal vessel thickness was 202.4 ± 50.8 µm in the PEHCR group and 160.6 ± 40.5 µm in the control group (P = 0.0235). CONCLUSION: Peripheral exudative hemorrhagic chorioretinopathy eyes showed progressively increasing choroidal thickness toward the temporal periphery, compared with age-matched and sex-matched controls. This gave rise to a club-shaped choroidal contour compared with the bowl-shaped contour seen in control eyes. Thicker choroid and pachyvessels favor inclusion of PEHCR in the pachychoroid disease spectrum.

Susceptibility of poultry associated bacterial pathogens to Momordica charantia fruits and evaluation of in vitro biological properties.

The emerging incidence of antibiotic resistance trait among the bacteria populating poultry presents a devastating public health issue. On the other hand, at present, diabetes and obesity are the most serious public health issues and are increasing subsequently at alarming rate. In view of this, the present in vitro context was aimed to investigate the antibacterial activities of Momordica charantia (M. charantia) fruits extracts against poultry associated Bacillus spp. and to assess further its phytoconstituents, alpha-(α)-glucosidase activities, and anti-obesity properties. The anti-pathogenic attributes of M. charantia fruit extracts were carried out using disc diffusion assay and results showed the pronounced antibacterial trait of ethanolic extract with maximum zone of inhibition of 28.3 ±â€¯1.2 mm against Bacillus licheniformis. The qualitative phytochemical analyses of fruit extracts illustrated the presence of diverse phytoconstituents. The α-glucosidase inhibition assay for the extracts was performed according to the α-glucosidase activity kit. The results depicted the lowest α-glucosidase activity (57.13 ±â€¯2.3 to 18.14 ±â€¯1.3 U/L) in the presence of ethanolic extract at varied concentrations. The anti-obesity potentialities of fruit extracts were demonstrated in terms of porcine pancreatic lipase (PPL type II) activity using p-nitro-phenyl butyrate (p-NPB) as a substrate. The ethanolic extract of M. charantia fruits was observed to exhibit maximum inhibition of pancreatic lipase ranging from 20.12 ±â€¯2.3 to 68.34 ±â€¯1.3% in a dose dependent manner with an IC50 value of 607.6 ±â€¯1.3 µg/mL. FTIR and GC-MS results indicated the presence of distinct compounds in the ethanol extract and major bioactive constituents were found to be Dimethyl sulfone (35.24%), 9-octadecanamide (20.52%), Pentadecanoic acid (6.64%), Lanost-9 (11)-en-18-oic acid, 23-(acetylxyl)-3-(4-bromobenzoyl) oxyl-20-hydroxyl-gamma-lactone (2.6%), and 2,2-sulfonyldiethanol (2.46%). In conclusion, M. charantia fruits could be of great concern in pharmaceutical industries due to its adequate biological properties and may also help in the management of poultry associated bacterial pathogens.

BIMANUAL MICROINCISION VITREOUS SURGERY FOR SEVERE PROLIFERATIVE DIABETIC RETINOPATHY: OUTCOME IN MORE THAN 300 EYES.

PURPOSE: To evaluate the visual and anatomical outcomes and safety of bimanual microincision vitreous surgery for severe proliferative diabetic retinopathy. METHODS: Retrospective review of 315 eyes of 282 patients who underwent 23-gauge or 25-gauge pars plana vitrectomy with bimanual membrane dissection for diabetic tractional detachment from January 2007 to September 2016. Minimum follow-up was 3 months, and the average duration of follow-up was 23 months (range 3-100 months; median 15 months). Outcome measures were best-corrected visual acuity, anatomical success, and postoperative complications. RESULTS: Postoperatively, 84.3% of eyes improved (>2 lines), 10.5% were stable, and 5.4% worsened (>2 lines). Comparing gauges, two-line improvement was seen in 87.4% of 23-gauge eyes compared with 79.7% of 25-gauge eyes (P = 0.029). Mean peak best-corrected visual acuity improved from 20/930 (1.67 ± 0.63) preoperatively to 20/120 (0.78 ± 0.63) postoperatively (P < 0.001). Primary reattachment was achieved in 310 eyes (98.4%) and final reattachment in 312 eyes (99%). Recurrent vitreous hemorrhage was the commonest postoperative complication (18.4%). Lower incidence of recurrent vitreous hemorrhage was seen with 25 gauge (13.5%) compared with 23 gauge (22%, P = 0.038). Epiretinal membrane formation (7.9%), intractable glaucoma (2.5%), and endophthalmitis (0.6%) were some of the other postoperative complications. CONCLUSION: Sustained visual improvement, anatomical restoration, and low complication rates were obtained in complex situations with bimanual microincision vitreous surgery in a large series. Visual outcomes were poorer in older age group, tractional retinal detachments involving macula, and eyes with extensive membranes and with silicone oil as tamponade. Both 23-gauge and 25-gauge groups were comparable in relation to visual improvement, anatomical success, and intraoperative and postoperative complications.

Palliative Care and Cardiovascular Disease and Stroke: A Policy Statement From the American Heart Association/American Stroke Association.

The mission of the American Heart Association/American Stroke Association includes increasing access to high-quality, evidence-based care that improves patient outcomes such as health-related quality of life and is consistent with the patients' values, preferences, and goals. Awareness of and access to palliative care interventions align with the American Heart Association/American Stroke Association mission. The purposes of this policy statement are to provide background on the importance of palliative care as it pertains to patients with advanced cardiovascular disease and stroke and their families and to make recommendations for policy decisions. Palliative care, defined as patient- and family-centered care that optimizes health-related quality of life by anticipating, preventing, and treating suffering, should be integrated into the care of all patients with advanced cardiovascular disease and stroke early in the disease trajectory. Palliative care focuses on communication, shared decision making about treatment options, advance care planning, and attention to physical, emotional, spiritual, and psychological distress with inclusion of the patient's family and care system. Our policy recommendations address the following: reimbursement for comprehensive delivery of palliative care services for patients with advanced cardiovascular disease and stroke; strong payer-provider relationships that involve data sharing to identify patients in need of palliative care, identification of better care and payment models, and establishment of quality standards and outcome measurements; healthcare system policies for the provision of comprehensive palliative care services during hospitalization, including goals of care, treatment decisions, needs of family caregivers, and transition to other care settings; and health professional education in palliative care as part of licensure requirements.

Phase II Study of First-Line Trebananib Plus Sorafenib in Patients with Advanced Hepatocellular Carcinoma.

LESSONS LEARNED: Trebananib leveraging anti-angiogenic mechanism that is distinct from the classic sorafenib anti-vascular endothelial growth factor inhibition did not demonstrate improved progression-free survival at 4 months in patients with advanced hepatocellular carcinoma (HCC).In support of previously reported high Ang-2 levels' association with poor outcome in HCC for patients, trebananib treatment with lower baseline Ang-2 at study entry was associated with improved overall survival to 22 months and may suggest future studies to be performed within the context of low baseline Ang-2. BACKGROUND: Ang-1 and Ang-2 are angiopoietins thought to promote neovascularization via activation of the Tie-2 angiopoietin receptor. Trebananib sequesters Ang-1 and Ang-2, preventing interaction with the Tie-2 receptor. Trebananib plus sorafenib combination has acceptable toxicity. Elevated Ang-2 levels are associated with poor prognosis in hepatocellular carcinoma (HCC). METHODS: Patients with HCC, Eastern Cooperative Oncology Group ≤2, and Childs-Pugh A received IV trebananib at 10 mg/kg or 15 mg/kg weekly plus sorafenib 400 mg orally twice daily. The study was planned for ≥78% progression-free survival (PFS) rate at 4 months relative to 62% for sorafenib historical control (power = 80% α = 0.20). Secondary endpoints included safety, tolerability, overall survival (OS), and multiple biomarkers, including serum Ang-2. RESULTS: Thirty patients were enrolled sequentially in each of the two nonrandomized cohorts. Demographics were comparable between the two arms and the historical controls. PFS rates at 4 months were 57% and 54% on the 10 mg/kg and 15 mg/kg trebananib cohorts, respectively. Median OS was 17 and 11 months, respectively. Grade 3 and above events noted in ≥10% of patients included fatigue, hypertension, diarrhea, liver failure, palmar-plantar erythrodysesthesia syndrome, dyspnea, and hypophosphatemia. One death was due to hepatic failure. Serum Ang-2 dichotomized at the median was associated with improved OS in both cohorts. CONCLUSION: There was no improvement in PFS rate at 4 months in either cohort, when compared with sorafenib historical control.

Atypical retinal pigment epithelial defects with retained photoreceptor layers: a so far disregarded finding in age related macular degeneration.

BACKGROUND: To report patients with age-related macular degeneration and atypical central retinal pigment epithelium (RPE) defects not attributable to geographic atrophy (GA) or RPE-tears with overlying preserved photoreceptor layers. METHODS: Multimodal imaging case-series evaluating the course of atypical RPE- defects in patients with AMD using Color fundus images, Optical coherence tomography (OCT), OCT-Angiography, fundus autofluorescence (FAF) and fluorescein-angiography (FA). RESULTS: Ten patients were identified. Three patients had a prior RPE-rip and were excluded. Seven patients with a mean follow-up period of 47 ± 38 months after the occurrence of the RPE-defect were included (age range 71-87 years). Mean distance Best corrected visual acuity (BCVA) at initial presentation was 0.36 ± 0.29logMAR and at last follow-up visit 0.51 ± 0.43logMAR. Patients presented with clinically apparent GA on funduscopy and FAF, but preserved photoreceptor layers on optical coherence tomography (OCT). On FA there was early hyperfluorescence and late pooling visible. Over time, migration of RPE/drusenoid material right above the Bruch's membrane with concomitant decrease of hypoautofluorescence was detectable in 4 cases. An enlargement of the RPE-defect was apparent in the remaining 3 cases. The majority (n = 4) showed a drusenoid pigment epithelium detachment (PED) preceding the lesion. CONCLUSIONS: Beside GA and characteristic RPE-tears, another atypical form of RPE-defect with overlying preserved photoreceptor layers are found in AMD. This so far disregarded subgroup of patients present with reasonable visual function and long-term survival of photoreceptors layers. Repair mechanisms such as ingrowth of RPE/drusenoid material and persistent subretinal fluid (SRF), but also a RPE-independent visual cycle for cone photopigment within the neurosensory retina may contribute to their favorable course.

A new approach to define acute kidney injury in term newborns with hypoxic ischemic encephalopathy.

BACKGROUND: Current definitions of acute kidney injury (AKI) are not sufficiently sensitive to identify all newborns with AKI during the first week of life. METHODS: To determine whether the rate of decline of serum creatinine (SCr) during the first week of life can be used to identify newborns with AKI, we reviewed the medical records of 106 term neonates at risk of AKI who were treated with hypothermia for hypoxic ischemic encephalopathy (HIE). RESULTS: Of the newborns enrolled in the study, 69 % showed a normal rate of decline of SCr to ≥50 % and/or reached SCr levels of ≤0.6 mg/dl before the 7th day of life, and therefore had an excellent clinical outcome (control group). Thirteen newborns with HIE (12 %) developed AKI according to an established neonatal definition (AKI-KIDGO group), and an additional 20 newborns (19 %) showed a rate of decline of SCr of <33, <40, and <46 % from birth to days 3, 5, or 7 of life, respectively (delayed rise in estimated SCr clearance group). Compared to the control group, newborns in the other two groups required more days of mechanical ventilation and vasopressor drugs and had higher gentamicin levels, more fluid overload, lower urinary epidermal growth factor levels, and a prolonged length of stay. CONCLUSIONS: The rate of decline of SCr provides a sensitive approach to identify term newborns with AKI during the first week of life.

Predictors of health care system and physician distrust in hospitalized cardiac patients.

Trusting relationships among patients, physicians, and the health care system is important in encouraging self-care behaviors in cardiovascular patients. This study aimed to assess the prevalence of health care system and physician distrust in this population, compare the 2 forms of distrust, and describe the demographic, socioeconomic, and psychosocial predictors of high distrust. A total of 1,232 hospitalized adults with acute coronary syndrome or heart failure were enrolled in a prospective, observational study assessing health care system distrust and physician distrust. High health care system distrust (35%) was observed across the population, with lower levels of interpersonal physician distrust (16%). In a multivariate analysis, poor social support and coping skills were strong predictors of both health care system (p=.026, p=.003) and physician distrust (p<.001, p=.006). Individuals with low or marginal health literacy had a higher likelihood of physician distrust (p<.001), but no relation was found between health literacy and health care system distrust. In conclusion, distrust is common among acutely ill cardiac patients. Those with low social support and low coping skills are more distrusting of physicians and the health care system.

Novel peptide inhibitor of human tumor necrosis factor-α has antiarthritic activity.

The inhibition of tumor necrosis factor (TNF)-α trimer formation renders it inactive for binding to its receptors, thus mitigating the vicious cycle of inflammation. We designed a peptide (PIYLGGVFQ) that simulates a sequence strand of human TNFα monomer using a series of in silico methods, such as active site finding (Acsite), protein-protein interaction (PPI), docking studies (GOLD and Flex-X) followed by molecular dynamics (MD) simulation studies. The MD studies confirmed the intermolecular interaction of the peptide with the TNFα. Fluorescence-activated cell sorting and fluorescence microscopy revealed that the peptide effectively inhibited the binding of TNF to the cell surface receptors. The cell culture assays showed that the peptide significantly inhibited the TNFα-mediated cell death. In addition, the nuclear translocation of the nuclear factor kappa B (NFκB) was significantly suppressed in the peptide-treated A549 cells, as observed in immunofluorescence and gel mobility-shift assays. Furthermore, the peptide protected against joint damage in the collagen-induced arthritis (CIA) mouse model, as revealed in the micro focal-CT scans. In conclusion, this TNFα antagonist would be helpful for the prevention and repair of inflammatory bone destruction and subsequent loss in the mouse model of CIA as well as human rheumatoid arthritis (RA) patients. This calls upon further clinical investigation to utilize its potential effect as an antiarthritic drug.

Patient-Reported Outcomes From the Phase III HIMALAYA Study of Tremelimumab Plus Durvalumab in Unresectable Hepatocellular Carcinoma.

PURPOSE: In the phase III HIMALAYA study (ClinicalTrials.gov identifier: NCT03298451) in unresectable hepatocellular carcinoma (uHCC), the Single Tremelimumab Regular Interval Durvalumab (STRIDE) regimen significantly improved overall survival versus sorafenib, and durvalumab monotherapy was noninferior to sorafenib. Patient-reported outcomes (PROs), a secondary outcome from HIMALAYA, are reported here. METHODS: Participants were randomly assigned to receive STRIDE, durvalumab, or sorafenib. PROs were assessed (preplanned secondary outcome) using the European Organization for Research and Treatment of Cancer 30-item Quality of Life Questionnaire and the 18-item HCC module. Time to deterioration (TTD), change from baseline and improvement rate in global health status/quality of life (GHS/QoL), functioning, and disease-related symptoms were analyzed. RESULTS: In total, 1,171 participants were randomly assigned to STRIDE (n = 393), durvalumab (n = 389), or sorafenib (n = 389) and were evaluable for PRO assessments. Across treatment arms, compliance rates for PROs were >77% at baseline and >70% overall. Baseline scores were comparable across treatment arms. TTD in GHS/QoL, physical functioning, fatigue, appetite loss, and abdominal pain was numerically longer for both STRIDE and durvalumab versus sorafenib. Clinically meaningful deterioration in PROs was not observed in any treatment arm. However, TTD in nausea and abdominal swelling was numerically longer for STRIDE versus sorafenib, and the likelihood of clinically meaningful improvement in GHS/QoL, role, emotional and social functioning, and disease-related symptoms was greater with STRIDE and durvalumab versus sorafenib. PROs with STRIDE and durvalumab were generally similar. CONCLUSION: Compared with sorafenib, STRIDE and durvalumab were associated with clinically meaningful, patient-centered GHS/QoL, functioning, and symptom benefits in people with uHCC. These findings support the benefits of the STRIDE regimen compared with sorafenib for a diverse population reflective of the global uHCC population.

Immunosuppression Monitoring-What Clinician Needs to Know?

The liver is well known for its immunotolerance, but rejection without immunosuppression is frequently encountered post liver transplantation, especially in humans.1 Indeed, the amount of immunosuppression required post liver transplant is less compared to other organ transplants like kidney, heart, and intestine.2 Reports of successful weaning of immunosuppression have been reported but are not practiced for fear of unwanted alloimmune response leading to rejection. Life-long immunosuppression is needed in most patients for graft survival but is associated with side effects like renal dysfunction, metabolic abnormalities, or risk of de novo malignancies. Also, the appropriate dose of immunosuppression to achieve adequate graft function and prevention of toxicities is very important. One shoe does not fit all. There are significant individual variations in response and side effect profile. Also, the level of immunosuppression varies with the underlying liver disease like autoimmune disease requires higher immunosuppression. Thus, monitoring the adequate immunosuppression with the minimization of drug toxicity is imperative post-transplant. Unfortunately, the current methods for immunosuppression monitoring rely on testing the immunosuppressive drug levels rather than the immune system activity. We have discussed the concept of alloreactivity, available methods of immunosuppression and drug monitoring and investigational methods in this review.

Drug Repurposing During The COVID-19 Pandemic: Lessons For Expediting Drug Development And Access.

The COVID-19 pandemic created a large, sudden unmet public health need for rapid access to safe and effective treatments. Against this backdrop, policy makers and researchers have looked to drug repurposing-using a drug previously approved for one indication to target a new indication-as a means to accelerate the identification and development of COVID-19 treatments. Using detailed data on US clinical trials initiated during the pandemic, we examined the trajectory and sources of drug repurposing initiatives for COVID-19. We found a rapid increase in repurposing efforts at the start of the pandemic, followed by a transition to greater de novo drug development. The drugs tested for repurposing treat a wide range of indications but were typically initially approved for other infectious diseases. Finally, we documented substantial variation by trial sponsor (academic, industry, or government) and generic status: Industry sponsorship for repurposing occurred much less frequently for drugs with generic competitors already on the market. Our findings inform drug repurposing policy for both future emerging diseases and drug development in general.

Structural clarity is brought to adhesion G protein-coupled receptor tethered agonism.

An elusive problem in the adhesion G protein-coupled receptor (AGPCR) field is full understanding of the activation mechanisms of the 33-member receptor class. With the recent solution of active-state structures of nearly one quarter of AGPCRs, clarity has been brought to how AGPCRs are activated in response to endogenous full agonists. AGPCRs are self-activated via a tethered peptide agonist (TA) that transitions from a concealed or encrypted location to a decrypted state that binds to a typical GPCR orthosteric binding pocket. Here, we summarize the key milestones that led to the discovery of the AGPCR TA activation mechanism and discuss how extracellular shear forces may initiate TA decryption in physiological contexts. We compare the new active-state AGPCR structures and note that the orthosteric site-engaged TAs adopt a remarkably similar partial α-helical hook-like conformation, despite divergence of overall receptor similarity. Further, we contrast the TA-bound AGPCR structures to a partially active AGPCR structure to highlight the transitions AGPCRs may undergo during activation. Finally, we provide commentary on the validity of alternative AGPCR activation mechanisms.

Design and Characterization of Citronella Oil-Loaded Micro-Emulgel for the Treatment of Candida Albicans Infection.

The purpose of the current study was to prepare and evaluate a citronella oil-loaded microemulsion-based micro-emulgel for the treatment of Candida albicans. The primary objective was to use the skin to transfer hydrophobic medications into the bloodstream. The formulation included cinnamon oil as an antifungal oil and citronella oil as an active pharmaceutical ingredient, respectively. Tween 80 and PEG 200 were used as the surfactant and co-surfactant, respectively, to create phase diagrams. Carbopol 940, one of the frequently used polymers, was investigated for its ability to prepare gel formulations. The optimized (F3) batch contained the highest percentage (87.05 ± 0.03%) of drug content and, according to the statistics provided, had the highest drug release rate of around 87.05% within 4 h. The Korsmeyer-Peppas model with n value of 0.82, which is in the range 0.5-1, had the highest r2 value, indicating that release following non-Fickian/anomalous diffusion provided a better dimension for all of the formulations. The optimized (F3) formulation had stronger antifungal activity in comparison to other formulations. This leads to the conclusion that citronella oil can be made into a micro-emulgel, which may improve its release in aqueous systems while maintaining a high level of drug release at the target site.

Population Pharmacokinetics and Exposure-Response Analysis of Tremelimumab 300 mg Single Dose Combined with Durvalumab 1500 mg Q4W (STRIDE) in Patients with Unresectable Hepatocellular Carcinoma.

A novel single-dose regimen of 300 mg tremelimumab in combination with durvalumab (STRIDE) has demonstrated a favorable benefit-risk profile in the phase 1/2 Study 22 trial (in patients with unresectable hepatocellular carcinoma, uHCC) and in the phase 3 HIMALAYA study. The current analysis evaluated the population pharmacokinetics (PopPK) of tremelimumab and durvalumab, and the exposure-response (ER) relationship for efficacy and safety of STRIDE in patients with uHCC. Previous PopPK models for tremelimumab and durvalumab were updated using data from previous studies in various cancers combined with data from Study 22 and HIMALAYA. Typical population mean parameters and associated inter- and intra-individual variability were assessed, as was the influence of covariates. Individual exposure metrics were derived from the individual empirical Bayes estimates as drivers for ER analysis related to efficacy and safety from HIMALAYA. The observed pharmacokinetics of tremelimumab in uHCC were well described by a 2-compartment model with both linear and time-dependent clearance. All identified covariates changed tremelimumab PK parameters by <25%, and thus had minimal clinical relevance; similar results were obtained from durvalumab PopPK analysis. None of tremelimumab or durvalumab exposure metrics were significantly associated with overall survival (OS), progression-free survival (PFS), or adverse events. Baseline aspartate aminotransferase and neutrophil-to-lymphocyte ratio (NLR) were associated with OS (P < .001) by the Cox proportional hazards model. No covariate was identified as a significant factor for PFS. No dose adjustment for tremelimumab or durvalumab is needed based on PopPK covariate analyses or ER analyses. Our findings support the novel STRIDE dosing regimen in patients with uHCC.