Comparing the Efficacy of Cancer Therapies between Subgroups in Basket Trials.
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ABSTRACT:
SUBMITTER: Palmer AC
PROVIDER: S-EPMC8022348 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Currently, genomic characterization has become standard of care for tumor types such as non-small cell lung cancer, breast cancer, melanoma, and colorectal cancer. A deep understanding of genomic alterations in different tumor types would help identify potentially actionable genomic changes which occur across a wide variety of tumor types. A basket trial is a new type of clinical trial for which eligibility is based on the presence of a specific genomic alteration, irrespective of histology. Basket trials are phase II screening trials for the off-label use of a targeted drug in patients with the same genomic alterations for which it was approved. Intractable cancer refers to a type or condition of cancer which is unresponsive or resistant to treatment; intractable cancers may be classified into five subtypes as follows: hard-to-treat condition of common advanced cancer after multiple-line therapy, rare cancer in which no standard of care has been recommended, advanced cancer in which standard of care does not work well, cancer accompanied with organ dysfunction, and cancers in older or younger cancer patients. Previous studies have demonstrated that in basket trials, genomic-guided therapy yields clinical benefits in intractable cancer, thereby providing novel insights into the optimal clinical management of such cancers. In this review, we describe a novel way to classify intractable cancer, and summarize the current knowledge on such cancers. We additionally provide information on the role of basket trials in intractable cancer.
| S-EPMC6473081 | biostudies-literature
Project description:With advances in genetic testing and its common usage, the field of precision medicine has exploded in the field of oncology. The National Cancer Institute is uniquely positioned to lead in this area of research through its wide network of investigators, partnerships with pharmaceutical companies in drug development, and laboratory capabilities. It has developed a portfolio of trials as part of a Precision Medicine Initiative that uses various basket/umbrella designs to increase the understanding of treatment of cancer through genetic selection and targeted therapies. This article describes these trials, ALCHEMIST, LungMAP, NCI/NRG ALK Trial, MPACT, NCI-MATCH, and pediatric MATCH, and their contributions to the area of precision medicine.
| S-EPMC6658131 | biostudies-literature
Project description:Background:The prospect for targeted therapies in advanced hepatocellular carcinoma (HCC) has dramatically changed since several recent clinical trials have yielded promising results. The number of second-line therapies is increasing, though the consequent challenge is to consider differences between these interventions. This is a comparative investigation of presently approved second-line drugs for HCC based on findings from phase III randomized controlled trials.Methods:Data related to treatment efficacy including overall survival (OS), progression-free survival (PFS) and objective response rate (ORR) were extracted and compared using a Bayesian approach. Adverse events (AEs) and the rate of discontinuation due to AEs were assessed and compared with provide a more complete understanding. OS and PFS in patients with alpha fetoprotein (AFP) values greater than 400 were compared and ranked as a subgroup.Results:A total of five trials involving 2571 patients were included. The comparison suggests that regorafenib and cabozantinib significantly prolong OS compared with placebo. The rate of AEs and treatment discontinuation did not significantly differ, although the types of AEs varied substantially. Subgroup analysis did not highlight a significant OS difference between regorafenib [hazard ratio (HR) 0.68; 95% confidence interval (CI) 0.50–0.92], cabozantinib (HR 0.71; CI 0.54–0.94) and ramucirumab (HR 0.69; CI 0.57–0.84). Conclusion: Among the four second-line HCC therapies compared, regorafenib and cabozantinib appear to be better choices in terms of OS. Cabozantinib, regorafenib and ramucirumab have similar levels of efficacy for those with AFP?>400, although ramucirumab has fewer side effects. No significant difference was observed in AEs, but some AEs related to each of these interventions should be given further consideration.
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Project description:Kidney transplant recipients often receive antibody induction. Previous studies of induction therapy were often limited by short follow-up and/or absence of information about complications. After linking Organ Procurement and Transplantation Network data with Medicare claims, we compared outcomes between three induction therapies for kidney recipients. Using novel matching techniques developed on the basis of 15 clinical and demographic characteristics, we generated 1:1 pairs of alemtuzumab-rabbit antithymocyte globulin (rATG) (5330 pairs) and basiliximab-rATG (9378 pairs) recipients. We used paired Cox regression to analyze the primary outcomes of death and death or allograft failure. Secondary outcomes included death or sepsis, death or lymphoma, death or melanoma, and healthcare resource utilization within 1 year. Compared with rATG recipients, alemtuzumab recipients had higher risk of death (hazard ratio [HR], 1.14; 95% confidence interval [95% CI], 1.03 to 1.26; P<0.01) and death or allograft failure (HR, 1.18; 95% CI, 1.09 to 1.28; P<0.001). Results for death as well as death or allograft failure were generally consistent among elderly and nonelderly subgroups and among pairs receiving oral prednisone. Compared with rATG recipients, basiliximab recipients had higher risk of death (HR, 1.08; 95% CI, 1.01 to 1.16; P=0.03) and death or lymphoma (HR, 1.12; 95% CI, 1.01 to 1.23; P=0.03), although these differences were not confirmed in subgroup analyses. One-year resource utilization was slightly lower among alemtuzumab recipients than among rATG recipients, but did not differ between basiliximab and rATG recipients. This observational evidence indicates that, compared with alemtuzumab and basiliximab, rATG associates with lower risk of adverse outcomes, including mortality.
| S-EPMC5491281 | biostudies-literature
Project description:Investigating targeted therapies can be challenging due to diverse tumor mutations and slow patient accrual for clinical studies. The Signature Program is a series of 8 phase 2, agent-specific basket protocols using a rapid study start-up approach involving no predetermined study sites. Each protocol evaluated 1 agent (buparlisib, dovitinib, binimetinib, encorafenib, sonidegib, BGJ398, ceritinib, or ribociclib) in patients with solid or hematologic malignancies and an actionable mutation. The primary endpoint of each study was the clinical benefit rate (ie, complete or partial response, or stable disease) at 16 weeks. A total of 192 individual sites were opened in the United States, with a median start-up time of 3.6 weeks. The most common tumor types among the 595 treated patients were colorectal (9.2%), non-small cell lung adenocarcinoma (9.1%), and ovarian (8.4%). Frequent genetic alterations were in PIK3CA, RAS, p16, and PTEN. Overall, 30 partial or complete responses were observed with 6 compounds in 16 tumor types. The Signature Program presents a unique and successful approach for rapid signal finding across multiple tumors and allowed various agents to be evaluated in patients with rare alterations. Incorporating these program features in conventional studies could lead to improved trial efficiencies and patient outcomes.
| S-EPMC5940401 | biostudies-literature
Project description:Assessment of efficacy in important subgroups - such as those defined by sex, age, race and region - in confirmatory trials is typically performed using separate analysis of the specific subgroup. This ignores relevant information from the complementary subgroup. Bayesian dynamic borrowing uses an informative prior based on analysis of the complementary subgroup and a weak prior distribution centred on a mean of zero to construct a robust mixture prior. This combination of priors allows for dynamic borrowing of prior information; the analysis learns how much of the complementary subgroup prior information to borrow based on the consistency between the subgroup of interest and the complementary subgroup. A tipping point analysis can be carried out to identify how much prior weight needs to be placed on the complementary subgroup component of the robust mixture prior to establish efficacy in the subgroup of interest. An attractive feature of the tipping point analysis is that it enables the evidence from the source subgroup, the evidence from the target subgroup, and the combined evidence to be displayed alongside each other. This method is illustrated with an example trial in severe asthma where efficacy in the adolescent subgroup was assessed using a mixture prior combining an informative prior from the adult data in the same trial with a non-informative prior.
| S-EPMC8247867 | biostudies-literature
Project description:BackgroundNovel precision oncology trial designs, such as basket and umbrella trials, are designed to test new anticancer agents in more effective and affordable ways. However, they present some ethical concerns referred to scientific validity, risk-benefit balance and informed consent. Our aim is to discuss these issues in basket and umbrella trials, giving examples of two ongoing cancer trials: NCI-MATCH (National Cancer Institute - Molecular Analysis for Therapy Choice) and Lung-MAP (Lung Cancer Master Protocol) study.Main bodyWe discuss three ethical requirements for clinical trials which may be challenged in basket and umbrella trial designs. Firstly, we consider scientific validity. Thanks to the new trial designs, patients with rare malignancies have the opportunity to be enrolled and benefit from the trial, but due to insufficient accrual, the trial may generate clinically insignificant findings. Inadequate sample size in study arms and the use of surrogate endpoints may result in a drug approval without confirmed efficacy. Moreover, complexity, limited quality and availability of tumor samples may not only introduce bias and result in unreliable and unrepresentative findings, but also can potentially harm patients and assign them to an inappropriate therapy arm. Secondly, we refer to benefits and risks. Novel clinical trials can gain important knowledge on the variety of tumors, which can be used in future trials to develop effective therapies. However, they offer limited direct benefits to patients. All potential participants must wait about 2 weeks for the results of the genetic screening, which may be stressful and produce anxiety. The enrollment of patients whose tumors harbor multiple mutations in treatments matching a single mutation may be controversial. As to informed consent - the third requirement we discuss, the excessive use of phrases like "personalized medicine", "tailored therapy" or "precision oncology" might be misleading and cause personal convictions that the study protocol is designed to fulfill the individual health-related needs of participants.ConclusionsWe suggest that further approaches should be implemented to enhance scientific validity, reduce misunderstandings and risks, thus maximizing the benefits to society and to trial participants.
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Project description:Whether anastrozole has superior effects to tamoxifen for breast cancer remains controversial. Therefore, we conducted this meta-analysis of randomized controlled trials (RCTs) to compare the efficacy and safety of anastrozole versus tamoxifen as adjuvant therapy in breast cancer. A systematic literature search of PubMed, Web of Science, Embase, and Cochrane library were performed to evaluate the survival benefits and toxicity profiles of patients with breast cancer who were treated with anastrozole or tamoxifen. The main outcome measures included disease-free survival (DFS), recurrence-free survival (RFS), overall survival (OS), overall response rate (ORR), and adverse events. Hazard ratios (HRs) or risk ratios (RRs) with 95% confidence intervals (CIs) were pooled using a fixed-effects model or random-effects model. Nine RCTs with a total of 15,300 patients met the inclusion criteria and were included in this meta-analysis. Pooled estimates suggested that, anastrozole was associated with a significantly improvement in DFS (HR=0.72, 95%CI: 0.55-0.94; P=0.016), and ORR (RR=1.21, 95% CI: 1.05-1.39; P=0.009) than tamoxifen. But it did not prolong OS (HR=0.96, 95%CI: 0.77-1.21; P=0.751). Compared with tamoxifen, anastrozole induced a higher incidence of arthralgia (RR=1.55, 95%CI: 1.20-1.99; P=0.001) and bone pain (RR=1.31, 95%CI: 1.05-1.62; P=0.015), as well as a lower incidence of vaginal bleeding (RR=0.51, 95%CI: 0.28-0.93; P=0.029), vaginal discharge (RR=0.31, 95%CI: 0.12-0.82; P=0.017), and thromboembolic events (RR=0.39, 95%CI: 0.28-0.55; P<0.001). Based on the current evidence, patients with breast cancer would benefit from the anastrozole treatment.
| S-EPMC5564654 | biostudies-other
Project description:Basket trials have emerged as a new class of efficient approaches in oncology to evaluate a new treatment in several patient subgroups simultaneously. In this article, we extend the key ideas to disease areas outside of oncology, developing a robust Bayesian methodology for randomized, placebo-controlled basket trials with a continuous endpoint to enable borrowing of information across subtrials with similar treatment effects. After adjusting for covariates, information from a complementary subtrial can be represented into a commensurate prior for the parameter that underpins the subtrial under consideration. We propose using distributional discrepancy to characterize the commensurability between subtrials for appropriate borrowing of information through a spike-and-slab prior, which is placed on the prior precision factor. When the basket trial has at least three subtrials, commensurate priors for point-to-point borrowing are combined into a marginal predictive prior, according to the weights transformed from the pairwise discrepancy measures. In this way, only information from subtrial(s) with the most commensurate treatment effect is leveraged. The marginal predictive prior is updated to a robust posterior by the contemporary subtrial data to inform decision making. Operating characteristics of the proposed methodology are evaluated through simulations motivated by a real basket trial in chronic diseases. The proposed methodology has advantages compared to other selected Bayesian analysis models, for (i) identifying the most commensurate source of information and (ii) gauging the degree of borrowing from specific subtrials. Numerical results also suggest that our methodology can improve the precision of estimates and, potentially, the statistical power for hypothesis testing.
| S-EPMC8759447 | biostudies-literature
Project description:B cells have an ever-increasing role in the etiopathology of a number of autoimmune neurological disorders, acting as antibody-producing cells and, most importantly, as sensors, coordinators, and regulators of the immune response. B cells, among other functions, regulate the T-cell activation process through their participation in antigen presentation and production of cytokines. The availability of monoclonal antibodies or fusion proteins against B-cell surface molecules or B-cell trophic factors bestows a rational approach for treating autoimmune neurological disorders, even when T cells are the main effector cells. This review summarizes basic aspects of B-cell biology, discusses the role(s) of B cells in neurological autoimmunity, and presents anti-B-cell drugs that are either currently on the market or are expected to be available in the near future for treating neurological autoimmune disorders.
| S-EPMC4720683 | biostudies-literature