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Background RECIST criteria for progressive disease, partial response, and complete response, reflecting +20%, −30%, and −100% tumor size changes, respectively, are critical outcome variables in oncology clinical trials. Herein, we evaluated post-immunotherapy tumor size change correlation with outcomes. Methods We used a unique clinical trial data resource, a multicenter basket trial in patients with rare solid tumors treated with nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4) between 2017 and 2023 (National Cancer Institute/Southwest Oncology Group-sponsored DART trial [NCT02834013]) (open at 1083 sites at its peak). Outcome associations were evaluated by survival analysis techniques including Martingale residuals. Results In 638 evaluable patients, we found strong linear relationships between percent change in tumor measurement up to a 40%-50% increase and progression-free (PFS) and overall survival (OS) (both Cox regression P  < .001; landmark analyses based on day 65). Pearson R correlation between survival estimates and tumor change category were −0.94, −0.89, and −0.89 (PFS) and −0.84, −0.90, and −0.90 (OS) for median, 6-month (PFS), and 1-year (OS) and for 1-year (PFS) and 2-year (OS) estimates. Conclusions Percent change in tumor measurement per RECISTv1.1 (the sum of longest dimensions of target lesions) has a linear association with PFS and OS up to a 40% to 50% increase in tumor measurement in this cohort of patients with rare cancers who received combination immune checkpoint blockade. Quantitative first scan tumor measurement changes include important information to evaluate the potential efficacy of a therapy beyond the proportion of patients who achieve an objective response. [ABSTRACT FROM AUTHOR]

Novel immune therapies are increasingly based on the molecular differentiation of disease patterns. The related clinical studies are thus more often characterized by the so-called adaptive study designs (umbrella or basket studies including platform studies), which are continuously adjusted based on novel results. This paper analyses new study designs beyond the often-postulated need for regulation in order to identify ethical problems based on typical structural features and to—whenever possible—suggest solutions. To do so, it addresses the following topics: the relationship between social and scientific values of a study as well as aspects of the scientific validity of new forms of evidence; the inclusion of study subjects under the condition of relative uncertainty; specific challenges in the process of ethical approval, and ethical and practical challenges in the process of informing patients and receiving informed consent. Additionally, the topic of a potential risk–benefit assessment of such therapies is addressed. [ABSTRACT FROM AUTHOR]

The main goal is to improve treatment outcomes of disseminated inoperable thyroid cancer through a personalized choice of targeted agents. Considering gene mutations in drug choice will further improve the survival of patients with rare mutations. Despite the small sample of patients, mutation detection, regardless of localization, and basket studies will allow future results to be obtained much faster than in a dozen years and use these results in this rare category of patients. Basket studies allow patients with rare disorders to receive personalized therapy according to mutations in tumor tissue, regardless of the affected organ.

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In the modern era of targeted and immune-based therapies, investigator and patient expectations of availability and efficacy in phase I trials have increased. We assessed availability of, and benefit from, early drug development trials, specifically in patients with gastrointestinal cancers. We reviewed computerized referral records of the Early Drug Development Service at our institution to identify patients internally referred from our Gastrointestinal Oncology Service in calendar year 2018. End points were treatment on a trial, 3- and 6-month progression-free survival (PFS), and any tumor shrinkage. Of 394 gastrointestinal cancer patients referred in 2018, 54 enrolled on a trial and 53 (13.5%) were treated (1 withdrew before treatment): 34 on immune-based and 19 on targeted (3 to phase II basket) studies. None of the 52 patients who had exhausted standard therapy achieved 6-month PFS, two (3.8%) met 3-month PFS with tumor growth below Response Evaluation Criteria in Solid Tumors progression at 3 months, and both came off study for progression at 4 months. One patient who was to receive an irinotecan-based regimen as standard therapy instead received irinotecan plus an investigational targeted agent and remained stable for 8 months. No patients achieved any degree of tumor shrinkage. The most common reasons for nonaccrual were lack of available protocol treatment openings and failure to meet eligibility criteria for specific trials. Thus, availability and benefit from investigational treatment in this treatment-refractory gastrointestinal cancer patient population was extremely modest. Expectations regarding both availability and efficacy of phase I investigational therapy in gastrointestinal cancer patients likely exceed what our experience suggests. [ABSTRACT FROM AUTHOR]

Cancer is a genetic disease resulting from germline or somatic genetic aberrations. Rapid progress in the field of genomics in recent years is allowing for increased characterization and understanding of the various forms of the disease. The Ontario-wide Cancer Targeted Nucleic Acid Evaluation (OCTANE) clinical trial, open at cancer centres across Ontario, aims to increase access to genomic sequencing of tumours and to facilitate the collection of clinical data related to enrolled patients and their clinical outcomes. The study is designed to assess the clinical utility of next-generation sequencing (NGS) in cancer patient care, including enhancement of treatment options available to patients. A core aim of the study is to encourage collaboration between cancer hospitals within Ontario while also increasing international collaboration in terms of sharing the newly generated data. The single-payer provincial health care system in Ontario provides a unique opportunity to develop a province-wide registry of NGS testing and a repository of genomically characterized, clinically annotated samples. It also provides an important opportunity to use province-wide real-world data to evaluate outcomes and the cost of NGS for patients with advanced cancer. The octane study is attempting to translate knowledge to help deliver precision oncology in a Canadian environment. In this article, we discuss the background to the study and its implementation, current status, and future directions. [ABSTRACT FROM AUTHOR]

The author comments on the implications of tumour profiling on the salivary gland cancer clinical trials in Great Britain. The topics discussed include the resistance of adenoid cystic carcinoma to different cytotoxic chemotherapy agents, cancers' molecular sub-classification, and advances in molecular profling.

Early successes in identifying and targeting individual oncogenic drivers, together with the increasing feasibility of sequencing tumor genomes, have brought forth the promise of genome-driven oncology care. As we expand the breadth and depth of genomic analyses, the biological and clinical complexity of its implementation will be unparalleled. Challenges include target credentialing and validation, implementing drug combinations, clinical trial designs, targeting tumor heterogeneity, and deploying technologies beyond DNA sequencing, among others. We review how contemporary approaches are tackling these challenges and will ultimately serve as an engine for biological discovery and increase our insight into cancer and its treatment. [ABSTRACT FROM AUTHOR]

Novel immune therapies are more and more based on the molecular differentiation of disease patterns and related clinical studies are thus more often characterized by so-called adaptive study designs (umbrella or basket studies including platform studies), which are continuously adjusted based on novel results. This paper analyses new study designs beyond the often-postulated need for regulation in order to identify ethical problems based on typical structural features and to - whenever possible - suggest solutions. Additionally to the relationship between social and scientific values of a study as well as aspects of the scientific validity of new forms of evidence, the inclusion of study subjects under the condition of relative uncertainty, specific challenges in the process of ethical approval, as well as ethical and practical challenges in the process of informing patients and receiving informed consent will be addressed.

Background Precision oncology, guided by high-resolution molecular diagnostics, refers to the ability to identify patients that are likely to respond to specific anticancer therapies. Although recent studies demonstrated the utility of comprehensive molecular profiling based on whole-exome/genome sequencing and transcriptome sequencing to guide therapeutic decisions in individual patients, many questions remain unanswered. Methods We report the clinical results of MASTER, a multicenter, cross-entity registry trial for prospective, biology-driven stratification of younger adults with advanced-stage cancer and patients with rare tumors conducted by NCT Heidelberg/Dresden and the German Cancer Consortium. From 2013 to 2018, we discussed the molecular profiles from 1,311 poor-prognosis patients in a cross-institutional molecular tumor board. Results Evaluation of the data based on a standardized bioinformatics workflow and manual curation by a team of translational oncologists allowed categorization into 7 intervention baskets and formulation of evidence-based recommendations for clinical management in more than 80% of patients, which could be acted upon in approximately one third of cases. Overall response and disease control rates on molecularly guided treatment were improved compared to prior systemic therapies, which translated into a progression-free survival ratio of greater than 1.3 in more than 30% of cases. Comprehensive genomic profiling also provided relevant diagnostic information that led to categorization of some tumors based on genotype and subsequent histopathologic reevaluation. Conclusions Our experience demonstrates that comprehensive molecular profiling in a multi-institutional clinical setting is feasible, complements and advances routine molecular diagnostics, and creates clinically meaningful therapeutic opportunities. Current and future initiatives of the MASTER network are focused on the standardization of variant classification and evidence levels in molecular tumor boards; the implementation of molecularly stratified basket trials; and the integration of additional layers of patient characterization. Legal entity responsible for the study The authors. Funding German Cancer Consortium, Heidelberg Institute for Personalized Oncology. Disclosure W. Weichert: Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): MSD; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): BMS; Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Merck; Advisory / Consultancy, Speaker Bureau / Expert testimony: Lilly; Advisory / Consultancy, Speaker Bureau / Expert testimony: Boehringer Ingelheim; Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Advisory / Consultancy, Speaker Bureau / Expert testimony: Takeda; Research grant / Funding (self): Bruker. All other authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]

A basket trial in oncology enrolls patient populations with a specific molecular status among several cancer types and often evaluates the treatment effect of an investigational agent across cancer types. MASTER KEY Project that is a platform trial with a registry study for rare cancers established by National Cancer Center Hospital in Japan includes several single-arm basket trials for rare cancers to evaluate the response rate of the targeted agents across the cancer types of interest. Novel cancer drugs for rare cancers have been occasionally approved with evidence from a single pivotal trial alone in Japan. Applicants consider to propose new drug application (NDA) based solely on the result of one pivotal basket trial; however, the difficulty lies the in the statistical evaluation of response rate across cancer types because of the limited sample size of basket trials. In this presentation, the recent advance of statistical methodologies for basket trials is overviewed and regulatory challenges we face in Japan are also introduced as well as the accelerated review system. [ABSTRACT FROM AUTHOR]