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Introduction
More than a decade has passed since the University of Texas MD Anderson Cancer Center (MDACC) conducted the novel phase II Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) program of personalized medicine from 2006 to 2009. The BATTLE was the first completed prospective, biomarker-driven, adaptively randomized study in heavily pretreated patients with non–small cell lung cancer (NSCLC) [1]. Since then, better understanding and expanded knowledge in tumor biology and biomarkers together with the advancement of diagnostic technology, including next-generation sequencing (NGS), have been driving the “one-size-fits-all” rationale of cancer treatments toward more personalized or tailored therapies according to the unique tumor molecular profile. The rise of novel clinical trial designs that aim to identify biomarker-matched subgroups of patients that would benefit the most from targeted agents accompanied the introduction of precision medicine in oncology [2].
Wider implementation of biomarker(s) in clinical trials has fueled the evolvement of an adaptive design, which allows prospectively planned modifications to one or more aspects of the design based on accumulating data from subjects in the trial [3]. The term master protocol is frequently used to describe such trials implementing an adaptive design, with various terms, such as umbrella, basket, or platform, describing specific designs [4]. The novel clinical trial designs, such as umbrella, basket, and platform trials, were initially commenced by cancer centers and/or research centers, such as MDACC, and quickly gained traction with government, academia, and pharmaceutical companies. Several investigator-initiated precision oncology clinical trials (IIPOCTs) have been undertaken from 2010 to 2016 under the leadership of the National Cancer Institute (NCI) (e.g., NCI-Molecular Analysis for Therapy Choice [MATCH] and NCI-Molecular Profiling-based Assignment of Cancer Therapy for Patients with Advanced Solid Tumor [MPACT] trials) or NCI-supported clinical trials group (e.g., A Biomarker-driven Master Protocol for Previously Treated Squamous Cell Lung Cancer [Lung-MAP] study conducted by Southwest Cancer Chemotherapy Study Group [SWOG]), American Society of Clinical Oncology (ASCO) (e.g., Targeted Agent and Profiling Utilization Registry [TAPUR]), the Netherlands Cancer Institute (e.g., The Drug Rediscovery Protocol [DRUP]), and European Organisation for Research and Treatment (EORTC) (e.g., Cross-tumoral phase 2 clinical trial exploring crizotinib in patients with advanced tumors induced by causal alterations of ALK and/or MET [CREATE]).
The innovative clinical trials were designed to assess the efficacy and safety of anticancer agent(s) in more efficient and faster ways [1]. They helped the investigators evaluate a single investigational drug and/or their combination in different populations defined by different cancers, disease stages for specific cancers, histology, number of previous therapies, genetic or other biomarkers, or demographic characteristics (i.e., basket trial) or evaluate multiple investigational drugs administered as single drugs or as their combination in single disease population (i.e., umbrella trial). The Platform trial is a clinical study that is designed to evaluate multiple investigational drugs and/or drug combination regimens across multiple tumor types [4].
Regulatory authorities, such as the United States Food and Drug Administration (U.S. FDA) have published guidelines regarding precision oncology clinical trials (POCTs) alongside this advancement [3,4]. IIPOCTs have been quickly translated into sponsor-initiated precision oncology clinical trials (SIPOCTs), which were conducted to gain regulatory approval for a new anticancer agent in less time with a smaller number of patients.
Early POCTs reported rather disappointing results and thus did not result in any regulatory approval, but trials have been conducted more recently yielded positive results and become the basis of regulatory approvals, frequently through accelerated pathways. Thus, we aimed to systematically review and analyze the efficacy and safety profile of POCTs as well as their infrastructure with funding sources, other operational statuses, and requirements.
Materials and Methods
We conducted a systematic literature search and analysis of selected precision oncology trials with phase II, biomarker-driven, adaptive design following standards for Meta-analysis Of Observational Studies in Epidemiology [5] and Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines [6]. Our systematic review protocol is registered at PROSPERO (ID: 502799) and the EQUATOR checklist for the systematic review is provided in S1 Table.
1. Literature search and study selection
We searched the EMBASE and PubMed from January 2015 to March 2023 using prespecified keywords related to POCTs (S2 and S3 Tables). Two teams of paired reviewers independently screened titles and abstracts for eligibility and listed the articles for exclusion and inclusion. To ensure consistency and minimize individual bias, each team cross-reviewed the titles and abstracts reviewed by the other team, and every sub-trial/arm was assessed by reading all relevant literature. Reviewers resolved disagreements and reached a consensus through discussion meetings. We individually reviewed the full text of selected articles as well as the master protocol/trial of these articles to select eligible clinical trials for further analysis after confirming the articles for inclusion.
Pairs of reviewers independently extracted data on efficacy, safety, and clinical trial infrastructure from each eligible study using a standardized form and a detailed instruction manual. We captured all patient-important clinical outcomes, as guided by the initiative on response evaluation and toxicity assessment in clinical trials (S4 Table).
Moreover, we searched the ClinicalTrials.gov registry to identify ongoing POCTs and manually added eligible studies that were not selected through EMBASE or PubMed searches (S5 Table).
2. Eligibility criteria
We selected clinical studies corresponding to an adaptive, biomarker-driven, phase II clinical study per PICOS criteria (S6 Table) and by further applying the exclusion conditions described below in order. We excluded retracted or duplicate articles and articles in languages other than English before the outset of the review.
We commenced the extraction of articles based on exclusion criteria predefined by researchers after pre-screening as follows: (1) noncancer disease and non-human studies; (2) nonintervention clinical studies, including music therapy, psychological treatment, behavioral therapy, cognitive therapy, etc., survey or online-based opinion gathering of patients with cancer, and clinical study design; (3) intervention trials but noncancer drug studies, including diagnostics (positron emission tomography–computed tomography [CT] scan, CT scan, and magnetic resonance imaging, etc.), screening, surgery, radiation therapy, photodynamic therapy, digital therapeutics, chemoprevention, etc.; (4) preclinical studies, including in vitro cell line and/or in vivo animal studies; (5) editorials, letters to the editor, news in brief, and comments; (6) case reports, case series, cross-sectional studies, review articles, systematic reviews, meta-analysis, cost-effectiveness analysis, pooled analysis, secondary analysis, and post-hoc analysis; (7) biomarker study, including retrospective biomarker analysis, correlative biomarker analysis and imaging biomarker study, genetic analysis, quality of life (QoL) assessment, management of adverse events (AEs) by oncologic drugs, and pharmacokinetics/pharmacodynamics study, mode of action or proof-of-concept study; (8) proposal of clinical study protocol alone with no clinical outcomes; (9) clinical study, excluding an adaptive design or master protocol; (10) phase I or III clinical study with adaptive, biomarker-driven master protocol design.
3. Categorization of POCTs
We selected adaptive, biomarker-driven, phase Ib/II or II clinical trials with basket, umbrella, and/or platform designs that explored the efficacy and safety of anticancer treatment for patients with cancer. We excluded phase Ia and III clinical trials because phase Ia is a dose-finding study, which makes efficacy identification difficult, and phase III is a confirmatory clinical study, making it unsuitable for analyzing the characteristics of adaptive design. We classified POCTs following the definitions of the master protocol described in the recent guidelines on the clinical development of oncology drugs provided by the U.S. FDA (S4 Table) [3,4].
Results
Duplicated, retracted, and non-English articles were excluded through the pre-screening process of 6,303 initially searched articles from PubMed and EMBASE. With the review of all the titles and abstracts of 5,902 prescreened articles according to the prespecified eligibility criteria, 73 articles were selected to meet the criteria of biomarker-driven, adaptive phase II POCTs (Fig. 1, Supplementary Material 1, S2 and S3 Tables). We thoroughly investigated the full text of the 73 articles with their master protocols and then, finalized the list of 29 POCTs for final inclusion in this study. Data collected regarding the infrastructure, biomarker screening, clinical efficacy, and safety profile of these 29 trials were put into a standardized format (S4 Table).
1. Infrastructure
Of the 29 POCTs, 17 were investigator initiated trials (IIT), including nine basket, six umbrella, and two platform trials, and 12 were sponsor-initiated trials (SIT). They were mainly domestic and multicenter trials. AcSé-eSMART [7-9] and CREATE [10-13] were Pan-European multicenter trials while Lung-MAP [14-24] and NCI-MATCH trilas [25-30] were multicenter trials led by NCI in the United States. Governmental agencies, cancer hospitals, academic societies, and non-profit research organizations conducted these trials. They were the institutions that had accumulated substantial experience from a variety of large-scale multicenter clinical trials over a long period. Most of all IITs were conducted with research funding from multiple sources, including additional support or drugs provided by pharmaceutical companies, as well as governmental and non-governmental organizations, except for three studies with a single research funding source (NCI-MATCH [25-30], NCI-MPACT [31], and ASCO-TAPUR [32-39]). Research funds were not disclosed in almost all clinical trials, thereby determining the size of research funds was impossible, but research funds were partially disclosed in the case of AcSé-eSMART [7-9] (Table 1).
All SIPOCTs led by several different pharmaceutical companies adopt basket design except for the Blood First Assay Screening Trial (BFAST) which was with umbrella design for patients with NSCLC [40,41]. They were international, multicenter clinical studies, except for an “Open-Label Phase IIa Study Evaluating Trastuzumab/Pertuzumab, Erlotinib, Vemurafenib/Cobimetinib, Vismodegib, Alectinib, and Atezolizumab in Patients Who Have Advanced Solid Tumors with Mutations or Gene Expression Abnormalities Predictive of Response to One of These Agents (MyPathway)”, which was led by Genentech as a multicenter trial in the United States [42-45].
Research and development expenses of the study sponsor, except a “Phase 1/2, Open-label Study Evaluating the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Efficacy of Sotorasib Monotherapy in Subjects With Advanced Solid Tumors With KRAS p.G12C Mutation and Sotorasib Combination Therapy in Subjects With Advanced NSCLC With KRAS p.G12C Mutation (CodeBreaK 100)” [46-48] and a “Study to Test the Effect of the Drug Larotrectinib in Adults and Children With NTRK-fusion Positive Solid Tumors (NAVIGATE)” [49-54], were used to conducted SIPOCTs. Several research grants, as well as the study sponsor, Amgen, supported the study sites for the CodeBreaK 100 study [46-48]. The NAVIGATE study was cofunded by the original developer, LOXO Oncology and Bayer, which obtained full rights to the global development and commercialization of larotrectinib (Table 2) [49-54].
2. Biomarker screening
Most of the POCTs (23/29) selected NGS as either a single screening method or one of multiple screening methods, and immunohistochemistry (IHC) was the most frequently used screening tool together with NGS. A Phase 2 Study of IMGN901 in Children With Relapsed or Refractory Wilms Tumor, Rhabdomyosarcoma, Neuroblastoma, Pleuropulmonary Blastoma, Malignant Peripheral Nerve Sheath Tumor and Synovial Sarcoma (ADVL1522) [55] and a Phase I/II Study of Pembrolizumab in Children With Advanced Melanoma or a PD-L1 Positive Advanced, Relapsed or Refractory Solid Tumor or Lymphoma (KEYNOTE-051) [56] used IHC, while CREATE [10-13] and Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging and Molecular Analysis 2 (I-SPY2) [57-63] utilized IHC along with fluorescence in situ hybridization (FISH) for biomarker screening. MyPathway [42-45] and Small cell lung cancer Umbrella Korea StudiES (SUKSES) [64] used other screening methods besides IHC and FISH. The ongoing DRUP study in the Netherlands [65-67] uses whole genome sequencing (WGS) as a screening method, whereas the AcSé-eSMART [7-9], MyPathway [42-45], and an Open-Label, Phase 2 Basket Study of Neratinib in Patients With Solid Tumors With Somatic Activating HER Mutation (SUMMIT) [68-71] have utilized WGS and/or whole exome sequencing along with the NGS as the main screening method.
The majority of POCTs screened the biomarker(s) with both tissue and blood samples collected from the study participants at a central or local laboratory. Additionally, the test results obtained from the local laboratory were centrally reviewed if described in the protocol. Table 3 summarizes the information on biomarker screening.
3. Independent central review committee, study endpoints, and evaluation criteria
Of the 29 studies, 15 (51.7%) clearly stated the existence of an independent central review committee (ICRC) in published papers or protocols to review the efficacy assessment to enhance reliability by securing objectivity. The ADVL1522 [55] and I-SPY2 [57-63] implemented a central review system to carefully examine specific cases, such as long-lasting stable disease, uncertain outcomes, etc. The primary endpoint in most studies (25/29) included objective response rate (ORR), excluding a “Randomized, Proof-of-concept, Phase II Trial Comparing Therapy Based on Tumor Molecular Profiling Versus Conventional Therapy in Patients with Refractory Cancer (SHIVA) (progression-free survival [PFS])” [72], Molecular selection of therapy in colorectal cancer (FOCUS4) (PFS) [73-76], I-SPY2 (pathologic complete response [pCR]) [57-63], and DRUP (clinical benefit rate [CBR]) [65-67]. Since I-SPY2 [57-63] was a phase II platform trial to assess investigational therapies in combination with standard chemotherapy as a preoperative neoadjuvant setting in patients at high risk of breast cancer, pCR was used as the primary endpoint defined as the absence of tumor cells in surgical specimens [57-63]. The DRUP [65-67], National Lung Matrix Trial [77,78], and TAPUR [32-39] studies measured CBR, durable clinical benefit rate, and disease control rate as either primary or co-primary endpoints. Meanwhile, ADVL1522 [55], ARROW [79-81], and DRUP [65-67] included toxicity profiles as the co-primary endpoint. Most studies considered survival outcomes, including PFS, duration of response, time to progression, and overall survival as well as toxicity and QoL, as secondary endpoints. Some studies measured relapse-free survival and pharmacokinetics parameters depending on the study characteristics such as objective, target disease, or experimental drug. ORR was selected as a primary endpoint in most studies, thus anticancer efficacy was assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria (ver. 1.1), and response assessment in neuro-oncology (RANO) was used together with RECIST v1.1 in AcSé-eSMART [7-9], ARROW [79-81], LIBRETTO-001 [82-86], and ROAR [87-93] depending on study objectives. Table 4 summarizes the information on the efficacy of the 29 POCTs.
4. Efficacy results and FDA approval
The ORR, which is a major endpoint for clinical efficacy, demonstrated widely varying results (0%-100%) from study to study, and 22 studies reported partially or completely meeting the primary endpoint (Table 4). Among those studies, 9, including ARROW [81], CodeBreaK 100 (NSCLC arm) [48], KEYNOTE-051 [56], LIBRETTO-001 [82-86], NAVIGATE [49-54], NCI-MATCH (subprotocol H) [28], ROAR [87-93], STARTRK-2 [94-97], and VE-BASKET (Erdheim-Chester disease [ECD] cohort) [98], provided the clinical evidence for the U.S. FDA to approve marketing authorization (Tables 4 and 5). Praseltinib and sotorasib received accelerated approvals from the U.S. FDA and are currently in use for RET fusion–positive and KRAS G12C mutation–positive NSCLC, respectively, based on the results of ARROW [81] and CodeBreaK 100 [48]. The U.S. FDA granted regular approval for praseltinib based on additional follow-up data with more patients, and the randomized phase III clinical study, which was a prerequisite for accelerated approval, is currently underway for sotorasib. The ROAR (BRAF V600E mutant solid tumors) [87,89-93] and VE-BASKET (ECD) [98] obtained accelerated and regular approval from the U.S. FDA, respectively, based on the results of the expansion cohort without a confirmative phase III study due to the rarity of the subject tumor. The results of the NCI-MATCH (subprotocol H) study [28], conducted as an IIT, were used together with the ROAR study [87-93] as the clinical evidence for obtaining the accelerated approval of dabrafenib in combination with trametinib in BRAF V600E mutation–positive solid tumors from the U.S. FDA. Table 5 summarizes the POCTs that received either accelerated or regular (full) approvals from the U.S. FDA.
5. Safety and QoL
We revealed a description of the preplanned safety monitoring in all the protocols of the clinical trials we analyzed. Overall, AEs that occurred during the period of clinical study were reported with detailed safety results in the body of the paper or the supplement, but the reporting format varied among individual clinical trials. “Treatment-related adverse event” was the most prominently mentioned item, but terms, such as “AEs”, “treatment-emergent AEs (TEAEs)” and “event (counts)” were used without uniformity, making it difficult to impart objectivity. Further, we investigated whether new safety signals were captured when subsequent phase III clinical trials were conducted or if more patients were added to the expansion cohorts. Two studies included the expansion cohorts and the other two studies conducted phase III clinical trials, but no new safety signals were reported in these four clinical studies. The data collection plan on health-related QoL (HRQoL) was described in the protocols of 7 POCTs (ARROW [79-81], CodeBreaK 100 [46-48], LIBRETTO-001 [82-86], SUMMIT [68-71], BFAST [40,41], FOCUS4 [73-76], and I-SPY2 [57-63]), and the patient-reported outcome (PRO) data, defined in terms, including post-treatment new symptoms and toxicities, separately from HRQoL, were collected in two studies (LIBRETTO-001 [82-86] and BFAST [40,41]). The HRQoL results were published in the papers in three out of eight studies described in the protocol, and BFAST [40,41] was the only study that included PRO results in the paper. Table 6 summarizes safety-related information.
Discussion
This study reviewed and analyzed phase II, biomarker-driven, adaptive design precision oncology trials, especially from the perspective of infrastructure, efficacy, and safety points.
Our analysis demonstrates that governmental agencies and/or academia/cancer clinical study groups have taken a leading role in the initiation of POCTs since the early 2010s in the form of IIT with the support of experimental drugs from pharmaceutical companies. These IIPOCTs were created based on consensus and understanding of the roles and responsibilities of each participating organization, with the common goal of providing better treatment options, especially for patients with cancer who have suffered from rare tumor types or have been heavily treated with many available and/or standard treatments. Most of these IIPOCTs have been multicenter studies led by research institutes/cancer centers/clinical study groups that have accumulated experience from many clinical trials over a long period and are supported by various funding sources. The most representative case was the NCI-MATCH study [46-48], which was led by NCI with over 1,400 participating centers across the United States [25-30].
Earlier IIPOCTs had been conducted for the heavily treated patients with no available treatment options, thereby demonstrating rather discouraging outcomes as observed in Lung-MAP [14-24], NCI-MPACT [31], and SHIVA [72]. However, recent precision clinical studies are increasingly moving toward treating patients with treatment-naïve, advanced cancer, or locally advanced cancer requiring neoadjuvant treatment, revealing more positive results than previously performed IIPOCTs.
Substantial experiences from IIPOCTs have been accumulated with meaningful results, either positive or negative, thus they were gradually translated into SIPOCTs, with many of them following the Industry Guidance by the U.S. FDA [4]. The SIPOCTs that were reviewed in this pooled analysis mostly used the basket design and were conducted as international multicenter clinical trials. Most of all drug approvals by the U.S. FDA reviewed in this study are based on the results from SIPOCTs using biomarker-driven adaptive design. This reveals that the pharmaceutical companies that led SIPOCTs aimed to achieve faster marketing authorization of novel anticancer drug(s) from the regulatory agency (frequently through accelerated approval) with as few biomarker-matched patients as possible in a certain rare tumor or tumor agonistic indication with a prominent molecular biomarker.
This analysis revealed that IIPOCTs substantially accepted central screening rather than biomarker screening results that are locally performed at each participating institute. The IIPOCTs in Europe (e.g., AcSé-eSMART [7-9], CREATE [10-13]) were frequently conducted as a pan-European multicenter study with no boundaries between countries, especially in terms of clinical trial infrastructure such as screening laboratories and review committees (i.e., molecular tumor board). In particular, AcSé-eSMART [7-9], led by Goustave Roussy in Paris, France, participated with seven cancer centers across six European countries and accepted biomarker screening results performed at 28 molecular genetic centers designated by the French NCI (Institut National du Cancer, INCa) [7-9]. The relevant Clinical Tumor Board of European molecular profiling programs (i.e., MAPPYACTS, INFORM, SM-PAEDS, iTHER, etc.) and the steering committee reviewed the screening results.
Conversely, SIPOCTs seemed to accept both central and local biomarker screening results. This may be because pharmaceutical companies, as sponsors, conducted POCTs, as they traditionally conducted international multicenter SITs through clinical research organizations, including biomarker-related vendors. SIPOCTs use central and local screening for different purposes. In particular, the sponsor in CodeBreaK 100 [46-48] and its subsequent phase III study, CodeBreaK 200 [99], accepts local screening results, which is essential for trial participation/eligibility, and concurrently, conducts central screening for additional biomarker testing for exploratory biomarker studies. Some SIPOCTs (e.g., LIBRETTO-001 [82-86], ROAR [87-93], STARTRK-2 [94-97], VE-BASKET [98,100,101]) are designed to accept local screening results initially, but to be reviewed centrally and then finally approved for study participation. This may be because molecular biomarker is considered an important element for new drug approval as its companion diagnostic.
Most of our reviewed phase II biomarker-driven, adaptive clinical trials adopted ORR as their primary endpoint [102]. This may be because ORR is a surrogate endpoint that can evaluate the efficacy of anticancer drugs in a short period, and can also represent survival time, but sometimes it does not match survival outcomes [103]. Meanwhile, all clinical studies that adopted ORR as the primary endpoint used RECIST criteria for response assessment, but some studies utilized the evaluation criteria, such as RANO, International Myeloma Working Group criteria, Immune-related Response Evaluation Criteria In Solid Tumors, International Neuroblastoma Response Criteria, etc., together with RECIST criteria according to the type of tumor or biomarker that was the target of the study. POCTs aimed to assess the efficacy of new treatment options, especially in rare types of tumors, and interestingly, the DRUP [65-67] and TAPUR studies [32-39] clearly stated their goal to extend the already approved indications of anticancer drugs (i.e., off-label use). Providing better treatment options for patients with advanced cancer with no available treatment options through rapid regulatory approval is the greatest benefit of POCTs [103]. With POCTs, eight out of nine anticancer drugs approved by the U.S. FDA have received “accelerated approval” for specific indications or drugs [104]. This number is expected to further increase in the near future, as many pharmaceutical companies are increasingly inclined to implement biomarker-driven adaptive design to gain faster marketing authorization from regulatory agencies.
All the POCTs in this study had regular and special safety monitoring plans regarding the safety of investigational drugs, and the detailed plans were described in the study protocol. AEs that occurred during the clinical trial period were graded by the most widely used NCI–Common Terminology Criteria for Adverse Events [105]. However, objectively summarizing them in the table was impossible because the “terms” or “indicators” expressing the degree of toxicity differed from trial to trial and were not unified. The toxicity profile for some clinical studies was not properly reported in the published papers or their supplements. This situation may be because study investigators tend to prioritize the clinical efficacy over the safety of an investigational drug or that “terms” or “indicators” expressing the degree of toxicity currently in use do not adequately reflect the actual patient condition. The term “laboratory abnormality only” was used to report the toxicity profile in some studies. This indicates the need for improving the description of the safety outcomes in a more appropriate and a more reliable method.
The importance of how much toxicities affect patients’ QoL is increasingly appreciated in recent clinical trials along with the toxicity profile of an investigational drug. Accordingly, the use of HRQoL and PRO has been significantly increased in line with the publication of their respective guidelines [106,107]. HRQoL is a tool that measures the subject’s self-perceived health status, whereas PRO is a more comprehensive concept, including symptoms, function, HRQoL, and the subject’s treatment perception and satisfaction. PROs containing HRQoL are being accepted as evidence for the U.S. FDA’s approval for anti-inflammatory, gastrointestinal, and allergic drugs [108-110]. A published systematic review on HRQoL or PRO, as a primary endpoint in phase I and I/II clinical trials, indicated the complementary role of HRQoL for traditional toxicity assessment in oncology clinical trials [110].
The current study included HRQoL measurements in seven study protocols (24.1%) and PROs in two studies among 29 POCTs (Table 6). Of these studies, only FOCUS4 reported the HRQoL results [73]. The following possibly explains this: many participants in these phase II studies may not be suitable for QoL assessment because they had multiple lines of treatments with relatively poor conditions, and obtaining sufficient feedback on the QoL questionnaire may be difficult because the treatment duration was relatively short, and sub-studies were frequently closed early due to insufficient efficacy of an experimental drug.
Debate remains ongoing among healthcare professionals about which assessment tools, HRQoL, PRO, or other tools, are most effective in measuring the QoL for patients with cancer receiving anticancer treatments. Additionally, no universally accepted tool is currently available for clinicians to evaluate a patient’s QoL, therefore requiring an ongoing discussion and consensus on this matter.
However, with the rise of HRQoL and PRO as novel evaluation tools in recent clinical trials, which prioritize the patient’s perspective, an increasing number of upcoming trials are anticipated to incorporate either of these as a fundamental outcome in the future.
During the independent review process, we did our best to resolve disagreements among reviewers through multiple meetings whenever necessary. However, this study has several limitations. It was difficult to objectively summarize their frequencies because each study had different way of expressing adverse drug reactions. In addition, some subclinical studies have already been completed, but the reasons for termination and study results could not be confirmed because published paper or oral presentation was not available.
In conclusion, a biomarker-driven, adaptive clinical trial is an effective design to evaluate the efficacy of an anticancer drug, especially in rare and infrequent tumor types. Additionally, not only close collaboration between the stakeholders, such as clinical researchers, pharmaceutical companies, and regulatory agencies but also the infrastructure and research funds, are the key elements of the successful POCT.
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