Precision Oncology Clinical Trials: A Systematic Review of Phase II Clinical Trials with Biomarker-Driven, Adaptive Design

Article information

Cancer Res Treat. 2024;56(4):991-1013
Publication date (electronic) : 2024 May 7
doi : https://doi.org/10.4143/crt.2024.128
1Department of Internal Medicine, Inha University Hospital, Inha University College of Medicine, Incheon, Korea
2Department of Internal Medicine, Yeouido St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
3Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
4Department of Internal Medicine, Dongguk University Ilsan Hospital, Goyang, Korea
5Division of Oncology, Department of Internal Medicine, St. Vincent’s Hospital, College of Medicine, The Catholic University of Korea, Suwon, Korea
6College of Pharmacy, Ewha Womans University, Seoul, Korea
7Division of Medical Oncology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
Correspondence: Hye-sung Park, Division of Medical Oncology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul 06591, Korea Tel: 82-2-2258-6043 Fax: 82-2-594-6043 E-mail: hye_sung_park@naver.com
Co-correspondence: Jin Hyoung Kang, Division of Medical Oncology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul 06591, Korea Tel: 82-2-2258-6043 Fax: 82-2-594-6043 E-mail: oncologykang@naver.com
*Hyerim Ha and Hee Yeon Lee contributed equally to this work.
Received 2024 February 5; Accepted 2024 April 29.

Abstract

Novel clinical trial designs are conducted in the precision medicine era. This study aimed to evaluate biomarker-driven, adaptive phase II trials in precision oncology, focusing on infrastructure, efficacy, and safety. We systematically reviewed and analyzed the target studies. EMBASE and PubMed searches from 2015 to 2023 generated 29 eligible trials. Data extraction included infrastructure, biomarker screening methodologies, efficacy, and safety profiles. Government agencies, cancer hospitals, and academic societies with accumulated experiences led investigator-initiated precision oncology clinical trials (IIPOCTs), which later guided sponsor-initiated precision oncology clinical trials (SIPOCTs). Most SIPOCTs were international studies with basket design. IIPOCTs primarily used the central laboratory for biomarker screening, but SIPOCTs used both central and local laboratories. Most of the studies adapted next-generation sequencing and/or immunohistochemistry for biomarker screening. Fifteen studies included an independent central review committee for outcome investigation. Efficacy assessments predominantly featured objective response rate as the primary endpoint, with varying results. Nine eligible studies contributed to the United States Food and Drug Administration’s marketing authorization. Safety monitoring was rigorous, but reporting formats lacked uniformity. Health-related quality of life and patient-reported outcomes were described in some protocols but rarely reported. Our results reveal that precision oncology trials with adaptive design rapidly and efficiently evaluate anticancer drugs’ efficacy and safety, particularly in specified biomarker-driven cohorts. The evolution from IIPOCT to SIPOCT has facilitated fast regulatory approval, providing valuable insights into the precision oncology landscape.

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.

The PRISMA diagram for the systematic reviews of precision oncology trials is provided in Fig. 1, and a complete list of articles/studies that are either included or excluded is provided in S7 Table with the reason for inclusion/exclusion.

Fig. 1.

The PRISMA diagram for systematic review of precision oncology clinical trials.

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).

Summary of infrastructure: investigator-initiated precision oncology trials

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].

Summary of infrastructure: sponsor-initiated precision oncology trials

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.

Summary of biomarker screening in precision oncology trials

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.

Summary of efficacy outcomes in precision oncology trials

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.

Precision oncology trials led to the FDA approval

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.

Summary of safety outcomes in precision oncology trials

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.

Notes

Ethical Statement

This study was approved by the Institutional Review Board (IRB) of Seoul St. Mary’s Hospital Catholic University of Korea (IRB No. KC22ENSE0441) and was conducted in accordance with the Declaration of Helsinki. Since this was a systematic review and meta-analysis, the need for informed consent was waived by the IRB.

Author Contributions

Conceived and designed the analysis: Ha H, Kim JH, Kim DY, An HJ, Park HS, Kang JH.

Collected the data: Ha H, Lee HY, Park HS, Kang JH.

Contributed data or analysis tools: Ha H, Lee HY, Kim JH, Bae S, Park HS, Kang JH.

Performed the analysis: Ha H, Lee HY, Bae S, Park HS.

Wrote the paper: Ha H, Lee HY, Kim JH, Kim DY, An HJ, Bae S, Park H, Kang JH.

Provision of study materials: Ha H, Lee HY, Kim DY, An HJ, Park HS.

Conflict of Interest

Conflict of interest relevant to this article was not reported.

Acknowledgements

This research was supported by a grant (22212MFDS261) from Ministry of Food and Drug Safety in 2022-2023. The authors want to thank Hi-sun Kim and Ju-Hye Kang (Ministry of Food and Drug Safety) for the study concept development and initiation, and Maehwa Yang and Jiyeon Kim (Korean Cancer Study Group) for their administrative support throughout this research.

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Article information Continued

Fig. 1.

The PRISMA diagram for systematic review of precision oncology clinical trials.

Table 1.

Summary of infrastructure: investigator-initiated precision oncology trials

Study title Study type Sponsor Study sites No. of sites Funding source
Type Details
Ado-Trastuzumab Emtansine Basket Trial Basket Cancer hospital MSKCC (USA) Domestic, single-institution/multicenter 7 Multiple Conquer Cancer Foundation
Genentech
Comprehensive Cancer Center Core Grant No. P30 CA008748 at MSKCC from the NIH
ADVL1522 Basket Cancer clinical trials group Children’s Oncology Group (USA) Domestic, multicenter 69 Multiple NCTN Operations Center Grant (U10CA180886)
NCTN Statistics & Data Center (U10CA180899)
The St. Baldrick’s Foundation
P30 CA015083
CREATE Basket Non-profit research org. EORTC (EU) International (Pan-European), multicenter 25 Multiple EORTC (Educational grant)
Supported by Pfizer as an IIT
DRUP Basket Cancer hospital Netherlands Cancer Institute Domestic, multicenter 35 Multiple Barcode for Life Foundation; Dutch Cancer Society (grant number 10014); and all participating pharmaceutical companies
NCI-MATCH Basket Governmental agency NCI (USA) International, multicenter 1,443 Single NCI
NCI-MPACT Basket Governmental agency NCI (USA) Domestic, multicenter 8 Single NCI
OLAPCO Basket Academia Yale Univ. (USA) Domestic, multicenter 4 Multiple AstraZeneca
Dana-Farber/Harvard Cancer Center Specialized Program of Research Excellence (SPORE) in Ovarian Cancer
NIH grant P50 CA240243 to G.I.S.
SHIVA Basket Non-profit research org. Institut Curie (FR) Domestic, multicenter 8 Multiple Institut Curie; grant ANR-10-EQPX-03 from the ANR (Investissements d’avenir) and SiRIC
High-throughput sequencing at the Institut Curie supported by grants ANR-10-EQPX-03 and ANR-10-INBS-09-08 from the ANR (investissements d’avenir) and the Canceropôle Ile-de-France
TAPUR Basket Academic society ASCO (USA) Domestic, multicenter 144 Single ASCO
FOCUS4 Umbrella Academia MRC CTU at Univ. College London (UK) Domestic, multicenter 88 Multiple Jointly funded by MRC/NIHR Efficacy and Mechanism Evaluation (EME) programme and CRUK
Additional funding and support provided by collaborating pharmaceutical companies
FUTURE Umbrella Academia Fudan University Domestic, single-center (China) 1 Multiple Hengrui Medicine Co., Ltd. (Lianyungang, China)
The National Natural Science Foundation of China (81922048, 81874112, 81874113 and 91959207)
The Fok Ying-Tong Education Foundation for College Young Teachers (171034)
The Training Plan of Excellent Talents in Shanghai Municipality Health System (2017YQ038)
The “Chen Guang” project supported by Shanghai
Municipal Education Commission, and Shanghai Education Development Foundation (17CG01), Shanghai Pujiang Program (18PJD007)
The Training Plan of Excellent Talents of Fudan University Shanghai Cancer Center (YJYQ201602)
The Municipal Project for Developing Emerging, and Frontier Technology in Shanghai Hospitals (SHDC12010116)
The Cooperation Project of Conquering Major Diseases in Shanghai Municipality Health System (2013ZYJB0302)
The Innovation Team of Ministry of Education (IRT1223)
The Shanghai Key Laboratory of Breast Cancer (12DZ2260100)
The Shanghai 3-year Action Plan for Traditional Chinese Medicine (ZY[2018-2020]-CCCX-2005-04)
Lung-MAP Umbrella Cancer clinical trials group SWOG (USA) International (North America), multicenter 1,004 Multiple NIH/NCI grants CA180888, CA180819, CA180820, CA180821, CA180868, CA189971, CA189821, CA189830, CA189858, CA189953, CA189860, CA189804, CA180801, CA180835, CA189808, CA180826, CA180858, CA180846, CA189873, CA189822, CA189954, CA189854, CA189972, CA189952, CA13612, CA46368, CA11083
Amgen, AstraZeneca, Bristol-Myers Squibb Company, Genentech and Pfizer through the Foundation for the NIH, in partnership with Friends of Cancer Research
National Lung Matrix Trial Umbrella Academia Univ. of Birmingham (UK) Domestic, multicenter 25 Multiple CRCTU, Univ. of Birmingham
plasmaMATCH Umbrella Academia The Institute of Cancer Research Domestic, multicenter 19 Multiple Cancer Research UK
Stand Up to Cancer
The Royal Marsden NHS Foundation Trust (UK) AstraZeneca
Puma Biotechnology
SUKSES Umbrella Cancer hospital Samsung Medical Center (ROK) Domestic, multicenter; currently single center 6; currently 1 Single NRF grant funded by the Korean government (NRF-2017R1A2B2008408)
AcSé-eSMART Platform Cancer hospital Goustave Roussy (FR) International (Pan-European), multicenter 7 Multiple Association Imagine for Margo - Children without Cancer
INCa
ARC Foundation
I-SPY2 Platform Non-profit research org. Quantum Leap Healthcare Collaborative (USA) Domestic, multicenter 35 Single Quantum Leap Healthcare Collaborative (Originally funded by the Foundation for the NIH)

ANR, Agence Nationale de le Recherche; ASCO, American Society of Clinical Oncology; CRCTU, Cancer Research UK Clinical Trials Unit; CRUK, Cancer Research UK; DRUP, Drug Rediscovery Protocol; EORTC, European Organisation for Research and Treatment of Cancer; INCa, Institut National du Cancer; MATCH, Molecular Analysis for Therapy Choice; MRC CTU, Medical Research Council Clinical Trials Unit; MSKCC, Memorial Sloan Kettering Cancer Center; NCI, National Cancer Institute; NCTN, National Clinical Trials Network; NIH, National Institute of Health; NIHR, National Institute for Health and Care Research; NRF, National Research Foundation of Korea; SiRIC, Site de Recherche Intégré contre le Cancer; SUKSES, Small cell lung cancer Umbrella Korea StudiES; SWOG, Southwest Cancer Chemotherapy Study Group; TAPUR, Targeted Agent and Profiling Utilization Registry.

Table 2.

Summary of infrastructure: sponsor-initiated precision oncology trials

Study title Study type Sponsor Study sites No. of sites Funding source
Type Details
ARROW Basket Roche International, multicenter 72 Single Blueprint Medicines
CodeBreaK 100 Basket Amgen International, multicenter 133 Multiple Amgen
 Cancer Center Core Grant (P30 CA008748 [to MSKCC])
 M.D.Anderson Cancer Center Support Grant (P30 CA016672)
 Clinical Translational Science Award (1UL1 TR003167)
 Grant(RP150535) from the Cancer Prevention Research Institute of Texas Precision Oncology Decision Support Core
 The Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy provided molecular and other services
JAVELIN PARP Medley Basket Pfizer International, multicenter 61 Single Pfizer
KEYNOTE-051 Basket MSD International, multicenter 33 Single MSD
LIBTRETTO-001 Basket Loxo Oncology International, multicenter 85 Single Loxo Oncology
MyPathway Basket Genentech Domestic, multicenter 32 Single Genentech
NAVIGATE Basket Bayer International, multicenter 87 Multiple Bayer and Loxo Oncology
ROAR Basket Novartis International, multicenter 27 Single Novartis
STARTRK-2 Basket Roche International, multicenter 150 Single Roche
SUMMIT Basket Puma Biotechnology International, multicenter 57 Single Puma Biotechnology
VE-BASKET Basket Roche International, multicenter 34 Single Roche
BFAST Umbrella Roche International, multicenter 27 Single Roche

Table 3.

Summary of biomarker screening in precision oncology trials

Study title Year started Target disease(s) Screening method(s) Specimen type Screening lab Results reviewed by
Basket trial
 IIT Ado-Trastuzumab Emtansine 2016 HER2-mutant or -amplified, advanced solid tumors NGS Tissue Local N/A
Basket Trial
ADVL1522 2015 Recurrent or refractory Wilms tumor, rhabdomyosarcoma, neuroblastoma, pleuropulmonary blastoma, MPNST, or synovial sarcoma in pts between 12 months-30 years old IHC Tissue, blood N/A N/A
CREATE 2012 A variety of tumors with ALK and/or MET alterations IHC, FISH Tissue, blood Central & local Central
DRUP 2016 Advanced or metastatic solid tumor, multiple myeloma or B-cell non-Hodgkin lymphoma WGS Tissue, blood Central Central
w/a known molecular variant but w/o standard-treatment options
NCI-MATCH 2015 Solid tumor, lymphoma, multiple myeloma NGS Tissue Central & local N/A
NCI-MPACT 2013 Advanced solid malignant neoplasm NGS Tissue Central N/A
OLAPCO 2015 DDR-deficient solid tumors NGS Tissue, blood Local N/A
SHIVA 2012 Recurrent or metastatic solid tumors NGS, IHC, Cytoscan HD Tissue, blood Central Central
TAPUR 2016 Solid tumors, multiple myeloma, or B-cell non-Hodgkin lymphoma (pts > 12 years old) NGS (incl. liquid biopsy), Tissue, blood Central Central
 SIT ARROW 2017 Advanced RET-positive solid tumors NGS, FISH Tissue, blood Local N/A
NanoString
CodeBreaK 100 2018 KRAS G12C-mutant NSCLC, colorectal and other solid tumors NGS, IHC Tissue, blood Central N/A
JAVELIN PARP Medley 2017 Locally advanced (primary or recurrent) or metastatic solid tumors NGS, IHC Tissue, blood Central & local N/A
KEYNOTE-051 2015 Advanced melanoma or PD-L1 positive advanced, relapsed or refractory solid tumor or lymphoma IHC Tissue Central N/A
LIBTRETTO-001 2017 Advanced RET-positive solid tumors NGS, FISH, PCR Tissue, blood Local Central (Sponsor)
MyPathway 2014 Advanced solid tumors with mutations or gene expression abnormalities predictive of response to trastuzumab/pertuzumab, erlotinib, vemurafenib/cobimetinib, vismodegib, alectinib, or atezolizumab NGS, WGS, WES, RNA sequencing, FISH, IHC, RT-PCR Tissue Local N/A
NAVIGATE 2015 NTRK fusion–positive solid tumors NGS, FISH Tissue, blood Central & local N/A
ROAR 2014 BRAF V600E–mutant rare cancers IHC, PCR, Sanger sequencing Tissue, blood Central & local N/A
STARTRK-2 2015 Solid tumors that harbor an NTRK1/2/3, ROS1, or ALK gene fusion NGS Tissue Local N/A
SUMMIT 2013 HER (EGFR, HER2) mutation–positive solid tumors NGS, WES Tissue Local N/A
VE-BASKET 2012 BRAF V600 mutation–positive cancers (excluding melanoma and papillary thyroid cancer) NGS, PCR, Sanger sequencing othersa) Tissue Central & local Central (Sponsor)
Umbrella trial
 IIT FOCUS4 2014 Metastatic colorectal cancer NGS, IHC Tissue, blood Central Central
FUTURE 2018 Refractory TNBC who had progressed after standard treatments NGS, IHC Tissue Central N/A
Lung-MAP 2014 sqNSCLC NGS, IHC Tissue, blood Central N/A
National Lung Matrix Trial 2015 NSCLC NGS Tissue Central N/A
plasmaMATCH 2016 Advanced or relapsed breast cancer NGS, PCR Blood, tissue Central N/A
SUKSES 2016 SCLC NGS, IHC NanoString CNV, FISH Tissue N/A N/A
 SIT BFAST 2017 Advanced or metastatic (stage IIIB or IV) NSCLC harboring actionable somatic mutations detected in blood NGS Blood Central N/A
Platform trial
 IIT AcSé-eSMART 2016 Relapsed or refractory tumor in pediatric pts (< 18 years old) WES, NGS (liquid biopsy), whole RNA sequencing Tissue, blood Local Central
I-SPY2 2010 Operable, stage II or III breast cancer in neoadjuvant setting IHC +/– FISH Tissue Central N/A

ALK, anaplastic lymphoma kinase; CNV, copy number variation; DDR, DNA damage response and repair; DRUP, Drug Rediscovery Protocol; EGFR, epidermal growth factor receptor; FISH, fluorescence in situ hybridization; HER2, human epidermal growth factor receptor; IHC, immunohistochemistry; IIT, investigator initiated trials; MATCH, Molecular Analysis for Therapy Choice; MPACT, Molecular Profiling-based Assignment of Cancer Therapy for Patients with Advanced Solid Tumor; MPNST, malignant peripheral nerve sheath tumor; N/A, not available; NCI, National Cancer Institute; NGS, next-generation sequencing; NSCLC, non–small cell lung cancer; PCR, polymerase chain reaction; PD-L1, programmed death-ligand 1; pts, patients; RT-PCR, reverse transcription polymerase chain reaction; SCLC, small cell lung cancer; SIT, sponsor-initiated trials; sqNSCLC, squamous cell non–small cell lung cancer; TAPUR; Targeted Agent and Profiling Utilization Registry; TNBC, triple negative breast cancer; WES, whole exome sequencing; WGS, whole genome sequencing.

a)

Others include capillary electrophoresis single-strand conformation analysis, single-strand conformation analysis, melting, locked nucleic acid, and pyrosequencing.

Table 4.

Summary of efficacy outcomes in precision oncology trials

Study title ICRC Primary endpoint Secondary endpoint Evaluation criteria Efficacy outcomes Met primary endpoint? FDA approval Expansion cohort or phase 3 study
Basket trial
 Ado-Trastuzumab Emtansine basket trial N ORR PFS, toxicity RECIST 44% (cohort 1) Y N N
 ADVL1522 Na) ORR, toxicity PK, CD56 RECIST 0-6.25% (stratum 2) N N N
 ARROW Y ORR, toxicity CBR, DoR, DCR, PFS, OS RECIST, RANO 57-71% Y Y Y
 CodeBreaK 100 Y ORR DoR, DCR, TTR, PFS, OS, Safety RECIST 9.7-37.1% Y (NSCLC) Y (NSCLC) Y (NSCLC)
 CREATE Y ORR Safety, PFS, OS, DCR, DoR RECIST 2.5-66.7% Y (IMFT) N N
 DRUP N CBR, toxicity PFS, OS, DoT RECIST, IMWG, Lugano, RANO, GCIG 34% Y N N
 JAVELIN PARP Medley Y ORR Safety, biochemical response RECIST, PCWG 11.1-63.6% Y (B1, B2, C2) N N
 KEYNOTE-051 Y ORR DoR, PFS, DCR, OS RECIST, irRECIST, IWG, INRC 5.9-60% Y (rrcHL) Y N
 LIBRETTO-001 Y ORR PCSD, DoR, CNS ORR, CNS DoR, TTR, CBR, PFS, OS, Aes RECIST, RANO 43.9-85% Y (1, 2, 3, 4, 7) Y N
 MyPathway Y ORR DCR, PFS, DoR, % of alive participants RECIST 23-60% Y (1) N N
 NCI-MATCH Y ORR OS, PFS RECIST 0-38% Y (H, Z1F) Y (H) N
 NCI-MPACT N ORR PFS rate at 4 mo RECIST 0-3.7% N N N
 NAVIGATE Y ORR DoR, CBR, PFS, OS, AEs, concordance coefficient b/w prior molecular profiling and sponsor’s diagnostic testing RECIST, RANO 30-92% Y Y N
 OLAPCO N ORR PFS, DoR, toxicity RECIST 6.7-8.3% N N N
 ROAR N ORR DoR, PFS, OS, AEs RECIST, RANO, NCCN, IMWG 0-89% Y (1, 2, 4, 7, 8, 9) Y Y
 SHIVA N PFS ORR, toxicity RECIST HR 0.88 N N N
 STARTRK-2 Y ORR DoR, TTP, CBR, intracranial tumor response, CNS PFS, PFS, OS, PK, AE, QoL, bone biomarker RECIST 57-67.1% Y Y N
 SUMMIT Y ORR PFS, ORR, CBR, DoR, OS, AE RECIST 0-39% Y (breast cancer) N N
 TAPUR Y ORR, DCRb) OS, PFS, DoR, toxicity RECIST ORR 0-58% N N N
DCR 0-69%
 VE-BASKET N ORRc) CBR, ORRc), DoR, TTR, TTP, PFS, OS, safety RECIST 7.4-61.5%d) Y (ECD) Y (ECD) Y (ECD)
Umbrella trial
 BFAST Y ORRe), PFS, DoR ORRe), DoR, PFS, OS, safety RECIST 87.4% (A), 4.5 vs. 4.3 mo (C) Y (A) N N
 FOCUS4 Y PFS Safety, toxicity, ORR, QoL RECIST 3.61-3.88 mo (HR 0.35-0.4) Y (C, N) N N
 FUTURE N ORR DCR, PFS, OS, safety RECIST 0-100% Y (C, E) N N
 Lung-MAP Y ORR PFS, toxicity RECIST 4-16% Y (A) N N
 National Lung Matrix Trial N ORR, DCB rate, PFS PCSD, TTP, OS, AE RECIST PFS 1.9-44.6 mo, DCB rate 7-85%, ORR 3-76% Y (E, G) N N
 plasmaMATCH N ORR DoR, CBR, PFS, safety/tolerability, mutation frequency, ctDNA accuracy RECIST 8-25% Y (B, C) N N
 SUKSES N ORR DoR, PFS, OS, DCR at 8 wk, AEs, ECG RECIST 0% N N N
Platform trial
 AcSé-eSMART N ORR PFS, DoR RECIST, RANO, INRC 0% N N N
 I-SPY2 Nf) pCRg) Predictive, prognostic indices for pCR, RCB, RFS, OS, AEs, MRI volume RCB calculation formulah), SER breast MRI technique for 2nd endpoint 30-72% Y (2, 6, 11) N N

AE, adverse event; CBR, clinical benefit rate; CNS, central nervous system; ctDNA, circulating tumor DNA; DCB, durable clinical benefit; DCR, disease control rate; DoR, duration of response; DoT, duration of treatment; DRUP, Drug Rediscovery Protocol; ECD, Erdheim-Chester Disease; FDA, U.S. Food and Drug Administration; ECG, electrocardiogram; GCIG, Gynecological Cancer Intergroup; HR, hazard ratio; ICRC, independent central review committee; IMFT, inflammatory myofibroblastic tumor; IMWG, international myeloma working group; INRC, international neuroblastoma response criteria; irRECIST, immune-related Response Evaluation Criteria In Solid Tumors; IWG, international working group; MATCH, Molecular Analysis for Therapy Choice; MPACT, Molecular Profiling-based Assignment of Cancer Therapy for Patients with Advanced Solid Tumor; MRI, magnetic resoance imaging; NCCN, National Comprehensive Cancer Network; NCI, National Cancer Institute; NSCLC, non–small cell lung cancer; ORR, objective response rate; OS, overall survival; pCR, pathologic complete response; PCSD, percentage change in sum of target lesion diameters; PCWG, Prostate Cancer Working Group; PFS, progressionfree survival; PK, pharmacokinetics; QoL, quality of life; RANO, Response Assessment in Neuro-oncology; RCB, residual cancer burden; RECIST, Response Evaluation Criteria in Solid Tumors; RFS, recurrence-free survival; rrcHL, relapsed or refractory classic Hodgkin lymphoma; SER, signal enhancement ratio; SUKSES, Small cell lung cancer Umbrella Korea StudiES; TAPUR, Targeted Agent and Profiling Utilization Registry; TTP, time to progression; TTR, time to response.

a)

Patients with long term stable disease were centrally reviewed,

b)

DCR at 16 weeks was assessed,

c)

Primary endpoint ORR was confirmed best ORR, and secondary endpoint ORR was ORR at 8 weeks,

d)

ORR at 8 weeks,

e)

Primary endpoints were investigator assessed ORR (cohort A, B, D, and F), PFS (cohort C and G), and DoR (cohort E). Secondary endpoint ORR was facility assessed,

f)

The Study Lead Pathologist made the final determination on any indeterminate or contested results,

g)

Complete absence of tumor cells on the breast and lymph node tissues obtained from surgical resection,

Table 5.

Precision oncology trials led to the FDA approval

Study title Study type Year/approval type and indication Drug(s)
IIT NCI-MATCH Subprotocol H Basket 2022/Accelerated approval for BRAF V600E mutated solid tumors Dabrafenib+trametinib
SIT ROAR Basket
SIT VE-BASKET Basket 2017/Regular approval for BRAF V600E mutated ECD Vemurafenib
KEYNOTE-051 Basket 2017/Accelerated approval for MSI-H/dMMR solid tumors Pembrolizumab
2023/Full approval for MSI-H/dMMR solid tumors
NAVIGATE Basket 2018/Accelerated approval for adult and pediatric patients with solid tumors that have a NTRK gene fusion without a known Larotrectinib
STARTRK-2 Basket 2019/Accelerated approval for NTRK fusion solid tumors and ROS1 positive NSCLC Entrectinib
ARROW Basket 2020/Accelerated approval for RET fusion–positive MTCa) Praseltinib
2020/Accelerated approval for RET fusion–positive NSCLC
2023/Regular approval for RET fusion–positive NSCLC
LIBTRETTO-001 Basket 2020/Accelerated approval for RET fusion–positive NSCLC and MTC Selpercatinib
2022/Regular approval for RET fusion–positive NSCLC and MTC
2022/Accelerated approval for RET fusion–positive solid tumors other than NSCLC, MTC
CodeBreaK 100 Basket 2021/Accelerated approval for KRAS G12C mutated NSCLC Sotorasib

dMMR, deficient mismatch repair; ECD, Erdheim-Chester disease; FDA, Food and Drug Administration; IIT, investigator initiated trials; MATCH, Molecular Analysis for Therapy Choice; MSI-H, microsatellite instability high; MTC, medullary thyroid cancer; NCI, National Cancer Institute; NSCLC, non–small cell lung cancer; NTRK, neurotrophic tyrosine receptor kinase; SIT, sponsor-initiated trials.

a)

Accelerated approval of praseltinib for MTC was voluntarily withdrawn by Genetech in 2023, following consultation with the FDA and the determination that the confirmatory phase 3 AcceleRET-MTC trial (NCT04760288) required to convert the agent’s accelerated approval to full approval will no longer be pursued due to feasibility.

Table 6.

Summary of safety outcomes in precision oncology trials

Study title Planned safety monitoring ≥ Gr3 TRAE New safety signalsa) HRQoL PROs
Basket trial
 Ado-Trastuzumab Emtansine basket trial Y 6% N N N
 ADVL1522 Y 20 Events/treatment cycles (n=203) N/A N N
 ARROW Y 49-69% N Y (protocol only)b) N
 CodeBreaK 100 Y 11-16% N Y (protocol only)b) N
 CREATE Y 23.10% N/A N N
 DRUP Y N/A N/A N N
 JAVELIN PARP Medley Y 57% N/A N N
 KEYNOTE-051 Y 8% N/A N N
 LIBRETTO-001 Y 28-40% N/A Y (protocol only)b),c) Y
 MyPathway Y 8-37%d) N/A N N
 NAVIGATE Y 2-25% N/A N N
 NCI-MATCH Y 16-57% N/A N N
 NCI-MPACT Y 45% N/A N N
 OLAPCO Y 32% N/A N N
 ROAR Y 63% N N N
 SHIVA Y 43%e) N/A N N
 STARTRK-2 Y N/A N/A N N
 SUMMIT Y 8% N/A Y (protocol only)f) N
 TAPUR Y 20-43%e) N/A N N
 VE-BASKET Y 17%d) N N N
Umbrella trial
 BFAST Y 18% (cohort C) N/A Y (protocol only)b) Y
 FOCUS4 Y 20% (arm D) N/A Y (N cohort)f) N
 FUTURE Y 22% (arm E) N/A N N
 Lung-MAP Y 39.5% (S1400I) N/A N N
 National Lung Matrix Trial Y 53% (arm E) N/A N N
 plasmaMATCH Y 22% (cohort D) N/A N N
 SUKSES Y 60% (arm N3) N/A N N
Platform trial
 AcSé-eSMART Y 73.9% (arm A) N/A N N
 I-SPY2 Y 71.0% (veliparib arm) N/A Y (protocol only)b) N

DRUP, Drug Rediscovery Protocol; HRQoL, health-related quality of life; MATCH, Molecular Analysis for Therapy Choice; MPACT, Molecular Profiling-based Assignment of Cancer Therapy for Patients with Advanced Solid Tumor; NCI, National Cancer Institute; PRO, patient-reported outcome; TAPUR, Targeted Agent and Profiling Utilization Registry; TRAE, treatment-related adverse event.

a)

N/A (not available): the trial didn’t proceed to phase 3 or newly open an expansion cohort; N (no): the trial proceed to phase 3 or newly opened an expansion cohort but not reported any new safety signal,

b)

EORTC-QLQ-C30,

c)

PedQL,

d)

Treatment-related treatment-emergent adverse event,

e)

Adverse event,

f)

EQ-5D.