The NCI-MATCH trial: lessons for precision oncology

O’Dwyer, Peter J.; Gray, Robert J.; Flaherty, Keith T.; Chen, Alice; Li, Shuli; Wang, Victoria; McShane, Lisa M.; Patton, David; Tricoli, James V.; Williams, P. Mickey; Iafrate, A. John; Sklar, Jeffrey; Mitchell, Edith P.; Takebe, Naoko; Sims, David; Coffey, Brent; Fu, Tony; Routbort, Mark J.; Rubinstein, Larry; Little, Richard F.; Arteaga, Carlos L.; Marinucci, D. M.; Hamilton, Stanley R.; Conley, Barbara A.; Harris, Lyndsay N.; Doroshow, James H.

doi:10.1038/s41591-023-02379-4

Cited by 54 publications

(23 citation statements)

References 59 publications

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“…Personalized precision therapy is of paramount importance in reducing EC mortality and enhancing the efficacy of therapeutic agents. However, our current understanding of molecular alterations in ESCC is incomplete and has not been fully translated into clinical practice 70 - 76 . Therefore, deepening our knowledge of precise molecular events driving ESCC heterogeneity and their correlation with clinical information will foster the discovery of novel treatment targets and assist us to identify patients who might be of drug resistance to certain therapies.…”

Section: Discussionmentioning

confidence: 99%

HMGA1 sensitizes esophageal squamous cell carcinoma to mTOR inhibitors through the ETS1-FKBP12 axis

Guo,

He,

Yuan

et al. 2024

Int. J. Biol. Sci.

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Esophageal carcinoma is amongst the prevalent malignancies worldwide, characterized by unclear molecular classifications and varying clinical outcomes. The PI3K/AKT/mTOR signaling, one of the frequently perturbed dysregulated pathways in human malignancies, has instigated the development of various inhibitory agents targeting this pathway, but many ESCC patients exhibit intrinsic or adaptive resistance to these inhibitors. Here, we aim to explore the reasons for the insensitivity of ESCC patients to mTOR inhibitors. We assessed the sensitivity to rapamycin in various ESCC cell lines by determining their respective IC50 values and found that cells with a low level of HMGA1 were more tolerant to rapamycin. Subsequent experiments have supported this finding. Through a transcriptome sequencing, we identified a crucial downstream effector of HMGA1, FKBP12, and found that FKBP12 was necessary for HMGA1-induced cell sensitivity to rapamycin. HMGA1 interacted with ETS1, and facilitated the transcription of FKBP12. Finally, we validated this regulatory axis in in vivo experiments, where HMGA1 deficiency in transplanted tumors rendered them resistance to rapamycin. Therefore, we speculate that mTOR inhibitor therapy for individuals exhibiting a reduced level of HMGA1 or FKBP12 may not work. Conversely, individuals exhibiting an elevated level of HMGA1 or FKBP12 are more suitable candidates for mTOR inhibitor treatment.

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Section: Discussionmentioning

confidence: 99%

HMGA1 sensitizes esophageal squamous cell carcinoma to mTOR inhibitors through the ETS1-FKBP12 axis

Guo,

He,

Yuan

et al. 2024

Int. J. Biol. Sci.

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“…In BOUQUET, PIK3CA, AKT1, PTEN, ERBB2, KRAS, NRAS and BRAF, are being used as biomarkers to plan individualized study treatment 35,36 . Other large ongoing studies on the effectiveness of targeted anti-cancer drugs and immunotherapy, in patients where the tumor is known to have specific genetic variants are NCI-MATCH (NCT02465060), DRUP (NCT02925234) and TAPUR (NCT02693535) [37][38][39][40] . Concerning tier-IIIA, OC tumors with FGFR1/2/3 pathogenic variants could be treated with FGFR-inhibitors.…”

Section: Discussionmentioning

confidence: 99%

Identification of potentially actionable genetic variants in epithelial ovarian cancer: A retrospective cohort study

Claes,

Fieuws,

Meulen

et al. 2023

Preprint

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Ovarian cancer is the most lethal gynecologic malignancy, mainly due to late-stage diagnosis, frequent recurrences, and eventually therapy resistance. To identify potentially actionable genetic variants, sequencing data of 351 Belgian ovarian cancer patients were retrospectively captured from electronic health records. The cohort included 286 (81%) patients with high-grade serous ovarian cancer, 17 (5%) with low-grade serous ovarian cancer, and 48 (14%) with other histotypes. Firstly, an overview of the prevalence and spectrum of the BRCA1/2 variants highlighted germline variants in 4% (11/250) and somatic variants in 11% (39/348) of patients. Secondly, application of a multi-gene panel in 168 tumors revealed a total of 214 variants in 28 genes beyond BRCA1/2 with a median of 1 (IQR, 1 to 2) genetic variant per patient. The ten most often altered genes were (in descending order): TP53, BRCA1, PIK3CA, BRCA2, KRAS, TERT promotor, RB1, PIK3R1, PTEN, and ERBB2 (HER2). Of note, the genetic landscape vastly differed between the studied histotypes. Finally, using ESCAT the clinical evidence of utility for every genetic variant was scored. Only BRCA1/2 pathogenic variants were classified as tier-I. Nearly all patients (151/168; 90%) had an ESCAT tier-II variant, most frequently in TP53 (74%), PIK3CA (9%) and KRAS (7%). In conclusion, our findings imply that although only a small proportion of genetic variants currently have direct impact on ovarian cancer treatment decisions, other variants could help to identify novel (personalized) treatment options to address the poor prognosis of ovarian cancer, particularly in rare histotypes.

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“…Here, multiple interventions or treatments are evaluated simultaneously in different cohorts or baskets of patients with different types of cancers or mutations, with the option to stop a particular treatment arm early if it is deemed futile or ineffective. For example, although the NCI‐MATCH trial had several arms, only a few arms met the primary end point 12 …”

Section: Statistical Challengesmentioning

confidence: 99%

“…The NCI‐MATCH trial, sponsored by the NCI, is one of the largest basket trials conducted to date 12,66 . The trial evaluated the efficacy of targeted therapies in patients who had solid tumors or lymphomas that harbored specific genetic alterations.…”

Section: Master Basket Trialsmentioning

confidence: 99%

“…Basket trials have gained significant attention and interest in recent years, as exemplified in the national organization of the National Cancer Institute-Molecular Analysis for Therapy Choice (NCI-MATCH) trial (ClinicalTrials.gov identifier NCT02465060), as a novel approach to precision medicine, aiming to identify the most effective treatments for patients with specific molecular alterations, regardless of the cancer type. 12 Moreover, several of these basket trials have led to drug approvals, providing patients access to novel therapies. This review delves into the evolution of basket studies in the development of cancer drugs, highlighting present obstacles and potential prospects for the future.…”

Section: Introductionmentioning

confidence: 99%

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Revolutionizing cancer drug development: Harnessing the potential of basket trials

Subbiah,

Burris,

Kurzrock

2023

Cancer

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The landscape of cancer therapy has been transformed by advances in clinical next‐generation sequencing, genomically targeted therapies, and immunotherapies. Well designed clinical trials and efficient clinical trial conduct are crucial for advancing our understanding of cancer, improving patient outcomes, and identifying personalized treatments. Basket trials have emerged as one of the efficient modern clinical trial designs that evaluate the efficacy of these therapies across multiple cancer types based on specific molecular alterations or biomarkers, irrespective of histology or anatomic location. This review delves into the evolution of basket trials in cancer drug development, highlighting their potential prospects and current obstacles. The design of basket trials involves screening patients for specific molecular alterations or biomarkers and enrolling them in the trial to receive the targeted therapy under investigation. Statistical considerations play a crucial role in the design, analysis, and interpretation of basket trials. Several notable examples of basket trials that have led to US Food and Drug Administration approval for uncommon molecular alterations (e.g., NTRK fusions, BRAF mutations, RET and FGFR1 alterations) are discussed, including LOXO‐TRK (ClinicalTrials.gov identifier NCT02122913)/SCOUT (ClinicalTrials.gov identifier NCT02637687)/NAVIGATE (ClinicalTrials.gov identifier NCT02576431)/STARTRK (ClinicalTrials.gov identifiers NT02097810, NT02568267), VE‐BASKET (ClinicalTrials.gov identifier NCT01524978), ROAR Basket (ClinicalTrials.gov identifier NCT02034110), LIBRETTO‐001 (ClinicalTrials.gov identifier NCT03157128), ARROW (ClinicalTrials.gov identifier NCT03037385), FIGHT‐203 (ClinicalTrials.gov identifier NCT03011372), and the National Cancer Institute‐Molecular Analysis for Therapy Choice trial (ClinicalTrials.gov identifier NCT02465060). Basket trials have the potential to revolutionize cancer treatment by identifying effective therapies for patients based on specific molecular alterations or biomarkers rather than traditional histology‐based approaches.Plain Language Summary To gain more knowledge about cancer, improve patient outcomes, and discover personalized treatments, it is crucial to conduct clinical trials efficiently. One effective type of clinical trial is called a basket trial. In basket trials, new treatments are tested on various types of cancer, regardless of their location in the body; instead, researchers focus on specific abnormalities in the cancer cells. Basket trials offer hope that we can find personalized treatments that are more effective for each individual battling cancer.

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The NCI-MATCH trial: lessons for precision oncology

Cited by 54 publications

References 59 publications

HMGA1 sensitizes esophageal squamous cell carcinoma to mTOR inhibitors through the ETS1-FKBP12 axis

HMGA1 sensitizes esophageal squamous cell carcinoma to mTOR inhibitors through the ETS1-FKBP12 axis

Identification of potentially actionable genetic variants in epithelial ovarian cancer: A retrospective cohort study

Revolutionizing cancer drug development: Harnessing the potential of basket trials

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