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Table 1 Precision oncology trial designs and representative trialsa

From: Clinical trial design in the era of precision medicine

Trial design

Representative trials

Design details

Biomarker used

Aim

ORR

Published data (first, last author, reference number)

First-generation designs

Basket

 

VE-BASKET

Early phase II

BRAF mutation

Efficacy of vemurafenib in patients with BRAF V600 mutation–positive cancers

NSCLC: ORR 42%, Erdheim–Chester disease or Langerhans’-cell histiocytosis: ORR 43%, colorectal cancer: ORR 0%

Hyman, Baselga [38]

 

LOXO-TRK-14001, SCOUT, NAVIGATE

Phase I trials

NTRK fusion

Efficacy and safety of larotrectinib in patients with NTRK fusions

ORR 75%

Drilon, Hyman [5]

 

ALKA, STARTRK-1 and STARTRK-2

Phase I-II

NTRK fusion

Efficacy and safety of entrectinib in patients with NTRK fusions

ORR 57%

Doebele, Demetri [6]

 

KEYNOTE-016, -164, -012, -028 and -158

Phase II

MSI-H/MMRd

Efficacy of pembrolizumab in previously treated, metastatic MSI-H/MMRd colorectal cancer

All patients combined (N=134): ORR 39.6%

Le, André [39]

Marabelle, Diaz [4]

 

MyPathway

Phase IIa

Alterations in HER2, EGFR, BRAF, and Hedgehog pathway

Efficacy and safety of selected targeted therapies in tumor types that harbor relevant genetic alterations

All patients: ORR 23%, HER2-amplified colorectal treated with trastuzumab and pertuzumab: ORR 38%, NSCLC BRAF V600 treated with vemurafenib: ORR 43%

Hainsworth, Kurzrock [40]

Umbrella

 

Lung-MAP (lung)

Phase II, parallel assignment

HRD, c-MET, STIK11, FGFR, Pi3K, RET, KRAS

Efficacy of biomarker-matched target therapies vs “non-match” treatments in patients with advanced lung squamous cell carcinoma

c-MET treated with telisotuzumab vedotin: ORR 9%, Squamous NSCLC treated with durvalumab: ORR 16%, squamous NSCLC homologous recombination repair-deficient treated with talazoparib: ORR 4%

Ferrarotto, Papadimitrakopoulou [41]

Redman, Herbst [42]

Waqar, Papadimitrakopoulou [43]

Borghaei, Papadimitrakopoulou [44]

Owonikoko, Gandara [45]

 

ALCHEMIST (lung)

Non-randomized, open label, parallel assignment

EGFR, ALK, and PD-L1

Use of genomic profiling in patients with operable lung adenocarcinoma to administer matched therapies and evaluate clonal architecture, clonal evolution, and mechanisms of resistance to therapy

Not applicable (adjuvant)

Govindan, Vokes [46]

 

PlasmaMATCH (breast)

Non-randomized, open label, parallel assignment

EDR1, HER2, AKT1, and PTEN

Accuracy of ctDNA testing in patients with advanced breast cancer and ability of ctDNA testing to select patients for mutation-directed therapy

In three different published cohorts ORR varied from 11 to 25%

Turner, Ring [47]

 

FOCUS4 (colorectal)

Phase 2–3 randomized

PIK3CA, KRAS, NRAS, TP53, and BRAF

Efficacy of targeted agents in patients with advanced colorectal cancer in molecularly stratified cohorts

Not yet reported

Adams, Maughan [48]

 

AML BEAT

Non-randomized, open label, parallel assignment

TET2, IDH1, IDH2, WT1, and TP53

Provides cytogenetic and mutational data to assign patient to a substudy based on the dominant clone

Not yet reported (ongoing)

Burd, Byrd [49]

Platform

 

MD Anderson IMPACT1

Navigational

Sequencing and IHC

Use of tumor molecular profiling to optimize the selection of targeted therapies for patients who will participate in a phase I clinical trial program

Patients treated with matched treatment versus not matched: ORR 11% vs. 5%

Tsimberidou, Kurzrock [50] Tsimberidou, Schilsky [51]

Tsimberidou, Kurzrock [52]

 

TAPUR

Non-randomized, open label

ALK, ROS1, MET, mTOR, TSC, HER2, BRCA, ATM, RET, VEGFR1/2/3, KIT, PDGFRβ, BRAFb

Evaluate efficacy of FDA-approved, targeted agents in patients whose tumors have actionable genomic alterations known to be targeted by the respective drug

In three different published cohorts ORR varied from 4 to 29%

Klute, Schilsky [53]

Gupta, Schilsky [54]

Meiri, Schilsky [55]

 

NCI-MATCH

Non-randomized, open label, parallel assignment

EGFR, HER2, MET, ALK, ROS1, BRAF, PIK3CA, FGFR, PTENNF1, cKITb

Evaluate the efficacy of matched targeted treatments in patients with refractory cancers, irrespectively of cancer histology

Patients with HER2 amplification treated with T-DM1: ORR 5.6%, patients with BRCA1/2 mutations treated with wee-1 kinase inhibitor: ORR 3.2%

Azad, Flaherty [56]

Jhaveri, Flaherty [57]

Kummar, Flaherty [58]

 

STAMPEDE

Multi-arm multi-stage, randomized, parallel assignment

No

Evaluate novel approaches for the treatment of men with hormone-naïve prostate cancer

Not yet reported

James, Sydes [59]

Parker, Sydes [60]

Clarke, James [61]

 

MD Anderson IMPACT2b

Randomized phase II study

Tumor molecular profiling

Compare progression—free survival in patients with advanced cancer who received matched treatments based on tumor genomic profiling results vs. those whose treatment was not selected based on genomic analysis

Not yet reported (ongoing)

NCT02152254

Tsimberidou, Meric-Bernstam [62]

 

I-PREDICT

UCSD

Prospective navigation

Molecular alterations, PD-L1, TMB and MSI

Assess whether personalized treatment with combination therapies would improve outcomes in patients with refractory malignancies.

Treatment-refractory, metastatic/advanced with high (>50%) matching score: ORR 45%, first-line, metastatic/advanced [63] and high (>60%) matching score: ORR 40%

Sicklick, Kurzrock [13]

 

SHIVA

Randomized, controlled, phase II

Alterations in hormone receptors, and PI3K/AKT/mTOR and RAF/MEK pathways

Assess the efficacy of molecularly targeted treatments matched to tumor molecular alterations versus conventional therapy

Patients with matched vs non-matched treatments: ORR 4.1% vs. 3.4%

Le Tourneau, Paoletti [64]

 

NCI-MPACT

Randomized, phase II

Alterations in DNA repair, PI3K and RAS/RAF/MEK pathways

Assess the utility of selecting treatment based on tumor DNA sequencing in patients with advanced cancer compared to not-matched treatment

All cohorts: ORR 2%

Chen, Doroshow [65]

 

DART

Multiple cohorts, phase II

Immunotherapy for rare cancers; biomarkers are assessed as correlates

Assess response rates of nivolumab and ipilimumab combination in multiple cohorts of rare and ultra-rare cancers

Four cohorts published:

ORR varies from 18% (metaplastic breast) to 44% (high-grade neuroendocrine

Patel, Kurzrock [66]

Patel, Kurzrock [67]

Adams, Kurzrock [68]

Wagner, Kurzrock [69]

Octopus

QUILT-3.055

Phase IIb

No

Assess the efficacy of combination immunotherapies in patients who have previously received treatment with PD-1/PD-L1 immune checkpoint inhibitors

N-803 and checkpoint inhibitor: ORR 8% (preliminary data)

Wrangle, Soon-Shiong [70]

Adaptive

 

I-SPY 2

Randomized, phase II, parallel assignment

ER, HER2, and MammaPrint

Evaluate multiple concurrent experimental arms and a shared control arm as neoadjuvant treatment of patients with breast cancer using response-adaptive randomization

Not applicable (neoadjuvant)

Barker, Esserman [71]

Nanda, Esserman [72]

Pusztai, Esserman [73]

 

BATTLE-2

Randomized, phase II, single group assignment

KRAS

Identify predictive biomarkers and evaluate the efficacy of matched targeted therapies in patients with non-small cell lung cancer

All cohorts: ORR 3%

Papadimitrakopoulou, Herbst [74]

Telescope (seamless)

 

GBM AGILE

Randomized, adaptive, parallel assignment, 2-staged

MGMT

Evaluate multiple agents within patient signatures compared against a common control in patients with glioblastoma

Not yet reported (ongoing)

Alexander, Barker [75]

Next-generation designs

N-of-1

 

I-PREDICT UCSD

Prospective navigation

Molecular alterations, PD-L1, TMB and MSI

Assessed the strategy/algorithm used (based on molecular profile) to individualize combination treatments in patients with both refractory and treatment-naïve, advanced lethal cancers

Treatment-refractory, metastatic/advanced with high (>50%) matching score: ORR 45% stable disease>6 months/partial/complete response rate = 50%);

First-line, metastatic/advanced and high (>60%) matching score: ORR 40% (stable disease>6 months/partial/complete response rate = 68%)

Sicklick, Kurzrock [13, 63]

 

WINTHER

Prospective navigation

Genomics and transcriptomics

Evaluate the use of genomics and transcriptomics to guide therapeutic decisions and individualize cancer treatment

All patients: ORR 11%

Rodon, Kurzrock [15]

 

Columbia University Medical Center

Prospective

Whole-genome DNA sequencing and RNA expression analysis

Use tumor profiling to identify actionable molecular alterations possibly targeted by FDA-approved drugs. Treatments are then evaluated on the patient’s tumor tissue, either in cell culture in a patient-derived xenograft)

Not yet reported (ongoing)

Califano [76]

Home-based trials

 

ALpha-T

Phase II, single arm, tissue-agnostic

ALK fusion

Evaluate the efficacy and safety of alectinib in patients with ALK-positive advanced solid tumors other than lung cancer

Not yet reported (ongoing)

Kurzrock, Lovely [77]

Novel mechanisms of data collection

Exceptional responders

 

Exceptional response to mTOR inhibitor (everolimus)

Translational

Whole-genome sequencing

Investigate the genetic basis of a durable remission of a patient with advanced bladder cancer after treatment with everolimus

Not applicable (selected population with exceptional response)

Iyer, Solit [78]

 

Exceptional response to EGFR inhibitor

Translational

EGFR mutation

Evaluate tumor molecular profiling in patients with non-small cell lung cancer with exceptional response to gefitinib to determine underlying mechanisms

Not applicable (selected population with exceptional response)

Lynch, Haber [79]

 

Exceptional response to ALK inhibitor

Phase 1 dose escalation trial

ALK fusion

Evaluate safety and efficacy of crizotinib in patients with advanced cancer

All patients: ORR 60.8%

Kwak, Salgia [80]

 

Molecular profiling of exceptional responders to cancer therapy

Translational

NA

Identify specific molecular alterations in exceptional responders, unravel mechanisms of response and predictive biomarkers

Not applicable (selected population with exceptional response)

Bilusic, Plimack [81]

Wagle, Rosenberg [82]

Registry protocols

 

ROOT

Collection of comprehensive data

NA

Create a model of an oncology-centric master observational (registry-type) trial with structured data entry

Not yet reported (ongoing)

Dickson, Kurzrock [18, 19]

Real-world data

 

Palbociclib in male breast cancer

Electronic health records

NA

Assess safety of palbociclib in male patients with advanced breast cancer

Not reported

Wedam, Beaver [17]

 

Pembrolizumab in part

Electronic health records

MSI/MMR

Assess safety and efficacy in patients with advanced cancer (post-marketing requirement)

Not reported

FDA [83]

 

Outcome and toxicity, and economic data for CDK4/6 inhibitors

Prospective-retrospective, and cost analysis

NO

Evaluate clinical outcome, toxicity data and treatment-related costs in patients with advanced breast cancer treated with CDK inhibitors

Not reported

Fountzilas, Koumakis [84]

 

Abiraterone acetate plus prednisone for the management of metastatic castration-resistant prostate cancer

Retrospective

NO

Assess treatment failure of patients with metastatic castration-resistant prostate cancer treated with abiraterone acetate plus prednisone

Not reported

Boegemann, Elliott [85]

Patient-reported outcomes

 

Measuring Quality of Life in Routine Oncology Practice

Randomized controlled

NA

Assess health-related quality of life, patient satisfaction and patients’ perspectives on continuity and coordination of their care

Not applicable (assess quality of life data)

Velikova, Selby [86]

  1. Abbreviations: ctDNA circulating tumor DNA, HER2 human epidermal growth factor receptor-2, MSI microsatellite instability, NA not applicable, NSCLC non-small cell lung cancer, ORR objective response rate, PD-L1 programmed death-ligand 1, TMB tumor mutational burden
  2. aNote that some trials such as IMPACT, I-PREDICT, and MyPathway fall under more than one category and are therefore listed more than once
  3. bExamples of molecular biomarkers used in the trial