Table 1.
Precision oncology trial designs and representative trialsa
| 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) |
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] | |
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
aNote that some trials such as IMPACT, I-PREDICT, and MyPathway fall under more than one category and are therefore listed more than once
bExamples of molecular biomarkers used in the trial