Expansion platform type II: testing a treatment strategy.

摘要: In The Lancet Oncology, Christophe Le Tourneau and colleagues report the results of SHIVA,1 a next-generation clinical trial first example using expansion platform design type IIB.2 Several designs have emerged to address challenges associated with implementation targeted therapies.2,3 Briefly, so-called exploratory (eg, BATTLE I-SPY2) start by randomly assigning patients several treatment groups, during course trial, further test newly discovered biomarker–drug signals in an adaptive fashion. Alternatively, assign therapy immediately based on predefined biomarker–treatment pairings, thus expanding previously derived match. IA is histology dependent conceptualised FOCUS4 colon cancer trial),4 whereas IB agnostic NCI-MATCH).3,5 Type I enable coordinated molecular profiling assignment, but each biomarker– group must meet individual statistical endpoints, hence large numbers be screened profiled adequately low incidence groups. which 647 were screened, authors suggested that accrual, this study design, would infeasible for biomarkers,5 as recognised.2 In anticipation these accrual most groups within designs, II concede loss scrutiny favour testing strategy pools multiple ideally comparison biomarker-stratified control group. IIA are PANGEA, gastroesophageal trial)6 IIB SHIVA).1 SHIVA required 200 assigned receive either molecularly agents matched alterations or at physicians' choice primary endpoint. Of 741 enrolled, samples successfully 496 (67%) patients. Only 195 (26%) could categorised into biomarker (n=99) (n=96). Treatment choices who received algorithm allocated them 11 prespecified divided ten regimens nine (with one regimen used backup option). Some leeway existed biology board decide alteration was relevant whether previous considerations should included decision. While practical, having provisions outside can make challenging reproduce others. Nevertheless, companion diagnostics mixture novel approved assays, including next generation sequencing, assessment copy number chip arrays, immunohistochemistry. SHIVA notable trial. It test, randomised control, idea off-label use commercial drugs biomarkers confers benefit. This approach often advocated basis few case reports, observational cohorts, meta-analyses, all no appropriate prospective controls. Unfortunately, properly run trials disprove intuition—statistics hypothesis sobering. negative, common occurrence after publication promising uncontrolled reports. However, careful consideration variables embedded warranted. These include assays positivity criteria,7 drugs, assignment algorithm, makeup, contributed aggregated SHIVA. nature design. Therefore, conclusions viewed context, specifics acknowledged overall personalised strategy. generalisability SHIVA other potential therefore limited.2 But fact does suggest any proposed strategies similarly tested before they accepted routine standard care. Importantly, although not significantly better than (defined HR 0·625 SHIVA), finding exclude possibility more drug pairings histologies truly beneficial, important shortcoming type-II design. Irrespective limitations, offers robust evidence deficiencies various loose associations between inhibitors provided diagnostic reports. manner restricted. Instead, encouraged participate well-designed iterative scientific build findings from such Future revised best-in-class necessarily already commercially available; combination therapies specific groups; repeated biological tumour progression intrapatient evolution resistance; modified algorithms; histological (ie, IIA); biomarkers; relegation biomarker-negative algorithm; definitions biomarker-positivity.2 A negative straightforward—the failed abandoned, amended then retested, subsets investigated classic population-enriched if feasible. However, meets endpoints remains problematic. A successful encompasses diagnostics, even challenge existing regulatory infrastructure. Would histology, simultaneously expanded indication confirmed phase 3 trial? What some available? done about development approval pathways incorporated diagnostics? Thus, pre-emptively tackle issues preparation future positive trials, regulation accompany through integration concept strategies, continue advance