#KEYNOTE 158 CLINICAL TRIALS.GOV TRIAL#

#KEYNOTE 158 CLINICAL TRIALS.GOV TRIAL#

Patients enrolled on trial were also required to have additional tissue available for retrospective biomarker assessment.

Molecular eligibility was determined by the Molecular tumour board (MTB), with either no actionable mutations to enrol on a biomarker-specified MoST trial (initial cohort, n=64), or enriched for intermediate/high TMB (expansion cohort, n=48). The panel assay employed for MoST screening evolved over time and included three in-house assays (MoST, CCPv2, CCPv2.2), Illumina TruSight Tumor 170, and Foundation Medicine (FMI). Documented unsuitability includes known hypersensitivity, organ dysfunction, or other patient factors that would make standard therapy unsuitable in the judgement of the responsible investigator.ĬGP was undertaken as part of the molecular screening and therapeutics (MoST) program using formalin-fixed, paraffin-embedded archival tumour ( 10). Patients were required to be progressing on, be intolerant of, or have documented unsuitability for further standard therapy for their tumour type and not have previously received treatment with a PD1, PD-L1, or CTLA-4 inhibitor. Key eligibility criteria included patients with pathologically confirmed, advanced or metastatic solid cancer of any histological type, excluding cancer types for which immunotherapy is already standard of care in Australia Eastern Cooperative Oncology Group performance status 0–1 adequate hepatic, renal and marrow function. An independent data and safety monitoring committee provided independent assessments of patient safety and trial progress. All patients provided written informed consent for participation in this trial. Central or institutional ethics and local research governance approval were obtained. The study was performed in accordance with the Declaration of Helsinki. Patients were treated at five sites across Australia. A range of correlative biomarkers were retrospectively examined for an association with clinical outcomes. The initial cohort of 64 subjects was unselected for biomarkers, while an expansion cohort of 48 subjects was enriched for intermediate/ high TMB. This trial formed part of the Molecular Screening and Therapeutics study ( 10), in which patients underwent comprehensive genomic profiling (CGP) prior to enrolment onto a range of therapeutic substudies.

We have conducted a tumour agnostic, signal-seeking trial of durvalumab and tremelimumab in mostly treatment-refractory patients, prioritising rare and less common cancers due to their under-representation in clinical trials. Finally, the activity of dual checkpoint blockade in a tumour agnostic setting, particulary in rare and less common cancers is unknown. Moreover, given histotypic variation in TMB and lack of standardization across sequencing platforms, the rationale for a TMB cut-off of 10 mutations/megabase across cancer types remains unclear ( 7- 9). Sarcomas, for example, comprise 50 histologic types and represented 10% of the cohort. This approval was based on the KEYNOTE-158 study, which included a limited sampling of 27 cancer types, with half represented by 4 cancers (endometrium, pancreas, biliary, gastric) ( 6). Pembrolizumab (PD-1 inhibitor) monotherapy has received FDA tumour agnostic approval for both mismatch repair deficiency/microsatellite instability, and increased TMB (≥ 10 mutations/megabase) using the FoundationOne CDx™ assay. While high PD-L1 expression or high tumour mutational burden (TMB) may increase the likelihood of favourable clinical outcomes in select cancer histologies, their presence or absence does not guarantee, or preclude a response ( 4, 5). Despite the targeted nature of these therapies, a clear biomarker has not been identified across cancer types.

Durvalumab and tremelimumab are both humanised immunoglobulin G monoclonal antibodies that bind respectively to the programmed death-ligand 1 (PD-L1) and the coinhibitory receptor CTLA-4, which are suppressors of T-cell activity in cancers ( 2, 3). Checkpoint inhibitors target tumour immune evasion, which appears broadly relevant to cancer development ( 1).

Keynote 158 clinical trials.gov