Results from three groundbreaking precision cancer medicine studies are published on 22 April 2019 in the Nature Medicine. The TARGET shows that sequencing of circulating tumour DNA (ctDNA) from cancer patients is a cost-efficient approach with turnaround time compatible with clinical practice to inform treatment decision-making in a phase I trial setting. The I-PREDICT, a prospective clinical study of cancer patients demonstrated the feasibility of matching genomic alterations found in tumours to combined drug treatments. In the WINTHER, prospective analysis of transcriptomic and genomic alterations increased the proportion of patients with solid tumours who are eligible for receiving matched therapies and shows promise in improving clinical outcomes.
Insights from the TARGET study
A group of authors led byCaroline Dive of the Cancer Research UK (CRUK) Manchester Institute and Matthew G. Krebs of the Christie NHS Foundation Trust, Manchester, UK wrote in study background that next-generation sequencing of ctDNA supports blood-based genomic profiling, but it is not yet routinely implemented in phase I trials.
Their study, TARGET is a molecular profiling programme with the primary aim to match patients with different types of advanced cancers to early phase clinical trials on the basis of analysis of both somatic mutations and copy number alterations across a 641 cancer-associated-gene panel in a single ctDNA assay.
ctDNA data in first 100 patients included in the study show good concordance with matched tumour and results were turned within a clinically acceptable timeframe for review by the molecular tumour board. Actionable mutations were identified in 41 of 100 patients, and 11 of these patients received a matched therapy.
The authors concluded that the data support the application of ctDNA in early phase trial setting.
The study was co-funded by The Christie Charitable Fund, by CRUK via core-funding to the CRUK Manchester Institute, the CRUK Manchester Centre, the CRUK Manchester Experimental Cancer Medicines Centre and the NIHR Manchester Biomedical Research Centre. It was supported by the NIHR Manchester Clinical Research Facility, the Manchester Academic Health Science Centre, the AstraZeneca iDECIDE Programme awarded to Manchester Cancer Research Centre, PCRF 2012 Project Grant, CRUK Precision Panc grant, the EU IMI consortium CANCER-ID and Roche Products, Ltd. through the provision of the Foundation Medicine tumour profiling service.
Insights from the I-PREDICT study
Jason K. Sicklick and Razelle Kurzrock of the University of California, San Diego, La Jolla, USA wrote in study background that until now precision cancer medicine trials have been based on molecular matching with monotherapies with very low matching rates and low response rates. They hypothesised that personalised treatment with combination therapies could improve outcomes in patients with refractory malignancies.
In cross-institutional prospective I-PREDICT study, the investigators used tumour DNA sequencing and timely recommendations for individualised treatment with combination therapies. Administration of multidrug regimens was feasible, with 49% of consented patients receiving personalised treatment.
Targeting of a larger fraction of identified molecular alterations, yielding a higher matching score, was correlated with significantly improved disease control rates, as well as longer progression-free and overall survival rates, compared to targeting of fewer somatic alterations.
The authors concluded that the current clinical trial paradigm in precision cancer medicine that pairs one driver mutation with one drug, may be optimised by treating molecularly complex and heterogeneous cancers with combination regimens.
This work was supported in part by Foundation Medicine, Inc., as well as the Joan and Irwin Jacobs Philanthropic Fund, the Jon Schneider Memorial Cancer Research Fund, and National Institutes of Health multiple grants. The authors also acknowledged the support of Pedal the Cause, The David Foundation, and Kristen Ann Carr Fund.
Insights from the WINTHER trial
The investigators from the Worldwide Innovative Network (WIN) Association–WIN Consortium, conducted the WINTHER trial in which the patients were selected for therapy on the basis of fresh biopsy-derived DNA sequencing (arm A; 236 gene panel) or RNA expression (arm B; comparing tumour to normal).
The clinical management committee comprised from the investigators from five countries recommended therapies, prioritising genomic matches. Matching scores were calculated post-hoc for each patient, according to drugs received: for DNA, the number of alterations matched divided by the total alteration number; for RNA, expression-matched drug ranks.
Overall, 303 patients consented and 107 were evaluable for therapy (69 in arm A and 38 in arm B). The median number of previous therapies was three. The most common diagnoses were colon, head and neck, and lung cancers.
The rate of stable disease ≥6 months and partial or complete response was 23.2% in arm A and 31.6% in arm B. The patient proportion with WINTHER versus previous therapy progression-free survival (PFS) ratio of >1.5 was 22.4%, which did not meet the pre-specified primary endpoint. Fewer previous therapies, better performance status and higher matching score correlated with longer PFS (all p < 0.05, multivariate).
The authors concluded that genomic and transcriptomic profiling are both useful for improving therapy recommendations and patient outcome.
The research has received funding from the European Union Seventh Framework Program. This work was funded in part by the ARC Foundation for Cancer Research (France), Pfizer Oncology, Lilly France SAS and Novartis Pharmaceuticals Corporation. This work was also funded in part by The Fero/J.P. Morgan Private Bank Clinical Oncology Research Grant, the National Cancer Institute grant, the Israeli Science Foundation grant, Instituto Salud Carlos III—Programa Rio Hortega Contract grant, the Canadian Institutes for Health Research and the Canadian Cancer Society grants.
Rothwell DG, Ayub M, Cook N, et al. Utility of ctDNA to support patient selection for early phase clinical trials: the TARGET study. Published online 22 April 2019; Nature Medicine. doi: 10.1038/s41591-019-0380-z.
Sicklick JK, Kato S, Okamura R, et al. Molecular profiling of cancer patients enables personalized combination therapy: the I-PREDICT study. Published online 22 April 2019; Nature Medicine. doi: 10.1038/s41591-019-0407-5.
Rodon J, Soria J-C, Berger R, et al. Genomic and transcriptomic profiling expands precision cancer medicine: the WINTHER trial. Published online 22 April 2019; Nature Medicine. doi: 10.1038/s41591-019-0424-4.