The PRAVO study – Pelvic Radiation and Vorinostat
This was the first reported study ever on the combination of radiotherapy and epigenetic modulation with a histone deacetylase (HDAC) inhibitor.
Together with her collaborators, Ree initiated the HDAC inhibitor and radiation program in 2004 on experimental CRC cell models, with publications in 2005-2008 (one in Nature Genetics).
In 2009 and 2012 they published the continuation of the preclinical program in animal models.
A 2010 Lancet Oncology paper reported the end point data from patients with end-stage bowel cancer in the phase 1 PRAVO study, including results from the integrated magnetic resonance imaging (MRI)-based and molecular biomarker programs.
The study toxicity data were reanalyzed with emphasis on the radiation effects, before the research group translated the program back to the laboratory in the quest of HDAC inhibitor biomarkers and involved molecular mechanisms in study patients’ biological specimens.
This program has been acknowledged as a template for how to integrate targeted drugs with radiotherapy.
(2007-2009; NCT00455351)
The LARC-RRP study – Locally Advanced Rectal Cancer—Radiation Response Predicton
The study enrolled more than 100 rectal cancer patients (2005-2010), who were given curative-intent and, in this case, experimental short-course oxaliplatin-based induction chemotherapy before routine chemoradiotherapy and pelvic surgery.
The entire study population, at high risk of metastatic progression, has now been followed for 10 years (in 2020) and shown remarkably good metastasis-free and overall survival.
The numerous PhD and postdoctoral projects the study has led to over the years have revealed that the advantageous long-term outcome reflects the induction and maintenance of tumor-defeating immunity invoked by the low-cost, well-tolerated, oxaliplatin-based chemotherapy.
(2005-2020; NCT00278694)
The METIMMOX study – Colorectal Cancer Metastasis—Shaping Anti-Tumor Immunity by Oxaliplatin
The study is still ongoing. This multicenter randomized phase 2 study is directly based on the findings that tumor-defeating immunity can be invoked by short-course oxaliplatin-based chemotherapy, and then strengthened by immune therapy in patients with previously untreated unresectable metastatic CRC with proficient DNA mismatch-repair function (pMMR).
The pMMR entity, affecting 90% of all advanced-stage CRC cases, is inherently non-immunogenic.
In the METIMMOX study, about half of patients assigned to the experimental treatment with alternating short-course immunogenic chemotherapy and immune therapy met an early occurring and simply measurable radiologic signal (on routine CT scan) of immune therapy responsiveness predicting significantly extended progression-free survival.
Of note, one fifth of patients have experienced durable complete response. Such first-line outcomes in metastatic pMMR-CRC are remarkable. The study also includes an investigator-designed biomarker program on functional MRI-, molecular-, and circulating immune factors for patient stratification.
(from 2018; NCT03388190)
The METIMMOX-2 study
The study is based on the observations from the first METIMMOX study.
In this nation-wide study, all enrolled patients (with previously untreated unresectable metastatic pMMR-CRC) receive the experimental METIMMOX treatment until the first post-baseline CT reassessment.
At this earliest possible time of treatment evaluation, patients who have met the pragmatic CT measure continue the investigational schedule with the intention to obtain extended progression-free survival as observed in the first study.
Patients who are negative for the CT marker are changed to standard chemotherapy, which averts the risk of compromising prognosis for patients with early failure to the immune therapy.
The METIMMOX-2 study also continues the investigator-designed biomarker program. (from 2022; NCT05504252)
The OxyTarget study – Functional MRI of Hypoxia-mediated Rectal Cancer Aggressiveness
This was a prospective population-based biomarker study that enrolled 180 patients representing the entire range of rectal cancer stages.
The study has become a rich source for exploring functional MRI-based and circulating biomarkers of the tumor microenvironment, illustrated by the 2020 publication in the premier radiology journal Radiology on a novel MRI biomarker for rectal cancer outcome prediction.
Several PhD and postdoctoral projects have originated and will continue to evolve from this unique study.
(2013-2017; NCT01816607)
The MetAction study – Actionable Targets in Cancer Metastasis
Exploring how tumor molecular vulnerabilities may predict therapy response, this study established the required diagnostic workflow for DNA sequencing and data interpretation (2014-2015) and used it to identify molecularly matched therapy in end-stage cancer (2016-2019).
The conduct of this first precision cancer medicine (PCM) study in Norway revealed the complexity of sensitivity versus resistance and patient safety in therapy decisions that reside in tumor sequence data.
Apart from the very few patients found eligible for immune therapy, which led to full recovery, the overall survival was essentially similar for study patients who did and did not receive molecularly matched therapy.
The MetAction findings, which were no worse than corresponding tumor genome-informed PCM studies on the international arena, have convinced Ree to express caution about PCM being considered a definitive game changer in end-stage cancer.
In fall 2022, Ree and colleagues published cost-effectiveness analysis of PCM in end-stage cancer, based on the MetAction data, which revealed that the costs of the PCM strategy were twice as high as the national willingness-to-pay threshold, driven by the high-priced molecularly matched medications with marginal patient benefit in end-stage cancer.
(2014-2019; NCT02142036)
Functional PCM for Metastatic CRC
In 2024, professor Ree will launch a randomized control trial (RCT) in Functional PCM for Metastatic CRC.
Clinical evidence of efficacy and safety of therapies, demonstrated in RCTs, provides the framework for oncology practice. This ought also be the premise for the prudent introduction of PCM.
However, over the past decade, it has been an unwelcome surprise to discover that tumor genome-informed PCM, as motivation for the off-label provision of molecularly matched medications to patients with advanced disease after all other systemic tumor-directed therapies have failed, has been to limited avail.
Also, there has been a scarcity of PCM trials that accurately reflect treatment effects compared to a pertinent control arm.
Moreover, costs for tumor genome-informed PCM are driven by expenses relating to next-generation sequencing and particularly the high-priced molecularly matched medications with marginal patient benefit in end-stage cancer, as professor Ree has reported in several publications.
The planned RCT will address each of these PCM challenges in patients with metastatic CRC. The TargetCRC study (from 2022) has developed the diagnostic functional precision medicine tool to be used in the RCT.