When a drug screen in organoids pointed us towards a new drug combination against a subtype of colorectal cancer, we wanted to test it in patients. The journey from lab to clinic took ten years, three disciplines, and a risk-tolerant funding model. It led us to an unexpected destination.
This article was originally written by the authors of the RASTRIC trial as part of a “Behind the Paper” blog post. It shares their perspective on the journey from lab to clinic, and the lessons learned along the way.
By Jeanine Roodhart (UMC Utrecht), with contributions from Hugo Snippert (Oncode Investigator, Prinses Máxima Centrum).
About half of the patients with metastatic colorectal cancer (CRC) have a specific mutation in genes that can drive tumour growth: RAS oncogenes. Patients with this subtype, RAS-mutant CRC, have fewer treatment options and a worse prognosis than those without the mutation.
In 2016, two researchers from the University Medical Center Utrecht (UMCU) who approached the disease from different angles started a collaboration to discover new treatment options. Hans Bos had studied RAS signalling for decades and understood the molecular biology behind why these tumours resist treatment. Hugo Snippert had built up expertise and know-how in the new field of patient-derived organoids, which support testing of drug combinations on living tumour tissue. They pooled their knowledge to perform a drug screen on organoids made from the cells of RAS-mutant CRC.
The team wanted to test whether shutting down RAS-mutant signaling with a combination of two classes of drugs, pan-HER and MEK inhibitors, could expose vulnerabilities in these cancer cells. The screen revealed one.
In 23 of 25 organoid models, tumour cells were killed when a third drug was added to the mix: a microtubule-targeting agent1,2. The combination was critical. Dual pan-HER and MEK inhibition only stalled tumour cell growth. The addition of the third drug made cells die. This looked like a lead worth pursuing, especially since microtubule-targeting agents are relatively commonly used chemotherapeutics.
Making the trial happen
That’s where I came in. As a medical oncologist, I see patients in need of better options every day, and was excited by the possibility of translating this laboratory finding into a new therapy. I joined the team to set up the RASTRIC clinical trial. It was no simple feat.
The challenge started when we approached pharmaceutical companies to supply drugs for the study. None were willing. The combination involved three agents from different manufacturers: the pan-HER inhibitor lapatinib alongside the MEK inhibitor trametinib, plus the microtubule-targeting agent vinorelbine. No single company owned the full regimen, so there was little commercial incentive to support an academic investigator-driven trial.
In the end, what made RASTRIC possible was Oncode Institute's Clinical Proof of Concept programme: a unique instrument designed to bridge exactly this translational gap between validated discoveries and early clinical testing. Unlike traditional schemes, the Clinical Proof of Concept programme supports investigator-driven trials that lack immediate commercial backing but hold strong biological rationale. This type of risk-tolerant investment was essential for RASTRIC. It allowed us to move forward when conventional funding pathways were not an option, and to run the trial from our own academic center.
However, this meant that we had to fund the drugs ourselves. That led to a practical choice. We had used trametinib as the MEK inhibitor in the organoid screen, but switched to binimetinib for the trial since it was expected to come off-patent first. If the combination proved effective, this could lower the price of the treatment.
We designed a dose-escalation study to find a safe regimen, followed by a two-stage evaluation of tumour responses. Organoids were not only the scientific rationale for the trial; they were also built into the study design. To better understand participating patients’ drug responses, we collected biopsies, grew organoid cultures from them, and tested drug sensitivity ex vivo alongside monitoring clinical response.
In August 2020, the first patient was enrolled.
What the trial taught us
The results3, now published in the British Journal of Cancer, did not show the efficacy we hoped for. There were no objective tumour responses across 33 evaluable patients. Nine patients had stable disease, three of whom maintained it for over three months. The study was terminated after the first stage of phase II. Nonetheless, RASTRIC’s two-way study design involving both patient monitoring and organoids still provided valuable lessons.3
First, others can learn from RASTRIC’s complex dose-escalation across seven dose levels and three different treatment schedules. Our paper describes the journey in detail: how weekly vinorelbine caused dose-limiting neutropenia, prompting a switch to a two-out-of-three-weeks schedule, and how we adopted a prophylactic budesonide/loperamide anti-diarrhoeal protocol from the breast cancer field. This led to an unexpected pharmacokinetic interaction: loperamide-induced constipation was associated with higher binimetinib exposure, possibly by prolonging gut transit time. The strict prophylaxis regimen at one dose level coincided with more toxicity and side effects, but after removing prophylactic loperamide while maintaining budesonide the regimen became tolerable. For anyone designing combination trials with oral targeted agents, our findings are directly relevant.
Another key insight came after the trial. The organoids used in the original drug screen were derived from chemotherapy-naïve tumours, whereas early-phase trials typically enroll heavily pretreated patients. When we generated tumour organoids from patients who had participated in RASTRIC, they were much more therapy-resistant than organoids used in the original screen. This suggests that organoids recapitulate therapy-induced resistance, and that if we would have had access to organoids from pre-treated patients earlier in development, we may have seen the limited efficacy of the triple therapy earlier. Then we could have chosen a different drug combination or patient population. This work is ongoing and will be reported separately.
Lastly, because we established organoids from trial participants and measured intratumoural drug levels, we can now ask more precise questions to understand drug response. We are now investigating if the lack of response was driven by tumour resistance, insufficient drug exposure, or both, using organoid sensitivity, pharmacokinetic, and clinical outcome data.
From one trial to a broader effort
Building RASTRIC from scratch, securing funding, navigating drug supply, and learning from a negative result fed into a broader conversation about how translational cancer research should be organised in the Netherlands. In 2023, Oncode Accelerator was launched with €325 million from the Dutch National Growth Fund, bringing together over 35 partners to build shared infrastructure for patient cohorts, organoid biobanks, and AI-supported cancer drug development.
As Lead of the Patient Cohorts Platform within Oncode Accelerator, I now work on the kind of infrastructure we would have benefitted from when we started RASTRIC. The goal is that future organoid-guided trials can draw on established cohorts and standardised models, rather than building everything from the ground up each time. Our experience also aligns with a central focus of Oncode Accelerator: developing laboratory models that closely mimic the situation in real patients.
Based on learnings from RASTRIC and other trials, the Dutch oncology ecosystem is now evolving into a more connected model, in which discovery, translation, and infrastructure are no longer isolated efforts. Oncode Institute and Oncode Accelerator play complementary roles in this landscape. Oncode Accelerator innovates and validates the preclinical oncology drug development infrastructure needed to de-risk oncology assets before they reach patients, and Oncode Institute enables high-risk translational steps through instruments such as the Clinical Proof of Concept programme that supported RASTRIC.
We are grateful to the forty patients who took part in this study. The organoid models and data they helped create continue to inform our work on matching and understanding drug combinations to individual patients. Their contribution reaches far beyond the results of any single trial.
Citations
1. Verissimo CS, Overmeer RM, Ponsioen B, Drost J, Mertens S, Verlaan-Klink I, van Gerwen B, van der Ven M, van de Wetering M, Egan DA, Bernards R, Clevers H, Bos JL, Snippert HJ (2016). Targeting mutant RAS in patient-derived colorectal cancer organoids by combinatorial drug screening eLife 5:e18489. doi: 10.7554/eLife.18489
2. Mertens S, Huismans MA, Verissimo CS, Ponsioen B, Overmeer R, Proost N, van Tellingen O, van de Ven M, Begthel H, Boj SF, Clevers H, Roodhart JML, Bos JL, Snippert HJG (2023). Drug-repurposing screen on patient-derived organoids identifies therapy-induced vulnerability in KRAS-mutant colon cancer. Cell Rep 25;42(4):112324. doi: 10.1016/j.celrep.2023.112324.
3. Huismans MA, Gort EH, van der Heijden LT, Guven Mese AM, Klein Wolterink HM, Braat MNGJA, Elias SG, de Vos FYFL, Devriese LA, Verheul HMW, Opdam FL, Koopman M, Nienhuis HH, Crommelin HA, Snippert HJG, Huitema ADR, Roodhart JML. Safety and efficacy of lapatinib, binimetinib, and vinorelbine for RAS mutant metastatic colorectal cancer: results of the RASTRIC phase I/II trial. BJC 2026, 10.1038/s41416-026-03398-x