Prospective experimental treatment of colorectal cancer patients based on organoid drug responses

Abstract

Background: Organoid technology has recently emerged as a powerful tool to assess drug sensitivity of individual patient tumors in vitro. Organoids may therefore represent a new avenue for precision medicine, as this circumvents many of the complexities associated with DNA- or transcriptional-profiling.

Materials and methods: The SENSOR trial was a single-arm, single-center, prospective intervention trial to evaluate the feasibility of patient-derived organoids to allocate patients for treatment with off-label or investigational agents. The primary endpoint was an objective response rate of ≥20%. Patients underwent a biopsy for culture before commencing their last round standard of care. Organoids were exposed to a panel of eight drugs and patients were treated after progression on standard-of-care treatment and when a clear signal of antitumor activity was identified in vitro.

Results: Sixty-one patients were included and we generated 31 organoids of 54 eligible patients. Twenty-five cultures were subjected to drug screening and 19 organoids exhibited substantial responses to one or more drugs. Three patients underwent treatment with vistusertib and three with capivasertib. Despite drug sensitivity of organoids, patients did not demonstrate objective clinical responses to the recommended treatment.

Conclusions: Organoid technology had limited value as a tool for precision medicine in this patient population because a large fraction of patients could not undergo treatment or because the recommended treatment did not elicit an objective response. We identified several essential parameters, such as the culture success rate, clinical deterioration of patients during standard of care, and rational design of drug panels that need to be accounted for in organoid-guided clinical studies.

Keywords: clinical trial; colorectal cancer; drug screening; experimental treatment; precision medicine; tumor organoids.

Figure 1

Development of a decision model based on drug screening of 16 organoids. The cohort of 16 organoids and their response to the GR_max concentration of each drug after 6 days. Effects were calculated using GR metrics. 1 = no effect, 0 = no growth, and <0 = a certain amount of cytotoxicity (up to −1). A cut-off of 0.1 was set, represented by the dotted line, discriminating between what was considered a hit versus no hit. All organoids were plotted on the x-axis and sorted from resistant to sensitive. All drug names were plotted at the top of each graph and the target(s) below. At the bottom of each graph we noted the number of virtual hits per drug. For selumetinib and gefitinib, additional, color-coded information on KRAS or the EGF-pathway status was added per organoid line. GR, growth-rate corrected metric; N/A, not available.

Figure 2

Enrolment and organoid drug profiling of patients in the SENSOR trial. (A) Outline of the SENSOR trial. Patients undergo a biopsy of a metastatic lesion for generation of organoids before start of their last line standard-of-care (SOC) treatment. 1. Patients underwent biopsy of a metastatc lesion. Part of the biopsies were also used for DNA sequencing. 2. Organoid cultures are generated from biopsies and frozen in master and working biobanks at low passage. 3. Organoids are profiled for their response to eight FDA-approved or investigational drugs. Patients received treatment when organoid drug response was qualified as a hit after two repeated experiments. In case organoids displayed sensitivity towards multiple drugs, patients received drug treatment with the strongest hit. 4. Patients received the drug identified in the drug screen after progression on SOC or went off study when no treatment option was available. Patient underwent a mandatory second biopsy before start of experimental treatment, which was used for a second confirmatory organoid culture. These were subjected to the same drug screen as identified in step 3 to control for potential change in drug sensitivity due to intermittent SOC treatment. (B) Flow chart on inclusion and dropout of patients in the SENSOR trial. (C) Heatmap with drug screening result of all organoids. Organoids were profiled for their drug response to the drug concentrations identified in Figure 1 (GR_max) and the average of two or, in the case of discrepant results, three independent replicates is given in the heatmap per drug and organoid. At the top, hits in six organoids were identified that subsequently led to treatment of the respective patients. The hits in the middle 13 organoids did not lead to treatment due to various reasons stated at the bottom of the flowchart. In the bottom six organoids, no hits were identified. (D) Patients that started treatment underwent a second biopsy after progression on SOC (represented by P#-2), and organoids were re-screened to control for potential shifts in drug sensitivity. GR, growth-rate corrected metric; mCRC, metastatic colorectal cancer; SOC, standard of care.