Precision medicine applied to metastatic colorectal cancer using tumor-derived organoids and in-vitro sensitivity testing: a phase 2, single-center, open-label, and non-comparative study

Abstract

Background Patients with colorectal metastatic disease have a poor prognosis, limited therapeutic options, and frequent development of resistance. Strategies based on tumor-derived organoids are a powerful tool to assess drug sensitivity at an individual level and to suggest new treatment options or re-challenge. Here, we evaluated the method’s feasibility and clinical outcome as applied to patients with no satisfactory treatment options. Methods In this phase 2, single-center, open-label, non-comparative study (ClinicalTrials.gov, register NCT03251612), we enrolled 90 patients with metastatic colorectal cancer following progression on or after standard therapy. Participants were 18 years or older with an Eastern Cooperative Oncology Group performance status of 0–2, adequate organ function, and metastasis available for biopsy. Biopsies from the metastatic site were cultured using organoids model. Sensitivity testing was performed with a panel of drugs with proven activity in phase II or III trials. At the discretion of the investigator considering toxicity, the drug with the highest relative activity was offered. The primary endpoint was the proportion of patients alive without disease progression at two months per local assessment. Results Biopsies available from 82 to 90 patients were processed for cell culture, of which 44 successfully generated organoids with at least one treatment suggested. The precision cohort of 34 patients started treatment and the primary endpoint, progression-free survival (PFS) at two months was met in 17 patients (50%, 95% CI 32–68), exceeding the pre-defined level (14 of 45; 31%). The median PFS was 67 days (95% CI 51–108), and the median overall survival was 189 days (95% CI 103–277). Conclusions Patient-derived organoids and in-vitro sensitivity testing were feasible in a cohort of metastatic colorectal cancer. The primary endpoint was met, as half of the patients were without progression at two months. Cancer patients may benefit from functional testing using tumor-derived organoids. Trial registration ClinicalTrials.gov, register NCT03251612.

Unified framework for patient-derived, tumor-organoid-based predictive testing of standard-of-care therapies in metastatic colorectal cancer

“…Previous studies sampling CRC biopsies from metastatic sites have reported culture success rates of 54%–63% using culture methods with PDTO embedment into solid support matrices. 13 , 37 , 38 In the AGITG FORECAST-1 study, we achieved a similar 63% overall success rate for PDTO LVM cultures 25 and identified CRC liver metastases as the optimal biopsy site for PDTO generation with a 75% success rate (compared to 50% for other sites). Nonetheless, PDTO culture success rate remains a major barrier to eventual clinical translation with biopsy size, tumor cell content, and viability established as critical factors for success 18 , 38 ; further improvements in PDTO success rate may be achieved by increasing biopsy number and/or size and by further optimization of culture conditions such as replacement of classic niche factors with emerging biomimetic compounds or introduction of new biopsy methods.…”

“…The duration of PDTO expansion prior to in vitro treatments depends on tumor cell proliferation rate and the required cell input and number of assay points. 13 , 37 , 38 For AGITG FORECAST-1, we required 4–21 weeks to examine 9 single agents in duplicate 9-step dose titrations and 2 drug combinations in duplicate 7 × 7 matrices. However, PDTO assay miniaturization to a 2-point window was found to maintain and potentially improve prediction accuracy and association with PFS.…”

“…This time frame is in line with that of a recent phase 2, single-arm study of PDTO-guided use of investigational agents in refractory mCRC ( ClinicalTrials.gov : NCT03251612 ), which achieved treatment assignment within a median of 51 days from enrollment for 38% study participants and reported improved PFS as compared to benchmark clinical trial data. 37 Additional efforts in assay miniaturization, including exploration of emerging organoid-on-a-chip approaches, 42 , 43 will be required for PDTO drug sensitivity testing to meet timelines required for clinical implementation.…”

Organoids as a biomarker for personalized treatment in metastatic colorectal cancer: drug screen optimization and correlation with patient response

“…Propidium iodide and Hoechst have previously demonstrated their suitability for high-throughput screening of colorectal adenoma PDOs [ 39 ]. CyQUANT was used previously in a prospective organoid-guided interventional trial with positive results, albeit with modest clinical benefit [ 40 ]. We confirmed that drug sensitivity measurements with the CyQUANT readout instead of the ATP-based CellTiter-Glo readout was possible in 3D-based screens and did not affect the correlation with patient response.…”

Emerging roles of 3D-culture systems in tackling tumor drug resistance

“…In a phase 2 study involving 90 mCRC patients with progression after standard therapy, organoids derived from metastatic biopsies were cultured and evaluated for sensitivity to a panel of drugs. Patients were treated with the drug demonstrating the highest relative activity, resulting in a 50% progression-free rate at two months [ 83 ] . Another study generated organoids from 40 mCRC patients and performed drug screenings, associating the results with patients’ responses.…”