10P - Multivariate analysis of functional organoid assays predicts patient responses in the clinic for colorectal and pancreatic cancer

Background

Precision oncology aims to deliver the right cancer treatment for each patient, and conversely for drug developers to find the right patients for each cancer treatment. To achieve this vision, new tools are needed. Functional assays testing drugs on patient-derived organoids (PDO) are a promising solution, however until now few studies have proven their relevance on large population-scale cohorts.

Methods

We have assembled a collection of 155 demographically and clinically relevant PDOs from pancreatic (70) and colorectal (85) cancers. Each PDO was challenged with the drugs the patient received in the clinic after the PDO-line establishment. Combining biochemical end point assay results and multimodal analysis, we developed a model to predict prospective patient responses.

Results

For the subset of patients with complete clinical outcomes, best-in-class clinical prospective predictions of overall response (n = 56; Se = 83%, Sp = 88%, AUROC = 90.3%) and progression-free survival (n = 53; Cox model C-score = 0.59, hazard ratio (HR) of prediction = 2.82, 95% CI (1.25, 6.33)) were achieved. Treatments identified as hits scored favorably on the growth modulation index (GMI) (n = 73, hit: GMI = 1.81, non-hit GMI = 0.78, p = 1.93e-04). Clinical outcomes are influenced by multiple factors. By including clinical and molecular variables to conduct multivariate predictions, we improve the accuracy of the survival outcome predictions (Cox model C-score = 0.69). The number of prior lines of treatment and the disease type influence the patient responses (HR = 1.37, p = 0.075, CI = (0.97, 1.95); HR = 1.89, p = 0.099, CI = (0.89, 1.58)) while ECOG at diagnosis does not (HR = 0.89, p = 0.69). This analysis shows that clinical and molecular variables act as confusion factors, and controlling for them strengthens the predictive value of the functional assay results (HR = 4.36, p = 0.0027, CI = (1.66, 11.41)).

Conclusions

The inclusion of different clinical and molecular variables significantly improves the predictive capabilities of functional screens conducted on PDOs. These results show that incorporating contextual variables to the PDO assays powers predictability in precision oncology.

Clinical trial identification

NCT04932525, NCT02517892, NCT0493252.

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Orakl Oncology.

Disclosure

A. Gryspeert: Financial Interests, Personal, Full or part-time Employment: Orakl Oncology. J. Cartry: Financial Interests, Personal, Stocks or ownership: Orakl Oncology; Financial Interests, Personal, Speaker, Consultant, Advisor: Orakl Oncology. A. Boileve: Non-Financial Interests, Institutional, Non financial benefits: Pfizer, Merck, Ipsen. G. Altay: Financial Interests, Personal, Full or part-time Employment: Orakl Oncology; Financial Interests, Personal, Stocks/Shares: Orakl Oncology. M.P. Ducreux: Financial Interests, Personal, Invited Speaker: Roche, Amgen, Pierre Fabre, Merck Kga, Pfizer, Bayer, Lilly, Servier, MSD, BeiGene; Financial Interests, Personal, Advisory Board: Roche, Basilea, Pierre Fabre, Boehringer Ingelheim, Rafael, Servier, Zymeworks, Ipsen, Bayer, HalioDX, Lilly, GSK, Daiichi Sankyo, MSD, Servier, BeiGene; Financial Interests, Institutional, Advisory Board: AstraZeneca; Financial Interests, Institutional, Funding, Partial funding of a trial evaluating the role of bevacizumab in NET: Roche; Financial Interests, Institutional, Funding, Partial funding of a trial evaluating the role of steptozotocin in NET: Keocyt; Financial Interests, Institutional, Local PI: Rafael, Amgen; Financial Interests, Institutional, Funding: Bayer; Other, My wife is head of the oncology business unit in the French Affiliate of Sandoz: Sandoz France. D. Pagès: Financial Interests, Personal, Stocks or ownership: Orakl Oncology; Financial Interests, Personal, Full or part-time Employment: Orakl Oncology. F. Jaulin: Financial Interests, Personal, Stocks or ownership: Orakl Oncology; Financial Interests, Personal, Full or part-time Employment: Orakl Oncology; Financial Interests, Institutional, Research Funding: AstraZeneca, Roche. G. Ronteix: Financial Interests, Personal, Full or part-time Employment: Orakl Oncology; Financial Interests, Personal, Ownership Interest: Orakl Oncology; Non-Financial Interests, Leadership Role: Orakl Oncology. All other authors have declared no conflicts of interest.