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New Oral Medication Approved for Metastatic Colorectal Cancer

According to the National Cancer Institute, Colorectal cancer (CRC) is the third most common non-skin cancer in men and women in the U.S. and the second leading cause of cancer-related death. In the last 10 years the number of disease-related deaths have declined, partly due to more frequent screenings. On September 22nd the U.S. FDA approved Lonsurf for patients with an advanced form of colorectal cancer who are no longer responding to other therapies.

Fluoropyrimidines are a category of drugs widely used in the treatment of a variety of cancer types including colorectal and breast cancer or cancers of the aerodigestive tract. They work by interfering with DNA synthesis leading to tumor cell death. 5-Fluorouracil (5-FU), one of the most popular drugs in this category, was first synthetized in 1957 but soon enough the need for more convenient and efficacious fluoropyrimidine therapy was evident since 5-FU needed to be administered over long periods of time via intravenous infusion and patients eventually relapsed, becoming resistant to treatment.

Trifluridine is the fluoropyrimidine component of Lonsurf. Phase I and Phase II clinical trials of intravenous trifluridine alone initially proved disappointing since the drug was rapidly degraded once in the blood stream and tumors rapidly recurred upon termination of therapy. Thanks to significant progress in the understanding of the pharmacokinetic of trifluridine, it became clear that when taken orally, the drug was more stable especially if administered in combination with a thymidine phosphorylase inhibitor (TPI), a compound that blocks trifluridine degradation.

The formulation of Lonsurf is based on the knowledge acquired over the years for this class of compounds. In Lonsurf trifluridine is combined with tipiracil – a TPI – and this combination is indicated for the treatment of patients with metastatic colorectal cancer who have been previously treated with fluoropyrimidine, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and an anti-EGFR therapy - in the case of patients with wild-type RAS.

Lonsurf efficacy and safety were evaluated in the RECOURSE international, randomized, double-blind trial involving 800 patients with previously treated metastatic colorectal cancer. The primary endpoint of the study was overall survival and the secondary endpoint was progression-free survival. Patients treated with Lonsurf lived longer compared to those treated with placebo and stayed disease-free for a longer period of time, providing patients and their oncologists with a novel oral therapy.

Lonsurf is manufactured by Taiho Oncology Inc., and was already approved in Japan early this year, based on findings from Phase II studies.

Crown Bioscience is happy to see that progress is being made in the treatment of metastatic CRC. At Crown we recognize that the high attrition rate in oncology drug development still represents a significant challenge for pharma and biotechs, with around 60% of failures coming in Phase II testing onwards. Most oncology drug failures are linked to efficacy issues (not toxicity) and can be attributed to poor preclinical strategies and a lack of an effective associated clinical plan. Translational platforms are needed which can identify the correct set of patient responders for a drug, in order to focus clinical study on using the right drug, for the correct indication, within the right cancer subpopulation.

At Crown Bioscience we are pioneers in the use of patient-derived xenograft (PDX) models to ensure the highest likelihood of success when moving new drugs in to the clinic. We have generated HuPrime® the world’s largest commercial collection of over 1,600 patient-derived xenograft models, which allows research into over 20 different cancer indications, and a variety of subtypes. Using these models in our Translational Platforms HuTrial, HuSignature, and HuMark allows clients to utilize precision profiling to identify molecular biomarkers and genetic signatures of response before entering the clinic. Finding your responder population before entering late-phase clinical trials is the best way to stratify potential clinical trial participants, increasing the likelihood of response, and reducing attrition rate.

Contact us today at busdev@crownbio.com for any further questions or information on our CRC PDX models and services.

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