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Next-Gen Sequencing, Statistical Tools Key to Trans-Tumor Drug Development

Posted 23 February 2018 | By Michael Mezher 

Next-Gen Sequencing, Statistical Tools Key to Trans-Tumor Drug Development

Key challenges to developing "trans-tumor" targeted therapies are outlined in an editorial in the New England Journal of Medicine published Thursday by Fabrice André, head of the predictive biomarkers and novel therapeutic strategies in oncology unit at the Institute Gustave Roussy.


With recent advances in genetic sequencing technology and greater understanding of the roles specific genes or mutations play in different diseases, drugmakers are increasingly focused on developing therapies that target specific genetic biomarkers.

Some of these rare genetic alterations occur in multiple types of cancer and are being pursued as targets for therapies that could potentially treat patients regardless of where the cancer is located in their bodies.

In May, FDA granted accelerated approval to Merck's Keytruda (pembrolizumab) to treat patients with unresectable or metastatic solid tumors that have a biomarker known as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), making it the first therapy approved with a "tissue-agnostic" or "trans-tumor" indication.

Trans-Tumor Therapy

André's editorial was published alongside a pooled analysis of three prospective single-arm clinical trials (Phase I, Phase I-II and Phase II) involving 55 adult and pediatric patients treated with Loxo Oncology's investigational drug larotrectinib.

Notably, the study enrolled patients with 12 different tumor types, including mammary analogue secretory carcinoma of the salivary gland, infantile fibrosarcoma and thyroid cancer, and did not find a difference in efficacy among them.

"This study is an illustration of what is likely to be the future of drug development in rare genomic entities," André writes.

Despite these results and Merck's recent tissue-agnostic indication for Keytruda, André writes that conducting randomized trials in cancers with rare genomic alterations will remain a challenge due to the low incidence of those markers.

As such, André writes that tools, such as the European Society of Medical Oncology's Magnitude of Clinical Benefit Scale, and large data sets such as the Genomics Evidence Neoplasia Information Exchange (GENE) project, developed by the American Association for Cancer Research, are needed to measure study results and establish baseline data about the natural history of various cancers where randomized trials are not feasible.

André also cautions that other basket trials looking for trans-tumor efficacy have been unsuccessful, such as Genentech's Zelboraf (vemurafenib) in patients with BRAF V600 mutation-positive nonmelanoma cancers, and says that researchers must develop a better understanding of why those therapies failed.

"Some challenges for the future of trans-tumor trials include the development of statistical tools to support a claim that a drug works across tumor types and a more in-depth understanding of the failure of some targets in a trans-tumor approach," André writes.

André says that the future success of targeted therapies hinges on the development of robust next-generation sequencing (NGS) based companion diagnostics that can test for many genomic alterations at once.

"The next challenge in the field of precision oncology will be to reconcile the concept of companion diagnostic testing with the use of multigene panels," André writes.

Lastly, André says that regulatory harmonization will help make efforts to study therapies for rare genetic alterations more feasible and facilitate global clinical trials.


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