Genetic biomarker trumps tissue type in landmark oncology approval

The FDA granted accelerated approval to Merck & Co.'s PD1 blocker pembrolizumab for all cancers with a specific genetic biomarker, regardless of which tissue type is involved. “This is an important first for the cancer community,” said the FDA's Richard Pazdur, acting director of the Office of Hematology and Oncology Products. “Until now, the FDA has approved cancer treatments based on where in the body the cancer started.”

The FDA has already approved pembrolizumab for several tissue-dependent indications, including melanoma, lung cancer and head and neck cancer. With the new supplementary approval, oncologists can now prescribe the checkpoint inhibitor for patients with any cancer type that has high microsatellite instability (MSI-H) or mismatch repair deficient (dMMR) tumours.

MSI-H and dMMR tumours carry genetic mutations that prevent proper DNA repair, leading to high mutational loads and increased production of mutated proteins that can act as antigens to activate the immune system. Drug developers hypothesized that checkpoint inhibitors such as pembrolizumab that stimulate the immune system might consequently be particularly effective in these cancers. When Merck administered its antibody to 149 MSI-H or dMMR patients — with 15 different cancer types, from 5 different clinical trials — treatment led to a complete or partial response rate of 40%.

Whereas Merck's initial development of pembrolizumab relied on a conventional tissue-dependent development programme, a few firms are now developing novel drugs under a tissue-agnostic approach. Loxo Oncology's tropomyosin receptor kinase (TRK) inhibitor larotrectinib could be the first of these to make it to market. In a preliminary analysis of 55 cancer patients who were treated on the basis of TRK fusions rather than tissue type, larotrectinib treatment led to a 76% confirmed objective response rate. The company plans to file for tissue-agnostic FDA approval by late 2017 or early 2018.

Ignyta is pursuing a similar strategy for its phase II TRK inhibitor entrectinib. Other companies that are embracing the tissue-agnostic approach include TP Therapeutics and Blueprint Medicines.


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Mullard, A. Genetic biomarker trumps tissue type in landmark oncology approval. Nat Rev Drug Discov 16, 447 (2017).

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