Roche's Pan-Cancer Therapy Entrectinib Granted Clinical Trial Approval in China for ROS1-Positive NSCLC and NTRK Fusion-Positive Solid Tumors

Recently, according to the latest public notice from the Center for Drug Evaluation (CDE) of China’s National Medical Products Administration, Roche’s “tumor-agnostic” therapy, entrectinib capsules, has received implicit approval for clinical trials. The drug is proposed for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring ROS1 positivity, or locally advanced or metastatic solid tumors with NTRK1/2/3 gene fusions.

In August this year, entrectinib received accelerated approval from the U.S. FDA for the treatment of adult and pediatric patients with advanced, recurrent solid tumors harboring neurotrophic tyrosine receptor kinase (NTRK) gene fusions. Concurrently, the FDA approved Rozlytrek for the treatment of metastatic non-small cell lung cancer (NSCLC) in patients with ROS1 gene mutations. This marks the third tumor-agnostic anticancer therapy approved by the FDA, following Keytruda and larotrectinib.

It is understood that TRK gene fusions are chromosomal alterations. When the NTRK1, NTRK2, or NTRK3 genes fuse with other genes, they result in the production of structurally abnormal TRK proteins (TRKA, TRKB, and TRKC), which activate signaling pathways associated with the proliferation of specific types of tumor cells, thereby inducing malignancies driven by NTRK gene fusions. The occurrence of NTRK gene fusions is independent of tumor location and patient age, and they can be found in various types of solid tumors, including pancreatic cancer, thyroid cancer, salivary gland cancer, breast cancer, colorectal cancer, and lung cancer. Entrectinib is a selective tyrosine kinase inhibitor designed to target NTRK and ROS1 gene fusions; it inhibits the kinase activity of TRKA/B/C and ROS1.

It is worth noting that entrectinib is not the first tumor-agnostic anticancer drug to receive implied approval for clinical trials in China. As early as March this year, larotrectinib was included in the list of drugs granted implied approval for clinical trials. Larotrectinib, jointly developed by Loxo Oncology and Bayer, is a new-generation, highly specific oral TRK inhibitor. It is also a tumor-agnostic drug that, from the early stages of development, has targeted specific genetic mutations rather than specific cancer types. It is indicated for all patients with tumors expressing tropomyosin receptor kinase (TRK), regardless of the tumor’s anatomical location.

On November 26, 2018, the FDA granted accelerated approval for the marketing of larotrectinib for the treatment of adult and pediatric patients with solid tumors harboring NTRK gene fusions, who have no known resistance mutations, present with widespread metastasis or poor outcomes from local surgical treatment, and whose disease has progressed on existing therapies or who have no alternative treatment options. However, like many drugs, long-term use of larotrectinib can lead to drug resistance. Currently, Bayer and Loxo Oncology are developing second-generation drugs targeting new mutations.

It is also worth noting that so-called broad-spectrum anticancer drugs do not imply efficacy against all cancers, nor do they suggest a cure for cancer. Rather, unlike earlier anticancer agents that were typically indicated only for specific tumor types defined by their anatomical site of origin, these drugs are administered to appropriately selected patients identified through biomarker testing for broad-spectrum anticancer therapies, thereby covering a relatively wider range of tumor types.