In 2018, Loxo Oncology’s “unlimited cancer” targeted therapy Vitrakvi was approved by FDA, becoming the first targeted therapy for patients with NTRK gene fusion variant solid tumors. Loxo, on the other hand, had begun to develop a new generation of TRK inhibitors before Vitrakvi was approved. Although Vitrakvi, as an TRK inhibitor, achieved a remission rate of 75 per cent in the treatment of solid tumors. However, with the passage of time, tumors will obtain gene mutations that are resistant to TRK inhibitors, so it is urgent to develop a new generation of inhibitors that can be effective against these tumors.

On April 2, Bayer announced the results of a new generation of TRK inhibitor LOXO-195 developed by Loxo in early clinical trials. After Loxo was acquired by Lilly, Bayer acquired an exclusive R&D interest in LOXO-195. LOXO-195 can inhibit the activity of TRK protein, which is already resistant to TRK inhibitors. The results showed that LOXO-195 achieved an objective remission rate (ORR) of 45 per cent in 20 patients with solid tumors who had been treated with an TRK inhibitor and were resistant to it. Although this study is still in its early clinical stages, it suggests that LOXO-195 may help address the unfinished medical needs of patients with solid tumors who are resistant to existing TRK inhibitors.

PARP inhibitors are a class of drugs that treat tumors carrying BRCA gene mutation or homologous recombination DNA repair mechanism deletion through a “synthetic lethal” mechanism. They have shown excellent efficacy in the treatment of ovarian and breast cancer. Recent studies have shown that these drugs can also play a role in other types of cancer. In February 2019, Lynparza, developed by AstraZeneca and Merck Sharp & Dohme (MSD), served as a maintenance therapy and reached the main end point in a phase 3 clinical trial for the treatment of pancreatic cancer. At the American Association for Cancer Research (AACR) meeting on April 3, Clovis’s PARP inhibitor Rubraca also obtained positive data in a phase II clinical trial of pancreatic cancer. These preliminary data, combined with Lynparza’s phase 3 data, suggest that PARP inhibitors may provide a new treatment for advanced pancreatic cancer.

Bispecific antibody and polyspecific antibody are becoming a new mode of cancer treatment. At the AACR meeting, Inovio presented preclinical data on the company’s innovative DNA-encoded bispecific T-cell engager (dBiTE). One end of the bispecific T cell engager (BiTE) can bind to the specific antigen on the tumor surface, while the other end can bind to the CD3 receptor on the T cell surface to recruit T cells around the tumor and play a role in killing tumor cells. One of the challenges faced by BiTE-type proteins is their poor stability, resulting in patients requiring frequent treatment. Inovio’s innovative strategy is to introduce DNA encoding BiTE protein into human cells, making human cells a “factory” for BiTE production, thereby continuing to provide BiTE protein.

Mechanisms of action of bispecific antibodies. (Figure from: Human Vaccines & Immunotherapeutics)

Preclinical studies published by AACR have shown that dBiTE targeting HER2 protein developed by Inovio can maintain a high level of BiTE protein expression in mouse model of breast and ovarian cancer after a single treatment for 4 months. Moreover, dBiTE targeting HER2 can effectively stimulate the cytotoxicity of T cells to tumor cells expressing HER2, resulting in close to complete tumor clearance. Dr. Joseph Kim, President and Chief Executive Officer of Inovio, said that based on these positive preclinical results, the company is ready to quickly push dBiTE into clinical development.