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RET (rearranged during transfection) is a proto-oncogene, located on chromosome 10. The RET protein encoded by the RET gene is a receptor tyrosine kinase (RTK) present on the cell membrane and belongs to the cadherin superfamily.

When the growth factor binds to the extracellular region of RET, it triggers a series of intracellular chain chemical reactions that cause the cell to divide, mature, and exert its functions, depending on the signal it receives. The RET protein plays an important role in the development of several types of nerves, including the gut and autonomic nervous system. RET protein is required for the development of normal kidneys and sperm production.

 

The incidence of RET gene fusion in NSCLC patients is approximately 1% to 2%, and in thyroid papillary carcinoma (accounting for approximately 85% of all thyroid cancers) the incidence is 10% to 20%. The most common fusion partners include KIF5B, TRIM33, CCDC6, and NCOA4. The incidence of RET gene mutation in medullary thyroid carcinoma is about 60%. The most common mutation site is M918T.

 

At present, the treatment of RET gene changes is mainly the use of multi-kinase inhibitor drugs, such as cabozantinib, vandetanib, due to poor targeting, VDR inhibition-related severe toxicity due to off-target usually occurs.

Blueprint Medicines Vs. Loxo Oncology

Blueprint Medicines and Loxo Oncology are the two companies with relatively recent names. They have received attention in phase I of the ongoing RET inhibitors BLU-667 and LOXO-292.

Blueprint Medicines had reached a cooperation with Keystone Pharmaceuticals on June 6th this year to license the Chinese development rights of 3 drugs including BLU-667 to the latter, with a total transaction value of 386 million U.S. dollars, including a down payment of 40 million U.S. dollars.

Loxo Oncology, a company that develops broad-spectrum antitumor drugs, shined ASCO 2017 with the TRK inhibitor larotrectinib (LOXO-101) last year. This year, LOXO-292 became one of the biggest winners of ASCO2018.

Blueprint Medicines released phase I data for BLU-667 at the AACR2018 conference. Loxo Oncology announced LOXO-292 phase I data at the ASCO conference. Only from the point of view of the data release and the trend of the stock price, it is apparent that Loxo Oncology temporarily won.

Comparison of Phase I Study Data of BLU-667 and LOXO-292

The phase I studies of both are mainly to assess the safety and preliminary efficacy of drug candidates. The baseline characteristics of the patients enrolled are shown in the following table. BLU-667 recruited more patients with refractory RET mutations. LOXO-292 recruited patients with poorer physical strength (2 points for ECOG score) and more patients who received excessive kinase inhibitor therapy.

In terms of safety, BLU-667 and LOXO-292 were well tolerated, and the incidence of grade 3 adverse events was relatively low. No serious grade 4 to 5 adverse events were observed. This point, both are superior to the existing clinical treatment of multi-kinase inhibitors.

In terms of efficacy, the response rates of LOXO-292 and BLU-667 were similar in patients with RET mutations, with ORRs of 45% and 40%, respectively; however, in patients with RET fusion tumors, LOXO-292 performed better than BLU-667. The ORR is 77% and 50% respectively.

As shown in the waterfall below, LOXO-292 shows a high ORR without considering the RET fusion object. For KIF5B-RET gene fusion NSCLC patients, LOXO-292 can achieve 81% of the objective response (tumor shrinkage of more than 30%), for non-KIF5B-RET gene fusion NSCLC patients, ORR of 82%.

The data published by AACR2018 showed that 19 patients with RET gene fusion who had previously received different regimens were treated with BLU-667. The median time of treatment was 3.9 months (0.4 to 11.4 months), and 14 patients were evaluated for clinical data. Among them, there were 0 cases of complete remission, 7 cases of partial remission, 5 cases of stable disease, 2 cases of disease progression, and ORR of 50%.

77% vs. 50%. This set of ORR comparison data shows that the novel RET inhibitors LOXO-292 and BLU-667 have therapeutic potential for patients with RET gene alterations and are expected to offer new treatment options for these patients.

The difference between the two can be used to explain the trend of the stock price and the investor’s current mood of voting with their feet. However, it is not enough to show that LOXO-292 is better than BLU-667. After all, the mechanism of action is the same, and the large-scale clinical There are still relatively large variables in the test development process.

Ignyta/Roche previously reported phase Ib studies of its RET inhibitor RXDX-105, with an ORR of 75% (6/8) in patients with non-KIF5B-RET gene fusion tumors, but in patients with KIF5B-RET gene fusion tumors. The ORR of RXDX-105 is 0% (0/14). Obviously, RXDX-105 does not have the potential to cover KIF5B-RET gene fusion.

In contrast, there are now well-established preclinical and clinical studies supporting the hypothesis that LOXO-292 and BLU-667 are superior to RXDX-105 in regulating KIF5B-RET fusion.

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