"The topic of this NSCLC trial structure and biometrics has been discussed ad nauseum by members of this board dating back at least 3 years, and EXEL management has been chastised at length for omitting the development of Cabo in the lung space. What gives?
What has changed? Why did this take so long?"
The opportunity to take advantage of the RET + NSCLC indication has come and gone. There are now more promising drugs coming on line. This could have been a low risk modestly profitable opportunity. Even more puzzling was the long delayed entry into the differentiated thyroid cancer space. There was a window in which EXEL could have challenged Nexavar as the 1L SOC in a fairly large indication. They already had the MTC experience and both cancers are RET and VEGF sensitive. Notice that the RET+ NSCLC trial is not EXEL sponsored, I think they likely stay in touch with the MSK group that did most of the work on the rare NSCLC mutations and realize that there are now better choices than Cabo.
"Chromosomal rearrangements involving the gene that encodes the RET tyrosine kinase are known oncogenic drivers in 1% to 2% of patients with non–small cell lung cancer (NSCLC). These RET rearrangements occur with characteristic partners, most commonly KIF5B, but also CCDC6, NCOA, TRIM33, CUX1, KIAA1217, FRMD4A, and KIAA1468. They are typically identified in young patients with adenocarcinoma histology and minimal smoking history. Therapeutic targeting of RET-fusion–driven NSCLCs has taken the form of treatment with broad-spectrum tyrosine kinase inhibitors with anti-RET activity, such as cabozantinib (Cabometyx; Cometriq), vandetanib (Caprelsa), lenvatinib (Lenvima), RXDX-105, and sunitinib (Sutent). Cabozantinib and vandetanib have been the most heavily studied multi-kinase inhibitors (MKIs), with response rates of 20% to 50% in largely pretreated patients with RET-rearranged NSCLC. Sunitinib has been used in fewer patients to date with initial results demonstrating a 22% response rate. RXDX-105 has exhibited uniquely impressive response rates (75%) in patients with non–KIF5B-RET-fusion NSCLC, compared with 0% response in patients with KIF5B-RET-fusion–positive NSCLC. BLU-667 has demonstrated an objective response rate of 50% in patients with RET-fusion positive NSCLC, and LOXO-292 reported a 74% ORR in patients with RET-fusion positive NSCLC. Notably, RXDX-105, BLU- 667, and LOXO-292 have all demonstrated some central nervous system activity in these early phase trials. Future directions of RET inhibition in patients with RET-rearranged NSCLC include additional clinical validation of the next generation RET-selective inhibitors RXDX-105, BLU-667, and LOXO-292 and comparing multikinase inhibitors with RET-selective inhibitors to determine the optimal sequencing of RET-targeted therapies."