Response to Cabozantinib in Patients with RET Fusion-Positive Lung Adenocarcinomas
The discovery of RET fusions in lung cancers has uncovered a new therapeutic target for patients whose tumors harbor these changes. In an unselected population of non-small cell lung cancers (NSCLCs), RET fusions are present in 1-2% of cases. This incidence rises substantially, however, in never-smokers with lung adenocarcinomas that lack other known driver oncogenes. While pre-clinical data provide experimental support for the use of RET inhibitors in the treatment of RET fusion-positive tumors, clinical data on response are lacking. We report preliminary data for the first three patients treated with the RET inhibitor cabozantinib on a prospective phase 2 trial for patients with RET fusion-positive NSCLCs (NCT01639508). Confirmed partial responses were observed in two patients, including one harboring a novel TRIM33-RET fusion. A third patient with a KIF5B-RET fusion has had prolonged stable disease approaching 8 months (31 weeks). All three patients remain progression-free on treatment.
This is from the "Cabozantinib in Patients With KIF5B/RET Positive Advanced Non-Small Cell Lung Cancer" trial which is being done by MSK at its NY/NJ facilities. It is recruiting 25 patients. There was also another RET positive patient treated in one of the Japanese studies who also had a PR. Four known patients so far with 3/4 PR's and one prolonged SD. For a long time I've said that Cabo's best chance for NCCN endorsement were in DTC and RET NSCLC. The ship sailed on DTC and for a variety of reasons it did not happen, but if the NSCLC results continue with this high ORR, look for NCCN action when the patient total gets a bit higher. The only problem I see is that Ret is not one of the oncogenes currently being tested for in newly diagnosed patients. Hopefully with an available treatment, testing for RET would be added to the panel of targets currently tested for in newly diagnosed patients. Even though we are only talking about 1-2% of the NSCLC population, it is still amuch larger indication than MTC and it appears as if the treatment could be reasonably long term. It is an indication for which Cabo is theoretically ideally suited as RET, VEGF, and MET would all play a role in the etiology of the disease.
The Cabo esperience in RET driven NSCLC is analogous to Pfizers experience with Crizotinib (XALKORI) in ALK driven NSCLC. ALK mutations are roughly 3 times more common than RET. Current XALKORI sales are about $100 million per year in the U.S. and rising as the drug was first approved in Aug 2011. As Xalkori was a new drug, NCCN did not consider it for off-label usage. It was approved on the basis of a phase 3 test with an ORR endpoint. The commercial opportunity is still niche, but better than MTC's nanoniche status and the path to off-lbel use and/or FAA approval is uncomplicated.
Copy from recent seekin alpha "Where Is Exelixis In The Cancer Therapeutics Market?":
Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancers. The American Cancer Society's estimates for lung cancer in the United States for 2013 are about 228,190 new cases of lung cancer will be diagnosed, and there will be an estimated 159,480 deaths from lung cancer.
According to Transparency Market Research, the NSCLC will increase from $4.3 billion in 2009 to $6.9 billion in 2019 and the market is growing with a compound annual growth rate of 4.84% from 2009 to 2019.
Memorial Sloan Kettering Cancer Center is sponsoring a Phase II clinical trial to ascertain what effects cabozantinib in patients whose tumors have a gene called KIF5B/RET. KIF5B/RET is an abnormal gene that leads to lung cancer cell growth. Sloan Kettering is currently enrolling in the trial that is expected to be completed in July 2015.
Mounting evidence suggests that the presence of the KIF5B/RET fusion may signify a new molecular subset of the disease. Cabozantinib is a potent inhibitor of RET that has shown strong clinical activity in another RET-driven cancer.
On September 30, 2012, Exelixis reported preliminary data from an ongoing Phase 1 dose escalation study of cabozantinib conducted at the National Cancer Center Hospital in Tokyo, Japan. The trial consisted of 14 patients with a variety of solid tumors. Of these patients, five had NSCLC.
Researchers found that four NSCLC patients had a complete partial response. All five NSCLC patients had tumor regression ranging from 33% to 41%.