Next-Generation RET Inhibitor

LOXO-260

Next-Generation RET Inhibitor

Mulligan LM1

Target
Rearranged during transfection (RET) fusions have been identified in approximately 2% of non-small cell lung cancer,2,3 10% to 20% of papillary thyroid cancer,4,5  and a subset of colon and other cancers.6-8  RET point mutations account for approximately 60% of medullary thyroid cancer.9-11 Cancers that harbor activating RET fusions or RET mutations depend primarily on this single constitutively activated kinase for their proliferation and survival. This dependency renders such tumors highly susceptible to small-molecule inhibitors targeting RET.

Recently, resistance to targeted RET treatment has been described in the clinic with secondary solvent front mutations or other oncogenic pathway activations emerging.12-14
Molecule
LOXO-260 is a selective small-molecule inhibitor of the RET receptor tyrosine kinase, developed to have activity against both solvent front and gatekeeper mutations, expressed alone or together, while maintaining the potency and selectivity of current selective RET inhibitors.15  LOXO-260 has demonstrated potent in vitro and in vivo activity as a selective inhibitor of both wild-type and oncogenic activated RET, including RET fusions, activating RET point mutations, and anticipated acquired resistant mutations.
Clinical Development
LOXO-260 is being investigated in a clinical trial in patients with RET fusion-positive solid tumors, medullary thyroid cancer, and other tumors with RET activation refractory to selective RET inhibitors.

References

  1. Mulligan LM. Nat Rev Cancer. 2014;14:173-186.
  2. Lipson D, et al. Nat Med. 2012;18(3):382-384.
  3. Takeuchi K, et al. Nat Med. 2012;18(3):378-381.
  4. Bounacer A, et al. Oncogene. 1997;15(11):1263-1273.
  5. Prescott JD, Zeiger MA. Cancer. 2015;121(13):2137-2146.
  6. Ballerini P, et al. Leukemia. 2012;26(11):2384-2389.
  7. Bossi D, et al. Mol Oncol. 2014;8(2):221-231.
  8. Stransky N, et al. Nat Commun. 2014;5:4846.
  9. Hofstra RM, et al. Nature. 1994;367(6461):375-376.
  10. Agrawal N, et al. J Clin Endocrinol Metab. 2013;98(2):E364-E369.
  11. Taccaliti A, et al. Curr Genomics. 2011;12(8):618-625.
  12. Solomon BJ, et al. J Thorac Oncol. 2020;15(4):541-549.
  13. Subbiah V, et al. Ann Oncol. 2021b;32(2):261-268.
  14. Rosen EY, et al. Clin Cancer Res. 2021;27(1):34-42.
  15. AACR disclosure. Kolakowski et al. Pre-clinical characterization of potent and selective next-generation RET inhibitors. Presented at AACR Annual Meeting 2021; April 10, 2021.
Clinical Development
LOXO-260 is being investigated in a clinical trial in patients with RET fusion-positive solid tumors, medullary thyroid cancer, and other tumors with RET activation refractory to selective RET inhibitors.

References

  1. Mulligan LM. Nat Rev Cancer. 2014;14:173-186.
  2. Lipson D, et al. Nat Med. 2012;18(3):382-384.
  3. Takeuchi K, et al. Nat Med. 2012;18(3):378-381.
  4. Bounacer A, et al. Oncogene. 1997;15(11):1263-1273.
  5. Prescott JD, Zeiger MA. Cancer. 2015;121(13):2137-2146.
  6. Ballerini P, et al. Leukemia. 2012;26(11):2384-2389.
  7. Bossi D, et al. Mol Oncol. 2014;8(2):221-231.
  8. Stransky N, et al. Nat Commun. 2014;5:4846.
  9. Hofstra RM, et al. Nature. 1994;367(6461):375-376.
  10. Agrawal N, et al. J Clin Endocrinol Metab. 2013;98(2):E364-E369.
  11. Taccaliti A, et al. Curr Genomics. 2011;12(8):618-625.
  12. Solomon BJ, et al. J Thorac Oncol. 2020;15(4):541-549.
  13. Subbiah V, et al. Ann Oncol. 2021b;32(2):261-268.
  14. Rosen EY, et al. Clin Cancer Res. 2021;27(1):34-42.
  15. AACR disclosure. Kolakowski et al. Pre-clinical characterization of potent and selective next-generation RET inhibitors. Presented at AACR Annual Meeting 2021; April 10, 2021.

The safety and efficacy of the agents under investigation have not been established. There is no guarantee that the agents will receive regulatory approval and become commercially available for the uses being investigated.

DISCOVER OTHER MOLECULES

VEGF Receptor-2 Antagonist

Learn More

CDK4 & 6 Inhibitor

Learn More

PI3Kα Inhibitor

Learn More